A double-blind, randomized, two-part, two-period crossover study to evaluate the pharmacokinetics of caffeine versus d9-caffeine in healthy subjects.

The deuterium kinetic isotope effect has been used to affect the cytochrome P450 metabolism of the deuterated versions of substances. This study compares the pharmacokinetics of caffeine, a Generally Recognized As Safe food and beverage ingredient, versus d9-caffeine, a potential caffeine alternative, and their respective metabolites at two dose levels in 20 healthy adults. A single dose of 50 mg or 250 mg of caffeine, or a molar-equivalent dose of d9-caffeine, were orally administered in solution with blood samples collected for up to 48 h post-dose. Plasma concentrations of parent and metabolites were analyzed using validated LC-MS/MS methods. Both d9-caffeine and caffeine were rapidly absorbed; however, d9-caffeine exhibited a higher (ca. 29%-43%) Cmax and 4-5-fold higher AUClast than caffeine, and lower Cmax, lower AUClast, and a 5-10-fold reduction in the relative exposure to the active metabolites of caffeine. Results were consistent in normal and rapid metabolizers, and both substances were well tolerated.

Beneficial effects of natural eggshell membrane versus placebo in exercise-induced joint pain, stiffness, and cartilage turnover in healthy, postmenopausal women.

PURPOSE: Despite its many health benefits, moderate exercise can induce joint discomfort when done infrequently or too intensely even in individuals with healthy joints. This study was designed to evaluate whether NEM® (natural eggshell membrane) would reduce exercise-induced cartilage turnover or alleviate joint pain or stiffness, either directly following exercise or 12 hours post exercise, versus placebo. PATIENTS AND METHODS: Sixty healthy, postmenopausal women were randomly assigned to receive either oral NEM 500 mg (n=30) or placebo (n=30) once daily for two consecutive weeks while performing an exercise regimen (50-100 steps per leg) on alternating days. The primary endpoint was any statistically significant reduction in exercise-induced cartilage turnover via the biomarker C-terminal cross-linked telopeptide of type-II collagen (CTX-II) versus placebo, evaluated at 1 and 2 weeks of treatment. Secondary endpoints were any reductions in either exercise-induced joint pain or stiffness versus placebo, evaluated daily via participant questionnaire. The clinical assessment was performed on the per protocol population. RESULTS: NEM produced a significant absolute treatment effect (TEabs) versus placebo for CTX-II after both 1 week (TEabs -17.2%, P=0.002) and 2 weeks of exercise (TEabs -9.9%, P=0.042). Immediate pain was not significantly different; however, rapid treatment responses were observed for immediate stiffness (Day 7) and recovery pain (Day 8) and recovery stiffness (Day 4). No serious adverse events occurred and the treatment was reported to be well tolerated by study participants. CONCLUSION: NEM rapidly improved recovery from exercise-induced joint pain (Day 8) and stiffness (Day 4) and reduced discomfort immediately following exercise (stiffness, Day 7). Moreover, a substantial chondroprotective effect was demonstrated via a decrease in the cartilage degradation biomarker CTX-II. Clinical Trial Registration number: NCT02751944.

Psychomotor effects, pharmacokinetics and safety of the orexin receptor antagonist suvorexant administered in combination with alcohol in healthy subjects.

A double-blind crossover study investigated psychomotor effects, pharmacokinetics, and safety of the orexin receptor antagonist suvorexant with and without alcohol. Healthy adults (n=31) were randomized to receive placebo or suvorexant (40 mg) plus placebo solution or alcohol (0.7 g/kg) in each of four treatments (single doses; morning administration). The US Food and Drug Administration approved suvorexant dose is 10 mg (up to 20 mg) daily. Pharmacodynamic effects were assessed using tests of digit vigilance (DVT; primary endpoint), choice reaction time, digit symbol substitution, numeric working memory, immediate/delayed word recall, body sway and subjective alertness. Suvorexant alone did not significantly affect DVT reaction time, but did impact some pharmacodynamic tests. Suvorexant with alcohol increased reaction time versus either alone (mean difference at 2 h: 44 ms versus suvorexant, p<0.001; 24 ms, versus alcohol, p<0.05) and had additive negative effects on tests of vigilance, working/episodic memory, postural stability and alertness. No effects of suvorexant alone or with alcohol were observed by 9 h. No important changes in pharmacokinetic parameters were observed upon co-administration. All treatments were generally well tolerated without serious adverse events. In conclusion, co-administration of 40 mg suvorexant and 0.7 g/kg alcohol had additive negative psychomotor effects. Patients are advised not to consume alcohol with suvorexant.

Pharmacokinetics of continuous once-a-week combination 17ß-Estradiol/Low- or high-dose levonorgestrel transdermal delivery systems in postmenopausal women.

Two open-label, randomized, two-period, crossover studies were performed to determine the safety, delivery rates, and pharmacokinetic properties of a combination estradiol (E2)/levonorgestrel (LNG) transdermal delivery system (TDS). Study 1 enrolled 24 postmenopausal women who received a single TDS containing 4.4 mg E2 and 1.39 mg of LNG (E2/LNG Low) or E2 0.050 mg/24 hours TDS and 0.090 mg LNG oral tablet. Study 2 enrolled 44 postmenopausal women who received either E2/LNG Low or TDS containing 4.4 mg E2 and 2.75 mg LNG (E2/LNG High) weekly for a period of 4 weeks. E2, estrone (E1), LNG, and sex hormone-binding globulin (SHBG) serum concentrations were determined. Overall, both E2/LNG TDS were well tolerated and had excellent adhesion properties. The average daily delivery for E2/LNG Low was 0.045 mg for E2 and 0.0132 mg for LNG. Following weekly delivery of E2/LNG Low or High for 4 weeks, the combination of E2 with two different strengths of LNG did not alter the pharmacokinetic profile of E2. SHBG, total cholesterol, and triglycerides concentrations significantly decreased compared to baseline. Both E2/LNG Low and High TDSs were well tolerated and provided continuous drug delivery over 7 days supporting the benefits of the transdermal route of administration in optimally delivering hormonal therapy.

Safety and immunogenicity of revaccination with reduced dose intradermal and standard dose intramuscular influenza vaccines in adults 18-64 years of age.

BACKGROUND: This clinical trial examined the safety and immunogenicity of annual revaccination with Fluzone(®) Intradermal (Sanofi Pasteur, Swiftwater, PA) vaccine compared to a standard intramuscular (IM) split-virion trivalent influenza vaccine (Fluzone(®), Sanofi Pasteur). METHODS: This phase II, active-controlled, multi-centre, open-label trial was conducted in 2009 and 2010, and enrolled 1250 adults 18-64 years of age who were randomly selected from participants in a phase III influenza vaccine trial the previous year (NCT00772109). Subjects who had previously received the ID vaccine were randomized 2:1 to be revaccinated with the ID or IM vaccine and those who previously received the IM vaccine were randomized 1:1. Solicited reactions were recorded on the day of vaccination and continuing for the next 7 days, non-serious adverse events for 28 days, and serious adverse events for 6 months after vaccination. Hemagglutination inhibition antibody titres were assessed pre-vaccination and at day 28. RESULTS: Reactions were well-tolerated and resolved in the first 7 days, but erythema, induration, swelling, pruritus and ecchymosis were reported by more subjects receiving the ID vaccine than the IM vaccine. Compared to receipt of IM vaccine in the previous year, ID vaccine in the previous year led to statistically higher rates of erythema, swelling and induration after IM vaccine in the second year. Injection-site pain and systemic reactions did not differ between ID and IM vaccines. No treatment-related serious adverse events were reported. Geometric mean antibody titres, seroprotection rates, and seroconversion rates were non-inferior for the ID and IM vaccines for all three viral strains. CONCLUSIONS: The ID vaccine was as immunogenic as the IM vaccine, and raised no safety concerns. It can be used interchangeably with the IM vaccine for annual revaccination in adults 18-64 years of age in consecutive years without safety concerns.

Evaluation of the pharmacodynamics of acetylsalicylic acid 81 mg with or without esomeprazole 20 mg in healthy volunteers.

BACKGROUND: The absence of a pharmacokinetic interaction between the proton pump inhibitor esomeprazole (40 mg) and acetylsalicylic acid (aspirin, ASA; 325 mg) has previously been established. OBJECTIVE: This study set out to investigate the potential for pharmacodynamic interaction between low-dose ASA and esomeprazole in healthy volunteers, by measuring ASA antiplatelet activity. STUDY DESIGN: This was a single-center, open-label, two-period, randomized crossover study. PARTICIPANTS: Healthy male and female volunteers aged 18-75 years were included. All volunteers received ASA 81 mg once daily for 5 days prior to the study (pre-screen). Subjects were eligible for inclusion if they had aspirin reactivity units (ARU, as measured by the VerifyNow ASA assay) of <550 on Day 6. INTERVENTION: After pre-screening and a washout period of at least 14 days, eligible volunteers received ASA 81 mg with or without esomeprazole 20 mg once daily for 5 days in randomized order, with a 14-day washout between treatments. MAIN OUTCOME MEASURE: The main outcome measure was the antiplatelet activity of ASA, as assessed by ARU ratio relative to baseline in the VerifyNow ASA assay; suppression of serum thromboxane B(2) (TXB(2)) was a secondary endpoint. Statistical comparisons were made using linear mixed models. RESULTS: A total of 29 volunteers (19 aged ≥50 years; 8 women; 21 men) were evaluable for pharmacodynamic analysis (per protocol). All volunteers on both treatments achieved ARU <550 at Day 6. The geometric mean ratio of Day 6 to Day 1 (baseline) platelet aggregation was 0.70 (95% confidence interval [CI] 0.68, 0.72) with ASA alone and 0.71 (95% CI 0.69, 0.74) with ASA + esomeprazole. The ratio of platelet aggregation (ASA + esomeprazole/ASA) was 1.02 (95% CI 0.99, 1.05). ASA administered alone or with esomeprazole reduced serum TXB(2) by more than 99.5%. The ratio of suppression of serum TXB(2) levels (ASA + esomeprazole/ASA) was 1.06 (95% CI 0.88, 1.29). The combination of ASA and esomeprazole was well tolerated. CONCLUSION: No pharmacodynamic interaction between low-dose ASA and esomeprazole was found with regard to platelet function. TRIAL REGISTRATION: Registered at ClinicalTrials. gov as NCT01199328.

A novel tetravalent dengue vaccine is well tolerated and immunogenic against all 4 serotypes in flavivirus-naive adults.

BACKGROUND. Sanofi Pasteur has developed a tetravalent dengue vaccine (TDV) against the world's most common arbovirus infection. METHODS. We assessed the safety and immunogenicity of the TDV in healthy adults randomized into 2 groups. Group 1 received 3 TDV injections at months 0, 4, and 12-15; group 2 received saline placebo at month 0 and then 2 TDV injections at months 4 and 12-15. Adverse events were recorded, and biological parameters and viremia levels were measured. Neutralizing antibodies against 4 World Health Organization (WHO) reference strains were measured before and after vaccinations. RESULTS. A total of 33 participants were enrolled in each group. Demographic characteristics were comparable. No vaccine-related serious adverse event was reported. The most common systemic reactions were headache, malaise, and myalgia. Low viremia levels were detected, mainly of serotype 4. Immune response increased with successive vaccine doses. All participants seroconverted against all 4 serotypes after receiving 3 doses at 0, 4, and 12-15-months, and almost all seroconverted after 2 doses given 8-11 months apart. CONCLUSIONS. Sanofi Pasteur's TDV was well tolerated and induced full seroconversion against all WHO reference strain serotypes after 3 doses.

Pharmacokinetics of an oral contraceptive containing oestradiol valerate and dienogest.

OBJECTIVE: To evaluate the pharmacokinetics of a combined oral contraceptive (OC) containing oestradiol valerate/dienogest (E2V/DNG) administered according to a four-phasic dosing regimen with an oestrogen step-down and a progestin step-up over 26 days of active treatment. METHODS: This Phase I, open-label study included healthy women aged 18-50 years. Treatment consisted of the administration of E2V 3 mg for 2 days, E2V 2 mg/DNG 2 mg for 5 days, E2V 2 mg/DNG 3 mg for 17 days, E2V 1 mg for 2 days, and placebo for 2 days. RESULTS: Pharmacokinetic data were analysed in 15 women. Stable E2 concentrations were maintained throughout the study. Minimum mean serum E2 levels were 33.6-64.7 pg/ml during E2V administration. The ratio of oestrone:E2 in serum was approximately 5:1. Minimum mean serum DNG levels were 6.8-15.1 ng/ml during DNG administration. Minimum concentrations of DNG increased only slightly during each phase of the regimen during which DNG was being administered. On day 24 the geometric mean C(max), C(ave) and t((1/2)) of DNG were 82.9 ng/ml, 33.7 ng/ml and 12.2 hours, respectively; the median t(max) was 1.5 hours. Serum sex hormone-binding globulin concentrations increased by 40% (within the normal range). Cortisol binding-globulin levels remained almost unchanged. Treatment was well tolerated. CONCLUSIONS: Treatment with an OC containing E2V and DNG was well tolerated and was associated with stable E2 concentrations over 28 days. The pharmacokinetics of DNG were consistent with previous findings. Minimum serum concentrations of DNG increased only slightly during phases of the regimen during which DNG was administered.

Steady-state pharmacokinetics of conjugated equine estrogens in healthy, postmenopausal women.

OBJECTIVE: To determine the steady-state exposure of conjugated and unconjugated estrogen components following oral administration of conjugated equine estrogens (2 0.625-mg tablets). STUDY DESIGN: A prospective, open-label, single-treatment study conducted at 1 clinical site with 12 healthy, postmenopausal women. Each subject received 7 daily doses of 2 conjugated equine estrogen (0.625-mg) tablets, and blood samples were taken on the last day of dosing for pharmacokinetic analysis of estrogen components. RESULTS: The major estrogen components after estrogen dosing (as determined by steady-state plasma concentration-time curves) were estrone (100 ng x h/mL), equilin (43.1 ng x h/mL) and delta8,9-dehydroestrone (13.6 ng x h/mL). Several 17beta-reduced forms of estrogen also had consistent plasma concentrations during a steady-state dosing interval. Mean t(max) values ranged from 6.2 to 9.0 hours after dosing, and the 24-hour profiles of the various plasma estrogen concentrations at steady state showed limited fluctuations. CONCLUSION: Oral dosing of conjugated equine estrogen at steady state resulted in consistent concentrations of estrogen components during a dosing interval.

A randomized, crossover study to evaluate the pharmacokinetics of amantadine and oseltamivir administered alone and in combination.

UNLABELLED: The threat of potential pandemic influenza requires a reevaluation of licensed therapies for the prophylaxis or treatment of avian H5N1 infection that may adapt to man. Among the therapies considered for use in pandemic influenza is the co-administration of ion channel and neuraminidase inhibitors, both to potentially increase efficacy as well as to decrease the emergence of resistant isolates. To better understand the potential for drug interactions, a cross-over, randomized, open-label trial was conducted with amantadine, 100 mg po bid, and oseltamivir, 75 mg po bid, given alone or in combination for 5 days. Each subject (N = 17) served as their own control and was administered each drug alone or in combination, with appropriate wash-out. Co-administration with oseltamivir had no clinically significant effect on the pharmacokinetics (PK) of amantadine [mean ratios (90% CI) for AUC(0-12) 0.93 (0.89, 0.98) and C(max) 0.96 (0.90, 1.02)]. Similarly, amantadine co-administration did not affect oseltamivir PK [AUC(0-12) 0.92 (0.86, 0.99) and C(max) 0.85 (0.73, 0.99)] or the PK of the metabolite, oseltamivir carboxylate [AUC(0-12) 0.98 (0.95, 1.02) and C(max) 0.95 (0.89, 1.01)]. In this small trial there was no evidence of an increase in adverse events. Although many more subjects would need to be studied to rule out a synergistic increase in adverse events, the combination in this small human drug-drug interaction trial appears safe and without pharmacokinetic consequences. TRIAL REGISTRATION: ClinicalTrials.gov NCT00416962.

Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax-DEN2) vaccine: Phase I clinical trial for safety and immunogenicity: effect of yellow fever pre-immunity in induction of cross neutralizing antibody responses to all 4 dengue serotypes.

A randomized double-blind Phase I Trial was conducted to evaluate safety, tolerability, and immunogenicity of a yellow fever (YF)-dengue 2 (DEN2) chimera (ChimeriVax-DEN2) in comparison to that of YF vaccine (YF-VAX). Forty-two healthy YF naïve adults randomly received a single dose of either ChimeriVax-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAX by the subcutaneous route (SC). To determine the effect of YF preimmunity on the ChimeriVax-DEN2 vaccine, 14 subjects previously vaccinated against YF received a high dose of ChimeriVax-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naïve subjects inoculated with 5.0 and 3.0 log10 PFU of ChimeriVax-DEN2, respectively, seroconverted to wt DEN2 (strain 16681); 92% of subjects inoculated with YF-VAX seroconverted to YF 17D virus but none of YF naïve subjects inoculated with ChimeriVax-DEN2 seroconverted to YF 17D virus. Low seroconversion rates to heterologous DEN serotypes 1, 3 and 4 were observed in YF naïve subjects inoculated with either ChimeriVax-DEN2 or YF-VAX. In contrast, 100% of YF immune subjects inoculated with ChimeriVax-DEN2 seroconverted to all 4 DEN serotypes. Surprisingly, levels of neutralizing antibodies to DEN 1, 2 and 3 viruses in YF immune subjects persisted after 1 year. These data demonstrated that (1) the safety and immunogenicity profile of the ChimeriVax-DEN2 vaccine is consistent with that of YF-VAX, and (2) preimmunity to YF virus does not interfere with ChimeriVax-DEN2 immunization, but induces a long lasting and cross neutralizing antibody response to all 4 DEN serotypes. The latter observation can have practical implications toward development of a dengue vaccine.

A novel, cell culture-derived smallpox vaccine in vaccinia-naive adults.

Despite the eradication of smallpox as a naturally occurring disease, concern persists over its potential use as a bioterrorist agent. The development of a new-generation smallpox vaccine represents an important contribution to a cogent biodefense strategy. We conducted a phase 2 randomized, double-blind, controlled trial at four sites in the United States to determine whether a clonal smallpox vaccine manufactured in cell culture, ACAM2000, is equivalent to the standard calf-lymph vaccine, Dryvax, in terms of cutaneous response rate, antibody responses and safety. Subjects received either Dryvax or one of four dose levels of ACAM2000 administered percutaneously using a bifurcated needle. All subjects in the highest ACAM2000 dose group and the Dryvax group experienced a successful vaccination. Dilution doses of ACAM2000 were associated with success rates below the 90% threshold established for efficacy. There were no differences in the proportion of subjects who developed neutralizing antibody: 94% in the highest ACAM2000 dose group (95% CI, 84-99) and 96% in the Dryvax group (95% CI, 86-100). No significant differences were seen between the effective ACAM2000 and Dryvax groups regarding the occurrence of adverse events. One subject who received ACAM2000 developed myopericarditis. In healthy, primary vaccines ACAM2000 has a similar vaccination success rate, antibody response, and safety profile to Dryvax.

A potential cause for kidney stone formation during space flights: enhanced growth of nanobacteria in microgravity.

BACKGROUND: Although some information is available regarding the cellular/molecular changes in immune system exposed to microgravity, little is known about the reasons of the increase in the kidney stone formation in astronauts during and/or after long duration missions at zero gravity (0 g). In our earlier studies, we have assessed a unique agent, nanobacteria (NB), in kidney stones and hypothesized that NB have an active role in calcium phosphate-carbonate deposition in kidney. In this research we studied effect of microgravity on multiplication and calcification of NB in vitro. METHODS: We examined NB cultures in High Aspect Rotating Vessels (HARVs) designed at the NASA's Johnson Space Center, which are designed to stimulate some aspects of microgravity. Multiplication rate and calcium phosphate composition of those NB were compared with NB cultured on stationary and shaker flasks. Collected aliquots of the cultures from different incubation periods were analyzed using spectrophotometer, SEM, TEM, EDX, and x-ray diffraction techniques. RESULTS: The results showed that NB multiplied 4.6x faster in HARVs compared to stationary cultures, and 3.2x faster than shaker flask conditions. X-ray diffraction and EDX analysis showed that the degree of apatite crystal formation and the properties of the apatite depend on the specific culture conditions used. CONCLUSION: We now report an increased multiplication rate of NB in microgravity-simulated conditions. Thus, NB infection may have a potential role in kidney stone formation in crew members during space flights. For further proof to this hypothesis, screening of the NB antigen and antibody level in flight crew before and after flight would be necessary.

Real-world use of evidence-based treatments in community behavioral health care.

It is one thing to tout "best practices" and another thing to actually employ them. The author of this month's column provides us with a "fly on the wall" view of the experience of one community mental health center in implementing evidence-based treatments for mental illnesses. If you have ever sat in a meeting at which you are supposed to be generating a best-practice approach and all you are hearing is a discussion of procedures rather than outcomes measurement, this column will be of interest.