Database: EMBASE <: international biomedical and pharmaceutical literature, 1988 - Jun 2000. [Trial access until 3/2001. Feedback welcome to medical.library@umich.edu] Search Strategy (You Saved Citations 1-92 From Set 76): ----------------------------------------------------------------------------- 1 Dental enamel/ 975 2 Dental enamel solubility/ 975 3 exp Tooth permeability/ 3 4 ((dentin or tooth or teeth or enamel) adj3 (solubility or 31 soluble or permeability or permeable)).mp. 5 exp Dentin/ 782 6 Dentin solubility/ 782 7 or/1-6 1574 8 exp Tooth demineralization/ 7624 9 demineralization.mp. 889 10 caries.mp. 1810 11 caires.mp. 0 12 craies.mp. 0 13 careis.mp. 1 14 carise.mp. 0 15 (teeth adj3 cavit:).mp. 32 16 (tooth adj3 cavit:).mp. 31 17 (dental adj3 cavit:).mp. 54 18 (dentin adj3 cavit:).mp. 14 19 (enamel adj3 cavit:).mp. 6 20 (teeth adj3 decay:).mp. 59 21 (tooth adj3 decay:).mp. 58 22 (dental adj3 decay:).mp. 47 23 (dentin adj3 decay:).mp. 0 24 (enamel adj3 decay:).mp. 1 25 (active adj decay).mp. 5 26 (rampant adj3 decay:).mp. 4 27 (recurrent adj3 decay:).mp. 3 28 (white adj spot:).mp. 226 29 carious.mp. 110 30 cariology.ti,ab. 2 31 (non-cavitated adj3 lesion:).mp. 0 32 (noncavitated adj3 lesion:).mp. 1 33 Tooth remineralization/ 800 34 (dental adj3 fissure:).mp. 7 35 (tooth adj3 fissure:).mp. 3 36 (teeth adj3 fissure:).mp. 1 37 caries-free.mp. 28 38 cariesfree.mp. 0 39 Cariogenic agents/ 3 40 precavit:.mp. 2 41 (filled adj3 teeth).mp. 46 42 (filled adj3 tooth).mp. 9 43 (oral adj fissure:).mp. 4 44 (tooth adj3 remineraliz:).mp. 1 45 (teeth adj3 remineraliz:).mp. 4 46 dft.mp. 560 47 dfs.mp. 992 48 dmf:.mp. 1254 49 cariogeni:.mp. 166 50 or/8-49 12451 51 7 or 50 13596 52 exp Dentifrices/ 351 53 dentifrice:.mp. 135 54 toothpaste$1.mp. 392 55 or/52-53 398 56 exp Dental materials/ 33923 57 (glass adj ionomer).mp. 176 58 composite:.mp. 9563 59 sealant$1.mp. 549 60 or/56-59 42531 61 exp Fluorides/ 3134 62 (fluoride: or fluoro:).mp. [mp=title, abstract, heading 71175 word, trade name, manufacturer name] 63 Delayed-action preparations/ 40 64 ((fluorid: or fluoro:) adj5 (releas: or sustain:)).mp. 615 65 Delayed-action preparations/ 40 66 (prolonged adj action).mp. 429 67 (sustain: adj releas:).mp. 8021 68 (time$1 adj releas:).mp. 346 69 (delay: adj (action or releas:)).mp. 357 70 or/63-69 9550 71 (55 or 60) and (61 or 62) 5705 72 71 and 70 208 73 limit 72 to english language 191 74 limit 73 to human 93 75 "in vitro"/ 27423 76 74 not 75 92 77 from 76 keep 1-92 92 *************************** <1> UI - 2000125275 AU - Yoshida H AU - Yamaoka Y AU - Shinoyama M AU - Kamiya A IN - A. Kamiya, Department of Pharmacy, Yamaguchi University Hospital, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505; Japan. TI - Novel drug delivery system using autologous fibrin glue - Release properties of anti-cancer drugs -. SO - Biological & Pharmaceutical Bulletin Vol 23(3) (pp 371-374), 2000. AB - To clarify the release properties of anti-cancer drugs from fibrin glue, a study was performed using several anti-cancer drugs with remarkably different physical properties. Concentrated fibrinogen, fibronectin, and coagulation factor XIII were prepared from healthy human plasma according to the cryoprecipitate method. Fibrin glue containing anti-cancer drugs was prepared as follows; the cryoprecipitate was mixed with each anti-cancer drug and aprotinin, then thrombin was added. These glues were incubated in PBS containing plasminogen and urokinase at 37 [degree] C for seven days, and the medium was then sampled several times after centrifugation. The drug concentration in each sample was measured using HPLC. Fibrin glue without aprotinin was quickly hemolyzed and disappeared after 2 - 4 h. That with aprotinin was only slightly hemolyzed and more than half remained after 7 days. Mitomycin C and fluorouracil were quickly released from the glue regardless of the presence or absence of aprotinin. However, enocitabine was gradually released from glue with aprotinin although quickly released from that without. The rate of release of each drug from the glue with aprotinin correlated well with its hydrophobicity. Thus, to establish a sustained release system using fibrin glue, one should use the more lipophilic anti-cancer drugs and a fibrinolytic enzyme inhibitor. [References: 17] <2> UI - 2000117358 AU - Vyas SP AU - Sihorkar V AU - Mishra V IN - S.P. Vyas, Drug Delivery Research Laboratory, Department Pharmaceutical Sciences, Dr. H. S. Gour University, Sagar (M.P.) 470 003; India. E-Mail: spvyas@bom6.vsnl.net.in. TI - Controlled and targeted drug delivery strategies towards intraperiodontal pocket diseases. SO - Journal of Clinical Pharmacy & Therapeutics Vol 25(1) (pp 21-42), 2000. AB - Advances in the understanding of the aetiology, epidemiology, pathogenesis and microbiology of periodontal pocket flora have revolutionized the strategies for the management of intraperiodontal pocket diseases. Intra-pocket, sustained release, drug delivery devices have been shown to be clinically effective in the treatment of periodontal infections. Several degradable and non-degradable devices are under investigation for the delivery of antimicrobial agents into the periodontal pocket including non-biodegradable fibres, films (biodegradable and non-biodegradable), bio-absorbable dental materials, biodegradable gels/ointments, injectables and microcapsules. With the realization that pocket bacteria accumulate as biofilms, studies are now being directed towards eliminating/killing biofilm concentrations rather than their planktonic (fluid phase) counterparts. Intraperiodontal pocket drug delivery has emerged as a novel paradigm for the future research. Similarly, bioadhesive delivery systems are explored that could significantly improve oral therapeutics for periodontal disease and mucosal lesions. A strategy is to target a wide range of molecular mediators of tissue destruction and hence arrest periodontal disease progression. Research into regenerating periodontal structures lost as a result of disease has also shown substantial progress in the last 25 years. [References: 129] <3> UI - 2000048908 AU - Von Tirpitz C AU - Klaus J AU - Bruckel J AU - Rieber A AU - Scholer A AU - Adler G AU - Bohm BO AU - Reinshagen M IN - Dr. M. Reinshagen, Department of Medicine I, University of Ulm, Robert-Koch-Str. 8, 89081 Ulm; Germany. E-Mail: max.reinshagen@medizin.uni-ulm.de. TI - Increase of bone mineral density with sodium fluoride in patients with Crohn's disease. SO - European Journal of Gastroenterology & Hepatology Vol 12(1) (pp 19-24), 2000. AB - Background and aims: Low bone density with an increased risk of vertebral fractures is a frequent complication in inflammatory bowel disease. Since the aetiology of osteopathia in these patients is different compared to postmenopausal or steroid-induced osteoporosis, no treatment strategy is established. Supplementation of calcium and vitamin D has been shown to prevent further bone loss, but no data are available showing the anabolic effect of sodium fluoride in Crohn's disease. Methods: We carried out a one-year prospective clinical trial in 33 patients with chronic active Crohn's disease who were randomly assigned to receive either calcium (500 mg b.i.d.) and 1000 IU vitamin D3 only, or retarded-release sodium fluoride (25 mg t.i.d.) additionally. The diagnosis of Crohn's disease had been made at least two years ago, and all patients had received systemic high-dose steroid therapy during the previous year. Eleven of 15 patients who received calcium/vitamin D and 15 of 18 patients who additionally received sodium fluoride completed the study. The primary endpoint of the study was the increase of bone mineral density, measured by dual energy X-ray absorptiometry (DXA) after one year of treatment. Bone-specific alkaline phosphatase and osteocalcin were used as markers for bone turnover. Results: In the calcium/vitamin D only group, bone density was not significantly changed after one year of treatment, whereas in the calcium/vitamin D/fluoride group, bone density of the lumbar spine increased from -1.39 +/- 0.3 (Z-score, mean +/- SEM) to -0.65 +/- 0.3 (P < 0.05) after one year of treatment. Increase of bone density was positively correlated to the osteoblastic markers bone-specific alkaline phosphatase (r = 0.53) and osteocalcin (r = 0.43). Conclusions: Sodium fluoride in combination with vitamin D and calcium is an effective, well-tolerated and inexpensive treatment to increase lumbar bone density in patients with chronic active Crohn's disease and osteoporosis. (C) 2000 Lippincott Williams and Wilkins. [References: 48] <4> UI - 2000003253 AU - Steinberg D AU - Friedman M IN - M. Friedman, Department of Pharmacy, School of Pharmacy, Hebrew University, PO Box 12065, Jerusalem 91120; Israel. E-Mail: dorons@cc.huji.ac.il. TI - Dental drug-delivery devices: Local and sustained-release applications. SO - Critical Reviews in Therapeutic Drug Carrier Systems Vol 16(5) (pp 425-459), 1999. AB - Dental diseases are among the most prevalent illnesses in humans. Many pharmaceutical dosage forms are used to prevent and treat these diseases. Toothpastes and mouthwashes are two of the most popular dental medicaments. A local delivery application that prolongs the release of the drug in the mouth offers great advantages in preventing and treating caries and periodontal diseases. Sustained-release devices are a relatively new concept in dentistry. This paper describes several types of sustained-release devices that are available commercially or are in the premarketing stage. [References: 133] <5> UI - 1999329236 AU - Raisz LG IN - Dr. L.G. Raisz, Univ. of Connecticut School of Med., Farmington, CT; United States. TI - Osteoporosis: 12 Questions physicians often ask. SO - Consultant Vol 39(3) (pp 772-782), 1999. AB - An estimated 20% of white women older than 70 years have osteoporosis. Obtain bone-density measurements in all patients at risk for osteoporosis because of early menopause, family history, low body weight, smoking, low calcium intake, or immobilization. Rule out a secondary cause or other manageable, aggravating condition to confirm a diagnosis of primary osteoporosis. For post-menopausal women, treatment consists of hormone replacement therapy (HRT), supplemental calcium, adequate vitamin D intake, and exercise. Alternatives to HRT include bisphosphonates, selective estrogen receptor modulators, and nasal calcitonin. Avoiding falls (particularly those that are likely to cause hip fractures) may be as important as maintaining bone mass. Investigational agents include low-dose, slow-release fluoride and parathyroid hormone. [References: 7] <6> UI - 1999245513 AU - Menei P AU - Venier M-C AU - Gamelin E AU - Saint-Andre J-P AU - Hayek G AU - Jadaud E AU - Fournier D AU - Mercier P AU - Guy G AU - Benoit J-P IN - Dr. P. Menei, Service de Neurochirurgie, Ctr. Hosp.-Universitaire d'Angers, 49033 Angers Cedex 01; France. TI - Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma: A pilot study. SO - Cancer 15 JUL 1999Vol 86(2) (pp 325-330), 1999. AB - BACKGROUND. The authors have developed a new method of drug delivery into the brain using implantable biodegradable microspheres. In this study, this method was used to provide localized and sustained delivery of 5- fluorouracil (5-FU) after the surgical resection of glioblastoma. This antimetabolite and radiosensitizing drug was selected in an attempt to decrease the rate of local recurrence of the tumor. METHODS. Eight patients with newly diagnosed glioblastoma were included in the study and 2 increasing amounts of 5-FU were studied (70 mg and 132 mg). After surgical resection of the tumor, poly(D-L lactide-co-glycolide) 5-FU-loaded microspheres with an average dimension of 45 mum were implanted in the wall of the surgical bed. External beam radiation (59.4 grays) was initiated before the seventh postsurgical day. Patients were followed by clinical examination, magnetic resonance imaging, and 5-FU assays in the blood and cerebrospinal fluid (CSF). RESULTS. 5-FU assays confirmed sustained concentrations in the CSF for at least 1 month. Concentrations of 5-FU in the blood were lower and transitory. Systemic tolerance to the treatment was good; one case of recurrent brain swelling was observed at the higher dose studied. At the time of last follow-up the overall median survival time was 98 weeks from the time of implantation and 2 patients had achieved disease remision at 139 and 153 weeks, respectively. CONCLUSIONS. This study demonstrates that biodegradable microspheres are efficient systems for drug delivery into the brain and may have future application in the treatment of brain tumors. Further studies are needed to confirm the potential of 5-FU-loaded microspheres for the radiosensitization of glioblastoma. [References: 35] <7> UI - 1998286856 AU - Anonymous TI - Fluoride and bone. (A second look). No use in osteoporosis. SO - Prescrire International Vol 7(36) (pp 110-111), 1998. AB - Data on fluoride efficacy in secondary prevention of osteoporotic fractures were contradictory when we last examined the file, in 1990. We now re-examine the clinical file on fluoride with more follow-up and new clinical trial data. In 354 postmenopausal women with a history of vertebral fracture (secondary prevention), a comparative trial (the FAVOS trial) showed that moderate-dose fluoride for 2 years did not reduce the incidence of new vertebral fractures relative to calcium plus vitamin D. Furthermore, fluoride caused more cases of lower-limb pain. In 110 postmenopausal women with a history of vertebral fracture, a trial showed that fluoride (sustained-release form) + calcium was more effective than calcium alone in preventing vertebral fractures. No pertinent trial on fluoride in primary prevention has been published since 1991. [References: 14] <8> UI - 1998183484 AU - McCabe JF TI - Resin-modified glass-ionomers. SO - Biomaterials Vol 19(6) (pp 521-527), 1998. AB - This paper reviews the current status of resin-modified glass-ionomers and presents the results of recent findings of research in some key areas. The debate on nomenclature pertaining to these products is perceived as being pointless and the need for application-based ISO standards is raised. Setting characteristics are similar in many respects to those of light-activated composites, although some products have limited working time due to the influence of the acid-base setting reaction and sensitivity to ambient light. Water absorption and swelling are generally very high. The clinical significance of swelling after water exposure is unknown. Mechanical properties of most materials lie between those of the composites and conventional glass-ionomers depending upon the resin content of the matrix phase of the set material. Some products demonstrate an inherent adhesion to enamel, although etching may be required in order to make the bond clinically effective. Bonding to dentine is probably through a more complex mechanism than that involved with conventional glass-ionomers. Conditioning and priming of dentine is often advocated. Fluoride release rates and their clinical significance is an area which requires clarification and standardization. The key factor appears to be the frequency with which the storage water is changed. Equilibration is reached within minutes for some materials and their true fluoride-releasing potential can only be judged under dynamic test conditions. [References: 59] <9> UI - 1998178966 AU - Forsten L IN - L. Forsten, Institute of Dentistry, University of Turku, Lemminkaisenkatu 2, 20520 Turku; Finland. TI - Fluoride release and uptake by glass-ionomers and related materials and its clinical effect. SO - Biomaterials Vol 19(6) (pp 503-508), 1998. AB - The anticariogenic effect of silicate cement is well known and considered a result of fluoride release. In several studies a similar fluoride release from conventional glass-ionomer cement (GIC) has been established. Therefore, an anticariogenic effect may be predicted from the GICs too. In my studies the fluoride release was studied by exposing the test specimens to a continuous flow of running tap water. At certain time periods the specimens were transferred for 1 week in a small amount of deionized water (5 ml). The determination of the fluoride content of the solution showed the fluoride release of the material at that time. There was an initial 'burst' effect of fluoride release and then the release gradually decreased, settling at a constant level. The long-term release from conventional GICs was shown to remain on the same level for at least 8 years. The amount of the constant release did not differ much between different brands. Resin-modified GICs released fluoride to the same extent and in the similar way as conventional GICs whereas polyacid-modified composites ('compomers') did not show an initial fluoride 'burst' effect. To study the fluoride binding ability of GICs, specimens which had been exposed to running water for different periods of time were treated with a 50 ppm fluoride solution. After this 'recharging' GIC and resin-modified GIC specimens released more than twice the amount of fluoride released before the treatment. The fluoride treatment had no effect on polyacid-modified composites or on fluoride-containing composites or on the amalgams. To get an impression of the clinical effect of GICs a questionnaire was handed out to practitioners attending courses in the Nordic countries and in Australia during the period 1991-1992 which resulted in 954 answers. Among other questions, the dentists were asked if they had observed caries and gingival inflammation in association with GIC and composite fillings. According to the opinion of most dentists caries and gingival inflammation had never or only seldom been observed in association with GIC fillings whereas most dentists had observed these complications often in connection with composite restorations. [References: 22] <10> UI - 1998065608 AU - Pak CYC AU - Sakhaee K AU - Rubin C AU - Rao S IN - Dr. C.Y.C. Pak, Center for Mineral Metabolism, 5323 Harry Hines Blvd., Dallas, TX 75235-8885; United States. TI - Update of fluoride in the treatment of osteoporosis. SO - Endocrinologist Vol 8(1) (pp 15-20), 1998. AB - Sustained-release sodium fluoride (SR-NaF or Neosten(TM), Mission Pharmacal Company, San Antonio, TX) opens an exciting new approach in the management of postmenopausal osteoporosis. Unlike available drugs that are antiresorptive agents [1], SR-NaF is a formation-stimulating agent [2]. Thus, SR-NaF has a greater potential for augmenting spinal bone mass and inhibiting spinal fractures than antiresorptive agents. However, the response to treatment is not due to the properties of SR-NaF alone, but also to the particular treatment format [3]. To capture the maximum benefits of SR-NaF, it must be provided intermittently with continuous calcium citrate (or Citracal(TM), Mission Pharmacal Company, San Antonio, TX) supplementation. In this review, the unique properties of SRNaF and features of the treatment format will be described first. Laboratory and clinical results of treatment then will be provided. [References: 9] <11> UI - 1997381249 AU - Zerwekh JE AU - Antich PP AU - Mehta S AU - Sakhaee K AU - Gottschalk F AU - Pak CYC IN - Dr. J.E. Zerwekh, University of Texas Southwestern, Medical Center at Dallas, 5323 Harry Haines Boulevard, Dallas, TX 75235-8885; United States. TI - Reflection ultrasound velocities and histomorphometric and connectivity analyses: Correlations and effect of slow-release sodium fluoride. SO - Journal of Bone & Mineral Research Vol 12(12) (pp 2068-2075), 1997. AB - To better understand how structural and functional bone properties contribute to the changes in bone biomechanical properties revealed by ultrasound critical angle reflectometry (UCR) analysis, we measured both UCR velocities and histomorphometric properties in bone biopsy specimens from 33 osteoporotic patients before and following intermittent slow-release sodium fluoride (SRNaF) and continuous calcium citrate administration. Mean skeletal fluoride exposure was 17 months, and mean skeletal fluoride content was 0.203 +/- 0.088 SD% bone ash. Intermittent SRNaF and continuous calcium citrate promoted significant increases in trabecular thickness (122 +/- 18 SD mum to 131 +/- 20, p = 0.020), mineral apposition rate (0.79 +/- 0.26 to 1.05 +/- 0.40 mum/day, p = 0.014), and a significant decline in eroded surface (3.9 +/- 1.6 to 2.8 +/- 1.4%, p = 0.002). There were also significant increases in node number (0.193 +/- 0.100 to 0368 +/- 0.245, p < 0.01) and node-to-node strut length (0.076 +/- 0.087 to 0.191 +/- 0.173, p < 0.01) relative to total cancellous area. Cortical UCR velocity did not change but cancellous velocity significantly increased by 97 m/s following therapy (p = 0.0005). When compared against the significant changes in bone histomorphometry and connectivity, the sum of both cancellous and cortical ultrasound velocities was significantly correlated with node number/area (R2 = 0305, p < 0.0001) and node-to-node strut length/area (R2 = 0372, p < 0.0001) and to a lesser extent with mineral apposition rate (R2 = 0.106, p = 0.032). Multiple regression analysis demonstrated that 40% of the variance in the sum of the UCR velocities can be accounted for by the variability in these histomorphometric and connectivity parameters. There were no significant correlations between the sum of cortical and cancellous ultrasound velocities and cancellous bone volume (R2 = 0.014, p = 0.533), trabecular thickness (R2 = 0.012, p = 0.47), or hone mineral density (R2 = 0.003, p = 0.80). These observations indicate that velocity measurements with the UCR methodology show an improvement in bone elasticity associated, in part, with an improvement in the rate of bone mineralization and an improvement in bone quality at the structural level as shown by microarchitecture. [References: 32] <12> UI - 1997381249 AU - Zerwekh JE AU - Antich PP AU - Mehta S AU - Sakhaee K AU - Gottschalk F AU - Pak CYC IN - Dr. J.E. Zerwekh, University of Texas Southwestern, Medical Center at Dallas, 5323 Harry Haines Boulevard, Dallas, TX 75235-8885; United States. TI - Reflection ultrasound velocities and histomorphometric and connectivity analyses: Correlations and effect of slow-release sodium fluoride. SO - Journal of Bone & Mineral Research Vol 12(12) (pp 2068-2075), 1997. AB - To better understand how structural and functional bone properties contribute to the changes in bone biomechanical properties revealed by ultrasound critical angle reflectometry (UCR) analysis, we measured both UCR velocities and histomorphometric properties in bone biopsy specimens from 33 osteoporotic patients before and following intermittent slow-release sodium fluoride (SRNaF) and continuous calcium citrate administration. Mean skeletal fluoride exposure was 17 months, and mean skeletal fluoride content was 0.203 +/- 0.088 SD% bone ash. Intermittent SRNaF and continuous calcium citrate promoted significant increases in trabecular thickness (122 +/- 18 SD mum to 131 +/- 20, p = 0.020), mineral apposition rate (0.79 +/- 0.26 to 1.05 +/- 0.40 mum/day, p = 0.014), and a significant decline in eroded surface (3.9 +/- 1.6 to 2.8 +/- 1.4%, p = 0.002). There were also significant increases in node number (0.193 +/- 0.100 to 0368 +/- 0.245, p < 0.01) and node-to-node strut length (0.076 +/- 0.087 to 0.191 +/- 0.173, p < 0.01) relative to total cancellous area. Cortical UCR velocity did not change but cancellous velocity significantly increased by 97 m/s following therapy (p = 0.0005). When compared against the significant changes in bone histomorphometry and connectivity, the sum of both cancellous and cortical ultrasound velocities was significantly correlated with node number/area (R2 = 0305, p < 0.0001) and node-to-node strut length/area (R2 = 0372, p < 0.0001) and to a lesser extent with mineral apposition rate (R2 = 0.106, p = 0.032). Multiple regression analysis demonstrated that 40% of the variance in the sum of the UCR velocities can be accounted for by the variability in these histomorphometric and connectivity parameters. There were no significant correlations between the sum of cortical and cancellous ultrasound velocities and cancellous bone volume (R2 = 0.014, p = 0.533), trabecular thickness (R2 = 0.012, p = 0.47), or hone mineral density (R2 = 0.003, p = 0.80). These observations indicate that velocity measurements with the UCR methodology show an improvement in bone elasticity associated, in part, with an improvement in the rate of bone mineralization and an improvement in bone quality at the structural level as shown by microarchitecture. [References: 32] <13> UI - 1997308826 AU - Zerwekh JE AU - Padalino P AU - Pak CYC IN - J.E. Zerwekh, CMMCR, UTSMC, 5323 Harry Hines Blvd., Dallas, TX 75235-8885; United States. TI - The effect of intermittent slow-release sodium fluoride and continuous calcium citrate therapy on calcitropic hormones, biochemical markers of bone metabolism, and blood chemistry in postmenopausal osteoporosis. SO - Calcified Tissue International Vol 61(4) (pp 272-278), 1997. AB - A detailed examination of calcitropic hormones and biochemical markers of bone turnover, serum chemistry, and blood hematology was performed in 75 postmenopausal women allocated to two groups: placebo plus calcium citrate (400 mg Ca B.I.D.) (n = 36) or intermittent slow-release sodium fluoride (SRNaF, 25 mg B.I.D.) plus calcium citrate (n = 39). After 2 years of therapy, a significant reduction in serum immunoreactive parathyroid hormone (PTH) was seen for both groups (43 +/- 18 SD-30 +/- 11 ng/liter, in placebo and 46 +/-24-36 +/- 10, in SRNaF P < 0.0001 for both groups). Serum 1,25(OH)2D significantly fell in placebo-treated patients (91 +/- 31-75 +/- 34 pmol/liter, P = 0.001) but did not change for SRNaF-treated patients. This difference in response between placebo and SRNaF-treated groups was significant, P = 0.005. Urinary hydroxyproline significantly declined during treatment in both groups (130 +/- 61-76 +/- 38 mumol/day, for placebo and 138 +/- 84-84 +/- 38 for SRNaF, P = 0.001). Similar decreases in urinary N-telopeptide of type I collagen were also observed for both groups (305 +/- 192-252 +/- 197 nmoles BCE/day for placebo and 356 +/- 230-220 +/- 197, P = 0.0001 for SRNaF). Serum carboxyterminal propeptide of type I collagen (PICP) declined significantly in both the placebo and SRNaF groups (118 +/- 38-101 +/- 36 mug/liter, and 116 +/- 47-105 +/- 39, P = 0.0027). Serum osteocalcin did not change significantly for either group, but bone-specific alkaline phosphatase (BS-ALPase), another marker of bone formation, demonstrated a significant fall in the placebo group at 2 years of therapy (16.2 +/- 6.7 U/liter-12.1 +/- 3.5, P = 0.009) and a small increase in the SRNaF-treated patients (13.0 +/- 4.1-15.0 +/- 4.5). The observed difference in response of BS-ALPase between the placebo and treated groups was significant (P = 0.007). There were no significant changes within or between treatment groups for blood hematology or serum chemistries. Mean values for all parameters remained within established normal ranges. These findings suggest that administration of calcium citrate inhibited PTH secretion and thereby reduced bone resorption in both groups, indicated by a decline in serum PTH, urinary hydroxyproline, and N-telopeptide. A low turnover state of bone may have been produced in the placebo group taking calcium citrate alone, since serum PICP, BS-ALPase, and 1,25(OH)2D also decreased. The addition of SRNaF prevented serum 1,25(OH)2D from falling by an unknown mechanism. However, its anabolic action on the skeleton was best reflected by changes in BS-ALPase. Moreover, SRNaF appeared to exert no deleterious effects on blood chemistries or hematology during 2 years of administration. [References: 29] <14> UI - 1997249477 AU - Schnitzler CM AU - Wing JR AU - Raal FJ AU - Van der Merwe MT AU - Mesquita JM AU - Gear KA AU - Robson HJ AU - Shires R IN - Prof. C.M. Schnitzler, Medical School, 7 York Road, Parktown, Johannesburg 2193; South Africa. TI - Fewer bone histomorphometric abnormalities with intermittent than with continuous slow-release sodium fluoride therapy. SO - Osteoporosis International Vol 7(4) (pp 376-389), 1997. AB - To help resolve the uncertainty whether sodium fluoride (NaF) therapy should be given intermittently or continuously, we examined iliac crest bone biopsies (before and after treatment) and fragility fracture rates in 35 intermittently treated (group I) and 69 continuously treated (group C) patients; all received calcium. The following statistically significant results were obtained. Reduction in vertebral fracture rate was similar in the two groups. Trabecular thickness and the structurally more important mineralized thickness increased only in group I. Group I also accumulated less excess osteoid (surface, volume). Mean osteoid thickness did not change in either group because of a bimodal distribution of wide seams with osteoblasts and double tetracycline labels, and thin seams without osteoblasts or labels. Osteoid was lamellar. Osteoid in abnormal sites (within bone marrow or bone, or around osteocytes) was found less frequently in group I. Adjusted apposition rate declined and mineralization lag time increased in both groups because of extended unlabelled osteoid seams. Erosion surface increased only in group C. Hook and/or tunnel erosion was seen less frequently in group I; it was closely associated with osteoid in abnormal sites and correlated with osteoid surface. Extended osteoid surface may have forced osteoclasts to hollow out trabeculae, leaving the empty osteoid shell in marrow. Excess osteoid volume and eroded surface and osteoid and erosion in abnormal sites correlated with bone fragility in group C. We conclude that intermittent therapy is to be preferred because it (1) increased mineralized trabecular thickness, (2) did not cause excessive osteoid accumulation and erosion, (3) showed less osteoid and erosion in abnormal sites and (4) led to a similar reduction in the vertebral fracture rate as did continuous treatment. The question of whether intermittency of therapy has some other effect independent of the cumulative dose of fluoride administered cannot be answered by this study. [References: 39] <15> UI - 1997171083 AU - Ahuja A AU - Khar RK AU - Ali J IN - A. Ahuja, Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062; India. TI - Mucoadhesive drug delivery systems. SO - Drug Development & Industrial Pharmacy Vol 23(5) (pp 489-515), 1997. AB - Mucoadhesion in drug delivery systems has recently gained interest among pharmaceutical scientists as a means of promoting dosage form residence time as well as improving intimacy of contact with various absorptive membranes of the biological system. Besides acting as platforms for sustained-release dosage forms, bioadhesive polymers can themselves exert some control over the rate and amount of drug release, and thus contribute to the therapeutic advantage of such systems. This paper describes some aspects of bioadhesion such as mucus layer, mucoadhesion, and theories of bioadhesion to explain the adhesion mechanism. The factors important to mucoadhesion, the methods used to study bioadhesion, and bioadhesive polymers are described. The methods that evaluate the mucoadhesive dosage forms and finally the bioadhesive drug delivery systems designed for several therapeutic purposes are presented. [References: 144] <16> UI - 1997116416 AU - Wu L-W AU - Hyun Koo Yoon AU - Baylink DJ AU - Graves LM AU - Lau K-HW IN - Dr. K.-H.W. Lau, Mineral Metabolism (151), Jerry L. Pettis MVAMC, 11201 Benton Street, Loma Linda, CA 92357; United States. E-Mail: LAUB@LLVAMC.VA.GOV. TI - Fluoride at mitogenic doses induces a sustained activation of p44(mapk), but not p42(mapk), in human TE85 osteosarcoma cells. SO - Journal of Clinical Endocrinology & Metabolism Vol 82(4) (pp 1126-1135), 1997. AB - Fluoride, at micromolar concentrations, stimulates bone cell proliferation in vitro. In this study, we sought to test whether fluoride at mitogenic doses increases the tyrosyl phosphorylation level and specific activity of a mitogen-activated protein kinase (MAPK) in human TE85 osteosarcoma cells. Analysis by immunoprecipitation with antiphosphotyrosine antibody followed by Western analysis using an anti-pan extracellular signal- regulated kinase antibody revealed that fluoride at the optimal mitogenic dose (i.e. 100 mumol/L) induced a time-dependent increase in the steady state tyrosyl phosphorylation level of p44(mapk), but not p42(mapk), with the maximal increase (4- to 13-fold) after 1-3 h fluoride treatment. The effect was sustained in that a 9-fold increase was seen after 12 h of the fluoride treatment. The sustained nature of the effect is consistent with an inhibition of dephosphorylation rather than a direct stimulation of phosphorylation. The fluoride effect on the tyrosyl phosphorylation level of p44(mapk) was dose dependent, with the optimal dose being 100 mumol/L fluoride. The mitogenic dose of fluoride also increased the specific activity and the in-gel kinase activity of p44(mapk), but not that of p42(mapk), in a time-dependent manner similar to the effect on the p44(mapk) tyrosyl phosphorylation level. Fluoride at the same micromolar doses did not increase cell proliferation, tyrosyl phosphorylation, or specific activity of any MAPK in human skin foreskin flbroblasts, which are fluoride-nonresponsive cells. Consistent with the interpretation that the effect of fluoride on the steady state tyrosyl phosphorylation level of p44(mapk) is a consequence of an inhibition of a phosphotyrosyl phosphatase (PTP), mitogenic doses of orthovanadate, a bone cell mitogen and a PTP inhibitor, also increased the steady state tyrosyl phosphorylation level of p44(mapk), but not p42(mapk), in a time-dependent sustained manner similar to that observed with fluoride. Together, these findings support the concept that inhibition of a PTP activity in bone cells could lead to an activation of MAPK activity. [References: 60] <17> UI - 1997080477 AU - Deal CL IN - Dr. C.L. Deal, Division of Rheumatic Diseases, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106; United States. TI - Osteoporosis: Prevention, diagnosis, and management. SO - American Journal of Medicine Vol 102(1 A) (pp 35S-39S), 1997. AB - Osteoporosis is a public health scourge that is usually eminently preventable. Some risk factors, such as low calcium intake, vitamin D deficiency, and physical inactivity, are amenable to early interventions that will help maximize peak bone density. Other risk factors subject to modification are cigarette smoking and excessive consumption of protein, caffeine, and alcohol. Hip fractures are the most serious outcome of osteoporosis, with enormous personal and public health consequences. The ongoing Study of Osteoporotic Fractures has identified additional independent predictors of hip fracture risk, including maternal hip fracture, absence of significant weight gain since age 25, height, hyperthyroldism, use of long- acting benzodiazepines or anticonvulsants, spending <4 hours a day on one's feet, inability to rise from a chair without using one's arms, poor visual depth perception and contrast sensitivity, and tachycardia. In an individual perimenopausal woman, the risk of osteoporotic fracture and the urgency of estrogen replacement therapy can be best estimated on the basis of bone mineral density, as measured by dual-energy x-ray absorptiometry, coupled with the presence or absence of existing fractures and clinical risk factors evident from the history and physical examination. Estrogen, calcitonin, and bisphosphonates have all been proved effective in retarding postmenopausal bone loss and therefore reducing the risk of fracture. The use of sodium fluoride is more controversial, although a recent study has suggested a possible role for slow-release fluoride combined with high-dose calcium supplementation. [References: 23] <18> UI - 1997054006 AU - Battmann A AU - Resch H AU - Libanati CR AU - Ludy D AU - Fischer M AU - Farley S AU - Baylink DJ IN - Dr. A. Battmann, Justus Liebig University, Institute of Pathology, Langhansstrasse 10, D-35385 Giessen; Germany. TI - Serum fluoride and serum osteocalcin levels in response to a novel sustained-release monofluorophosphate preparation: Comparison with plain monofluorophosphate. SO - Osteoporosis International Vol 7(1) (pp 48-51), 1997. AB - In a previous study we found that sustained-release monofluorophosphate (MFP-SR), a novel, sustained-release MFP preparation, acutely maintained the basal therapeutic serum fluoride levels without causing the high serum peak levels associated with plain MFP administration. The objective of the present study was to determine (a) whether chronic MFP-SR administration would provide therapeutic serum fluoride levels, and (b) whether treatment with this new preparation would result in an increase in bone formation similar to that achieved with plain MFP. Bone formation was assessed by serum osteocalcin (OC) determination. We studied 17 postmenopausal women older than 60 years and suffering from primary osteoporosis. All had received a minimum of 6 months of continuous treatment with plain MFP at a dose of 152 mg/day (76 mg b.i.d.), Upon entering the study, the subjects were randomized, in a double-masked protocol, to receive either MFP-SR (76 mg b.i.d.) (n = 9) or placebo (n = 8) for 2 months, after which all, subjects returned to the original plain MFP regimen. Serum fluoride and serum OC levels were determined monthly for 3 months. At the beginning of the study serum fluoride levels were in the accepted therapeutic range (5-10 muM) in all patients. Serum fluoride levels were maintained in the patients switched to MFP-SR. In contrast, serum fluoride levels decreased significantly (p < 0.005) in the placebo-treated control subjects and returned to therapeutic levels upon switching back to plain MFP. Similarly, serum OC levels remained elevated in the subjects switched to MFP-SR but dropped significantly (p < 0.001) in the placebo-treated group. Our results demonstrate that chronic MFP-SR administration, at a dose of 152 mg/day, results in maintenance of therapeutic serum fluoride levels and in stimulation of bone formation. Because we have previously reported that high, supratherapeutic post-absorptive serum fluoride levels are avoided by MFP-SR administration, this novel preparation may prevent side effects associated with plain MFP by reducing the amount of fluoride deposited in bone. [References: 16] <19> UI - 1997037234 AU - Isenbarger DW AU - Chapin BL IN - B.L. Chapin, Department of Medicine, William Beaumont Army Med. Center, 5005 Piedras St, El Paso, TX 79920-5001; United States. TI - Osteoporosis: Current pharmacologic options for prevention and treatment. SO - Postgraduate Medicine Vol 101(1) (pp 129-132+136-137+141-142), 1997. AB - For virtually all asymptomatic postmenopausal women, moderate exercise and supplementation with calcium and vitamin D are recommended. In addition, most postmenopausal women without contraindications would benefit from estrogen replacement therapy, primarily because of its cardiovascular benefits. In patients with contraindications or an aversion to hormone therapy, bone densitometry should be performed to determine risks before expensive nonhormonal treatment is initiated. Therapy with alendronate sodium (Fosamax) or calcitonin (Calcimar, Miacalcin) is clearly indicated in women with established osteoporosis and may be appropriate for early postmenopausal women with osteopenia. Calcitonin is a good option in patients with disabling spinal bone pain. Slow-release sodium fluoride, although still considered experimental, may eventually be given for vertebral fracture in patients with mild to moderate disease. [References: 21] <20> UI - 1997026302 AU - Pak CYC AU - Sakhaee K AU - Rubin CD AU - Zerwekh JE IN - Dr. C.Y.C. Pak, Texas Univ. Southwestern Med. Sch., 5323 Harry Hines Boulevard, Dallas, TX 75235-8885; United States. TI - Sustained-release sodium fluoride in the management of established postmenopausal osteoporosis. SO - American Journal of the Medical Sciences Vol 313(1) (pp 23-32), 1997. AB - A unique treatment format for established postmenopausal osteoporosis was developed. SR-NaF administered with Ca citrate restricted fluoride bioavailability, attenuated circadian fluctuation in serum fluoride (40 ng/mL to 60 ng/mL), and prolonged T(1/2). It maintained peak and basal levels of serum fluoride within the narrow therapeutic window (95 ng/mL to 190 ng/mL), and it kept the skeletal fluoride well below the toxic threshold during the recommended 4 years of treatment. In the completed randomized trial in established postmenopausal osteoporosis, SR-NaF decreased the spinal fracture rate by approximately 70%. From pooled data derived from the study of 233 patients who were treated with SR-NaF and from 83 patients who were administered a placebo, it was concluded that SR-NaF eliminated virtually all spinal fractures among patients with mild to moderate bone loss. The decline in the spinal fracture rate was approximately 91%, with fractures developing in only 2.7% of the patients. In severe bone loss, SR- NaF produced a modest but significant decline of 40% in the fracture rate. In the SR-NaF group, L2-L4 bone mass increased by approximately 5% per cycle through four cycles; femoral neck BD increased by 1% per cycle to 2% per cycle during the first two cycles. Radial shaft BD did not change. In the placebo groups, L2-L4 BD rose significantly by 1.5% during the first cycle but not in remaining cycles. Femoral neck BD and radial shaft BD did not change. The above effects of SR-NaF on spinal fractures and bone mass, disclosed in established postmenopausal osteoporosis, were just as marked in idiopathic osteoporosis, but they were less prominent in steroid-induced osteoporosis. Histomorphometrically, SR-NaF stimulated bone formation and inhibited resorption (probably from administered Ca citrate) without altering mineralization. Results of a back-scattered electron imaging of mineralized structures and the results of a transmission electron microscopy were normal. Trabecular connectivity improved, especially in mild to moderate bone loss. This accounted for the marked anti-fracture efficacy for SR-NaF. Functionally, SR-NaF improved cancellous bone quality while it maintained the quality of cortical bone. No gastric ulcers developed. Microfractures developed only in patients treated with steroids. The hip fracture rate and other appendicular fracture rates of the SR-NaF group did not differ from rates of the placebo group. Minor side effects were the same as in the group treated with a placebo. In conclusion, SR-NaF plus Ca citrate maintained serum fluoride within the therapeutic window, kept skeletal fluoride below the toxic threshold, augmented spinal bone mass by 5% per cycle for four cycles, inhibited spinal fractures by 70% to 80%, and was safe to use in established postmenopausal osteoporosis. In contrast, MFP, EC-NaF, and plan NaF were reported to have either no effect or a marginal effect on spinal fracture occurrence, despite a marked augmentation of spinal bone mass. Thus, the response to fluoride treatment is dependent on the fluoride formulations and the treatment format. [References: 30] <21> UI - 1997005191 AU - Levien T AU - Baker DE IN - T. Levien, College of Pharmacy, Washington State University, 601 West First Avenue, Spokane, WA 99204-0399; United States. TI - Reviews of cidofovir and sodium fluoride, slow release. SO - Hospital Pharmacy Vol 31(12) (pp 1604+1607-1608+1611-1612+1615), 1996. <22> UI - 1996313774 AU - Murray TM AU - Ste-Marie L-G AU - Bowyer M IN - Osteoporosis Society of Canada, 33 Laird Dr.,Toronto, Ont. M4G 3S9; Canada. TI - Fluoride therapy for osteoporosis. SO - Canadian Medical Association Journal Vol 155(7) (pp 949-954), 1996. AB - Objective: To present the latest findings on the use of fluoride in the treatment of osteoporosis. Options: Plain sodium fluoride (NaF), enteric-coated sodium fluoride (EC-NaF), sodium monofluorophosphate (Na2FPO4), slow-release sodium fluoride (SR-NaF); fluoride with a calcium supplement. Outcomes: Fracture and loss of bone mineral density in osteoporosis; increased bone mass, prevention of fractures and improved quality of life associated with treatment. Evidence: Relevant clinical studies and reports were examined, with an emphasis on recent prospective, randomized, controlled trials. Clinical practices in European countries were also considered. Values: Reducing fractures, increasing bone mineral density and minimizing side effects of treatment were given a high value. Benefits, harms and costs: NaF therapy stimulates bone formation and may be effective in preventing osteoporotic fractures. It may be an acceptable alternative treatment to estrogen or bisphosphonate therapy and useful in premenopausal and corticosteroid-induced osteoporosis and in some patients with mild osteogenesis imperfecta. Toxic effects are dependent on formulation and dosage. They include a range of gastrointestinal and musculoskeletal conditions. EC-NaF is associated with less toxicity than plain NaF; its gastrointestinal toxicity is negligible. Na2FPO4 has no gastrointestinal toxicity, but can give rise to skeletal toxicity. SR-NaF appears to have no side effects when given intermittently. Carcinogenicity has not been found in vivo with fluoride therapy, despite in vitro results. Recommendations: New data indicate that fluoride therapy should be re-evaluated as a potentially effective treatment of osteoporosis with minimal side effects. More studies are needed of slow-release fluoride formulations, intermittent treatment schedules and calcium supplementation of fluoride. Studies should be undertaken to see if it is advantageous to initiate treatment with antiresorptive agents before or in combination with fluoride. Conclusive data have not been presented regarding the benefit of any specific type of calcium supplement. Further studies on the basic mechanism of action of fluoride on the skeleton are necessary to evaluate fluoride's potential to stimulate bone formation therapeutically. Validation: These recommendations were developed by the Scientific Advisory Board of the Osteoporosis Society of Canada at its 1995 Consensus Conference. They are in agreement with and supplement the consensus statement of the First International Workshop on Fluoride and Bone, Niagara-on-the-Lake, Ont., 1988. <23> UI - 1996260939 AU - Turner CH AU - Zerwekh JE AU - Antich P AU - Pak CYC IN - Indiana University Medical Center, 541 Clinical Drive,Indianapolis, IN 46202; United States. TI - Fluoride and the FDA: A curious case. SO - Journal of Bone & Mineral Research Vol 11(9) (pp 1369-1371), 1996. <24> UI - 1996247146 AU - Abbott III TA AU - Lawrence BJ AU - Wallach S IN - Pharmacoeconomics, Sandoz Pharmaceuticals Corporation, 59 Route 10,East Hanover, NJ 07936-1080; United States. TI - Osteoporosis: The need for comprehensive treatment guidelines. SO - Clinical Therapeutics Vol 18(1) (pp 127-149), 1996. AB - Osteoporosis is a debilitating disease that results in nearly 1.3 million fractures per year in the United States. The cost of treating these fractures has been estimated to be as high as $10 billion per year. These costs are expected to more than double during the next 50 years unless comprehensive programs of prevention and treatment are initiated. Both pharmacologic and nonpharmacologic interventions leg, diet and exercise) have been shown to have a significant impact on the incidence of osteoporosis, depending on the time of their application. Unfortunately, osteoporosis is often not diagnosed until after fractures have occurred, when it may be too late for treatment to have a major impact. To be most effective, therapy should be started early, before serious bone loss has occurred. Because of its efficacy and relatively low acquisition cost, long-term hormone replacement therapy (HRT) is considered first-line pharmacologic therapy for the prevention of osteoporosis. However, for various reasons, less than 25% of US women who might benefit from HRT are receiving it. Aside from HRT, the only other products approved by the US Food and Drug Administration for the treatment of osteoporosis are salmon calcitonin and alendronate. Several other agents are under development, including sustained-release fluoride and other products in the bisphosphonate class. The development and adoption of early detection programs and treatment guidelines are crucial to help ease the economic burden of osteoporosis. These guidelines should incorporate preventive measures such as diet and exercise, risk assessment through proper screening programs, and the appropriate use of pharmaceutical products. The purpose of this paper is to discuss relevant economic issues associated with osteoporosis and discuss the need for a management algorithm that could be used to more efficiently prevent and treat this disease. We conclude that further modeling is needed to determine which programs and treatments are most cost-effective within each at-risk subgroup. As clinicians better understand the need for preventive care and the advantages of the various pharmacologic therapies, patients with osteoporosis will receive higher-quality and more efficient medical care. <25> UI - 1996218456 AU - Thomas AB AU - Hashimoto H AU - Baylink DJ AU - Lau K-HW IN - Mineral Metabolism (151), J.L.P. Memorial Veterans Med. Center, 11201 Benton Street,Loma Linda, CA 92357; United States. TI - Fluoride at mitogenic concentrations increases the steady state phosphotyrosyl phosphorylation level of cellular proteins in human bone cells. SO - Journal of Clinical Endocrinology & Metabolism Vol 81(7) (pp 2570-2578), 1996. AB - This study was designed to test the hypothesis that treatment of human bone cells with mitogenic concentrations of fluoride would lead to an increase in the steady state level of tyrosyl phosphorylation of specific cellular proteins. With an immunoblot assay method, it was found that mitogenic concentrations of fluoride (i.e. 50-200 mumol/L) induced a dose- and time-dependent increase in the level of tyrosyl phosphorylation of at least 13 cellular proteins in both normal human bone cells and human TE85 osteosarcoma cells. Time-course studies revealed that a statistically significant increase in tyrosyl phosphorylation of these 13 cellular proteins in human bone cells was observed after 3-6 h of fluoride treatment and was sustained for up to 24 h. This time course was not compatible with a direct activation of tyrosyl kinases, as epidermal growth factor, which activates tyrosyl kinase activity, induced an immediate and acute response that was rapidly reversible within 1 h. Although fluoride increased the steady state tyrosyl phosphorylation of the cellular proteins in human bone cells, the same micromolar doses of fluoride had no effect on human skin fibroblasts, which are fluoride-nonresponsive cells. The effects of fluoride were rapidly reversible in the absence of fluoride and could be acutely potentiated by pretreatment with epidermal growth factor. In summary, we have shown for the first time that mitogenic concentrations (i.e. 50-200 mumol/L) of fluoride increased the steady state level of tyrosyl phosphorylation of at least 13 cellular proteins in human bone cells, and that the increases were relatively slow in onset and sustained. In conclusion, these findings are consistent with the hypothesis that the osteogenic actions of fluoride are mediated at least in part by an inhibition of the activity of one or more fluoride- sensitive phosphotyrosyl protein phosphatases in human bone cells. <26> UI - 1996189161 AU - Watts NB AU - Blevins Jr LS IN - Emory University School of Medicine,Atlanta, GA; United States. TI - Endocrinology. SO - Journal of the American Medical Association Vol 275(23) (pp 1806-1807), 1996. <27> UI - 1996166186 AU - Steffansen B AU - Ashton P AU - Buur A IN - Royal Danish School of Pharmacy, Department of Pharmaceutics, 2 Universitetsparken,DK-2100 Copenhagen; Denmark. TI - Intraocular drug delivery. In vitro release studies of 5-fluorouracil from N1-alkoxycarbonyl prodrugs in silicone oil. SO - International Journal of Pharmaceutics Vol 132(1-2) (pp 243-250), 1996. AB - Various N1-alkoxycarbonyl prodrugs of 5-fluorouracil (5-FU) ranging from 5 to 18 carbon units in the pro-moiety were synthesized. The compounds were physico-chemically characterized by determining the ionization constant (K(a)), aqueous solubility (S), octanol/water partition coefficient (P), and the degradation rate in aqueous solution at different pH values. The in vitro degradation rate of the prodrugs in calf serum, human plasma, and rabbit vitreous humor was also investigated. Drug delivery systems were prepared by dissolving or dispersing 5-FU prodrugs in silicone oil 1000 (SO-1000). The release of 5-FU seemed to follow the square root of time kinetics until more than 60% of the drug had been released. The release rate of 5-FU was found to decrease with increased lipophilicity of the prodrug. <28> UI - 1996163099 AU - Barzel US IN - Div. of Endocrinology and Metabolism, Montefiore Medical Center,Bronx, NY; United States. TI - Osteoporosis: Taking a fresh look. SO - Hospital Practice Vol 31(5) (pp 59-64+67-68), 1996. AB - Risk factors are being refined; old ones are being dropped and new ones are being added. Early detection-before fracture occurs-with bone-density assessment represents another important advance. Severe strategies are now available to inhibit bone loss, and means are in prospect to promote bone formation directly. Of these, alendronate and slow-release fluoride appear to have particular promise. <29> UI - 1996127732 AU - Pak CYC AU - Zerwekh JE AU - Antich PP AU - Bell NH AU - Singer FR IN - Texas University SW Medical Center,Dallas, TX; United States. TI - Slow-release sodium fluoride in osteoporosis. SO - Journal of Bone & Mineral Research Vol 11(5) (pp 561-564), 1996. AB - The concern with SR-NaF is that only one placebo-controlled randomized trial had been completed. Other forms of fluoride have already been approved in 14 foreign countries. Conventional fluoride has already been shown to be efficacious in inhibiting spinal fractures. SR-NaF has been found to be even more effective in averting spinal fractures than conventional preparations. This finding has been supported by open trials in objective comparison at the same strata of baseline L2-L4 BMD. The main issue with fluoride is its safety. With SR-NaF, skeletal fluoride was kept below the toxic threshold, and structural integrity and improved quality of bone were demonstrated. Safety of SR-NaF was shown in 507 patients who were followed over 1325 patient-years. No patient developed gastric ulcers. Microfractures developed only in steroid-treated patients. The hip fracture rate was comparable to that of normal postmenopausal women and less than that of untreated patients with postmenopausal osteoporosis or those treated with plain NaF. Minor side effects were the same as in the placebo-treated group. Finally, the indication of SR-NaF is for treatment of established postmenopausal osteoporosis with prevalent fractures. Although only one randomized trial has been completed, the results convincingly showed both efficacy and safety of SR-NaF. The treatment is particularly effective in patients with mild- moderate bone loss. A less marked response in those with severe disease emphasizes the need for early intervention. <30> UI - 1996051117 AU - Lee JR IN - 9620 Bodega Highway,Sebastopol, CA 95472; United States. TI - Treatment of postmenopausal osteoporosis with slow-release sodium fluoride: Critique of final report from C Y C Park et al. SO - Fluoride - Quarterly Reports Vol 29(1) (pp 36-37), 1996. <31> UI - 1996058220 AU - Pak CYC AU - Sakhaee K AU - Bell NH AU - Licata A AU - Johnston C AU - Rubin B AU - Bonnick S AU - Piziak V AU - Graham H AU - Ballard J AU - Berger R AU - Fears W AU - Breslau N AU - Rubin C AU - Adams-Huet B IN - Texas University SW Medical Center, 5323 Harry Hines Boulevard,Dallas, TX 75235; United States. TI - Comparison of nonrandomized trials with slow-release sodium fluoride with a randomized placebo-controlled trial in postmenopausal osteoporosis. SO - Journal of Bone & Mineral Research Vol 11(2) (pp 160-168), 1996. AB - The results of slow-release sodium fluoride (SR-NaF) treatment in two nonrandomized trials involving 65 patients with postmenopausal osteoporosis from the primary site and 121 patients from collaborative sites were compared with those obtained from 54 treated patients and 56 patients taking placebo from a randomized controlled trial. Spinal fracture data were analyzed separately in mild to moderate bone loss of lumbar spine (baseline L2-L4 bone density [BD] >= 65% young normal) and in severe bone loss (BD < 65%). Since demographic and fracture data were similar among fluoride-treated patients from the three trials at each stratum of bone loss, their data were combined. In mild to moderate bone loss, SR-NaF treatment in the combined group virtually eliminated new spinal fractures with 96.6% of patients remaining fracture-free. The Fluoride group had a markedly lower individual vertebral fracture rate (0.025 vs. 0.188/patient year, p = 0.0001) and group vertebral fracture rate (0.029 vs. 0.175/patient year, relative risk [RR] 0.12, p = 0.0001) than the Placebo group. In severe bone loss, the combined treated group had a significantly lower new spinal fracture rate than the Placebo group, although the differences were not as marked (group vertebral fracture rate of 0.150 vs. 0.276/patient year, RR 0.54, p = 0.03). In the combined fluoride-treated group, the L2-L4 bone mass rose by 4-6%/year for 4 years, and the femoral neck BD increased by 1-2%/year during first 2 years. The radial shaft BD did not change. The Placebo group did not show a change in bone mass at any site. The prevalence (percentage) of patients with related gastrointestinal side effects and nonvertebral fracture rates did not differ significantly between the combined SR-NaF group and the Placebo group (hip fracture rate of 0.0045/patient year in SR-NaF and 0.0053/patient year in Placebo; appendicular fracture other than hip (see text) rate of 0.0193/patient year in SR-NaF and 0.0159/patient year in Placebo). A subgroup analysis showed a low baseline L2-L4 BD, high prevalent spinal fractures, and reduced body weight to be important determinants of the development of spinal fracture during SR-NaF treatment. Concomitant medications (estrogen, vitamin D, thiazide and thyroid hormone) were not independent predictors of the spinal fracture risk. Only 17% of fluoride-treated patients were nonresponders (new spinal fractures or a fall/no change in L2-L4 bone mass). Thus, the effects of SR-NaF treatment on the spinal fracture rate from nonrandomized trials were similar to those of the treated group of the randomized trial but different from those of the Placebo group. The similarity of response of nonrandomized trials with that of the randomized controlled trial and the resultant combined analysis further validate the efficacy and safety of SR-NaF in the treatment of postmenopausal osteoporosis. <32> UI - 1996035590 AU - Pouton CW AU - Akhtar S IN - School of Pharmacy/Pharmacology, University of Bath,Clavertown Down, Bath BA2 7 AY; United Kingdom. TI - Biosynthetic polyhydroxyalkanoates and their potential in drug delivery. SO - Advanced Drug Delivery Reviews Vol 18(2) (pp 133-162), 1996. AB - Polyhydroxyalkanoates (PHAs) are naturally occurring biodegradable polyesters produced as energy storage materials by many bacteria. The most common PHA, poly(3-hydroxybutyrate) (PHB), can be produced in high yield by fermentation of a variety of bacterial strains. PHB is a isotactic semi-crystalline polyester with great potential as a biodegradable commodity; it has useful physico-mechanical properties and appears to be biocompatible. Hydrolytic degradation occurs by surface erosion which makes it an attractive material for controlled release applications. The homopolymer PHB has a relatively high melting point and crystallizes rapidly, making entrapment of drug technically difficult. The related copolymers with 3-hydroxyvalerate, P(HB-HV)s, have similar semi-crystalline properties though their slower rates of crystallization result in matrices with different: properties; this merits further investigation. Release of low molecular weight drugs from PHB and P(HB-HV) matrices tends to proceed by penetration of water and pore formation, at least above loadings of approximately 5% drug. Release from such matrices is predominantly independent of polymer erosion; though at lower loadings it is possible to trap drug more effectively. PHB and P(HB-HV) matrices lose mass very slowly when compared to bulk-degrading poly(lactide-glycolide) systems. Therefore the applications of these materials in drug delivery are likely to depend on the formulation of suitable blends with other biocompatible polymers. Porosity, erosion rate and hence drug release rate can be controlled by blending techniques. At a more fundamental level there is considerable potential for design and bioengineering of other PHAs for applications in drug delivery. For example, medium chain PHAs are rubbery materials with low melting points which may be much more suitable as matrices for applications in drug delivery. <33> UI - 1996014247 AU - Anonymous TI - New drugs for osteoporosis. SO - Medical Letter on Drugs & Therapeutics Vol 38(965) (pp 1-3), 1996. <34> UI - 1996003169 AU - Anonymous TI - A monthly critical overview of current medicine. SO - Hospital Practice Vol 30(11) (pp 21-23), 1995. <35> UI - 1995358683 AU - Anonymous TI - Slow-release fluoride significantly cuts 3-year fracture rate. SO - Geriatrics Vol 50(11) (pp 20+23), 1995. <36> UI - 1995290221 AU - Pak CYC AU - Sakhaee K AU - Adams-Huet B AU - Piziak V AU - Peterson RD AU - Poindexter JR IN - Texas University SW Medical Center, 5323 Harry Hines Boulevard,Dallas, TX 75235-8885; United States. TI - Treatment of postmenopausal osteoporosis with slow-release sodium fluoride: Final report of a randomized controlled trial. SO - Annals of Internal Medicine Vol 123(6) (pp 401-408), 1995. AB - Objective: To test whether slow-release sodium fluoride inhibits spinal fractures and is safe to use. Design: Placebo-controlled randomized trial. Interventions: Slow-release sodium fluoride, 25 mg twice daily, in four 14- month cycles (12 months receiving sodium fluoride followed by 2 months not receiving it) compared with placebo. Calcium citrate, 400 mg calcium twice daily, continuously in both groups. Patients: 48 of 54 patients who received sodium fluoride and 51 of 56 patients who received placebo completed at least 1 year of the study. All patients had postmenopausal osteoporosis. Results: Compared with the placebo group, the fluoride group had a lower individual vertebral fracture rate (0.064 +/- 0.182 per patient-year compared with 0.205 +/- 0.297 per patient-year; P = 0.002), a higher unadjusted fracture-free rate (85.4% compared with 56.9%; P = 0.001), and a greater survival estimate (relative risk, 0.3 [95% CI, 0.12 to 0.76]) for new fractures. The recurrent spinal fracture rate did not differ between the two groups. The fluoride group had a substantial increase in L2-L4 bone mass of 4% to 5% per year for 4 years, a mean increase in femoral neck bone density of 2.38% +/- 3.33% per year, and no change in radial shaft bone density. The frequency with which minor side effects and appendicular fractures occurred was similar in the two groups; no patients developed microfractures or gastric ulcers. Conclusion: Slow-release sodium fluoride and calcium citrate administered for 4 years inhibits new vertebral fractures (but not recurrent fractures), augments spinal and femoral neck bone mass, and is safe to use. <37> UI - 1995270690 AU - Conzen PF AU - Nuscheler M AU - Melotte A AU - Verhaegen M AU - Leupolt T AU - Van Aken H AU - Peter K IN - Institute of Anesthesiology, Ludwig-Maximilians-Universitat, Klinikum Grosshadern, Marchioninistr. 15,81377 Munchen; Germany. TI - Renal function and serum fluoride concentrations in patients with stable renal insufficiency after anesthesia with sevoflurane or enflurane. SO - Anesthesia & Analgesia Vol 81(3) (pp 569-575), 1995. AB - Sevoflurane is metabolized to hexa-fluoro-isopropanol and inorganic fluoride by the human liver. Its use as an anesthetic may lead to peak plasma fluoride concentrations exceeding those seen after enflurane. Although there is no nephrotoxicity after sevoflurane anesthesia in humans with normal kidneys, those with chronically impaired renal function might be at increased risk because of increased fluoride load due to prolonged elimination half- life. In this study, measures of renal function after sevoflurane anesthesia were compared to those after enflurane in patients with chronically impaired renal function. Forty-one elective surgical patients with a stable preoperative serum creatinine concentration >= 1.5 mg/dL were randomly allocated to receive sevoflurane (n = 21) or enflurane (n = 20) at a fresh gas inflow rate of 4 L/min for maintenance of anesthesia. Serum fluoride concentrations were measured by ion-selective electrode. Renal function (creatinine, urea, sodium, osmolality) was assessed in serum and urine preoperatively and for up to 7 days postoperatively. Peak serum inorganic fluoride concentrations were significantly higher after sevoflurane than after enflurane anesthesia (25.0 +/- 2.2 vs 13.3 +/- 1.1 muM; mean +/- SEM). Laboratory measures of renal function remained stable throughout the postoperative period in both groups. No patient suffered a permanent deterioration of preexisting renal insufficiency and none required dialysis. Thus, neither sevoflurane nor enflurane deteriorated postoperative renal function in these patients with preexisting renal insufficiency. There is no evidence that fluoride released by metabolism of sevoflurane metabolism worsened renal function in these patients with stable, permanent serum creatinine concentrations more than 1.5 mg/dL. Our data also suggest that the peak fluoride concentrations measured in peripheral blood may not be a good predictor of nephrotoxic potential after sevoflurane anesthesia in these patients. <38> UI - 1995251917 AU - Peyman GA AU - Ganiban GJ IN - LSU Eye Institute, Louisiana State Univ. Medical Center, School of Medicine, 2020 Gravier Street,New Orleans, LA 70112-2234; United States. TI - Delivery systems for intraocular routes. SO - Advanced Drug Delivery Reviews Vol 16(1) (pp 107-123), 1995. AB - Intravitreal drug delivery has been developed to treat posterior segment diseases because the blood-ocular barrier prevents treatment by topical, systemic, or subconjunctival routes from attaining therapeutic levels in the vitreous. Endophthalmitis, uveitis, proliferative vitreoretinopathy, and viral retinitis are treated by intravitreal injection. Efforts to sustain drug delivery have included encapsulation of drugs in liposomes (made of lipids) or microspheres (made of polymers). In many instances the drug's toxicity to the retina was reduced and the clearance time was slowed. However, these methods cause clouding of the vitreous and can prolong drug delivery for only one month. Implantable devices have been used, such as an osmotic minipump, a drug pellet coated with polyvinyl alcohol and ethylene vinyl acetate, and polysulfone capillary fiber. Biodegradable devices are under investigation, including a drug matrix and a porous reservoir system, both made of polymers; these devices would not require surgical removal. <39> UI - 1995201991 AU - Shern RJ IN - Clin. Investig./Patient Care Branch, National Inst. of Dental Research, National Institutes of Health,Bethesda, MD; United States. TI - New approaches to delivery of fluorides. SO - Journal of Clinical Dentistry Vol 6(1) (pp 124-129), 1995. AB - This review focuses on two novel strategies for increasing the effectiveness of fluoride without increasing the systemic exposure to fluoride. One strategy is to elevate saliva-borne fluoride for extended periods of time by applying prolonged-release (time dependent and time independent) technologies to control the oral exposure to fluoride. The second strategy involves enhancing the affinity of tooth enamel for fluoride by using a unique calcium phosphate formulation as a pretreatment. Results from preclinical and clinical studies of CPS and the IFRD attest to their safety, pharmacologic adequacy and presumptive efficacy. In addition, other inventions for providing increased levels of enamel-bound or saliva-borne fluoride without increasing systemic exposure are reviewed. Further clinical studies are needed to define the usefulness of these strategies for restricting the incidence of dental caries. <40> UI - 1995143262 AU - Kasturi R AU - White DJ AU - Lanzalaco AC AU - Macksood D AU - Cox ER AU - Bacca L AU - Liang N AU - Baker R IN - Procter and Gamble Company, Sharon Woods Technical Center,Cincinnati, OH; United States. TI - Effects of nine weeks' use of a new stabilized stannous fluoride dentifrice on intrinsic plaque virulence expressed as acidogenicity and regrowth: A modified PGRM study. SO - Journal of Clinical Dentistry Vol 6(SPEC. ISS. II) (pp 71-79), 1995. AB - A new stabilized stannous fluoride dentifrice, currently marketed as Crest(TM) Gum Gare has been examined for its effects on intrinsic plaque metabolic and regrowth activity and effects on plaque resistance to SnF2 throughout nine weeks of toothbrushing. Subjects brushed their teeth 1x, 2x or 3x/day with stabilized stannous fluoride dentifrice or placebo dentifrice for nine weeks, presenting in the morning on weeks 3, 6-9 for plaque sampling. Following nine weeks, subjects were crossed-over and repeated the experiment on their alternative assigned product (active SnF2/placebo). Sampled dental plaques were evaluated for standardized glycolysis and regrowth activity using the 'Plaque Glycolysis and Regrowth Method' (PGRM). Following the second nine-week treatment period, subjects concluding either placebo or SnF2 toothbrushing participated in a single-treatment PGRM experiment using stabilized stannous fluoride dentifrice. Toothbrushing with stabilized stannous fluoride dentifrice in this experiment produced significant and sustained reductions in both plaque glycolytic and regrowth activity as compared to placebo treated plaques. In the concluding single-brushing PGRM experiment, SnF2 dentifrice was shown to produce equal inhibitory actions in plaque from subjects completing stannous fluoride or placebo treatments. This result confirmed that nine weeks toothbrushing with stabilized stannous fluoride dentifrice produced no development of resistance of plaque to SnF2 inhibition. These results support the strong in vivo antimicrobial actions of the stabilized stannous fluoride dentifrice, Crest Gum Care. <41> UI - 1995111445 AU - Erlacher L AU - Templ H AU - Magometschnigg D IN - Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Waehringerguertel 18-20,A-1090 Vienna; Austria. TI - A comparative bioavailability study on two new sustained-release formulations of disodiummonofluorophosphate versus a nonsustained-release formulation in healthy volunteers. SO - Calcified Tissue International Vol 56(3) (pp 196-200), 1995. AB - In 12 healthy volunteers the pharmacokinetic parameters of two new sustained-release formulations of disodiummonofluorophosphate (MFP) (B and C) were compared with those of a nonsustained-release reference preparation (A). This randomized study had a single-dose, triple-cross over design and consisted of 3 trial days separated by a 1-week washout period. Serial blood samples were obtained over a period of 24 hours and 24-hour urine was collected. Serum and urine fluoride concentrations were determined using an ion-sensitive electrode (Orion Research). The results of this study showed a significant reduction of the area under the serum concentration versus time curve (AUC) for the sustained-release formulations (AUC B: 1487 +/- 354 ng/ml x hour, AUC C: 1369 +/- 384 ng/ml x hour) compared with the reference preparation (AUC A: 2374 +/- 652 ng/ml x hour) (B/A: 63%, C/A: 58%) (P < 0.001). Furthermore, the peak serum concentrations of fluoride (C(max)) for B and C (C(maxB): 166 +/- 42 ng/ml, C(maxC): 110 +/- 48 ng/ml) were significantly lower than for A (C(maxA): 380 +/- 77 ng/ml) (P < 0.001). The 24-hour urine fluoride recovery rates were 5.6 +/- 0.7 mg fluoride for A, 3.6 +/- 0.8 mg for B, and 3.2 +/- 1.1 mg for C and corresponded well to the relative fluoride bioavailability, as concluded from the serum fluoride concentration. In conclusion, the sustained-release preparations of MFP led to a decrease of fluoride bioavailability and avoided high peak serum concentrations. <42> UI - 1995082543 AU - Cousins SW IN - Department of Ophthalmology, Bascom Palmer Eye Institute, Miami University School of Medicine,Miami, FL 33101; United States. TI - Intraocular immunosuppression as treatment for uveitis: Rationale, preliminary results, and future prospects. SO - Regional Immunology Vol 6(1-2) (pp 191-201), 1994. AB - Intraocular immunosuppression by direct inhibition of T-cell activation within the eye has not yet been established as a strategy for treatment of ocular inflammation. Demonstration of such a principal might initiate new ideas for the treatment of uveitis. In this review, speculations are advanced regarding the rationale and requirements for proceeding with an anti- inflammatory therapy based on the concept of intraocular immunosuppression. In addition, result of preliminary experiments exploring local immunosuppressive therapy with a novel device for the intravitreal (i.vit.) sustained-release of 5-fluorouracil (5-FU) will be reviewed. Local immunosuppression may be a reasonable adjunct to traditional corticosteroid anti-inflammatory therapy for the treatment of uveitis. <43> UI - 1995019887 AU - Ashton P AU - Blandford DL AU - Pearson PA AU - Jaffe GJ AU - Martin DF AU - Nussenblatt RB IN - Department of Ophthalmology, E-312 Kentucky Clinic, University of Kentucky,Lexington, KY 40536; United States. TI - Review: Implants. SO - Journal of Ocular Pharmacology Vol 10(4) (pp 691-701), 1994. AB - An implantable sustained release device has been developed to treat chronic disorders of the eye. The device, consisting of a central core of drug encased in layers of permeable and impermeable polymers, can be implanted subconjunctivally or intravitreally. This technique was used to develop a ganciclovir device which, when implanted into the vitreous, maintains therapeutic vitreous levels of drug for 8 months. Initial studies in patients with cytomegalovirus (CMV) retinitis indicate that this treatment may offer better control of the disease and fewer side effects than existing therapies. Cyclosporine A devices were prepared for the treatment of uveitis. Early data suggests that these devices maintain therapeutic levels in the vitreous for approximately 3 years. Work on efficacy and toxicity is continuing. Although clinical applications of these devices are likely to be restricted to diseases requiring chronic drug therapy, they can be used to investigate optimal delivery rates. Subconjunctivally implanted devices releasing 5-FU for 12 days maintained filters in cynomolgus monkeys for 3 months. Similar devices maintained low intraocular pressure in 75% of high risk filter patients. <44> UI - 1994340450 AU - Kubo O AU - Tajika Y AU - Muragaki Y AU - Hiyama H AU - Takakura K AU - Yoshida M AU - Kumakura M IN - Department of Neurosurgery, Tokyo Women's Medical College,Tokyo; Japan. TI - Local chemotherapy with slowly-releasing anticancer drug-polymers for malignant brain tumors. SO - Journal of Controlled Release Vol 32(1) (pp 1-8), 1994. AB - Malignant brain tumors are resistant to many treatments. This report presents the methodology and results of a clinical trial of local chemotherapy of malignant glioma based on slowly releasing anticancer drug-polymers made by our groups. These slowly releasing drug polymer composites were prepared by combining and mutually dispersing anticancer agents with classified monomers containing 10% polymetacrylic methyl acid; this compound was then frozen at - 70 [degree] C and exposed to 1 X 106 Rad cobalt 60 gamma-rays. Thus we prepared a compound of polymers and anticancer agents (mitomycin, adriamycin, 5-Fu and ACNU). We administered locally to the malignant glioma with these polymers. The following techniques were employed for implanting these polymers: (1) implantation into the remaining tumor wall at the resection; (2) implantation into the tumor by the CT-guided stereotactic method. The polymers were implanted into tumors (120 cases) using a combination of radiotherapy and systemic chemotherapy. <45> UI - 1994327535 AU - Zerwekh JE AU - Hagler HK AU - Sakhaee K AU - Gottschalk F AU - Peterson RD AU - Pak CYC IN - Mineral Metab./Clinical Res. Center, Texas University SW Medical Center, 5323 Harry Hines Blvd.,Dallas, TX 75235-8885; United States. TI - Effect of slow-release sodium fluoride on cancellous bone histology and connectivity in osteoporosis. SO - Bone Vol 15(6) (pp 691-699), 1994. AB - We have previously demonstrated that a treatment regimen of slow-release sodium fluoride (SRNaF) and continuous calcium citrate increases lumbar bone mass, improves cancellous bone material quality, and significantly reduces vertebral fracture rate in osteoporotic patients. In order to assess whether such treatment also improves trabecular structure, we quantitated cancellous bone connectivity, before and following 2 years of therapy with SRNaF in 23 patients with osteoporosis and vertebral fractures. In addition, we performed bone histomorphometry on the same sections used for connectivity measurements. There was a significant increase in L2-L4 bone mineral density during therapy (0.827 +/- 0.176 g/cm2 SD to 0.872 +/- 0.166, p = 0.0004). Significant histomorphometric changes were represented by increases in mineral apposition rate (0.6 +/- 0.4 mum/d to 1.1 +/- 0.7, p = 0.0078) and adjusted apposition rate (0.4 +/- 0.3 mum/d to 0.6 +/- 0.4, p = 0.016). On the other hand, trabecular spacing significantly declined (from 1375 +/- 878 mum to 1052 +/- 541, p = 0.05). Two-dimensional quantitation of trabecular struts on iliac crest histological sections disclosed significant increases in mean node number per mm2 of cancellous tissue area (0.22 +/- 0.12 vs. 0.39 +/- 0.27, p = 0.0077), the mean node to free-end ratio (0.23 +/- 0.21 vs. 0.41 +/- 0.46, p < 0.05), and in the mean node to node strut length per mm2 of cancellous area (0.098 +/- 0.101 vs. 0.212 +/- 0.183, p < 0.01). There were no significant changes in any of the measurements associated with free-end number or free-end to free-end strut length. When patients were divided into those with severe and mild-modest spinal bone loss (based upon initial lumbar bone density) the significant changes in connectivity occurred in patients with mild-moderate bone loss, but not in those with severe bone loss, suggesting that fluoride's effect is in part dependent on the presence of a certain critical amount of bone. This finding in combination with the previously reported increases in bone mass and bone material quality may explain the significant reduction in vertebral fracture rate observed with this particular fluoride regimen. <46> UI - 1994323902 AU - Lee JR TI - Slow-release sodium fluoride in the management of postmenopausal osteoporosis. SO - Fluoride - Quarterly Reports Vol 27(4) (pp 227-228), 1994. <47> UI - 1994318461 AU - Kroger H AU - Alhava E AU - Honkanen R AU - Tuppurainen M AU - Saarikoski S IN - Department of Surgery, Kuopio University Hospital,FIN-70210 Kuopio; Finland. TI - The effect of fluoridated drinking water on axial bone mineral density - A population-based study. SO - Bone & Mineral Vol 27(1) (pp 33-41), 1994. AB - Bone mineral density (BMD) of the spine and femoral neck was measured in a random stratified sample of 3222 perimenopausal women aged 47-59 years. A total of 969 women had used fluoridated drinking water (1.0-1.2 mg/l) for over 10 years. These women were compared with 2253 women with low levels of fluoride in drinking water (<0.3 mg/l). BMD of the spine was significantly higher in the fluoride group than in the non-fluoride group (1.138 +/- 0.165 vs. 1.123 +/- 0.156 g/cm2, P = 0.026). Femoral neck BMDs did not differ between the groups. When the BMD values were adjusted for confounding factors (age, weight, menopausal status, calcium intake, physical activity level, deliveries, alcohol consumption and estrogen use), the differences between the groups increased (P < 0.001 for the spine and P = 0.004 for the femoral neck, respectively). There was no significant difference between the groups in the prevalence of self-reported fractures sustained during 1980-1989. We propose that the fluoridation of drinking water has a slight increasing effect on axial BMD in women in low fluoride areas. <48> UI - 1994231423 AU - Anonymous TI - Treatment of osteoporosis: Fluoride revisited. SO - Hospital Practice Vol 29(7) (pp 24), 1994. <49> UI - 1994116170 AU - Joshi A IN - Allergan, 2525 Dupont Drive,Irvine, CA 92713-9534; United States. TI - Microparticulates for ophthalmic drug delivery. SO - Journal of Ocular Pharmacology Vol 10(1) (pp 29-45), 1994. AB - Microparticulates are drug-containing small polymeric particles (erodible, non-erodible or ion-exchange resins) that are suspended in a liquid carrier medium. Upon administration of particle suspension in the eye, the particles reside at the delivery site (cul-de-sac, sub conjunctiva or vitreous cavity) and the drug is released from the particles through diffusion, chemical reaction, polymer degradation, or ion-exchange mechanism. Several distinct approaches have been used to formulate drugs in microparticulate dosage form for intraocular and topical application. These include erodible microparticulates, swelling mucoadhesive particulates, pH responsive microparticulates, nanoparticles/latex systems, ion-exchange resins, etc. Injection of bioerodible microparticulates in the vitreous for treating infections of posterior segment and the release of acceptable levels of drug up to two weeks has been demonstrated. Both corneal and non-corneal routes of drug entry in the eye from topical instillations are postulated. The in vitro and in vivo studies have shown that this dosage form holds great promise for sustained drug release in the eye. However, several formulation challenges, including production of stable suspensions, uniform dose per unit volume, efficient drug entrapment, reproducible and large scale manufacturing, uniform particle size, etc., have to be addressed. Fruitful resolution of technological challenges will result in a superior dosage form for both topical and intraocular ophthalmic application. Recent developments and future challenges of microparticulate ophthalmic drug delivery system are discussed in this review. <50> UI - 1994113836 AU - Heaney RP IN - Creighton University, 601 North 30th Street,Omaha, NE 68131; United States. TI - Fluoride and osteoporosis. SO - Annals of Internal Medicine Vol 120(8) (pp 689-690), 1994. <51> UI - 1994113826 AU - Pak CYC AU - Sakhaee K AU - Piziak V AU - Peterson RD AU - Breslau NA AU - Boyd P AU - Poindexter JR AU - Herzog J AU - Heard-Sakhaee A AU - Haynes S AU - Adams-Huet B AU - Reisch JS IN - Texas Southwestern Med. Ctr. Univ., 5323 Harry Hines Boulevard,Dallas, TX 75235-8885; United States. TI - Slow-release sodium fluoride in the management of postmenopausal osteoporosis: A randomized controlled trial. SO - Annals of Internal Medicine Vol 120(8) (pp 625-632), 1994. AB - Objective: To test whether intermittent treatment with slow-release sodium fluoride and continuous calcium citrate supplementation inhibits vertebral fractures without causing fluoride complications. Design: A placebo- controlled, randomized trial. Setting: Outpatient setting of specialty clinics in Dallas and Temple, Texas. Interventions: Slow-release sodium fluoride (25 mg twice daily) in repeated 14-month cycles (12 months on treatment followed by 2 months off treatment) compared with placebo. Both groups took calcium citrate (400 mg calcium twice daily) continuously. Patients: 110 patients with postmenopausal osteoporosis were randomly assigned to two groups. In the slow-release sodium fluoride group, 48 of 54 patients completed more than 1 cycle of treatment (mean, 2.44 cycles/patient), whereas 51 of 56 patients in the placebo group completed at least 1 cycle (mean, 2.14 cycles/patient) in this interim analysis. Measurements: Vertebral fracture rate and lumbar bone mineral content. Vertebral fractures were quantified from yearly radiographs. Bone mass was determined annually by densitometry. Results: In the sodium fluoride group, the mean L2 to L4 bone mineral content increased by 4% to 6% in each cycle and the mean femoral neck bone density increased by 4.1% and 2.1% during the first two cycles, but the radial bone density did not change. The placebo group showed no statistical change in bone mass at any site. Compared with the placebo group, the sodium fluoride group had a lower individual new vertebral fracture rate (0.057/patient cycle compared with 0.204/patient cycle, P = 0.017), a higher fracture-free rate (83.3% compared with 64.7%, P = 0.042), and a lower group fracture rate (0.085/patient cycle compared with 0.239/patient cycle, P = 0.006). The side-effect profile was similar for the two groups; no patient developed microfractures, hip fractures, or blood loss anemia. Conclusions: Intermittent slow-release sodium fluoride plus continuous calcium citrate, administered for about 2.5 years, inhibits new vertebral fractures, increases the mean spinal bone mass without decreasing the radial shaft bone density, and is safe to use. <52> UI - 1994079749 AU - Kenna JG AU - Van Pelt FNAM IN - Dept. of Pharmacology/Toxicology, St Mary's Hospital Medical School, Imperial Coll. Sci., Technol./Med., Norfolk Place,London W2 1PG; United Kingdom. TI - The metabolism and toxicity of inhaled anaesthetic agents. SO - Anaesthetic Pharmacology Review Vol 2(1) (pp 29-42), 1994. AB - The potential of the volatile anaesthetic agents to elicit hepatotoxicity and nephrotoxicity is a consequence of their metabolism by hepatic cytochromes P450. The rank order of extents of metabolism of these drugs is: halothane>sevoflurane [similar] enflurane>isoflurane>desflurane. Their nephrotoxic potential is due to metabolic release of inorganic fluoride. Inorganic fluoride is directly nephrotoxic when its concentration in plasma exceeds 50 muM for a prolonged period of time, as has been shown to occur in patients anaesthetised with methoxyflurane. Methoxyflurane is very similar in structure to enflurane, isoflurane and desflurane but is much more susceptible to cytochrome P450-mediated oxidative defluorination and exhibits markedly greater tissue solubility. Plasma concentrations of inorganic fluoride may, under certain circumstances, approach or exceed 50 muM in patients anaesthetised with enflurane, isoflurane, or sevoflurane but these elevated values are short-lived and are not associated with overt nephrotoxicity. 'Risk factors' which act to promote metabolism of enflurane isoflurane and sevoflurane to inorganic fluoride, and which should be born in mind when using these anaesthetics, are obesity, very prolonged anaesthesia and/or treatment of patients with drugs (including isoniazid or ethanol) which induce cytochrome P450 isoenzyme 2El. Potentially nephrotoxic levels of inorganic fluoride are not reached in patients anaesthetised with halothane, because the major route of metabolism of this drug does not result in liberation of inorganic fluoride, or in patients anaesthetised with desflurane, which is extremely resistant to metabolism. Severe anaesthetic-induced hepatotoxicity is very rare but is potentially life-threatening. Apparently this occurs via immune responses to anaesthetic metabolite-modified hepatic protein antigens. This adverse reaction is well documented following anaesthesia with halothane where the incidence is about one in several thousand, is much rarer following anaesthesia with enflurane and is rarer still following anaesthesia with isoflurane. Thus the incidence of anaesthetic-induced hepatotoxicity is correlated with the extent of metabolism of the drugs and hence the levels of expression of metabolite-protein antigens. Why a very small proportion of anaesthetised patients develop this form of liver damage but the vast majority do not is unclear at the present time. Metabolism of sevoflurane does not appear to proceed via reactive species which bind covalently to proteins, while the extent of metabolism of desflurane is so limited that formation of metabolite-modified protein antigens in livers of patients anaesthetised with this drug should be minimal. Therefore, based upon information available at the present time, one would anticipate that neither anaesthetic is likely to cause immune-mediated hepatotoxicity in man. Use of sevoflurane in low-flow anaesthetic circuits may pose problems because this drug is degraded by soda-lime to several toxic compounds. At the present time, it is unclear whether the concentrations of toxic degradation products of sevoflurane which are reached in low-flow circuits are sufficient to pose a hazard to health. In the case of halothane, enflurane, isoflurane and desflurane, degradation by soda-lime is not considered to be of toxicological importance. Diagnosis of anaesthetic-induced hepatotoxicity can be verified by testing patients' sera for antibodies to the metabolite-modified hepatic protein antigens. Appropriate antibody assays are available in several centres and currently we offer such a service. Clearly a patient who is sensitised to halothane must never be exposed to that agent again. Whether such a patient can safely be exposed to enflurane or isoflurane is less clear. In some instances this may be safe; in others, it may not be. As regards hepatotoxic potential, the most appropriate volatile anaesthetic agent to administer to a patient who is sensitised to halothane will be one which leads to minimal production of metabolite-modified hepatic protein antigens. Currently this is isoflurane, although both sevoflurane and desflurane offer considerable promise for the future. <53> UI - 1994033336 AU - Rassing MR IN - Department of Pharmaceutics, Royal Danish School of Pharmacy, 2 Universitetsparken,DK-2100 Copenhagen; Denmark. TI - Chewing gum as a drug delivery system. SO - Advanced Drug Delivery Reviews Vol 13(1-2) (pp 89-121), 1994. AB - The potential of chewing gum as a drug delivery system together with different formulation principles and methods of assessment are discussed in this article. The release of a drug from chewing gum is dependent upon its water solubility. Water-soluble substances are released rapidly and completely from chewing gum and methods are available which retard their release from chewing gum to provide an extended release profile. Slightly water-soluble drugs are released slowly and incompletely from chewing gum and require special formulation techniques to produce a satisfactory release profile. Studies evaluating the potential application of medicated and non-medicated chewing gum in the treatment of local diseases in the oral cavity are described. Specific examples of the use of chewing gum as a delivery system for dental health, smoking cessation and antifungal therapy are cited. Few drugs are suitable candidates for incorporation into chewing gum formulations for the intention of their systemic delivery. Know-how derived from the development and manufacture of already existing medicated and non-medicated chewing gum, supplemented with today's knowledge of the principles of pharmaceutical formulation, constitute the basis for the development of the medicinal chewing gum of tomorrow. <54> UI - 1994012485 AU - Resch H AU - Libanati C AU - Talbot J AU - Tabuenca M AU - Farley S AU - Bettica P AU - Tritthart W AU - Baylink D IN - Department of Medicine, Loma Linda University, Jerry L. Pettis VA Hospital, Benton Street 11201,Loma Linda, CA 92357; United States. TI - Pharmacokinetic profile of a new fluoride preparation: Sustained-release monofluorophosphate. SO - Calcified Tissue International Vol 54(1) (pp 7-11), 1994. AB - The pharmacokinetic profiles of a sustained-release monofluorophosphate (MFP-SR) preparation (76 mg) and of plain MFP (76 mg) were compared in six osteoporotic females. These studies were performed in a randomized, crossover, double-blind design to select a preparation that would result in therapeutic serum levels while avoiding high serum peak values. Following a single dose of 76 mg MFP-SR, the serum fluoride levels remained within the accepted therapeutic range (5-10 muM/liter) for 24 hours. In contrast, following a single dose of 76 mg plain MFP, serum fluoride levels exhibited a wide circadian fluctuation and serum levels approximately threefold higher than those of the MFP-SR preparation (9.5 +/- 1.6 vs 3.5 +/- 0.8 muM/liter, P < 0.005). Compared with plain MFP, the sustained-release MFP had a significantly lower peak concentration (C(max) MFP-SR: 10.6 +/- 3 vs C(max) MFP: 18.9 +/- 5 muM/liter, P < 0.005) and a significantly longer absorption lag time (T(max) MFP-SR 7.3 +/- 1.6 vs T(max) MFP: 3.0 +/- 0.6 h, P < 0.05). Twenty-four-hour urinary fluoride excretion after ingestion of plain or SR fluoride was significantly increased from pretreatment values documenting absorption with either MFP formulation. Our results show that the use of sustained-release MFP preparation that we tested prevents the development of high peak levels associated with the use of plain MFP preparations. Furthermore, a single dose of MFP-SR resulted in serum fluoride levels within the accepted range of 5-10 muM/liter for 24 hours. <55> UI - 1993359413 AU - Kanis JA IN - Human Metabol./Clin. Biochem. Dept., Sheffield Medical School, Beech Hill Road,Sheffield S10 2RX; United Kingdom. TI - Treatment of symptomatic osteoporosis with fluoride. SO - American Journal of Medicine Vol 95(5 A) (pp 53S-61S), 1993. AB - Fluoride has been used for >30 years in the management of osteoporosis. It is one of the few agents that has marked anabolic effects on the skeleton. Indeed, treatment results in continued increments in cancellous bone volume so that cancellous bone volume can be restored to normal in patients with advanced osteoporosis. Despite its long history, both the efficacy and risks of fluoride regimens continue to be the subject of controversy. One of its problems is its age, and much of the early work undertaken utilized methodology and proofs that are today unacceptable. A further problem is that sodium fluoride as a treatment is cheap and not patented (although some formulations are), so that it has been difficult for investigators or industry to make the investments required to provide a modern program of evaluation. <56> UI - 1993330502 AU - Whatmore J AU - Quinn P AU - Allen D IN - Department of Physiology, University College, University Street,London WC1E 6JJ; United Kingdom. TI - Plasma membrane vesicles from BHK and HL60 cells treated with merocyanine 540 and iodoacetamide. SO - Biochimica et Biophysica Acta - Biomembranes Vol 1152(2) (pp 300-306), 1993. AB - Treatment of BHK or HL60 cell lines with merocyanine 540 in the presence of the sulphydryl blocker iodoacetamide caused budding of the cell surface to release vesicles about 50-100 nm in diameter which accounted for up to 25% of the total surface membrane lipid. Smaller amounts of vesicular material were released in the presence of fluoride and merocyanine 540. The vesicles had a membrane lipid composition which was characteristic of other purified plasma membranes, with large amounts of sphingomyelin, phosphatidylserine and cholesterol and low proportions of phosphatidylinositol, phosphatidylcholine, triacylglycerol and cholesterol ester. This procedure for the isolation of vesicles should be a general method for the purification of plasma membrane components from a wide range of different cell types. <57> UI - 1993149150 AU - Warneke G AU - Setnikar I IN - Via Valosa di Sopra 7,I-20052 Monza; Italy. TI - Bioavailability and pharmacokinetics of fluoride from two glutamine monofluorophosphate preparations. SO - Arzneimittel-Forschung Vol 43(5) (pp 584-590), 1993. AB - A two-way cross-over study was conducted on 12 Caucasian male healthy volunteers aged between 25 and 38 years in order to determine the bioavailability and pharmacokinetics of fluoride after single oral administration in fasting conditions of two products (tablets and powder for oral use) of L-glutamine monofluorophosphate (G-MFP, CAS 116420-36-1). The two products contained the equivalent of 10 mg F and the equivalent of 300 mg CA as calcium gluconate and calcium citrate. The two products were found bioequivalent with regard to the release of fluoride, both on the basis of the AUC and C(max) of fluoride in plasma and of the urinary excretion of fluoride during the 48 h following the administration. The pharmacokinetics of fluoride in plasma is characterized by a short lag time (<6 min), a rapid absorption, a peak which is reached 0.5-1.0 h after administration, followed by a biphasic elimination. The first phase with a k(alpha) of 1.8 h-1 is followed by a slower phase with a K(beta) of 0.14 h-1. Probably the terminal elimination rate is slower, about 0.05 h-1. The urinary excretion of fluoride during the 48 h after administration accounted for 40-50% of the administered dose of fluoride. The results are consistent with those found in previous studies after administration in fasting conditions of sodium fluoride or sodium monofluorophosphate alone or in combination with calcium salts. <58> UI - 1993095895 AU - Antich PP AU - Pak CYC AU - Gonzales J AU - Anderson J AU - Sakhaee K AU - Rubin C IN - Department of Radiology, Texas University SW Medical Center,Dallas, TX 75235-9058; United States. TI - Measurement of intrinsic bone quality in vivo by reflection ultrasound: Correction of impaired quality with slow-release sodium fluoride and calcium citrate. SO - Journal of Bone & Mineral Research Vol 8(3) (pp 301-311), 1993. AB - The intrinsic (material) quality of cancellous and cortical bone was evaluated in vivo from the measurement of reflection ultrasound velocities in the ulna. In cancellous bone, the reflection ultrasound velocity was inversely correlated with age in normal women (r = -0.48, p = 0.001), with a significantly lower mean value in 32 normal postmenopausal women than in 14 premenopausal women (3124 versus 3341 m/s, p < 0.0001). In 32 untreated osteoporotic women the cancellous bone velocity was lower than in normal postmenopausal subjects (2906 versus 3124 m/s, p = 0.0001). Following treatment with slow-release sodium fluoride plus calcium citrate (mean 2.4 years in 33 osteoporotic patients with no fracture during treatment), the cancellous bone velocity was significantly higher than in untreated osteoporotic women (3082 versus 2906 m/s, p = 0.0002) and was not significantly different from that in normal postmenopausal women. The cortical bone velocity displayed similar trends, but the changes did not attain statistical significance. The measurements were repeated approximately 9 months later in 9 untreated and in 20 treated patients; in 5 additional patients, the measurements were made both before and after 9 months of treatment with slow-release sodium fluoride and calcium citrate. The cancellous bone velocity increased significantly (p = 0.046) in these patients, from 3008 m/s before treatment to 3112 m/s after the first 9 months of treatment. The velocity rose significantly from 3037 to 3167 m/s (p = 0.017) in patients treated for a short time (12-30 months at first measurement), but it did not change in untreated patients or those treated for more than 30 months. Thus, the material quality of cancellous bone decreases with normal aging and is reduced further with the osteoporotic process. This impaired quality may be corrected by treatment with slow- release sodium fluoride plus calcium citrate. <59> UI - 1992347491 AU - Greenwald M AU - Brandli D AU - Spector S AU - Silverman S AU - Golde G IN - Osteoporosis Medical Center, 450 North Bedford,Beverly Hills, CA 90210; United States. TI - Corticosteroid-induced osteoporosis: Effects of a treatment with slow-release sodium fluoride. SO - Osteoporosis International Vol 2(6) (pp 303-304), 1992. <60> UI - 1992270946 AU - Bottenberg P AU - Cleymaet R AU - De Muynck C AU - Remon JP AU - Coomans D AU - Slop D IN - Clinic for Conservative Dentistry/, Periodontology, RWTH Aachen, Pauwelsstrasse,W-5100 Aachen; Germany. TI - Comparison of salivary fluoride concentrations after administration of a bioadhesive slow-release tablet and a conventional fluoride tablet. SO - Journal of Pharmacy & Pharmacology Vol 44(8) (pp 684-686), 1992. AB - The in-vitro and in-vivo fluoride release of bioadhesive, slow-release tablets prepared from a mixture of polyethylene glycol polymers, containing 0.1 mg of fluoride as NaF was studied, and their ability to sustain fluoride levels in saliva were compared with conventional fluoride tablets with the same fluoride content. In-vitro release experiments showed that the bioadhesive tablets needed 8 h to release all their fluoride compared with < 1 h for the conventional fluoride tablets. In-vivo, the bioadhesive tablets had a retention period of 6 h and could sustain a salivary fluoride level of more than 10 muM above the baseline for 7 h. The conventional fluoride tablets achieved a peak concentration of 0.5 mM directly after dissolution in the mouth, but the fluoride level could not be sustained for longer than 1 h. A good agreement was found between the in-vitro swelling behaviour of the bioadhesive tablets and their in-vitro and in-vivo release characteristics and their in-vivo retention time. <61> UI - 1992266822 AU - Duncan R IN - Farmitalia Carlo Erba, Via Carlo Imbonati 24,20159 Milan; Italy. TI - Drug-polymer conjugates: Potential for improved chemotherapy. SO - Anti-Cancer Drugs Vol 3(3) (pp 175-210), 1992. AB - Use of polymeric drug delivery systems is rapidly becoming an established approach for improvement of cancer chemotherapy. Zoladex(TM), a poly lactide-co-glycolide subcutaneous implant that delivers a luteinizing hormone releasing hormone analog over 28 days, is now the treatment of choice for prostate cancer, and a polyanhydride matrix containing BCNU is currently in phase III evaluation for treatment of glioma multiforme. Soluble polymers were first proposed as targetable drug carriers in the mid-1970s, and although the first conjugates are still at an early stage of development some, e.g. SMANCS (styrene maleic acid-neocarzinostatin) and monomethoxypolyethyleneglycolasparaginase, are now undergoing clinical evaluation and show considerable promise. Polymeric drug delivery systems are usually designed to produce an improved pharmacokinetic profile of an antitumor agent (controlled release) and in addition soluble carriers can achieve either first-order (organ specific) or second-order (tumor specific) drug targeting by virtue of the fact that they are usually administered intravenously and should theoretically access primary and secondary disease. Soluble polymeric carriers have the potential to improve the activity of conventional antitumor agents, peptide and protein drugs, and have recently been used in constructs for delivery of oligonucleotides. With increased awareness that the successful design of a polymeric drug delivery systems can only be achieved with prior consideration of the pathology and stage of the disease, tumor accessibility, biochemistry and cell biology of the target site, choice of appropriate therapeutic agent(s) and understanding of their fundamental mode of action, we have seen the emergence of a number of exciting and potentially more selective antitumor therapies based on polymer technologies. Here, the basic principles for design of soluble polymeric drug delivery systems are explained and illustrated using examples drawn from our studies on the development of N-(2-hydroxypropyl)methacrylamide copolymer conjugates for use in cancer chemotherapy. Those soluble polymeric carriers that are undergoing clinical evaluation are briefly reviewed. <62> UI - 1992207944 AU - Herschler J AU - Sherwood MB IN - Eye Clinic of Northern Wyoming, 350 S Brooks,Sheridan, WY 82801; United States. TI - Long-term results of trabeculectomy with collagen sponge implant containing low-dose antimetabolite. SO - Ophthalmology Vol 99(5) (pp 666-671), 1992. AB - Eighteen eyes of 15 patients with uncontrolled glaucoma (neovascular, intracapsular aphakia, uveitic, previous filtration failure) at high risk for failure of standard filtration underwent trabeculectomy with implantation of a purified collagen sponge containing 100 mug of antimetabolite (5- fluorouracil or bleomycin). Follow-up ranged from 3 months to 5 years. At the end of follow-up, 14 eyes (78%) had intraocular pressure below 21 mmHg and functional filtration blebs. No corneal toxicity was encountered at any time. Two patients (both successes) had partial or complete erosion of the collagen sponge. Although the differences were not statistically significant, patients receiving bleomycin had better success rates (8 of 9 versus 6 of 9) and lower intraocular pressure levels (11.88 mmHg versus 14.63 mmHg) than those receiving 5-fluorouracil. The collagen sponge implant demonstrates the clear advantages of drug delivery devices for the administration of antimetabolites after filtration surgery. <63> UI - 1992198026 AU - Corpron RE AU - More FG AU - Mount G IN - School of Dentistry, University of Michigan,Ann Arbor, MI 48109-1078; Canada. TI - Comparison of fluoride profiles by SIMS with mineral density of subsurface enamel lesions treated intra-orally with a fluoride-releasing device. SO - Journal of Dental Research Vol 71(SPEC. ISS.) (pp 828-831), 1992. <64> UI - 1992188182 AU - Zerwekh JE AU - Antich PP AU - Sakhaee K AU - Prior J AU - Gonzalez J AU - Gottschalk F AU - Pak CYC IN - Ct. Mineral Metabolism/Clin. Res., Univ. of Texas Southwestern Med. Ct., 5323 Harry Hines Boulevard,Dallas, TX 72535-8885; United States. TI - Lack of deleterious effect of slow-release sodium fluoride treatment on cortical bone histology and quality in osteoporotic patients. SO - Bone & Mineral Vol 18(1) (pp 65-76), 1992. AB - We evaluated the effects of intermittent slow-release sodium fluoride (SRNaF) and continuous calcium citrate therapy on cortical bone histology, reflection ultrasound velocity (material strength) and back-scattered electron image analysis (BEI) in 26 osteoporotic patients before and following therapy. All measurements were made on transiliac crest bone biopsies obtained before and following 2 years of therapy in each patient. For all 26 patients there were no significant changes in cortical bone histomorphometric parameters. In 15 patients in whom bone material quality was assessed by reflection ultrasound, there was no change in velocity (4000 +/- 227SD to 4013 +/- 240 m/s). BEI disclosed no mineralization defects or the presence of woven bone. Mean atomic number (density) of bone increased slightly, but significantly (9.261 +/- 0.311 to 9.457 +/- 0.223, P = 0.031). While these changes are less marked than those observed for cancellous bone, they indicate that this form of therapy does not adversely affect cortical bone remodelling. <65> UI - 1992157077 AU - Gordon SL AU - Corbin SB IN - NIAMS/NIH, 5333 Westbard Avenue,Bethesda, MD 20892; United States. TI - Summary of Workshop on Drinking Water Fluoride Influence on Hip Fracture on Bone Health (National Institutes of Health, 10 April, 1991). SO - Osteoporosis International Vol 2(3) (pp 109-117), 1992. <66> UI - 1992001839 AU - Anderson PA AU - Copenhaver JC AU - Tencer AF AU - Clark JM IN - Department of Orthopaedics, ZA-48, Harborview Medical Center, 325 Ninth Avenue, Seattle, WA 98104; United States. TI - Response of cortical bone to local controlled release of sodium fluoride: The effect of implant insertion site. SO - Journal of Orthopaedic Research Vol 9(6) (pp 890-901), 1991. AB - In a previous experiment, sodium fluoride in a biodegradable polymer matrix was introduced into the femoral canal of the rabbit and bone formation was compared with contralateral controls. We noted significant bone formation, but only in the distal third of the periosteal surface of the femur. The experiment was performed to distinguish fluoride-induced periosteal bone formation from that due to the reactive osteogenic changes associated with local injury caused by the process of implantation. A proximal approach on the right leg and a distal approach on the left were used for the insertion of the implants in rabbits. Femurs were removed after 30 days and tested for stiffness and load to failure. The cross-sectional area of mineralized bone was determined at proximal, midshaft, and distal locations. Fluorescent bone tissue growth labels were injected at weekly intervals to measure the rate of new periosteal bone formation. The results were compared with a control group that received sham implants. Results showed no difference between measured properties in right and left femurs in the control group or in those exposed to fluoride. A significant increase was found in the fluoride group in load to failure, along with cross-sectional area of mineralized bone, and periosteal growth rates compared with the control group, but no difference was seen in stiffness. No difference was detected between the response proximally and distally in the fluoride group regardless of the location of insertion. There were no detectable changes in serum fluoride level after implantation of the poly L-lactic acid/sodium fluoride matrix. These results show that fluoride exerts its osteogenic effects equally at proximal, midshaft, and distal regions of diaphyseal bone and is uninfluenced by the site of local injury due to insertion of the implant. <67> UI - 1991283817 AU - McLean JW IN - Institute of Dental Surgery, Eastman Dental Hospital, Grays Inn Road, London WC1X 8LD; United Kingdom. TI - The clinical use of Glass-ionomer cements - Future and current developments. SO - Clinical Materials Vol 7(4) (pp 283-288), 1991. AB - Although the glass-ionomer cements were developed in the 1970s, it is only recently that their clinical use has expanded internationally. Improvements in formulation have resulted in better mechanical strengths, increased translucency and, more importantly, faster setting times. Their use as 'dentine substitutes' has expanded the versatility of laminate restorations in anterior and posterior teeth and the introduction of the silver-cermet ionomers provided materials with increased abrasion resistance. Glass-ionomer cements have a number of unique properties, including adhesion to moist tooth structure, biological compatibility, and anticariogenic properties due to their fluoride release. One of their major roles is the treatment of early carious lesions using microcavity preparation. However, like all materials, glass-ionomer cements have their weaknesses, the prime ones being lack of toughness, early water sensitivity, and porosity leading to poor surface polish. Future research should concentrate on correcting these deficiencies. <68> UI - 1991243868 AU - Skartveit L AU - Gjerdet NR AU - Selvig KA IN - Department of Dental Research, University of Bergen, School of Dentistry, Aarstadveien 17, N-5009 Bergen; Norway. TI - Release of fluoride and metal ions from root surfaces after topical application of TiF4, SnF2, and NaF in vitro. SO - Acta Odontologica Scandinavica Vol 49(3) (pp 127-131), 1991. <69> UI - 1991234590 AU - Sakhaee K AU - Pak CYC IN - Center for Mineral Metabolism, and Clinical Research, University of Texas, 5323 Harry Hines Blvd.,Dallas, TX 75235-8885; United States. TI - Fluoride bioavailability from immediate-release sodium fluoride with calcium carbonate compared with slow-release sodium fluoride with calcium citrate. SO - Bone & Mineral Vol 14(2) (pp 131-136), 1991. AB - The circadian variation in serum fluoride was compared between treatment with immediate-release sodium fluoride (IR-NaF) (30 mg) and calcium carbonate (500 mg calcium) and slow-release sodium fluoride (SR-NaF) (25 mg) and calcium citrate (400 mg calcium) in seven patients with postmenopausal osteoporosis maintained on long-term fluoride treatment. During 12 h following a dose of SR-NaF, serum fluoride levels could be largely kept within the therapeutic window (believed to be 95-190 ng/ml or 5-10 mumol/l). In contrast, IR-NaF produced a wide circadian fluctuation with peak-to-trough change of about 200 ng/ml. Compared to SR-NaF, IR-NaF caused a significantly higher peak fluoride concentration in serum (322 vs. 158 ng/ml), and greater area under the curve (2269 vs. 1321 ng.h/ml) and urinary fluoride (6.72 vs. 3.80 mg/12 h). Thus, fluoride absorption from IR-NaF was twice as high as that from SR-NaF. <70> UI - 1991226242 AU - English D AU - Taylor G AU - Garcia JGN IN - Bone Marrow Trans. Laboratory, Methodist Hospital of Indiana, PO Box 1367,Indianapolis, IN 46206; United States. TI - Diacylglycerol generation in fluoride-treated neutrophils: Involvement of phospholipase D. SO - Blood Vol 77(12) (pp 2746-2756), 1991. AB - Neutrophils exposed to fluoride ion (F-) respond with a delayed and sustained burst of superoxide anion release that is both preceded by and dependent on the influx of Ca2+ from the extracellular medium. The results of this study demonstrate a similarly delayed and sustained generation of 1,2-diglyceride in F--treated neutrophils, over 90% of which was 1,2-diacylglycerol. Diacylglycerol generation was not dependent on the presence of extracellular Ca2+. Conversely, in contrast to results obtained with other agonists, removal of extracellular Ca2+ markedly potentiated synthesis of diacylglycerol in F--treated neutrophils. This effect was accompanied by a corresponding decrease in the recovery of phosphatidic acid. In either the presence or absence of extracellular Ca2+, phosphatidic acid accumulated before diacylglycerol in F--treated cells, suggesting the latter was derived from the former. Consistent with this hypothesis, the phosphatidic acid phosphohydrolase inhibitor, propranolol, suppressed generation of diacylglycerol as it potentiated the accumulation of phosphatidic acid in F--treated neutrophils. This effect was observed both in the presence and absence of extracellular Ca2+. Moreover, high levels of propranolol (160 mumol/L) effected complete inhibition of diacylglycerol generation in F--treated neutrophils with a corresponding increase in phosphatidic acid generation. Phosphatidylethanol accumulated in neutrophils stimulated with F- in the presence of ethanol. The extent of phosphatidylethanol accumulation at all time points after addition of F- corresponded to decreased levels of both phosphatidic acid and diacylglycerol, indicating that phosphatidylethanol was derived from the phospholipase D-catalysed transphosphatidylation reaction. The results indicate that F- activates a Ca2+-independent phospholipase D, which appears to be the major, if not sole, catalyst for both phosphatidic acid and diacylglycerol generation in F--treated neutrophils. Ca2+, mobilized as a result of F- stimulation and possibly as a consequence of phospholipase D activation, exerts a profound effect on cellular second messenger levels by modulati