100-mg Capsules Research Articles

Dosing Celecoxib in Pediatric Patients With Juvenile Rheumatoid Arthritis

The objective was to derive dosing recommendations for the use of celecoxib in patients with juvenile rheumatoid arthritis (JRA) using pharmacokinetic (PK) and exposure-response data. PK and efficacy data from a randomized, double-blind, 12-week study of celecoxib dosed at 3 and 6 mg/kg twice a day (bid) as an investigational suspension formulation in 152 JRA patients aged 2 to 17 years, PK data from 36 adult RA patients, and relative bioavailability data in healthy adults comparing suspension or capsule sprinkles with the commercial capsule were analyzed. Typical oral clearance (L/h) values were 40% and 24% lower in patients weighing 10 and 25 kg, respectively, compared with a 70-kg patient. Longitudinal, logistic pharmacodynamic models incorporating linear effects of dose/area under the plasma concentration-time curve (AUC) over 0 to 12 hours (AUC(0-12)) suggested that the percentage of responders increased with celecoxib exposure. Systemic exposures (AUC) were similar for the suspension, capsule sprinkles, and intact capsule. Administration of a 50-mg bid capsule (or sprinkles) for patients weighing 10 to 25 kg and 100 mg bid for patients >25 kg was predicted to yield similar exposures and response rates as those observed in the JRA trial. Doses and dosage forms not studied in the JRA trial were approved based on the results of this analysis.

Effect of Cyclosporine on the Pharmacokinetics of Colchicine in Healthy Subjects

Objective: Colchicine and cyclosporine are often administered together, particularly in patients who have undergone solid–organ transplantation. However, the potential for drug–drug interactions between these agents resulting in colchicine toxicity is high. Methods: This study sought to determine the effect of cyclosporine (100-mg capsule) on the pharmacokinetics of the US Food and Drug Administration–approved formulation of colchicine (0.6-mg tablet) after single oral–dose administration in 24 healthy subjects under fasted conditions in a phase 1, single–sequence, 2-period drug–drug interaction trial. Results: Coadministration of cyclosporine increased colchicine maximum observed plasma concentration, area under the plasma concentration–time curve to the last measurable time point, and area under the plasma concentration–time curve to time infinity on average by 224%, 216%, and 215% (ie, almost doubled), respectively, and decreased colchicine oral clearance on average by 72% (from 48.24 to 13.42 L/h), indicating substantially higher colchicine exposures when combined with cyclosporine, compared with colchicine alone. Conclusion: The dose of colchicine should be reduced by ≥ 50% when colchicine and cyclosporine are administered concurrently for treatment and prophylaxis of gout fares or treatment of patients with familial Mediterranean fever. Health care professionals should be vigilant for potential adverse events during colchicine/cyclosporine coadministration, notably in patients who have undergone solid–organ transplantation.

Antimalarial Efficacy of a Quantified Extract of Nauclea pobeguinii Stem Bark in Human Adult Volunteers with Diagnosed Uncomplicated falciparum Malaria. Part 2: A Clinical Phase IIB Trial

According to the promising results of the Phase I and Phase IIA clinical trials with the herbal medicinal product PR 259 CT1 consisting of an 80 % ethanolic extract of the stem bark of Nauclea pobeguinii containing 5.6 % strictosamide, a Phase IIB study was conducted as a single blind prospective trial in 65 patients with proven Plasmodium falciparum malaria to evaluate the effectiveness and safety of this herbal drug. The study was carried out simultaneously using an artesunate-amodiaquine combination (Coarsucam®) as a positive control. This combination is the standard first-line treatment for uncomplicated malaria recommended by the National Programme of Malaria Control in the Democratic Republic of Congo (DR Congo). With regard to PR 259 CT1, patients were treated with a drug regimen of two 500-mg capsules three times daily for three days in the inpatient clinic, followed by out-patient treatment of one 500-mg capsule three times daily during the next four days; the positive control group received two tablets containing 100 mg artesunate and 270 mg amodiaquine (fixed-dose) once daily during three consecutive days. Antimalarial responses were evaluated according to the WHO 2003 guideline for a 14-day test. The results from the physical and laboratory examinations did not show any significant changes in values of vital signs, ECG, biochemical, and haematological parameters. The study showed a significant decreased parasitaemia in patients treated with PR 29 CT1 and artesunate-amodiaquine with adequate clinical parasitological responses (APCR) at day 14 of 87.9 and 96.9 %, respectively. The former product was better tolerated than the latter since more side effects were observed for the artesunate-amodiaquine combination. These results indicated that PR 259 CT1 can be considered as a promising candidate for the development of a herbal medicine for the treatment of uncomplicated falciparum malaria.

Pharmacokinetics and Safety of Dexlansoprazole MR in Adolescents With Symptomatic GERD

Dexlansoprazole MR 30 mg once daily (QD) is approved in adults for the treatment of symptomatic nonerosive gastroesophageal reflux disease (GERD) and maintenance of healed erosive esophagitis (EE); 60 mg is approved for healing EE. The present study assesses the pharmacokinetic (PK) profile and safety of dexlansoprazole MR in adolescent patients. Phase 1, open-label, parallel-group, multicenter study in male and female adolescents (12-17 years) with GERD. Patients were randomized to receive dexlansoprazole MR (30 or 60 mg, QD) for 7 days. Blood samples to determine dexlansoprazole plasma concentrations were drawn over a 24-hour period after dosing on day 7. Dexlansoprazole plasma concentrations and PK parameters were summarized by dose group. Safety assessments included monitoring of adverse events (AEs). Thirty-six patients (mean age 14.6 years), 14 boys and 22 girls, were randomized, with PK data available for 35 patients. The overall exposure of dexlansoprazole after administration of the 60-mg capsule was slightly less than double the exposure from the 30-mg capsule. Cmax (691 and 1136 ng/mL) and area under the plasma concentration time curve (2886 and 5120 ng · h/mL) values for the 30- and 60-mg doses, respectively, were similar to results from previous phase 1 studies in healthy adults. Twelve of 36 patients (33.3%) experienced a total of 21 treatment-emergent AEs. All of the AEs were considered to be of mild severity. The PK data for dexlansoprazole MR 30- and 60-mg capsules in adolescent patients with symptomatic GERD were similar to those in healthy adults. Both doses were well tolerated.

Stability of an extemporaneously prepared thalidomide suspension

The short-term physical and chemical stability of an oral suspension of thalidomide 20 mg/mL was studied. An oral suspension of thalidomide 20 mg/mL was prepared by emptying the contents of 12 100-mg thalidomide capsules into a glass mortar; 30 mL of Ora-Plus and 30 mL of Ora-Sweet were mixed and added to the thalidomide powder to make a final volume of 60 mL. Three identical samples of the formulation were prepared and placed in 2-oz amber plastic bottles with child-resistant caps and stored under refrigeration (3-5 °C). A 1-mL sample was withdrawn from each of the three samples with a micropipette immediately after preparation and at 7, 14, 21, 28, and 35 days. After further dilution to an expected concentration of 20 μg/mL with acetonitrile-methanol and then dilution with mobile phase, the samples were assayed in duplicate using stability-indicating high-performance liquid chromatography. Stability was determined by evaluating the percentage of the initial concentration remaining at each time point; stability was defined as the retention of at least 90% of the initial concentration of thalidomide. At least 92% of the initial thalidomide concentration remained throughout the 35-day study period. There were no detectable changes in color, odor, or pH and no visible microbial growth in any sample. An extemporaneously prepared suspension of thalidomide 20 mg/mL in a 1:1 mixture of Ora-Plus and Ora-Sweet was stable for at least 35 days when stored in 2-oz amber plastic bottles under refrigeration.

Effect of buspirone, a 5-HT1A receptor agonist, on esophageal motility in healthy volunteers

There are limited data concerning the effects of 5-HT(1A) receptor activation on esophageal motility. Sumatriptan, a 5-HT(1A) receptor agonist, was recently reported to enhance esophageal peristalsis after intravenous administration. Buspirone, an orally available 5-HT(1A) receptor agonist, was shown to modulate gastroduodenal motor function. Our aim was to evaluate the effect of buspirone on esophageal motility of healthy volunteers. On two separate visits, 20 healthy volunteers aged 21-29 years (nine women) underwent esophageal manometry before and 10, 30, and 60 minutes after the administration of buspirone 20-mg or placebo capsule, according to a double-blind crossover design. At each time point, we compared buspirone and placebo effects on: resting pressure of the lower esophageal sphincter (LES); residual pressure and duration of LES relaxation; amplitude, duration, and onset velocity of esophageal body contractions, during 10 swallows of 5 mL of water. Significant analysis of variance differences (P < 0.05) are presented as mean ± standard deviation. Buspirone significantly increased mean distal esophageal wave amplitude (151 vs. 87 mmHg, P < 0.05) and duration (6.1 vs. 4.2 seconds, P < 0.05). Similarly, buspirone significantly increased mean LES resting pressure (26 vs. 21 mmHg, P < 0.05) and mean residual LES pressure (7.9 vs. 2 mmHg, P < 0.05), whereas reduced mean LES relaxation duration (7.2 vs. 8.0 seconds, P < 0.05) and mean distal onset velocity (7.6 vs. 14.7 cm/second, P < 0.05). Buspirone enhances esophageal peristalsis and LES function in healthy volunteers. Further study is warranted on the effects of buspirone on esophageal function and symptoms in patients with ineffective esophageal motility.

Effects of Yogurt and Applesauce on the Oral Bioavailability of Nilotinib in Healthy Volunteers

Nilotinib, a potent orally bioavailable BCR-ABL tyrosine kinase inhibitor, is currently available as a hard gelatin capsule that must be swallowed whole. For patients who may have difficulty swallowing the intact capsule, an alternative mode of administration is desirable. The authors compared the bioavailability of nilotinib from the following administrations in 48 healthy subjects: (1) 400 mg nilotinib given as two 200-mg nilotinib intact capsules; (2) contents of two 200-mg nilotinib capsules, each capsule dispersed in 1 teaspoon of nonfat plain yogurt; and (3) contents of two 200-mg nilotinib capsules, each capsule dispersed in 1 teaspoon of applesauce. Nilotinib absorption was modestly increased following the administration of nilotinib dispersed in yogurt. The geometric mean ratios (90% confidence intervals) for nilotinib C(max), AUC(0-tlast), and AUC(0-inf) were 1.31 (1.22-1.41), 1.11 (1.05-1.16), and 1.08 (1.02-1.15), respectively. Administration of nilotinib dispersed in applesauce showed equivalent bioavailability compared with administration of nilotinib as intact capsules. The geometric mean ratios (90% confidence intervals) for nilotinib C(max), AUC(0-tlast), and AUC(0-inf) were 0.95 (0.88-1.02), 0.99 (0.94-1.04), and 0.97 (0.90-1.03), respectively. Each treatment was well tolerated in the study subjects. The data support a feasible alternative method of nilotinib administration; each capsule's contents may be dispersed in 1 teaspoon of applesauce and taken immediately.

Attenuation of the Pressor Response to Tracheal Intubation in Severe Preeclampsia: Relative Efficacies of Nitroglycerine Infusion, Sublingual Nifedipine, and Intravenous Hydralazine

Background: The pressor response to laryngoscopy is known to be exaggerated in patients with severe preeclampsia. Objectives: The aim of the present study was to compare the efficacies of continuous intravenous (IV) infusion of nitroglycerine, IV hydralazine, or sublingual nifedipine in modifying cardiovascular responses to endotracheal intubation, in women with severe preeclampsia undergoing cesarean delivery under general anesthesia. Patients and Methods: A total of 120 patients undergoing cesarean delivery were randomly divided into 3 groups, each receiving one of the following drugs before intubation: 5 µg/min nitroglycerine administered by continuous IV infusion (Group NTG, n = 40); a 10-mg capsule of nifedipine deposited sublingually (Group NIF, n = 40); or 5–10 mg hydralazine intravenously (Group H, n = 40). Heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP) were simultaneously recorded in the mother at pre-induction, pre-intubation, and at 1, 3, 5, and 10 min after intubation. Results: In contrast to those in group NIF and group H, the patients in group NTG showed no significant increases in HR, SAP, DAP, or MAP after intubation, compared to baseline. The incidence of hypotension was significantly greater in group NIF than in group H or group NTG [15 (37. 5%) vs. 8 (20%) vs. 5 (12. 5%) respectively, P = 0. 025]. Conclusions: In patients with severe preeclampsia undergoing cesarean delivery, a continuous IV infusion of nitroglycerine was able to attenuate the cardiovascular response to intubation to a greater extent than the use of sublingual nifedipine or IV hydralazine, without significant adverse effects on the newborn.

A Patient's Guide to Taking Dabigatran Etexilate

Dabigatran etexilate is a prescription medication used to slow and inhibit the formation of blood clots. Dabigatran is known by the trade name Pradaxa in the United States and all other countries in which it is marketed except Japan (Prazaxa) and Canada (Pradax). Although forming blood clots is a normal and important body function needed to stop bleeding, for some people the blood clot formation process can become harmful. For example, people with an irregular heart rhythm known as atrial fibrillation are at an increased risk of stroke because of the formation of harmful blood clots. Dabigatran is an anticoagulant type of medication. Anticoagulants prevent blood clots from forming. The medication warfarin (Coumadin) is another example of an anticoagulant. Anticoagulants are also commonly called blood thinners, although they work by preventing blood clot formation and not by making the blood thinner. The formation of blood clots in the body is a very complex process that requires multiple steps occurring in a particular order. Substances known as clotting factors are used and produced in each step in the process. One of the final steps of clot formation involves a clotting factor known as thrombin. Dabigatran works in the blood by blocking the action of thrombin, which inhibits the clot-making process. Dabigatran has been approved in the United States to reduce the risk of stroke and other harmful blood clots in people with nonvalvular atrial fibrillation. Dabigatran is available as a capsule in doses of 75 and 150 mg (Figure, A and B). The usual dose of dabigatran is a 150-mg capsule twice a day by mouth. For people with certain types of kidney problems, the dose may be decreased to 75 mg twice a day. The dabigatran capsule may …

Bioequivalence of Venlafaxine Modified-Release Capsule Revisited with an Innovative Approach Using Experimental and Predictive Models

To evaluate the venlafaxine:O-desmethyl venlafaxine (active metabolite) in vivo formation ratio (MR) in three independent bioequivalence (BE) studies consisting of single-dosed (under fasted and fed conditions) and multiple-dosed clinical trials on healthy subjects. The pooled data pharmacokinetic (PK) analysis demonstrates a model to conduct enantiomer/racemate/active metabolite bioanalysis for regulatory submission of bioavailability/bioequivalence (BA/BE) studies using an interesting MR concept. BE was established for all three studies. Moreover, the venlafaxine:O-desmethyl venlafaxine MR for C(max) and AUC(last) differed by more than 50% for fasted and fed single-dosed studies, while pooled data analysis found the MR for C(max) to be approximately 0.63 and the AUC to be approximately 0.36 for both test and reference drugs. However, negligible variation was observed for both rate and extent of drug and active metabolite absorption into the systemic circulation at steady state, as the MR for both C(max) and AUC was approximately 0.62. The applications/consequences of the above results are immense. First, an achiral assay for venlafaxine and O-desmethyl venlafaxine estimation in human plasma has been justified for the regulatory acceptance of BA/BE studies, supported with both single- and multiple-dosed PK data showing negligible variation in terms of MR at C(max). Second, the current investigation shows the MR to be within ±10% when compared with the single-dosed reported study on a western population. Third, the racial effect would not lead to any significant clinical outcome using an interchangeable venlafaxine 150-mg capsule manufactured by Ranbaxy with an Efexor 150-mg capsule manufactured by Wyeth. Furthermore, a decision tree is proposed to evaluate if a racemate or an enantiomer drug and active metabolite bioanalysis should be executed for BA/BE regulatory submission using respective achiral or chiral assays when the drug moiety is a racemate or an enantiomer, formulated in modified-release dosage forms.

High failure rate of the dissolution tests for 500-mg amoxicillin capsules sold in Cambodia: is it because of the product or the test method?

During the survey of substandard medicines in Cambodia in 2007, it was found that more than 90% of 500-mg amoxicillin (AMPC) capsules failed the United States Pharmacopeia (USP) 30 TEST 1 dissolution test. In the USP, several monographs provide multiple methods for performing the dissolution test. By using the 500-mg AMPC capsule as an example, we aimed to identify the problems and implications of the USP methods adopted for the dissolution test as a global standard. All AMPC samples were collected from the Cambodian market in 2007. For the quantitative test, we referred to USP 30. We performed the USP 28 and USP 30 TEST 2 dissolution tests and compared these results with those of the USP 30 TEST 1. All 500-mg AMPC capsules used for the comparison passed the quantitative test. Samples that passed the USP 28 and USP 30 TEST 2 dissolution tests were identical, and the pass rate was 97.1% (34/35), whereas the pass rate with the USP 30 TEST 1 was 8.6% (3/35). The difference in the dissolution results between the three methods was significant (P<0.0001). This study revealed that many users would select the most stringent method when multiple methods exist in the USP. This may lead to a high failure rate of the tests. Because USP is a global standard, we recommend that it take into consideration the developing countries and create a more detailed user-friendly manual for selection for appropriate methods.

A bioequivalence comparison of two formulations of rifampicin (300- vs 150-mg capsules): An open-label, randomized, two-treatment, two-way crossover study in healthy volunteers

Background: Rifampicin is a semisynthetic antibiotic derivative of rifamycin used worldwide for the treatment of various forms of tuberculosis. Objective: The objective of this study was to compare, under fasting conditions in healthy volunteers, the rate and extent of absorption of a generic rifampicin capsule in oral dosage form versus the proprietary equivalent formulation for the purpose of registration approval of the test formulation. Methods: This was an open-label, randomized, 2-treatment, 2-way crossover study with an 8-week washout period between the 2 study arms. Healthy volunteers received a 300-mg capsule of the test formulation (Idaman Pharma Manufacturing Sdn. Bhd.) or two 150-mg capsules of the reference formulation. Blood samples were collected predose and at 45 minutes and 1.25, 1.5, 2, 2.25, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours postdose. Plasma concentrations of rifampicin and its metabolite, 25-desacetyl rifampicin, were analyzed using a validated HPLC method. The formulations were considered bioequivalent if the 90% CIs for C max and AUC were within the predetermined bioequivalence range (80%–125%, according to the guidelines of the US Food and Drug Administration, or 75%–133% for Cmax only, as set by the European Commission-European Medicines Agency and the National Pharmaceutical Control Bureau of Malaysia). Tolerability was assessed by verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects (serious or mild) were recorded on adverse-event forms. Results: Fourteen healthy subjects (10 males, 4 females) with a mean age of 22.6 years (range, 20–28 years) and a mean body mass index of 22.2 kg/m 2 (range, 18.3-29.9 kg/m2) were enrolled in the study; all 14 completed the trial as outlined in the protocol. The mean values for C max, T max , AUC 0–24, and AUC 0−∞) with the test formulation of rifampicin were 7.20 μg/mL, 1.32 hours, 37.12 μg/mL · h, and 39.69 μg/mL · h, respectively; for the reference formulation, the values were 7.65 μg/mL, 1.71 hours, 38.92 μg/mL · h, and 42.24 μg/ mL · h. For 25-desacetyl rifampicin, the mean values for C max, T max, AUC 0−24, and AUC 0−∞) with the test formulation were 0.63 μg/mL, 3.45 hours, 4.92 μg/mL · h, and 6.27 μg/mL · h; for the reference formulation, the values were 0.7 μg/mL, 3.27 hours, 5.23 μg/mL · h, and 6.84 μg/mL · h. For rifampicin, the 90% CIs for the test formulation/reference formulation ratio for the logarithmic transformations of both C max and AUC 0−∞) were within the bioequivalence limit of 80% to 125% (80.9109.7 and 80.7–103.2, respectively). For 25-desacetyl rifampicin, the 90% CI for the test formulation/reference formulation ratio for the logarithmic transformations of AUC 0–24 (80.0–104.7) was within the bioequivalence limit of 80% to 125%. However, the 90% CI for C max (78.4–102.2) was outside this limit but still within the acceptance limit for Cmax when adhering to the bioequivalence range of 75% to 133%. No adverse events were reported during the study. Conclusions: This study found that the 300-mg test capsule and the 150-mg reference capsules of rifampicin met the regulatory criteria for assuming bioequivalence in these fasting healthy volunteers. Both formulations appeared to be well tolerated in the population studied.

The relative bioavailability and fasting pharmacokinetics of three formulations of olmesartan medoxomil 20-mg capsules and tablets in healthy Chinese male volunteers: An open-label, randomized-sequence, single-dose, three-way crossover study

Background: Olmesartan medoxomil is an angiotensin II-receptor antagonist used in the treatment of hypertension. It is a prodrug and is converted to the pharmacologically active compound on de-esterification by arylesterase in the gastrointestinal tract. Objective: This study investigated the relative bioavail-ability and fasting pharmacokinetic properties of olmesartan after single doses of a 20-mg test tablet, a 20-mg test capsule, and a commercially available 20-mg reference tablet in healthy Chinese male volunteers. The study was conducted to satisfy Chinese State Food and Drug Administration regulatory requirements for approval of a generic formulation of olmesartan medoxomil. Methods: This study had an open-label, randomized-sequence, single-dose, 3-treatment, 3-period crossover design. Healthy volunteers were randomly assigned in a 1:1:1 ratio to receive a single 20-mg dose of the test tablet, test capsule, or reference tablet, each administered after a 12-hour overnight fast, followed by a 1-week washout period and administration of the alternate formulation. Blood samples were obtained at baseline and at 0.5, 1, 1.5,2,2.5,3,4,6,8,12,24,36, and 48 hours after dosing. Tolerability was assessed based on vital signs and laboratory values obtained before and after administration of study drug. The formulations were assumed to be bioequivalent if the 90% CIs for the log-transformed ratios of C max, AUC 0–t, and AUC 0–∞ were within the predetermined equivalence range (70%–143% for C max; 80%–125% for AUC 0–t and AUC 0–∞), as established by the Chinese State Food and Drug Administration. Results: Twenty-one healthy male subjects (mean age, 21 years [range, 18–25 years]; weight, 62.1 kg [range, 54.0–80.0 kg]) were enrolled in and completed the study. No period or sequence effect was observed. The mean AUC 0–∞ values for the test tablet, test capsule, and reference tablet were 3993 (1070), 3567 (850), and 3849 (872) ng/mL/h, respectively. The 90% CIs for the log-transformed ratios of test tablet to reference tablet for C max, AUC 0–48, and AUC 0–∞ were 103.9 to 124.9, 94.0 to 111.5, and 94.4 to 111.7, respectively (all, P = NS). The corresponding 90% CIs for the log-transformed ratios of test capsule to reference tablet were 90.8 to 109.2, 84.9 to 107.9, and 85.1 to 100.7 (all, P = NS). Ten adverse events were reported during the study; 7 subjects complained of pain during blood sampling, and 3 had a blocked venous catheter. No treatment-related adverse events were reported or observed. Conclusions: In this single-dose crossover study in healthy Chinese male volunteers, the test and reference formulations of olmesartan medoxomil 20-mg capsules and tablets met the regulatory criteria for assuming bioequivalence. The 3 formulations were well tolerated.

Abstract 2600: Effect of green tea intake on pharmacokinetics of oral etoposide in cancer patients

Abstract BACKGROUND: Habitual consumption of green tea has been epidemiologically correlated with low risk of cancer. Among various constituents of green tea, catechins are experimentally suggested to have benefitial activity. Especially, (-)-epigallocatechin gallate (EGCG) is the most bioactive constituent. Decreased activation of carcinogenic compounds by inhibition CYP3A4 is proposed as one of mechanisms of anticarcinogenic effect. Green tea is one of the most popular beverages in Japan and Asian countries, and patients often take drugs with green tea beverages. Co-administration of oral cancer medicine which is metabolized by CYP3A4 with green tea may cause harmful interactions. PURPOSE: We investigated the effect of green tea beverage intake on pharmacokinetics of etoposide in an open label, single-dose, randomized, two-way crossover study. METHODS: Patients with various cancers were randomly assigned to receive an etoposide 50-mg capsule either with 600mL green tea beverage or 600mL of water, separated by at least 72-hours washout period. Blood samples were collected for 24 hours. Etoposide concentrations in plasma were determined by high performance liquid chromatography. Plasma pharmacokinetic parameters, including area under the curve (AUC), maximum concentration (Cmax) and elimination half-life (t1/2) were calculated by non-compartment analysis using WinNonlin software. RESULTS: Twenty-five cancer patients (11 males, 14 females; median (range) age, 63 years (46 to 81 years)) participated in this study. Co-administration with green tea resulted in an unexpected decrease by 24.8% in the AUC (p= 0.0003) of etoposide (Table). Carry-over effect was denied. CONCLUSION: Green tea reduces rather than increases exposure to orally administered etoposide.Mean pharmacokinetic parameters of etoposideParameters Water Green teaP-valueAUC 337.61257.45P=0.0003(mg*min/ml) Cmax (mcg/ml) 2.97252.1284P=0.0004t1/2 (h) 7.43116.7696P=0.0771 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2600.

Forskolin Compared with Beclomethasone for Prevention of Asthma Attacks: A Single-Blind Clinical Trial

This single-blind study compared the efficacy of oral forskolin versus inhaled beclomethasone for mild or moderately persistent adult asthma. Patients were randomly assigned to receive forskolin (one 10-mg capsule orally per day; n = 30) or beclomethasone (two 50 microg inhalations every 12 h; n = 30) for 2 months. No statistically significant improvement occurred in any lung function parameter in the forskolin-treated patients. Subjects in the beclomethasone-treated group presented a slight but statistically significant improvement in percentage forced expiratory volume in 1 s (FEV(1)), percentage forced expiratory flow in the middle (25 - 75%) expiratory phase (FEF(25 - 75%)) and percentage forced vital capacity (FVC) after 2 months of treatment, though the improvement in absolute values for FEV(1), FEF(25 - 75%), FVC and FEV(1):FVC did not reach statistical significance. There was no statistically significant difference between the forskolin and beclomethasone treatment groups for any lung function parameter at baseline or after treatment. None of the beclomethasone-treated patients had an asthma attack and one forskolin-treated patient had a mild asthma attack during the 2-month study period. More studies are needed in adult asthma patients to confirm whether forskolin may be a useful preventive treatment for mild or moderately persistent adult asthma.

Drug Prevention of Reperfusion Lesions during Thrombolytic Therapy for Myocardial Infarction

Objective: to evaluate the efficacy of mexicor used to protect cardiac metabolism in patients with myocardial infarction during thrombolytic therapy with streptokinase. Subjects and methods. Fifty-four patients (mean age 51.2±5.5 years) with myocardial infarction, who underwent thrombolytic therapy with streptokinase from 30 minutes to 2 hours after the onset of the disease, were examined and cured. During the basic treatment, 28 patients received the mexicor regimen: 5—6 mg/kg intravenously before thrombolysis, then 50 mg/day as continuous infusions for 3 days with its further use as 200-mg capsules thrice daily until they were discharged from hospital. The time course of changes in £ST, the parameters of cardiac hemodynamics, systemic circulation, the activities of creatine phosphokinase-MB and malondi-aldehyde, and the values of the antioxidant system were analyzed during and after thrombolysis. Results. It was established that after administration of mexicor, the patients showed a less pronounced tendency for hypodynamic circulation and postinfarction left ventricular dilatation at the thrombolytic stages and in the postperfusion period. The frequency of high-grade reperfusion arrhythmias (after B. Lown) was 2.18-fold less and the rate of ST-segment isoelectric line achievement was higher. During hospital mexicor treatment, the frequency of heart failure and postinfarct angina pectoris episodes was decreased from 30.8 to 17.7% and from 19.2 to 10.7%, respectively; recurrent infarctions occurred 2.68-fold less frequently. Conclusion. The use of mexicor during thrombolytic therapy for myocardial infarction promotes cardiac metabolic protection during and after thrombolysis. Administration of mexicor results in a more complete recovery of cardiovascular function, cardiac hemodynamics, and metabolism in patients after thrombolysis and favors a reduction in the number of disease complications in the hospital treatment stage. Key words: myocardial infarction, thrombolysis, reperfusion, mexicor, streptokinase.

Bioavailability in healthy adults of efavirenz capsule contents mixed with a small amount of food

The effect of mixing the contents of efavirenz capsules (sprinkles) with a small amount of food on the bioavailability and pharmacokinetics of efavirenz in healthy adults was evaluated. In a randomized, three-period, crossover study, 24 healthy adult subjects were divided equally into two groups. Group I received treatments A, B, and C, and those in group II received treatments A, D, and E. Treatment A was three efavirenz 200-mg intact capsules under fasting conditions. Treatments B, C, D, and E were three efavirenz 200-mg capsule contents mixed with two teaspoons of applesauce, grape jelly, yogurt, or infant formula, respectively. A single dose was given on days 1, 21, and 41. The steady-state mean maximum observed concentration, time of maximum observed concentration, area under the concentration-time curve (AUC) half-life, taste, and safety were assessed. The AUC after administration of a single 600-mg dose of efavirenz sprinkles mixed with two teaspoons of any of the food vehicles to healthy adults was bioequivalent to a 600-mg efavirenz dose given as intact capsules under fasting conditions. Subjects rated efavirenz mixed with grape jelly as the most palatable. Adverse events and laboratory abnormalities were similar for all treatments. The AUC of efavirenz 600 mg administered as capsule sprinkles with two teaspoons of applesauce, grape jelly, yogurt, or infant formula was bioequivalent to a single dose of efavirenz 600 mg given as intact capsules under fasting conditions in healthy adults.

Evaluation of Subantimicrobial Dose Doxycycline as an Adjunct to Scaling and Root Planing in Chronic Periodontitis Patients with Diabetes: A Randomized, Placebo-Controlled Clinical Trial

Diabetic patients have more severe periodontal destruction, but periodontal therapy can improve metabolic control. Recently, interest has focused on the use of subantimicrobial dose doxycycline (SDD) as a treatment paradigm. Therefore, this study was undertaken to evaluate clinical efficacy of SDD with scaling and root planning (SRP) in chronic periodontitis patients with diabetes. Twenty chronic periodontitis patients with diabetes mellitus were randomly allocated to either a test and a control group. Clinical measurements were recorded at baseline and at six months for probing pocket depth (PPD), clinical attachment level (CAL), and gingival recession (GR). After SRP, patients in the test group were instructed to take SDD 20-mg capsules twice a day while patients in the control group took a placebo twice a day. Both groups were on this regimen for a six-month period. A greater reduction in mean PPD was demonstrated in patients in the test group compared to the control group. The mean CAL increase observed in the test group was significantly greater (0.67 mm) than that in the control group. It can be concluded that SRP, in conjunction with the SDD therapy described, is more effective then SRP alone in terms of CAL gain and PPD reduction in diabetic patients with severe periodontal disease. Given the widespread prevalence of both chronic periodontitis and diabetes, the proposed treatment approach will prove to be of great value and contribute significantly to the overall health of the patients.

Effects of a low-fat meal on the oral bioavailability of UFT and leucovorin in patients with colorectal cancer

UFT is composed of tegafur, a prodrug of 5-fluorouracil, and uracil, at a fixed ratio of 1: 4. UFT is widely used with leucovorin as adjuvant chemotherapy in patients with colon cancer. As reported, UFT/leucovorin should not be taken simultaneously with food because a high fat content will reduce the systemic exposure to the active cytotoxic moiety of UFT. In this single-dose, randomized, two-way crossover study, we investigated the effects of a low-fat Japanese meal on the pharmacokinetics and oral bioavailability of UFT (2 x 100-mg capsules; dose in terms of tegafur) and leucovorin (1 x 25-mg tablet). Patients (n = 12) were randomly assigned to receive both drugs after an overnight fast or 5 min after eating a standard Japanese breakfast (641 kcal), with a 3-day washout period between treatments. Pharmacokinetics (n = 12) were determined for tegafur, 5-fluorouracil, uracil, leucovorin, and 5-methyltetrahydrofolate (an active metabolite of leucovorin). For 5-fluorouracil pharmacokinetics, the maximum plasma concentration and the area under the curve were reduced by 73.7% and 47.4%, respectively, when UFT was taken postprandially, and the maximum plasma concentration and the area under the curve for uracil were reduced by 84.1% and 68.9%, respectively, compared with dosing on an empty stomach. These decreases in the systemic exposure to 5-fluorouracil were quite marked and may have an impact on its antitumor effect. A low-fat meal affects the pharmacokinetics of UFT similarly to a high-fat meal.

Using Modafinil to Treat Fatigue in Parkinson Disease

Fatigue is a major nonmotor symptom in Parkinson disease(PD). It is associated with reduced activity and lower quality of life. To determine if modafinil improves subjective fatigue and physical fatigability in PD. Nineteen PD patients who reported significant fatigue in the Multidimensional Fatigue Inventory (MFI) participated in this 8-week study. Subjects took their regular medications and were randomly assigned to the treatment group (9 subjects, modafinil 100-mg capsule BID) or placebo group (10 subjects). We used the MFI to measure subjective fatigue and used finger tapping and intermittent force generation to evaluate physical fatigability. Subjects also completed the Epworth Sleepiness Scale (ESS) and the Center of Epidemiological Study-Depression Scale. There were no significant differences at baseline and at 1 month in finger tapping and ESS between the modafinil and placebo groups. At 2 months, the modafinil group had a higher tapping frequency (P<0.05), shorter dwell time (P<0.05), and less fatigability in finger tapping and tended to have lower ESS scores (P<0.12) than the placebo group. However, there was no difference between groups over time for any dimension of the MFI . This small study demonstrated that although modafinil may be effective in reducing physical fatigability in PD, it did not improve fatigue symptoms.