Development of Azeliragon, an Oral Small Molecule Antagonist of the Receptor for Advanced Glycation Endproducts, for the Potential Slowing of Loss of Cognition in Mild Alzheimer's Disease.

Increasing evidence supports the role of the Receptor for Advanced Glycation Endproducts (RAGE) in the pathology of Alzheimer's disease. Azeliragon (TTP488) is an orally bioavailable small molecule inhibitor of RAGE in Phase 3 development as a potential treatment to slow disease progression in patients mild AD. Preclinical studies in animal models of AD (tgAPPSwedish/London) have shown azeliragon to decrease Aß plaque deposition; reduce total Aß brain concentration while increasing plasma Aß levels; decreases sAPPß while increasing sAPPα; reduce levels of inflammatory cytokines; and slow cognitive decline and improve cerebral blood flow. In the Phase 2b study, 18-months treatment in patients with mild-to-moderate AD indicated a baseline to endpoint change in ADAS-cog of 3.1 points in favor of drug. A greater magnitude of effect was evident in the sub-group of patients with mild AD (MMSE 21-26) with a baseline to endpoint change of 4 points on the ADAS-cog in favor of azeliragon and a 1 point change in CDR-sb in favor of drug. Azeliragon 5 mg/day delayed time to cognitive deterioration (7-point change in ADAS-cog from baseline, logrank p=0.0149). Based on promising results from the Phase 2b study, a Phase 3 registration program (STEADFAST) is being conducted under a Special Protocol Assessment from FDA. The ongoing Phase 3 program, if successful may demonstrate azeliragon can slow cognitive decline in mild AD patients.

Lack of a pharmacokinetic interaction between a new smoking cessation therapy, varenicline, and digoxin in adult smokers.

OBJECTIVE: This study investigated the effect of varenicline on the multiple-dose pharmacokinetics of digoxin. METHODS: Eighteen smokers were randomized to receive digoxin (Lanoxicaps 0.2 mg QD) with varenicline 1 mg BID or placebo for 14 days. RESULTS: Varenicline had no clinically relevant effect on the digoxin steady-state exposure, as evidenced by the 90% confidence intervals for the ratios of AUC(0-24) (87.5-108%) and C(min) (83.8-116%) wholly contained within 80-125%. Digoxin C(max) and T(max) remained unchanged in the presence of varenicline, consistent with no apparent alteration in digoxin bioavailability. A minimal 11.3% increase in digoxin renal clearance was noted during varenicline treatment while having no impact on its systemic exposure. Results are supported by mechanistic evidence in Caco-2 cell monolayers that varenicline is neither a P-gp substrate nor an inhibitor of P-gp-mediated efflux of digoxin. Co-administration of varenicline and digoxin was well tolerated. CONCLUSION: The results suggest that digoxin can be safely administered with varenicline without the need for dose adjustment.

Human abuse liability of the smoking cessation drug varenicline in smokers and nonsmokers.

Varenicline is an alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist developed as an aid for smoking cessation. This study evaluated varenicline's potential for abuse by smokers (n = 23) and nonsmokers (n = 22). The study used a randomized, double-blind, placebo-controlled, double-dummy crossover design with five treatment periods: 15 and 30 mg amphetamine, 1 and 3 mg varenicline, and placebo. Following each treatment, the participants were assessed on aspects relating to potential abuse of the drug (e.g., drug liking, drug high, and drug monetary value). The positive effects measured for 3 mg varenicline were similar to those for the placebo, and significantly lower than those for amphetamine in both smokers and nonsmokers. Unpleasant effects were reported for 3 mg varenicline in both participant groups. For 1 mg varenicline, the overall patterns were similar, with the exception that the nonsmokers group showed some small positive effects balanced by some negative effects when compared with the effects of placebo. These findings lead to the conclusion that varenicline is unlikely to be abused.

Effect of human renal cationic transporter inhibition on the pharmacokinetics of varenicline, a new therapy for smoking cessation: an in vitro-in vivo study.

Varenicline is predominantly eliminated unchanged in urine, and active tubular secretion partially contributes to its renal elimination. Transporter inhibition assays using human embryonic kidney 293 cells transfected with human renal transporters demonstrated that high concentrations of varenicline inhibited substrate uptake by hOCT2 (IC(50)=890 microM), with very weak or no measurable interactions with the other transporters hOAT1, hOAT3, hOCTN1, and hOCTN2. Varenicline was characterized as a moderate-affinity substrate for hOCT2 (K(m)=370 microM) and its hOCT2-mediated uptake was partially inhibited by cimetidine. Co-administration of cimetidine (1,200 mg/day) reduced the renal clearance of varenicline in 12 smokers, resulting in a 29.0% (90% CI: 21.5%-36.9%) increase in systemic exposure. This increase is not considered clinically relevant, as it should not give rise to safety concerns. Consequently, it can be reasonably expected that other inhibitors of hOCT2 would not cause greater renal interactions with varenicline than that seen with the efficient hOCT2 inhibitor cimetidine.

Pilot trial of 1-octanol in essential tremor.

1-Octanol (an 8-C alcohol currently used as a food-flavoring agent) is known to inhibit tremor in essential tremor (ET) animal models at a much lower dose than ethyl alcohol. The authors conducted a randomized, placebo-controlled pilot trial of a single oral dose of 1 mg/kg of 1-octanol in 12 patients with ET. No significant side effects or signs of intoxication were observed. 1-Octanol significantly decreased tremor amplitude for up to 90 minutes. The results suggest 1-octanol as a well-tolerated and safe potential treatment for ET. Further trials are warranted.

Cholinergic influences on use-dependent plasticity.

Motor practice elicits use-dependent plasticity in humans as well as in animals. Given the influence of cholinergic neurotransmission on learning and memory processes, we evaluated the effects of scopolamine (a muscarinic receptor antagonist) on use-dependent plasticity and corticomotor excitability in a double-blind placebo-controlled randomized design study. Use-dependent plasticity was substantially attenuated by scopolamine in the absence of global changes in corticomotor excitability. These results identify a facilitatory role for cholinergic influences in use-dependent plasticity in the human motor system.

Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations.

Aminoglycosides have previously been shown to suppress nonsense mutations, allowing translation of full-length proteins in vitro and in animal models. In the mdx mouse, where muscular dystrophy is due to a nonsense mutation in the dystrophin gene, gentamicin suppressed truncation of the protein and ameliorated the phenotype. A subset of patients with Duchenne and Becker muscular dystrophy similarly possess a nonsense mutation, causing premature termination of dystrophin translation. Four such patients, with various stop codon sequences, were treated once daily with intravenous gentamicin at 7.5 mg/kg/day for 2 weeks. No ototoxicity or nephrotoxicity was detected. Full-length dystrophin was not detected in pre- and post-treatment muscle biopsies.

Fludarabine pharmacokinetics after subcutaneous and intravenous administration in patients with lupus nephritis.

STUDY OBJECTIVE: To compare the pharmacokinetics of subcutaneous and intravenous fludarabine in patients with lupus nephritis. DESIGN: Open-label, randomized, crossover trial conducted with a phase I-II trial. SETTING: Government research hospital. PATIENTS: Five patients with lupus nephritis. INTERVENTION: Fludarabine 30 mg/m2/day was administered either subcutaneously or as a 0.5-hour intravenous infusion for 3 consecutive days. All patients received oral cyclophosphamide 0.5 g/m2 on the first day of each cycle. MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected before and 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the first dose. Urine was collected at 6-hour intervals for 24 hours. Plasma and urine were analyzed for fluoro-arabinofuranosyladenine (F-ara-A), fludarabine's main metabolite, using high-performance liquid chromatography. Compartmental techniques were used to determine the pharmacokinetics of F-ara-A; a linear two-compartment model best described them. Comparison of the pharmacokinetics between subcutaneous and intravenous administration was done by using a Wilcoxon signed rank test. No significant differences were found between subcutaneous and intravenous administration in median (interquartile range) maximum concentrations of 0.51 (0.38-0.56) and 0.75 (0.52-0.91) mg/L, respectively, or in fitted area under the concentration-time curves from 0-24 hours of 4.65 (4.17-4.98) and 4.55 (3.5-4.94) mg x hour/L, respectively. Bioavailability of F-ara-A after subcutaneous dosing was approximately 105% of the bioavailability after intravenous administration. Differences in renal clearance and percentage of dose excreted in urine for subcutaneous and intravenous administration were nonsignificant. No injection site reactions were seen with subcutaneous dosing. CONCLUSION: Subcutaneous and intravenous administration of fludarabine appear to have similar pharmacokinetics in patients with lupus nephritis. Subcutaneous injection may offer a convenient alternative to intravenous administration.

Phenylacetate pharmacokinetics based on iterative two-stage population analysis.

STUDY OBJECTIVE: To determine the population pharmacokinetics of phenylacetate using iterative two-stage analysis implemented with ADAPT 11 software. SETTING: United States government research hospital. DESIGN: Retrospective pharmacokinetic analysis. SUBJECTS: Sixty-seven patients with refractory solid tumors. INTERVENTION: Subjects received from 1-10 courses/individual (total 141 courses) of therapy with either twice-daily administration or continuous infusions of phenylacetate. MEASUREMENTS AND MAIN RESULTS: Extensive plasma concentration measurements were performed after the initial dose or start of infusion, with sparse sampling during subsequent courses of therapy. Phenylacetate plasma concentration-time profiles were described by a one-compartment, capacity-limited clearance model with incorporation of parameters to describe extent of induction of clearance and the rate of induction. Median estimates for volume of distribution, maximum rate of drug elimination, Michaelis-Menten constant, and induction factor, and rate of onset of induction of drug clearance were 0.33 (0.26, 0.48) L/kg, 21.8 (16.3, 28.0) mg/kg/hour, 94.6 (48.8, 153.0) mg/L, 1.28 (1.06, 1.66), and 0.0038 (0.0019, 0.0058) hour(-1), respectively. CONCLUSION: The results of this study are similar to previous pharmacokinetic evaluations using the Abbottbase PKS system but suggest that earlier analyses were suboptimal.

Revisión Histórica del control de la Lepra en el Perú

Se hace una sumaria revisión cronológica de los hechos más destacados en la historia y el control de la lepra en el Perú, hasta llegar a la situación actual, señalándose las bases doctrinarias y las perspectivas futuras del Programa Nacional de Control de la Lepra, con el propósito de lograr la eliminación de esta enfermeclad en el país como problema de salud pública. Finalmente, se brinda información de la situación epidemiológica de esta endemia al año 2000.

A summary chronological overhaul becomes of the most outstanding facts in the history and the control of the leprosy in Peru, until arriving at the present situation, being indicated to the doctrinarias bases and the future perspective of the National Program of Control of the Leprosy, in order to obtain the elimination of this disease in the country like problem of public health. Finally, epidemiologist of this offers information of the situation enclemia to year 2000.

Efficacy of the cation exchange resin, sodium polystyrene sulfonate, to decrease iron absorption.

BACKGROUND: Iron is not bound by charcoal; therefore, a method of binding iron in the gastrointestinal tract to prevent absorption in iron overdose is needed. This study investigated the efficacy and safety of sodium polystyrene sulfonate to prevent absorption of iron in human volunteers. METHODS: Six adult volunteers completed this prospective crossover trial. Following an oral dose of elemental iron 10 mg/kg, each subject received sodium polystyrene sulfonate 30 g or water as control. Baseline and serial serum iron samples were drawn to determine pharmacokinetic parameters. RESULTS: A trend toward increased time to peak following sodium polystyrene sulfonate compared to the control arm (5.7 vs 3.6 hours) was observed but was not statistically significant (p = 0.517). A trend toward smaller area-under-the-curve for the sodium polystyrene sulfonate was evident but was not statistically significant (p = 0.77). Iron concentration increased on average 298 mcg/dL and 370 mcg/dL above baseline in the treatment and control arms (p = 0.44). Sodium polystyrene sulfonate is not an effective method of decontamination for iron overdose.

Impact of Parkinson's disease and its pharmacologic treatment on quality of life and economic outcomes.

The impact of Parkinson's disease (PD) and its pharmacologic treatment on health-related quality of life (HRQL) and economic outcomes is reviewed. PD is a chronic and progressive neurologic disorder characterized by specific motor deficits resulting from the degeneration of dopaminergic neurons in the substantia nigra. The cardinal symptoms are tremor, rigidity, bradykinesia, and loss of postural reflexes. PD markedly reduces HRQL and places an economic burden on society of up to $25 billion per year. Patients' inability to move freely and to perform everyday tasks restricts their independence and leads to increased reliance on caregivers and assistive devices. Emotional and psychosocial well-being is also negatively affected. As the disease progresses, the response to levodopa typically decreases and various motor complications develop; these are difficult to treat and result in further declines in HRQL. The economic costs of PD include both direct health care costs (for drugs, physician services, and hospitalization) and indirect costs (for lost worker productivity). Economic analyses of PD and its treatments can help guide effective allocation of health care resources. Various antiparkinsonian agents and formulations, such as extended-release levodopa-carbidopa and pramipexole, have been found to be cost-effective relative to other agents. The newest antiparkinsonian drugs, cathechol-O-methyltransferase inhibitors, also have the potential to improve HRQL and economic outcomes, although more study is needed to confirm this. The total impact of PD and its treatment can be fully appreciated only when HRQL and economic outcomes, in addition to clinical outcomes, are examined.

St John's Wort: effect on CYP3A4 activity.

BACKGROUND: St John's Wort is a widely used herbal product. Information regarding its potential for drug interactions is required for responsible treatment of patients using St John's Wort. CYP3A4 is a metabolic enzyme implicated in most clinically significant drug-drug interactions. OBJECTIVE: To determine the in vivo effect of reagent-grade St John's Wort extract on CYP3A4 activity through evaluation of urinary 6-beta-hydroxycortisol/cortisol ratios. METHODS: Thirteen subjects ranging in age from 18 to 25 years participated in this unblinded, multiple-dose, single-treatment before-after trial conducted in a university-based pharmacokinetics and biopharmaceutics laboratory. Each subject ingested a 300-mg tablet of reagent-grade St John's Wort extract standardized to 0.3% hypericin three times a day for 14 days. Baseline and posttreatment CYP3A4 activity was assessed with the urinary 6-beta-hydroxycortisol/cortisol ratio after a 24-hour urine collection. RESULTS: The mean +/- SD urinary 6-beta-hydroxycortisol/cortisol ratio significantly increased (P = .003) from a baseline value of 7.1 +/- 4.5 to 13 +/- 4.9. The mean +/- SD percentage increase was 114% +/- 95%, with a range from -25% to 259%. All but one subject had an increase in the ratio. CONCLUSIONS: Treatment with St John's Wort for 14 days resulted in significant increases in the urinary 6-beta-hydroxycortisol/cortisol ratio. This finding suggests that St John's Wort is an inducer of CYP3A4.

Absorption of phenytoin from rectal suppositories formulated with a polyethylene glycol base.

STUDY OBJECTIVE: To compare phenytoin pharmacokinetics following administration of an oral suspension and a rectal suppository formulated with a polyethylene glycol base. DESIGN: Unblinded, single-dose, randomized, crossover trial. SETTING: University-affiliated pharmacokinetics and biopharmaceutics laboratory. SUBJECTS: Six healthy subjects. INTERVENTION: Subjects were given a single 200-mg dose of phenytoin as an oral suspension and a rectal suppository separated by a 1-week washout. MEASUREMENTS AND MAIN RESULTS: Blood for plasma phenytoin concentrations was obtained at baseline and 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours after administration. Plasma was analyzed by high-performance liquid chromatography (coefficient of variation < 6%) for total phenytoin concentration. Phenytoin maximum concentration (Cmax), time to Cmax (Tmax), time to first measurable concentration (Tlag), and area under the curve from time zero to time of last measurable concentration (AUClast) were estimated for oral and rectal administration by WinNonlin (v 1.1) and compared using Wilcoxon's signed rank test (p<0.05 for statistical significance). Two subjects did not have detectable plasma phenytoin concentrations after rectal administration. For the other four subjects, median rectal Cmax was significantly lower than oral Cmax (0.4 vs 1.9 microg/ml, p=0.028), median rectal Tmax did not differ from oral Tmax (11.9 vs 8.0 hrs, p=0.465), and median rectal AUClast, although highly variable, was significantly lower than oral AUClast (5.4 vs 36.2 microg x hr/ml, p=0.046). No Tlag was seen after oral administration, but with rectal administration the median Tlag was 2 hours. The estimated relative bioavailability of rectal phenytoin suppositories based on AUC0-24 was 4.7%, with individual values ranging from 0-58.3%. CONCLUSION: It appears that absorption of phenytoin from polyethylene glycol rectal suppositories in healthy subjects is highly variable and unpredictable. Thus this formulation is not recommended.

Indinavir concentrations and St John's wort.

St John's wort reduced the area under the curve of the HIV-1 protease inhibitor indinavir by a mean of 57% (SD 19) and decreased the extrapolated 8-h indinavir trough by 81% (16) in healthy volunteers. A reduction in indinavir exposure of this magnitude could lead to the development of drug resistance and treatment failure.