bluuebunny/crossref_metadata_2025 huggingface dataset:
Proton Pump Activation in Stimulated Parietal Cells Is Regulated by Gastric Acid Secretory Capacity: A Human Study
Authors: Metz David C. , Ferron Geraldine M. , Paul Jeffrey , Turner Mary Beth , Soffer Elaine , Pisegna Joseph R. , Bochenek Wieslaw J.
Published: July 2003

Under normal physiological conditions, gastric acid production is controlled by a negative feedback mechanism. Proton pump inhibitors, such as pantoprazole, inhibit gastric acid secretion by irreversibly binding and inactivating luminally active hydrogen potassium ATPase. Recovery of acid production after treatment with a proton pump inhibitor is driven by new pump synthesis, activation of existing cytoplasmic pumps, or reversal of proton pump inhibition. The authors measured the time course of the inhibition and recovery of acid secretion in healthy volunteers following intravenous administration of pantoprazole to determine the rate of proton pump activation under maximally stimulated conditions. Gastric acid production was measured in 27 Helicobacter pylori negative healthy volunteers (mean age = 31 ± 7 years; 17 men, 10 women) who received single doses of intravenous pantoprazole (20, 40, 80, or 120 mg) in the presence of a continuous intravenous infusion of 1 ug/kg/h of pentagastrin. From the time profile of acid secretion, the authors described the rate of change of acid output using an irreversible pharmacodynamic response model represented by the equation dR/dt = −k ṁ R ṁ Cpanto + Ln2/PPR ṁ (Ro‐R) and correlated the parameter values with demographic factors and gastric acid measurements. Mean stimulated acid output secretion was 21.6 ± 18.4 mEq/h (range: 1.6–90.5) prior to the administration of pantoprazole and remained steady for 25 hours after placebo administration. Intravenous pantoprazole inhibited acid output in a dose‐response fashion, with maximal inhibition (99.9%) occurring after an 80 mg dose. Mean proton pump recovery time was 37.1 ± 21.0 hours (range: 6.7–75), and recovery was independent of the dose of pantoprazole. There was no association noted between proton pump recovery time and gender, age, race, body weight, or pantoprazole dose. However, there was an inverse correlation between acid output during baseline stimulation and recovery of acid secretion. Mean proton pump recovery time in stimulated normal human volunteers was 37.1 ± 21.0 hours, with a range of 6.7 to 75 hours. The authors hypothesize that there may be a normal homeostatic mechanism that maintains acid secretory capability within a normal range by altering the rate of proton pump activation dependent on the individual's parietal cell mass. Abnormalities of this process may be responsible for the development of acid peptic disease in susceptible individuals.
Single‐ and Multiple‐Dose Pharmacokinetics of Fiduxosin under Nonfasting Conditions in Healthy Male Subjects
Authors: Dutta Sandeep , Zhang Yiming , Daszkowski Daniel J. , Granneman G. Richard , Verlinden Marleen
Published: July 2003

Selective α1a‐adrenoreceptor antagonists are effective agents for treatment of benign prostatic hyperplasia, a disorder occurring in middle‐aged and elderly males. The objective of this study was to determine the single‐ and multiple‐dose pharmacokinetics of fiduxosin, a novel, selective α1a‐adrenoreceptor antagonist. This was a Phase I, randomized, double‐blind, placebo‐controlled, parallel‐group, single and multiple oral dose study of fiduxosin. Single daily oral doses of 30, 60, or 90 mg of fiduxosin or placebo were administered to healthy adult male subjects (N = 36; 8 active and 4 placebo per dosing group) on Day 1 and Days 5 to 11 (7 consecutive days) after a high‐fat breakfast. Fiduxosin plasma concentration‐time profiles for Days 1 and 11 were used to assess fiduxosin pharmacokinetics. Fiduxosin single‐dose and steady‐state pharmacokinetics were dose independent after oral administration under nonfasting conditions. Steady state was achieved after 4 days of qd dosing. Approximately 28% of the oral dose was eliminated by the fecal route as unchanged drug. Less than 1% of the unchanged drug was recovered in the urine after oral administration.
Bioequivalence of Two Formulations of Didanosine, Encapsulated Enteric‐Coated Beads and Buffered Tablet, in Healthy Volunteers and HIV‐Infected Subjects
Authors: Damle Bharat D. , Kaul Sanjeev , Behr Douglas , Knupp Catherine
Published: July 2003

Didanosine is an acid labile drug and hence has been given with buffering agents. To avoid the need for concurrent administration with antacids, an encapsulated enteric‐coated bead formulation of didanosine was developed. The objective of this study was to assess the bioequivalence of the encapsulated enteric‐coated beads compared to the buffered tablet. Two separate open‐label, randomized, two‐way crossover studies were conducted, one in healthy subjects and the other in HIV‐infected subjects (with CD4 cell counts > 200 cells/mm3). All subjects received a 400‐mg dose of the buffered tablet (reference formulation) and the encapsulated enteric‐coated beads (test formulation). Blood samples were collected over 12 hours, and plasma levels of didanosine were determined using a validated assay. The 90% confidence interval (CI) of the ratio of the geometric means of log‐transformed Cmax and AUC∞ values were used to assess bioequivalence between the two formulations using the equivalence interval of 0.80 and 1.25. In healthy volunteers (n = 46), the point estimate and 90% CI of the ratios of Cmax and AUC∞ values were 0.58 (0.52, 0.64) and 1.02 (0.95, 1.01), respectively. In HIV‐infected subjects (n = 30), the point estimate and 90% CI of the ratios of Cmax and AUC∞ values were 0.64 (0.56, 0.72) and 0.95 (0.86, 1.06), respectively. Median tmax value increased significantly from 0.67 hours for the buffered tablet in both studies to 2.33 hours (in healthy subjects) or 2.0 hours (in HIV‐infected subjects) for the enteric‐coated beads. The mean half‐life of didanosine was similar between treatments and ranged between 1.60 and 1.70 hours across healthy and HIV‐infected subjects. It was concluded that the encapsulated enteric‐coated bead formulation of didanosine is equivalent to the buffered tablet in the extent of exposure but differs in the rate of absorption. The pharmacokinetic profile of the enteric formulation appears to be similar in healthy and HIV‐infected subjects.
Evaluation of Renal Function in Transplant Patients on Tacrolimus Therapy
Authors: Agarwala Sangeeta , Culligan Emma , Jain Ashok , McCauley Jerry , Shapiro Ron , Chakrabarti Pradip , Burckart Gilbert , Venkataramanan Raman
Published: July 2003

Glomerular filtration rate (GFR), as measured by 24‐hour creatinine clearance and clearance of iothalamate, and effective renal plasma flow (ERPF), as measured by the clearance of para‐aminohippuric acid (PAH), were evaluated at 2 weeks, 1 month, and 3 months after transplantation in 8 renal transplant patients and at 1 month and 1 year after transplantation in 9 liver transplant patients receiving tacrolimus (Prograf®) therapy. In renal transplant patients, there was a significant increase in GFR after transplantation. There was no change in GFR at 1 and 3 months as compared to 2 weeks after transplantation, while ERPF (ml/min/1.73 m2) was lower (p < 0.05) at 3 months (212 ± 42) compared to 1 month (306 ± 118) after transplantation. In liver transplant patients, GFR and ERPF were below normal despite normal serum creatinine concentrations, but there was no difference in GFR or ERPF at 1 month and 1 year after transplantation. Although below normal, renal function was well preserved in transplant patients while receiving chronic tacrolimus therapy overthe study period. Dosage alterations of renally eliminated drugs may be required for drugs with a narrow therapeutic index.
Advanced Science Education in the Regulatory Arena: The Center for Drug Evaluation and Research Experience at the Food and Drug Administration
Authors: Ajayi Funmilayo O. , Wilcox Dale F. , Uhl Kathleen , Quinn John
Published: July 2003

A challenge faced by the Center for Drug Evaluation and Research (CDER) in effectively carrying out its mission requires it to integrate the disciplines of science, medicine, law, and public policy. One way to do that is by ensuring a highly trained multidisciplinary staff. The CDER has been able to meet this requirement by identifying the core competencies needed to accomplish its mission. The use of a competencybased training model in the planning, development, and delivery of its advanced scientific education program allows CDER staff to maintain current knowledge as well as prepare for future scientific education needs. The CDER educational model could be readily adapted to meet the educational needs of other organizations.
Systemic Availability and Pharmacokinetics of Thymol in Humans
Authors: Kohlert Claudia , Schindler Gernot , März Reinhard W , Abel Gudrun , Brinkhaus Benno , Derendorf Hartmut , Gräfe Eva‐Ulrike , Veit Markus
Published: July 2003

Essential oil compounds such as found in thyme extract are established for the therapy of chronic and acute bronchitis. Various pharmacodynamic activities for thyme extract and the essential thyme oil, respectively, have been demonstrated in vitro, but availability of these compounds in the respective target organs has not been proven. Thus, investigation of absorption, distribution, metabolism, and excretion are necessary to provide the link between in vitro effects and in vivo studies. To determine the systemic availability and the pharmacokinetics of thymol after oral application to humans, a clinical trial was carried out in 12 healthy volunteers. Each subject received a single dose of a Bronchipret® TP tablet, which is equivalent to 1.08 mg thymol. No thymol could be detected in plasma or urine. However, the metabolites thymol sulfate and thymol glucuronide were found in urine and identified by LC‐MS/MS. Plasma and urine samples were analyzed after enzymatic hydrolysis of the metabolites by headspace solid‐phase microextraction prior to GC analysis and flame ionization detection. Thymol sulfate, but not thymol glucuronide, was detectable in plasma. Peak plasma concentrations were 93.1 ± 24.5 ng ml−1 and were reached after 2.0 ± 0.8 hours. The mean terminal elimination half‐life was 10.2 hours. Thymol sulfate was detectable up to 41 hours after administration. Urinary excretion could be followed over 24 hours. The amount of both thymol sulfate and glucuronide excreted in 24‐hour urine was 16.2% ± 4.5% of the dose.
Comparative Effects on Dynamic Renal Potassium Excretion of ACE Inhibition versus Angiotensin Receptor Blockade in Hypertensive Patients with Type II Diabetes Mellitus
Authors: Preston Richard A. , Baltodano Neyton M. , Alonso Alberto B. , Epstein Murray
Published: July 2003

Both ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) are renoprotective beyond their effects on blood pressure (BP), but their widespread use is limited by theirtendency to provoke hyperkalemia. The comparative effects of ACEI and ARB on potassium handling have not been investigated. The objective of this study was to determine whether there are differences in dynamic renal potassium handling between ACEI and ARB in response to an oral potassium challenge. This was a randomized crossover study of candesartan versus lisinopril titrated to control BP followed by an inpatient study of renal potassium handling in 24 hypertensive patients with type II diabetes mellitus (DMII) and preserved renal function. Following an oral potassium challenge (0.75 mmol/kg), differences in hourly serum K (mmol/L), rate of urinary potassium excretion (UkV, micromol/min), and fractional excretion of potassium (FEK) were assessed by repeated‐measures ANOVA. Hourly UkV (p = .45) and FEK (p = .19) were similar for candesartan and lisinopril, although FEK at 2 hours for candesartan tended to exceed that for lisinopril (.34 [.04] vs. .26 [.03]) and approached significance (p = .096). UkV for candesartan at hour 2 was 177 (26) and 121 (21) for lisinopril and also approached significance (p = .10). Serial serum potassium did not differ (p = .70). No statistical differences were discovered in renal potassium handling between candesartan and lisinopril in patients with DM II and preserved renal function. Whether there are differences between the drug classes in renal impairment remains to be determined.
Toxicity of High‐Dose Carboplatin: Ultrafiltered and Not Total Plasma Pharmacokinetics Is of Clinical Relevance
Authors: Kloft Charlotte , Siegert Wolfgang , Beyer Joerg , Jaehde Ulrich
Published: July 2003

Combination chemotherapy containing high‐dose carboplatin is a therapeutic option for patients with poor‐risk germ cell tumors. Since such treatment is relatively toxic, pharmacokinetic characteristics of total and ultrafiltered platinum, representing different species of platinum complexes formed, were investigated in 29 patients in relation to toxicity. The goodness‐of‐fit parameters revealed that a two‐compartment model with weighting (1/C2i) resulted in the best fit. The terminal half‐life of total platinum < 5 days was fourfold longer than that of ultrafiltered platinum, indicating long‐term retention. At stem cell rescue, an ultrafiltered concentration of ≤ 0.223 μg/ml did not impair hematological recovery. Ultrafiltered but not total platinum concentrations or AUC values were significantly correlated to an increase in creatinine concentration and different types of toxicity associated with high‐dose treatment. Since the fraction unbound is time dependent and highly variable among patients, measuring ultrafiltered concentrations is highly recommended as they represent the clinically relevant platinum complexes in high‐dose treatment.
Pharmacokinetics of Histamine Dihydrochloride in Healthy Volunteers and Cancer Patients: Implications for Combined Immunotherapy with Interleukin‐2
Authors: Middleton Mark , Sarno Mark , Agarwala Sanjiv S. , Glaspy John , Laurent Aziz , McMasters Kelly , Naredi Peter , O'Day Steven , Whitman Eric , Danson Sarah , Cosford Rebecca , Gehlsen Kurt
Published: July 2003

Recent clinical trials in melanoma and leukemia have demonstrated potential for increased survival time and improved remission when histamine dihydrochloride is added to cytokine monotherapy. In the present study, the pharmacokinetics of subcutaneous histamine (1 mg) in 21 healthy subjects and 12 melanoma patients was determined via model‐dependent methods. Drug‐druginteractions with subcutaneous interleukin‐2 (1.1 mg) were evaluated in a combined cohort of patients with melanoma (n = 8) or renal cell carcinoma (n = 4). Histamine dihydrochloride administered over 10 minutes in healthy subjects peaked at 18 minutes (Cmax 38 nmol/L), attained a distribution volume of 59 L, and was eliminated at 6%/min. The results were similar in a 20‐minute infusion in melanoma patients. No gender effects were observed (p > 0.05). Interleukin‐2 injected either 10 minutes prior to or 10 minutes following histamine dihydrochloride had no effect on histamine kinetics. Histamine dihydrochloride administered 10 minutes priorto injection of interleukin‐2 also had no effect on interleukin‐2 kinetics. Maximal concentration of interleukin‐2 (2,442 pg/ml) occurred at 2.5 hours with an elimination half‐life of 1.7 hours, area under the curve (AUC) of 15,746 pg·h/ml, and volume of distribution and plasma clearance of 194 L and 74 L/h, respectively. However, interleukin‐2 Cmax (1,758 pg/ml) and AUC (12,448 pg·h/ml) were reduced when histamine dihydrochloride was infused 10 minutes following interleukin‐2, likely due to the pharmacodynamic effects of histamine, including increased heart rate and reduced blood pressure. It is concluded that histamine dihydrochloride and interleukin‐2 can be safely coadministered with minimal interaction.
Pharmacology of 3‐Hydroxy‐3‐Methylglutaryl‐Coenzyme A Reductase Inhibitors (Statins), Including Rosuvastatin and Pitavastatin
Authors: Igel Michael , Sudhop Thomas , von Bergmann Klaus
Published: July 2003

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in the Western world, with hypercholesterolemia as the major risk factor. The 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors represent the most efficient drugs for the treatment of hypercholesterolemia. They lower plasma cholesterol due to the inhibition of endogenous cholesterol synthesis in the liver and subsequent increased expression of low‐density lipoprotein (LDL) receptors, resulting in an up‐regulated catabolic rate for plasma LDL. The beneficial effect of statins on the incidence of CHD was clearly demonstrated in several large‐scale clinical trials. Currently, five statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) are available, and two novel compounds (pitavastatin, rosuvastatin) are undergoing clinical investigation. To point out potential mechanisms leading to increased toxicity and to compare the novel statins with the established ones, this article summarizes their pharmacological data since the prevalence of adverse events can be explained at least in part by their pharmacokinetic differences.
An Introduction to Clinical Research and Drug Development for Pharmacy and Pharmacology Graduate Students
Authors: Smith Judith A.
Published: July 2003

Recently at the University of Houston College of Pharmacy, a new course was introduced to provide an overview of each phase of drug development research, from the initial chemistry assays and cell biology studies to animal experiments and finally clinical trials for drug approval. The course, entitled “Clinical Research and Drug Development,” is a three‐credit elective introduced this past year for the entry‐level Doctor of Pharmacy (PharmD) students and graduate students during the summer session at the college. Overall, the intent of this course is to develop students' interest in the topic of clinical research and drug development and provide a foundation of knowledge of basic research skills used in the drug development process. The approach for this course was to break the topics into three general modules: laboratory techniques, both analytical and cell biology/molecular, used in the drug development process; aspects of clinical research process; and writing grants and protocols. Throughout the course, students were strongly encouraged to consider pursuing independent research projects to help continue to develop their research skills in preparation for postgraduate training. As a result, on completion of the course, four students requested an opportunity to complete an independent research project. This course has introduced the various components of drug development and of conducting clinical research to students in the PharmD and graduate programs at the University of Houston College of Pharmacy.
A Double‐Blind, Placebo‐Controlled, Dose‐Response Study of the Effectiveness and Safety of Enalapril for Children with Hypertension
Authors: Wells Thomas , Frame Virginia , Soffer Beth , Shaw Wayne , Zhang Zhongxin , Herrera Pamela , Shahinfar Shahnaz ,   Enalapril Pediatric Hypertension Collaborative Study Group
Published: July 2003

Despite widespread use to treat childhood hypertension, enalapril has never been studied systematically to determine effectiveness, dose response, and safety in a pediatric population. This study was conducted prospectivelyin 110hypertensive children ages 6 to 16 years in two sequential phases. The primary outcome variable for both phases of the study was trough (24‐h postdose) sitting diastolic blood pressure. The primary objective of the first phase of the study was to determine whether enalapril lowered blood pressure in children in a dose‐dependent manner. During a 2‐week, double‐blind, randomized, dose‐response period, patients were stratified by weight (< 50 kg or ≥50 kg), then assigned to one of three dosing groups: low (0.625 or 1.25 mg), middle (2.5 or 5 mg), or high dose (20 or 40 mg). Reduction in blood pressure was examined as a function of dose ratio (1:4:32) and on a weight‐adjusted basis. On completion of the dose‐response phase of the study, patients entered a 2‐week, double‐blind, randomized withdrawal to either enalapril or placebo. Antihypertensive effectiveness, defined as the difference in sitting diastolic blood pressure between the placebo and enalapril groups, was determined. Adverse events were carefully recorded throughout the study. The dose‐response relationship for enalapril had a negative slope and was linear over the chosen dosingrange, suggesting that larger doses of enalapril were associated with a greater reduction in blood pressure. Randomized withdrawal to active drug or placebo confirmed the antihypertensive effectiveness of enalapril in the middle‐ and high‐dose groups. The antihypertensive effect of enalapril was maintained across age, gender, race, and Tanner stage. Enalapril appears to be an effective and generally well‐tolerated antihypertensive agent in children ages 6 to 16 years. An initial dose of 2.5 mg in children weighing < 50 kg and 5 mg in children weighing ≥50 kg (mean = 0.08 mg/kg) administered once daily effectively lowered blood pressure within 2 weeks in most patients. Blood pressure was reduced in a dose‐dependent fashion, with larger doses resulting in a greater reduction.
Effects of Meloxicam on Platelet Function in Healthy Adults: A Randomized, Double‐Blind, Placebo‐Controlled Trial
Authors: Rinder Henry M. , Tracey Jayne B. , Souhrada Magdalena , Wang Chao , Gagnier R. Paul , Wood Chester C.
Published: July 2003

Nonsteroidal anti‐inflammatory drugs (NSAIDs) inhibit cyclooxygenase‐1 (COX‐1), thereby inhibiting platelet function via blockade of thromboxane A2 (TxA2) formation, and COX‐2, the enzyme that mediates inflammatory responses. Meloxicam is a relatively COX‐2‐selective anti‐arthritis drug that shows significant TxA2 inhibition, albeit less than traditional NSAIDs. A randomized, double‐blind, placebo‐controlled trial was conducted in 79 healthy adults to compare the effects of once‐daily therapeutic (7.5 mg, 15 mg) and supratherapeutic (30 mg) doses of meloxicam with extended‐release indomethacin (Indo‐ER 75 mg once daily) on bleeding time, TxA2 formation, and platelet aggregation. The authors measured platelet aggregation to COX‐1‐dependent (ADP, arachidonate) and COX‐1‐independent (high‐dose collagen) agonists, bleedingtime, serum TxB2, and clottingtimes (aPTT and PT) after 8 days' administration and at 3 and 6 hours after steady‐state dosing. Meloxicam significantly decreased TxB2 production compared with placebo in a dose‐dependent fashion, reaching a peak of 77% inhibition 6 hours after 30 mg meloxicam; Indo‐ER blocked TxB2 formation by 96% at the same time point. However, neither acute nor 8 days' administration of meloxicam at any dose caused a significant increase in bleeding time or inhibition of platelet aggregation to any agonist when compared with placebo. By contrast, Indo‐ER significantly increased the bleeding time and inhibited platelet aggregation to COX‐1‐dependent agonists 6 hours after dosing. Clotting times were unaffected by any drug. It was concluded that unlike nonselective NSAIDs, meloxicam's blockade of TxA2 formation (even at supratherapeutic doses) does not reach levels that result in decreased in vivo platelet function, as measured bybleeding time and aggregometry. In this study of healthy subjects, meloxicam did not interfere with platelet‐mediated hemostasis.
Pharmacokinetics of GW433908, a Prodrug of Amprenavir, in Healthy Male Volunteers
Authors: Falcoz Christine , Jenkins Julian M. , Bye Carole , Hardman Timothy C. , Kenney Kathy B. , Studenberg Scott , Fuder H. , Prince William T.
Published: July 2003

These two Phase I, open‐label, single‐dose, randomized, crossover studies in 40 healthy male subjects investigated the pharmacokinetic and safety profiles of various formulations of the amprenavir prodrug GW433908 in the presence and absence of food compared with amprenavir capsules. GW433908 is a phosphate ester prodrug of the antiretroviral protease inhibitor amprenavir, with improved solubility over the parent molecule and a potential for reduced pill burden on current dosing regimens. The calcium salt of the prodrug, GW433908G, was selected for further investigation, as it appeared to offer the greatest potential for the development of new drug formulations. In the fasting state, (1) GW433908G tablet and suspension were bioequivalent in terms of both AUC and Cmax' and (2) GW433908G tablet and suspension were bioequivalent to amprenavir capsules for AUC; however, Cmax was lower with GW433908G. After a high‐fat meal compared with fasting, (1) the bioavailability of GW433908G suspension was decreased by 20% and Cmax by 41%, and (2) for GW433908G tablets, there was no influence on AUC (12% lower Cmax). After a low‐fat meal compared with fasting, (1) there was bioequivalence for GW433908G tablets, but (2) bioavailability was decreased by 23% for amprenavir capsules (Cmax was also lower, by 46%). Overall, for GW433908G and amprenavir capsules, food had a negligible influence on plasma concentration at 12 hours postdose (C12). Whether administered as tablets or suspension, GW433908G pharmacokinetics was only slightly affected by food. GW433908G tablets were well tolerated and delivered plasma amprenavir concentrations equivalent to the recommended therapeutic amprenavir dose but with fewer tablets. The possibility of a lower pill burden offered by GW433908 may be of clinical benefit in the treatment of HIV infection.
Transcutaneous Electrical Acupoint Stimulation Potentiates Analgesic Effect of Morphine
Authors: Yuan Chun‐Su , Attele Anoja S. , Dey Lucy , Lynch James P. , Guan Xiongfei
Published: July 2003

Pain is the major complaint of patients who choose acupuncture treatment. Transcutaneous electrical acupoint stimulation (TEAS) provides a safe, standardized technique without needle insertion. TEAS can be tested with the cold‐pressor test, a simple, reliable, and widely used model in humans for the induction of tonic pain. In this controlled study, the effects of TEAS on cold‐pressor‐induced pain were evaluated in 20 healthy human subjects. Electrical stimulation electrodes were applied to He‐Gu (LI 4) and Nui‐Guan (P 6) acupoints. The effects of saline plus no TEAS, 15‐minute TEAS alone, 0.05 mg/kg morphine alone, and 15‐minute TEAS plus morphine were assessed. Pain score ratings were evaluated at four time points from 30 to 170 seconds during the cold‐pressor test. The authors observed analgesic effects in both TEAS‐alone and morphine‐alone sessions, and pain score rating reductions were statistically significant compared to unstimulated control (both p < 0.01). The degree of TEAS analgesia combined with 0.05 mg/kg morphine was significantly higher than TEAS alone (p < 0.01). The results support the efficacy of TEAS analgesia and suggest that combination of TEAS with low‐dose morphine can achieve better pain control in a variety of clinical settings.
Plasminogen Activator Inhibitor‐1: Physiologic Role, Regulation, and the Influence of Common Pharmacologic Agents
Authors: Tsikouris James P. , Suarez Jose A. , Meyerrose Gary E.
Published: July 2003

Plasminogen activator inhibitor‐1 (PAI‐1) is the major inhibitor of endogenous thrombolysis, thereby promoting thrombosis. PAI‐1 is also a primary contributor to the development and recurrence of acute myocardial infarction. The renin angiotensin system, hypertriglyceridemia, hyperglycemia and hyperinsulinemia, and estrogen all influence the fibrinolytic system and PAI‐1 in particular. Available data strongly suggest that angiotensin‐converting enzyme (ACE) inhibitors and hormone replacement therapy with estrogen beneficially reduce PAI‐1 production. Metformin, an agent commonly used for non‐insulin‐dependent diabetes mellitus (NIDDM), appears to favorably decrease PAI‐1 production in NIDDM patients but not nondiabetic patients. Among the cholesterollowering statins, clinical literature evaluating pravastatin provides the most compelling data to support this agent's favorable effect on PAI‐1. Other available statins either have not displayed an effect on PAI‐1 or do not have clear data to conclusively define their effects on the fibrinolytic system.
Effect of Terbinafine on the Pharmacokinetics and Pharmacodynamics of Desipramine in Healthy Volunteers Identified as Cytochrome P450 2D6 (CYP2D6) Extensive Metabolizers
Authors: Madani Soraya , Barilla Denise , Cramer Jeffrey , Wang Yibin , Paul Carle
Published: July 2003

Terbinafine‐CYP2D6 inhibition was evaluated by assessing 48‐hour concentration‐time profiles of the tricyclic antidepressant desipramine in 12 healthy volunteers identified as extensive cytochrome P450 2D6 (CYP2D6) metabolizers by genotyping and phenotyping. Pharmacokinetics was evaluated at baseline (50 mg oral desipramine given alone), steady state (after 250 mg oral terbinafine for 21 days), and 2 and 4 weeks after terbinafine discontinuation. Pharmacodynamics was evaluated before and 2 hours after each desipramine administration, using Mini‐Mental Status Examination (MMSE) and ECG. Terbinafine administration inhibited CYP2D6 metabolism, as indicated by the significant increase in desipramine Cmax (19 ng/ml vs. 36 ng/ml) and AUC0‐∞ (482 ng•h/ml vs. 2383 ng•h/ml) and decrease in AUC0–24 and Cmax of the CYP2D6‐mediated metabolite, 2‐hydroxydesipramine. In addition, the Cmax and AUC0‐∞ of desipramine and metabolite were still elevated 4 weeks after terbinafine discontinuation. Caution should be exercised when coprescribing terbinafine and drugs metabolized by CYP2D6, particularly those with a narrow therapeutic index.
Pharmacokinetics, Dose Proportionality, and Tolerability of Single and Repeat Doses of a Nasal Spray Formulation of Zolmitriptan in Healthy Volunteers
Authors: Yates Roger , Nairn Kevin , Dixon Ruth , Kemp J. V. , Dane A. L.
Published: July 2003

The objective of this study was to investigate the pharmacokinetics, dose proportionality, and tolerability of a range of single and multiple doses of a nasal spray formulation of zolmitriptan in a randomized, double‐blind, placebocontrolled, balanced, incomplete crossover study. Thirty healthy male or female volunteers received two of five dose levels of zolmitriptan nasal spray: 0 (placebo), 0.5,1,2.5, and 5 mg. At each level, treatment comprised a single dose on day 1 and two doses (separated by 2 h) on each of days 2, 3, and 4. Zolmitriptan was well tolerated, and symptoms were generally mild and of short duration. The most commonly reported adverse events were taste disturbance, paresthesia, hyperesthesia, headache, and nasal/throat discomfort. Volunteers generally reported fewer adverse events during the multiple‐dose phase than after the single‐dose phase. Zolmitriptan was detectable in plasma within 15 minutes, and tmax was similar for each dose and after single and multiple dosing. Dose proportionality was shown for the Cmax and AUC of both zolmitriptan and its active metabolite, 183C91. Mean t1/2 for zolmitriptan and 183C91 was approximately 3 hours. It was concluded that the pharmacokinetics (Cmax and AUC) for both zolmitriptan and 183C91 was proportional to dose after both single and multiple dosing. Nasal spray zolmitriptan was well tolerated; the frequency and nature of adverse events did not increase after multiple dosing.
Sequential First‐Pass Metabolism of Nortilidine: The Active Metabolite of the Synthetic Opioid Drug Tilidine
Authors: Hajda Jacek Piotr , Jähnchen Eberhard , Øie Svein , Trenk Dietmar
Published: July 2003

The disposition of nortildine, the active metabolite of the synthetic opioid drug tilidine, was investigated in healthy volunteers in a randomized, single‐dose, three‐way crossover design. Three different treatments were administered: tilidine 50 mg intravenously, tilidine 50 mg orally, and nortilidine 10 mg intravenously. The plasma concentrations of tilidine, nortilidine, and bisnortilidine were determined and subjected to pharmacokinetic analysis using noncompartmental methods. The systemic bioavailability of tilidine was low (7.6% ± 5.3%) due to a pronounced first‐pass metabolism. The areas under the plasma concentration versus time curves (AUC) of nortilidine were similar following either oral or intravenous administration of tilidine 50 mg (375 ± 184 vs. 364 ± 124 ng•h•ml−1). AUC of nortilidine was 229 ± 42 ng•h•ml−1 after IV infusion of nortilidine 10 mg and thus much greater than after IV tilidine corrected for differences in dose. Nortilidine had a much lower volume of distribution (275 ± 79 vs. 1326 ± 477 L) and a somewhat lower clearance (749 ± 119 vs. 1198 ± 228 ml/min) than tilidine. About two‐thirds of the dose of tilidine was metabolized to nortilidine, although only half of the latter fraction was available in the peripheral circulation. Nortilidine was subsequently metabolized to bisnortilidine. The mean ratio of the AUC of bisnortilidine to nortilidine was 0.65 ± 0.14 following IV administration of nortilidine but 1.69 ± 0.38 and 1.40 ± 0.27 following oral and intravenous administration of tilidine, respectively. The shapes of the plasma concentration‐time curves of the metabolites and parent drug declined in parallel, indicating that the disposition of the metabolites is formation rate limited. Thus, although two‐thirds of the dose of tilidine is metabolized to nortilidine, only one‐third of the dose is available systemically as nortilidine for interaction with the opiate receptors after both intravenous and oral dosing of tilidine. The remaining part of nortilidine is retained in the liver and is subsequently metabolized to bisnortilidine and yet unknown compounds.
Pharmacokinetics and Pharmacodynamics of a New Formulation of Recombinant Human Growth Hormone Administered by ZomaJet 2 Vision, a New Needle‐Free Device, Compared to Subcutaneous Administration Using a Conventional Syringe
Authors: Agersø Henrik , Møller‐Pedersen Jane , Cappi Silvana , Thomann Peter , Jesussek Bernd , Senderovitz Thomas
Published: July 2003

The objective of the present study was to investigate the applicability of a new human growth hormone (Zomacton®) formulation, administered both by a conventional syringe and by a new needle‐free device (ZomaJet 2 Vision). The study was performed according to a randomized, controlled, three‐period crossover design. On 3 separate days, all subjects received in a random order a single subcutaneous injection of 1.67 mg hGH as follows: Zomacton® 4 mg/ml conventional syringe administration (Treatment A), Zomacton® 10 mg/ml conventional syringe administration (Treatment B), or Zomacton® 10 mg/ml ZomaJet 2 Vision administration (Treatment C). The pharmacokinetic parameters were assessed for the individual subjects in each group by noncompartmental methods. Bioequivalence was assessed based on log‐transformed AUC and Cmax values. To investigate the effectiveness of two formulations and the different administration methods, the pharmacodynamic parameters (insulin‐like growth factor‐1 [IGF‐1] and free fatty acids [FFA]) were also evaluated. No subjects were withdrawn due to adverse events. The local tolerance assessment (assessed by inspection) revealed no differences between ZomaJet 2 Vision application and conventional injections by syringe. Administration of the new hGH formulation by syringe was found to be bioequivalent with the reference treatment, both based on AUC and Cmax values; the new formulation administered by use of ZomaJet 2 Vision was found to be bioequivalent based on AUC values only. When using the ZomaJet 2 Vision, the absorption of hGH was faster, resulting in higher Cmax values. The maximum hGH serum concentration of around 20 ng/ml was observed 3.5 to 4 hours after drug administration. The terminal half‐life was found to be around 2.5 hours. Comparison of the pharmacodynamic profiles (both IGF‐1 and FFA) demonstrated bioequieffectiveness. These results support the use of jet injectors as a viable alternative to the traditional injection pens.
Fexofenadine Transport in Caco‐2 Cells: Inhibition with Verapamil and Ritonavir
Authors: Perloff Michael D. , von Moltke Lisa L. , Greenblatt David J.
Published: July 2003

This study investigated fexofenadine (FXD) transport and the inhibition of FXD transport in Caco‐2 cell monolayer transwells, usingrhodamine 123 (RH123) transport as a positive control. FXD transport from the basolateral (B) to apical (A) compartment was fivefold higher than A to B transport. FXD transport was linear with respect to time (up to 270 min) and concentration (up to 300 μm). Similar results were seen with the positive control RH123. Ritonavir (100 μM) and verapamil (100 μm) reduced transport of FXD and RH123 by more than 80%, whereas transport was not inhibited by 100 m indomethacin or 2 mM probenecid. This suggests predominantly P‐glycoprotein (P‐gp)‐mediated transport as opposed to transport by multidrug resistance protein. In concentration‐response experiments, FXD transport was inhibited by verapamil and ritonavir with IC50 values of 6.5 μm and 5.4 μm, respectively. Results from this in vitro study demonstrate differential transport of FXD across Caco‐2 cell monolayers and inhibition of FXD transport by established P‐gp inhibitors. The findings support the use of FXD as an index or probe compound to reflect P‐gp activity in vivo.
Impairment of Mycophenolate Mofetil Absorption by Calcium Polycarbophil
Authors: Kato Ryuji , Ooi Kazuya , Ikura‐Morii Megumi , Tsuchishita Yoshimasa , Hashimoto Hiroshi , Yoshimura Hironori , Uenishi Kohji , Kawai Masayuki , Tanaka Kazuhiko , Ueno Kazuyuki
Published: July 2003

The effect of calcium polycarbophil on the absorption of mycophenolate mofetil, an immunosuppressive agent, was evaluated in healthy subjects. In vitro studies were performed to further evaluate the mechanism of the potential interaction. In the in vitro study, the release of mycophenolate mofetil from a cellulose membrane in the presence orabsence of metal cations was measured using the dissolution test procedure. In the in vivo study, a randomized crossover design with two phases was used. In one phase, 6 male healthy volunteers received 1000 mg of mycophenolate mofetil alone (treatment 1); in the other phase, they received 1000 mg of mycophenolate mofetil and 2400 mg of calcium polycarbophil fine granules concomitantly (treatment 2). They received 30 mg of lansoprazole for 5 days and, on the 6th day, received mycophenolate mofetil and 2400 mg of calcium polycarbophil fine granules concomitantly (treatment 3). The serum concentration of mycophenolic acid was measured by high‐performance liquid chromatography. In the in vitro study, the release from a cellulose membrane in the presence of calcium or iron ions was slower than that in the absence of these metal ions. In the in vivo study, the AUC0–12 and Cmax in treatment 2 were less than those in treatment 1. About 50% and 25% decreases in AUC0–12 in treatment 2 and treatment 3 were observed compared with those in treatment 1, respectively. These findings suggest that when mycophenolate mofetil and calcium polycarbophil were coadministered concomitantly, a decrease in mycophenolate mofetil absorption was observed. Therefore, it appears clear that the concomitant administration of mycophenolate mofetil and calcium polycarbophil should be avoided.
A Double‐Blind, Placebo‐Controlled, Ascending‐Dose Evaluation of the Pharmacokinetics and Tolerability of Modafinil Tablets in Healthy Male Volunteers
Authors: Wong Y. Nancy , Simcoe Donna , Hartman Linda N. , Laughton Watson B. , King S. Peter , McCormick George C. , Grebow Peter E.
Published: July 2003

A randomized, double‐blind, placebo‐controlled, ascending‐dose study was conducted to evaluate the pharmacokinetic and safety profiles of increasing modafinil doses (200 mg, 400 mg, 600 mg, 800 mg) administered orally over a 7‐day period in normal healthy male volunteers. Eight subjects (six modafinil; two placebo) were randomized to each of the four dose groups. Modafinil or a placebo was administered once daily for 7 days. Serial blood samples were obtained following administration of the day 1 and day 7 doses for characterization of pharmacokinetics, and trough samples were obtained prior to dosing on days 2 through 6 to assess the time to reach the steady state. Pharmacokinetic parameters were calculated using noncompartmental methods. Modafinil steady state was reached after three daily doses. Modafinil pharmacokinetics were dose and time independent over the range of 200 mg to 800 mg. Steady‐state pharmacokinetics of modafinil were characterized by a rapid oral absorption rate, a low plasma clearance of ∼50 mL/min, a volume of distribution of ∼0.8 L/kg, and a long half‐life of ∼15 hr. Modafinil was primarily eliminated by metabolism. Modafinil acid was the major urinary metabolite. Stereospecific pharmacokinetics of modafinil were demonstrated. The d‐modafinil enantiomer was eliminated at a threefold faster rate than l‐modafinil. Modafinil 200 mg, 400 mg, and 600 mg doses were generally well tolerated. The modafinil 800 mg dose panel was discontinued after 3 days of treatment due to the observation of increased blood pressure and pulse rate. The safety data from this study suggest that the maximum tolerable single daily oral modafinil dose, without titration, may be 600 mg.
Long‐Term Systemic Exposure of Orlistat, a Lipase Inhibitor, and Its Metabolites in Obese Patients
Authors: Zhi Jianguo , Mulligan Thomas E. , Hauptman Jonathan B.
Published: July 2003

Orlistat, a lipase inhibitor, acts locally in the gastrointestinal tract; its systemic exposure is not required for its efficacy. However, knowledge of the extent of its systemic exposure is important for its safe use in obese patients, the intended target population. Pharmacokinetic screening in obese patients was carried out by monitoring plasma concentrations of unchanged orlistat and its metabolites in five key double‐blind, placebo‐controlled phase II/III studies. Results of these studies involving the monitoring of plasma samples indicate that detection of intact orlistat in plasma was sporadic, and measurable concentrations were low (<10 ng/mL or 0.02 μM) without evidence of accumulation, which is consistent with minimal absorption. It is concluded that systemic exposure of orlistat is negligible; at a clinically efficacious dose level, orlistat is unlikely to produce systemic lipase inhibition.
Pharmacokinetics and Tolerability of Intravenous Trecovirsen (GEM®91), an Antisense Phosphorothioate Oligonucleotide, in HIV‐Positive Subjects
Authors: Séréni Daniel , Tubiana Roland , Lascoux Caroline , Katlama Christine , Taulera Oliver , Bourque Andre , Cohen Aharon , Dvorchik Barry , Martin R. Russell , Tournerie Christophe , Gouyette Alain , Schechter Paul J.
Published: July 2003

Trecovirsen, a 25‐mer antisense phosphorothioate oligonucleotide targeted at the gag site of the HIV gene, was administered to HIV‐positive volunteers as an IV infusion. Single doses ranged from 0.1 to 2.5 mg/kg in an ascending escalation in cohorts of 6 to 12 subjects. Plasma trecovirsen concentrations and pharmacokinetic parameters could be assessed at doses ≥0.3 mg/kg. Peak plasma concentrations and AUC values increased disproportionately with increasing dose while elimination half‐life increased and plasma clearance decreased, indicating a saturable process over this dose range. The only significant adverse event observed was an isolated, transitory increase in activated partial thromboplastin time at doses ≥ 2.0 mg/kg that was related to plasma trecovirsen concentrations and is attributed to the polyanionic character of the molecule. Thus, trecovirsen administration was well tolerated in single IV doses up to 2.5 mg/kg.
Carbamazepine Levels in Head Hair of Patients under Long‐Term Treatment: A Method to Evaluate the History of Drug Use
Authors: Psillakis Th. , Tsatsakis A. M. , Christodoulou P. , Michalodimitrakis M. , Paritsis N. , Helidonis E.
Published: July 2003

Carbamazepine (CBZ) concentrations were determined in the sections of head hair from 40 patients (22 males and 18 females), ages 5 to 81, who were receiving this drug systemically. Hair treatment included dissolution, liquid phase extraction procedures, and immunoassay (Abbott TDx) or high‐pressure liquid chromatography (HPLC) analytical techniques. The mean values of CBZ levels in the hair from the 1st section (close to hair root) to the 5th section for female patients were 26.82, 19.18, 17.28, 15.09, and 14.62 μg/g according to HPLC measurements. Immunoassay gave generally slightly higher results. The mean values of CBZ in the hair sections according to the immunoassay technique were 30.53, 21.90, 19.83, 17.45, and 16.99 μg/g, respectively, from the 1st to the 5th sections. The corresponding mean values for male patients by HPLC and immunoassay techniques were 21.97, 17.30, 15.03, 13.02, and 11.21 μg/g and 25.98, 20.52, 17.15, 14.87, and 12.31 μg/g. Generally, a reduction of drug concentrations in hair from the first to the subsequent segments was observed. Higher amounts of CBZ were deposited in black, untreated hair (e.g., not dyed or permed). CBZ concentrations in hair sections were found to be dependent on the dosage (r = 0.979, p ≤ 0.001) but not on the gender. The data indicate the possible use of hair section testing as a marker of the dosage history and the compliance of patients under long‐term treatment with CBZ.
The Effects of Acetaminophen on Pharmacokinetics and Pharmacodynamics of Warfarin
Authors: Kwan Debora , Bartle William R. , Walker Scott E.
Published: July 2003

The oral anticoagulant warfarin is clinically administered as a racemic mixture of two enantiomers, (R) and (S). Many relevant drug interactions with warfarin have been attributed to the specific metabolic inhibition of the elimination of the more pharmacologically active (S)‐enantiomer. To investigate reports that acetaminophen can potentiate the anticoagulant effect of warfarin, 20 healthy male volunteers were each given single oral 20 mg doses of racemic warfarin on three separate occasions: (1) alone, (2) after 1 day of acetaminophen (4 g/d), and (3) after 2 weeks of acetaminophen (4 g/d). The urinary excretion pattern of acetaminophen and its metabolites was not significantly altered over its course of administration. The (R)‐ and (S)‐enantiomers of warfarin exhibited significantly different pharmacokinetic properties. However, acetaminophen did not alter the disposition of either (R)‐ or (S)‐warfarin. All subjects exhibited a pharmacodynamic response to racemic warfarin. The response was not significantly altered in the presence of acute or chronic acetaminophen dosing, as assessed by prothrombin time and factor VII concentrations.