Early changes in bone turnover and bone mineral density after discontinuation of long-term oral bisphosphonates: a post hoc analysis.

This post hoc analysis of a randomized, double-blind study of postmenopausal women with osteoporosis found that there were early increases in bone turnover markers and decreases in bone mineral density after discontinuation of long-term alendronate. These findings might help guide treatment decisions, including monitoring after alendronate withdrawal. INTRODUCTION: The short-term effects of discontinuing long-term bisphosphonates are poorly characterized. This post hoc analysis investigated 1-12-month changes in bone mineral density (BMD) and bone turnover markers (BTM) after alendronate (ALN) discontinuation. METHODS: Data were from a randomized, double-blind trial of MK-5442 (calcium-sensing receptor antagonist) following oral bisphosphonates, with placebo and continued ALN controls ( ClinicalTrials.gov NCT00996801). Postmenopausal women with osteoporosis had received oral bisphosphonate (≥ 3-4 preceding years; ALN for the 12 months pre-screening), continuing on ALN 70 mg/week (n = 87) or placebo (n = 88). RESULTS: At 12 months, least-squares mean percent changes from baseline BMD (placebo vs. ALN) were lumbar spine (LS): - 0.36 vs. 1.29, total hip: - 1.44 vs. 0.46, and femoral neck (FN): - 1.26 vs. - 0.08 (all P < 0.05). BTM levels increased by 1-3 months, to 12 months, with placebo vs. ALN (P < 0.001). FN BMD decline was greater in the placebo subgroup with higher urinary N-terminal cross-linked telopeptides of type I collagen/creatinine [uNTx/Cr] (P < 0.01), and higher serum N-terminal pro-peptide of type 1 collagen [P1NP] levels (P < 0.05), at baseline. There was a trend toward greater FN BMD loss with higher BTM levels at 3 and/or 6 months. Younger age and higher LS BMD at baseline were associated with greater LS BMD loss at 12 months (P = 0.04 and < 0.01, respectively); higher baseline FN BMD predicted greater FN BMD loss (P = 0.04). CONCLUSION: Early changes in BTM levels and BMD were observed after discontinuation of long-term ALN. Further characterization of factors associated with patients' risk of bone loss upon bisphosphonate discontinuation is warranted.

Discharge of lubricant from air turbine handpieces.

OBJECTIVE: To demonstrate and quantify the discharge of lubricating oil from high-speed air turbine handpieces whilst running. MATERIALS AND METHODS: Dye-marked oil (Kavospray, KaVo) was used to lubricate four handpieces (Quiet-Air, Midwest) and the air discharged from around the lower bearing was directed at the moving chart paper on a recorder whilst running for 40 minutes. Secondly, seven new handpieces (Quiet-Air, 300SE, Midwest; Topair 796, Topair 795, W+H; VIP-Sigma, Pana-air, NSK; Lares, Lares Research) were cleaned, weighed and then lubricated with unmarked oil (Kavospray, KaVo). Oil discharge was determined gravimetrically over runs of 240 minutes. Data were fitted to the logistic dose response function. RESULT: The dye-marked oil tests showed that oil was discharged for at least 40 minutes in the direction of the bur. The gravimetric tests showed that oil continued to be discharged up to at least 240 minutes, and that the usual practice of removing excess lubricant by running for 1-2 minutes was ineffective in preventing cut-surface contamination. SIGNIFICANCE: Bonding procedures in dentistry may be jeopardised by oil contamination from handpiece lubricants. Decontamination with a detergent is suggested as a means of ensuring effective adhesive dentistry.

Propargylamines induce antiapoptotic new protein synthesis in serum- and nerve growth factor (NGF)-withdrawn, NGF-differentiated PC-12 cells.

(-)-Deprenyl and structurally related propargylamines increase neuronal survival independently of monoamine oxidase B (MAO-B) inhibition, in part by decreasing apoptosis. We found that deprenyl and two other propargylamines, one of which does not inhibit monoamine oxidase B, increased survival in trophically withdrawn 6-day nerve growth factor (NGF)- and 9-day NGF-differentiated PC-12 cells but not in NGF naive or 3-day NGF-differentiated PC-12 cells. Four days of prior NGF exposure were required for the propargylamine-mediated antiapoptosis. Studies using actinomycin D, cycloheximide, and camptothecin revealed that the maintenance of both transcription and translation, particularly between 2 and 6 h after trophic withdrawal, was required for propargylamine-mediated antiapoptosis. Metabolic labeling of newly synthesized proteins for two-dimensional protein gel autoradiography and scintillation counting showed that the propargylamines either increased or reduced the levels of new synthesis or induced de novo synthesis of a number of different proteins, most notably proteins in the mitochondrial and nuclear subfractions. Western blotting for whole cell or subcellular fraction lysates showed that the timing of new protein synthesis changes or subcellular redistribution of apoptosis-related proteins induced by the propargylamines were appropriate to antiapoptosis. The apoptosis-related proteins included superoxide dismutases (SOD1 and SOD2), glutathione peroxidase, c-JUN, and glyceraldehyde-3-phosphate dehydrogenase. Most notable were the prevention of apoptotic decreases in BCL-2 levels and increases in mitochondrial BAX levels. In general, (-)-deprenyl-related propargylamines appear to reduce apoptosis by altering the levels or subcellular localization of proteins that affect mitochondrial membrane permeability, scavenge oxidative radicals, or participate in specific apoptosis signaling pathways.

Comparison of bracketing and matrixing designs for a two-year stability study.

In the U.S. Food and Drug Administration (FDA) guidelines for stability testing of new drug products, both bracketing and matrixing designs were suggested as the statistical designs. More recently, they have increasing attention from pharmaceutical companies, because both designs reduce the cost of stability studies. The purpose of this paper is to investigate both designs in terms of the power of detection of significant difference between slopes, and use the mean square error to evaluate the precision of estimated drug shelf life. Additionally, the distributions of both designs are compared by using 1000 simulations.

An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen.

This open-label, multicenter study evaluated the efficacy, safety, and cycle control of Yasmin, a new low-dose, monophasic oral contraceptive containing the unique progestogen drospirenone (DRSP) 3 mg and ethinyl estradiol (EE) 30 microg. DRSP is a synthetic progestogen that has antiandrogenic and antimineralocorticoid effects. In this study, 326 women were evaluated and 220 (67%) completed all 13 treatment cycles. The corrected Pearl Index was 0. 407. Of the 151 subjects who experienced intermenstrual bleeding at any time during the study, the majority (64%) had bleeding during only one or two pill cycles. Breakthrough bleeding without spotting occurred in 1% of all cycles, spotting without breakthrough bleeding in 9.3% of all cycles, and breakthrough bleeding with spotting in 3% of all cycles. Amenorrhea was observed in 3% of all cycles. In all, 20 subjects (6%) discontinued participation in the study because of adverse events. No serious adverse events related to the study drug were reported. No clinically significant changes in weight, blood pressure, or lipids were reported. The impact of the new progestogen DRSP on the women's self-perception of menstrual health was also evaluated. Subjects reported that symptoms of water retention, negative affect, and increased appetite significantly improved at cycle 6 from baseline. This study demonstrates that Yasmin is an effective oral contraceptive that is safe and well tolerated.

Reduced apoptosis after nerve growth factor and serum withdrawal: conversion of tetrameric glyceraldehyde-3-phosphate dehydrogenase to a dimer.

Antisense oligonucleotides against the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) are able to reduce some forms of apoptosis. In those forms, overall GAPDH levels increase and the enzyme accumulates in the nucleus. The monoamine oxidase B (MAO-B) inhibitor, (-)-deprenyl (DEP), its metabolite (-)-desmethyldeprenyl, and a tricyclic DEP analog, CGP3466, can reduce apoptosis independently of MAO-B inhibition and have been found to bind to GAPDH. We used neuronally differentiated PC12 cells to show that DEP, DES, and CGP3466 reduce apoptosis caused by serum and nerve growth factor withdrawal over the concentration range of 10(-) to 10(-13) M. We provide evidence that the DEP-like compounds bind to GAPDH in the PC12 cells and that they prevent both the apoptotic increases in GAPDH levels and nuclear accumulation of GAPDH. In vitro, the compounds enhanced the conversion of NAD(+) to NADH by GAPDH in the presence of AUUUA-rich RNA and converted GAPDH from its usual tetrameric form to a dimeric form. Using cell lysates, we found a marked increase in rates of NAD(+) to NADH conversion in early apoptosis, which was returned toward control values by the DEP-like compounds. Accordingly, the DEP-like compounds appear to decrease glycolysis by preventing the GAPDH increases in early apoptosis. GAPDH dimer may not have the capacity to contribute to apoptosis in a similar manner to the tetramer, which might account for the antiapoptotic capacity of the compounds. These actions on GAPDH, rather than MAO-B inhibition, may contribute to the improvements in Parkinson's and Huntington's diseases found with DEP treatment.

Activity of moxifloxacin against pathogens with decreased susceptibility to ciprofloxacin.

A panel of 279 clinical isolates of Gram-positive cocci and Gram-negative bacilli with varying levels of resistance to ciprofloxacin were analysed for susceptibility to moxifloxacin, ciprofloxacin, ofloxacin and nalidixic acid. Moxifloxacin was eight- to 32-fold more potent than ciprofloxacin and ofloxacin against staphylococci and Streptococcus pneumoniae, and equivalent to eight-fold more potent against enterococci. Although ciprofloxacin was intrinsically more potent than the other quinolones against highly susceptible Gram-negative isolates, the percentages of Gram-negative isolates susceptible to 1 mg/L of moxifloxacin or ciprofloxacin, or 2 mg/L of ofloxacin were 78%, 80% and 76%, indicating in-vitro equivalence of the agents against a collection that included isolates with diminished quinolone susceptibility. Staphylococci were analysed according to their ciprofloxacin susceptibility status. As ciprofloxacin resistance increased to high levels, all quinolone MICs increased, but moxifloxacin and ofloxacin MICs increased less than ciprofloxacin MICs. In mutational studies moxifloxacin inhibited more mutants (69%) at a concentration of 1 mg/L than did ciprofloxacin (63%) at 1 mg/L or ofloxacin at 2 mg/L (31%). The study indicated that moxifloxacin is more potent than ciprofloxacin and ofloxacin against Gram-positive pathogens, may be comparable in activity against less quinolone-susceptible Gram-negative isolates (other than Pseudomonas aeruginosa), and is less affected than ciprofloxacin by mechanisms responsible for increasing quinolone resistance in staphylococci.

Bacterial meningitis and the newborn infant.

Bacterial meningitis in the neonate differs from meningitis in the older infant and child in a number of ways. Bacterial pathogens primarily are associated with the maternal genitourinary tract. Symptoms and physical findings may be nonspecific, and a high index of suspicion is needed. Management may vary depending on the maturity of the infant and the bacterial pathogen that is isolated.

Glucose protection from MPP+-induced apoptosis depends on mitochondrial membrane potential and ATP synthase.

MPP+ inhibits mitochondrial complex I and alpha-ketoglutarate dehydrogenase causing necrosis or apoptosis of catecholaminergic neurons. Low glucose levels or glycolytic blockade has been shown to potentiate MPP+ toxicity. We found that MPP+ caused concentration-dependent apoptosis of neuronally differentiated PC12 cells and that glucose, but not pyruvate, supplementation reduced apoptosis. Oligomycin concentrations sufficient to inhibit ATP synthase blocked the decreased apoptosis afforded by glucose supplementation. Laser-scanning confocal microscope imaging of chloromethyl-tetramethylrosamine methyl ester fluorescence to estimate DeltaPsiM showed that MPP+ and atractyloside reduced DeltaPsiM, while cyclosporin A (CSA) and glucose supplementation reversed decreases in DeltaPsiM caused by MPP+. Oligomycin blocked the effect of glucose supplementation on DeltaPsiM. These findings show that (i) MPP+-induced and atractyloside-induced apoptosis are associated with reduced DeltaPsiM; (ii) CSA maintains DeltaPsiM and reduces MPP+-induced apoptosis; and (iii) glucose supplementation maintains DeltaPsiM, likely by glycolytic ATP-dependent proton pumping at ATP synthase and reduces MPP+-induced apoptosis.

Tuberculosis screening at 2 San Diego high schools with high-risk populations.

BACKGROUND: High immigration rates contribute to the high incidence of pediatric tuberculosis (TB) in San Diego, Calif. Adolescents frequently have poor access to health care and may not receive appropriate TB screening. School-based screening has been ineffective in detecting TB in other parts of the country. OBJECTIVE: To determine the prevalence of TB infection and disease in a high-risk population of high school students through school-based screening. DESIGN AND PARTICIPANTS: Cross-sectional study of TB prevalence and an analysis of risk factors for TB infection in students attending 2 San Diego high schools with high percentages of non-US-born students. MAIN OUTCOME MEASURES: Positive induration (> or =10 mm) with Mantoux tuberculin skin test. A chest radiograph or clinical findings consistent with active TB. RESULTS: A total of 744 (36%) students at high school 1 and 860 (57%) students at high school 2 participated. Ninety-five (12.8%) and 207 (24.1%) students, respectively, had positive tuberculin skin test results. One student had a chest radiograph that showed active TB. Smear for acid-fast bacteria and culture for Mycobacterium tuberculosis had negative results. Vietnamese, Filipino, and Latino ethnic groups were significantly more likely to have positive tuberculin skin test results than the white population (P<.05). Non-US-born students were significantly more likely to have positive tuberculin skin test results than US-born students in all ethnic groups except the Latino group. CONCLUSION: Although treatment of TB coupled with aggressive public health investigation is the most cost-beneficial way of preventing TB, targeted school-based screening may be an effective way of detecting TB infection in high-risk populations with poor access to health care.

A comparison of triamcinolone acetonide nasal aerosol spray and fluticasone propionate aqueous solution spray in the treatment of spring allergic rhinitis.

BACKGROUND: Many nasal corticosteroids with different potencies and formulations are available, but they have all been proven safe and effective. The clinical relevance, if any, of these differences is not yet completely established. OBJECTIVE: We sought to compare the efficacy, safety, and patients' acceptance of triamcinolone acetonide aerosol spray and fluticasone propionate aqueous solution in the treatment of spring allergic rhinitis. METHODS: After a drug-free baseline evaluation, patients with rhinitis were randomized to receive either a triamcinolone aerosol spray of 110 microg in each nostril once daily (n = 117) or a fluticasone solution spray of 100 microg in each nostril once daily (n = 116) in a single-blind, parallel-group study. The Rhinitis Index Score (sum of scores of symptoms on a scale from 0 to 3) was evaluated daily, in the morning before drug administration, for 21 days. The efficacy of each treatment was assessed by the mean reduction from baseline in the Rhinitis Index Score and in individual symptom scores. Patients' acceptance of the study drugs was also monitored by a daily questionnaire. RESULTS: Reductions of the Rhinitis Index Score (mean +/- SEM) were 4.20 +/- 0.21 and 4.60 +/- 0.21 for triamcinolone and fluticasone, respectively (p = 0.23). There were no statistically significant differences between the drugs in the reduction of any of the individual symptoms. Patients expressed statistically significant differences between the drugs regarding acceptance; different properties of the aerosol and the solution were appreciated differently. CONCLUSIONS: This study shows that triamcinolone acetonide aerosol and fluticasone propionate solution sprays are both clinically equally effective, safe, and well tolerated for the treatment of spring pollen allergic rhinitis.

Rationale behind high-dose amoxicillin therapy for acute otitis media due to penicillin-nonsusceptible pneumococci: support from in vitro pharmacodynamic studies.

To evaluate whether increased doses of amoxicillin should be used to treat acute pneumococcal otitis media, an in vitro pharmacokinetic model was used to evaluate the killing of pneumococci by amoxicillin when middle ear pharmacokinetics were simulated. Logarithmic-phase cultures were exposed to peak concentrations of 3, 6, and 9 microg of amoxicillin per ml every 12 h, and an elimination half-life of 1.6 h was simulated. Changes in viable bacterial counts were measured over 36 h. All three doses rapidly decreased the viable bacterial counts of penicillin-susceptible strains below the 10-CFU/ml limit of detection by 6 to 10 h and maintained counts below this limit through 36 h. The 3-microg/ml peak dose was much less effective against two of three strains with intermediate penicillin resistance and all three penicillin-resistant strains, with bacterial counts approaching those in drug-free control cultures by 12 h. The 6-microg/ml peak dose completely eliminated two of three strains with intermediate penicillin resistance and maintained viable counts of the other nonsusceptible strains at 1.5 to 2 logs below the initial inoculum through 36 h. The 9-microg/ml peak dose was most effective, completely eliminating all three strains with intermediate penicillin resistance and maintaining the viable counts of the resistant strains at 3 to 4 logs below the original inoculum. The pharmacodynamics observed in this study suggest that peak concentrations of amoxicillin of 6 to 9 microg/ml may be sufficient for the elimination of penicillin-nonsusceptible pneumococcal strains causing otitis media, especially those with intermediate resistance to amoxicillin. In vivo pharmacokinetic studies are needed to determine if these levels can be achieved in middle ear fluid with amoxicillin at 70 to 90 mg/kg/day divided into two daily doses. If these levels are reliably achieved, then clinical studies are warranted.

Acetaminophen anaphylaxis with aspirin and sodium salicylate sensitivity: a case report.

BACKGROUND: Aspirin idiosyncrasy can present with bronchospasm or cutaneous reactions, but combined pulmonary and cutaneous reactions are rare. High-dose acetaminophen has been reported to provoke bronchospasm in aspirin-sensitive asthmatic patients. CASE HISTORY: We report an asthmatic adolescent female who had anaphylaxis with 650 mg acetaminophen after tolerating 325-mg doses for years. She subsequently in sequence had urticaria with aspirin and ibuprofen, and anaphylaxis with sodium salicylate. She was then challenged with acetaminophen, 325 mg orally. RESULTS: Approximately 30 minutes after acetaminophen challenge, she developed rhinoconjunctivitis, urticaria, pruritus, cough, and bronchospasm reversed with antihistamines and bronchodilators. CONCLUSIONS: Aspirin sensitivity has not frequently been described in younger age groups. This patient also had several unusual features in that she presented first with sensitivity to acetaminophen that was then followed by aspirin sensitivity. She had urticaria with both aspirin and sodium salicylate; she had combined pulmonary and cutaneous reactions to both acetaminophen and aspirin, which are rarely described; and she had anaphylaxis with low-dose acetaminophen.

Comparison of CNS adverse effects between astemizole and chlorpheniramine in children: a randomized, double-blind study.

OBJECTIVE: To assess the central nervous system side effects of chlorpheniramine and astemizole in children. DESIGN: Prospective, randomized, double-blind cross-over study. SETTING: Children were recruited from the out-patient allergy clinic and from respondents to an advertisement in a local newspaper. The study was conducted in the outpatient clinics of the ambulatory care services of the Children's Hospital of Eastern Ontario. PATIENTS, PARTICIPANTS: Children 8-16 years of age, with isolated allergic rhinitis or hay fever, were eligible for the study. We excluded children with: (1) chronic conditions (specifically asthma, atopic dermatitis, learning disabilities, or current treatment with oral corticosteroid medication); (2) known allergy to the study medications; (3) recent use of any antihistamine medication. One hundred and three children entered the study and 92 completed it. INTERVENTIONS: Children were stratified by age and randomly allocated to treatment with one of the two medication sequences. Over a period of 13 weeks both groups had 1 week of baseline studies, 3 weeks of one study medication, either chlorpheniramine or astemizole, a 6-week wash-out period and then 3 weeks of the other study medication for a second treatment period. MAIN OUTCOME MEASURES: Attention span (continuous performance test), short-term auditory and visual memory (visual aural digit span test), visual memory for geometric shapes (Benton visual retention test), motor coordination and visual-motor integration (grooved pegboard test), tapping speed and fine motor coordination (finger tapping test), physical side effects (such as sleepiness and dizziness), and compliance. RESULTS: One hundred and three patients were enrolled in the study, 92 (89%) completed the study. There were no significant drug effects on the visual retention test and the continuous performance test. On the visual aural digit span test, patients treated with astemizole scored higher than at baseline. There were no clinical or statistical differences in adverse effects between the two medications or between each medication and baseline. CONCLUSIONS: The two antihistamines studied had no adverse effects on the performance of children.

Central nervous system side-effects of antihistamines in schoolchildren.

There are no studies available in the literature on the effects of classical antihistamines on the central nervous system (CNS) in children. Clinical studies indicate that somnolence occurs more often with classical antihistamines than with placebo. There is no difference in inducing somnolence in children between placebo and astemizole or terfenadine, two new antihistamines that have thoroughly been shown to have no sedative effect greater than placebo in adults. A double-blind, cross-over trial investigating the CNS-effects of astemizole and chlorpheniramine in schoolchildren failed to show a negative effect of either of these drugs on performance.