bluuebunny/crossref_metadata_2025 huggingface dataset:
Dependency of Cortisol Suppression on the Administration Time of Inhaled Corticosteroids
Authors: Meibohm Bernd , Hochhaus Günther , Rohatagi Shashank , Möllmann Helmut , Barth Jürgen , Wagner Melanie , Krieg Michael , Stöckmann Ricarda , Derendorf Hartmut
Published: March 2013

Endogenous cortisol suppression is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. A previously developed pharmacokinetic/pharmacodynamic approach was used to evaluate the influence of administration time on the cumulative cortisol suppression (CCS) after single doses of the inhaled corticosteroids flunisolide and fluticasone propionate. Administration time‐dependent simulations of CCS were performed with drug‐specific pharmacokinetic and pharmacodynamic parameters obtained from previous clinical trials. Both drugs showed similar diurnal variation in CCS, dependent on the administration time, with maximum suppression when administered in the early morning at approximately 3 am. The optimum administration time for minimized CCS was in the afternoon but was shifted from 3 pm for fluticasone propionate to later time points around 7 pm for flunisolide, probably because of the shorter terminal elimination half‐life of flunisolide. Regarding peak to trough fluctuation, however, CCS after fluticasone propionate showed only half the administration time dependency as after flunisolide. Therefore, the ratio between CCS after flunisolide and after fluticasone propionate also followed administration time‐dependent variations. This led to the conclusion that administration time has to be considered as a pivotal influential factor in clinical studies comparing CCS among different inhaled corticosteroids.
Pharmacokinetics of Bupropion and its Metabolites in Cigarette Smokers versus Nonsmokers
Authors: Hsyu Poe‐Hirr , Singh Ashish , Giargiari Tracie D. , Dunn John A. , Ascher John A. , Johnston J. Andrew
Published: March 2013

Bupropion is an antidepressant agent that is also effective as an aid to quit cigarette smoking. A single 150‐mg tablet of sustained‐release bupropion hydrochloride was administered to two groups of volunteers, cigarette smokers and nonsmokers, who were matched for race, gender, body frame, age, and weight. Pharmacokinetic parameters were calculated for bupropion, and three major metabolites (hydroxybupropion and the aminoalcohol isomers, threohydrobupropion and erythrohydrobupropion, expressed as a composite total). Mean (±SD) values of area under the concentration‐time curve from time 0 extrapolated to infinity (AUC0–∞), maximum concentration (Cmax), time to reach Cmax (tmax), and half‐life (t1/2) of bupropion in smokers and nonsmokers, respectively, were 1,164 ± 220 ng · hr/mL and 1,161 ± 292 ng · hr/mL; 144 ± 28 ng/mL and 143 ± 39 ng/mL; 3.00 ± 0.50 hours and 2.88 ± 0.49 hours; and 19 ± 5 hours and 18 ± 3 hours. No clinically significant differences between smokers and nonsmokers or between male and female volunteers were observed for the pharmacokinetics of bupropion or its metabolites. The absence of pharmacokinetic differences indicates that dosage adjustments are not necessary when bupropion is prescribed to male and female cigarette smokers.
Effect of Patient and Family Insight on Compliance of Schizophrenic Patients
Authors: Smith Cedric M. , Barzman Drew , Pristach Cynthia A.
Published: March 2013

Insight on the part of both patients and their significant others is thought to be an important factor influencing compliance with medication and treatment of schizophrenic patients. Using the Scale to Assess Unawareness of Mental Disorder, the insight and the awareness of patients and of their significant others were studied with respect to symptoms, behaviors, and medication effects. The participants who were more aware of their mental illnesses and of the beneficial effects of medication were more likely to be compliant with prescribed medications. Both awareness and insight of the patient and their family members appears to have a beneficial impact on compliance. Participants whose significant others subsequently failed to cooperate with scheduled interviews had less awareness of their illnesses, and less appreciation of the beneficial effects of medications. Although not statistically significant, there was a trend for the patients who had no medication side effects to be compliant with prescribed medications. Abuse of alcohol or other substances in this population was low; only marijuana use was associated with noncompliance. Educating both patients and their family members to identify disease symptoms, drug effects and side effects has the potential to improve compliance in schizophrenic patients.
Eprosartan, an Angiotensin II Receptor Antagonist, Does Not Affect the Pharmacodynamics of Glyburide in Patients with Type II Diabetes Mellitus
Authors: Martin David E. , DeCherney G. Stephen , Ilson Bernard E. , Jones Beverly A. , Boike Steven C. , Freed Martin I. , Jorkasky Diane K.
Published: March 2013

The potential for eprosartan, a nonbiphenyl tetrazole angiotensin II receptor antagonist, to affect the 24‐hour plasma glucose profiles in type II diabetic patients treated with glyburide was investigated in this randomized, placebo‐controlled, double‐blind (eprosartan—placebo phase only), two‐period, period‐balanced, crossover study. All patients received a stable oral dose (3.75–10 mg/day) of glyburide for at least 30 days before the first dose of double‐blind study medication was administered. Patients were randomized to receive either 200‐mg oral doses of eprosartan twice daily or matching oral placebo doses concomitantly with glyburide for 7 days during each treatment period. After a minimum washout period of 14 days, patients were crossed over to the alternate treatment. Serial samples to measure glucose concentrations in plasma were collected over a 24‐hour period on the day before administration of eprosartan or placebo and again on day 7. Mean glucose concentrations were comparable between treatment groups before administration of eprosartan or placebo. The point estimate (90% confidence interval) for the ratio of the average mean 24‐hour plasma glucose concentrations of eprosartan + glyburide to placebo + glyburide after 7 days of administration was 0.96 (0.90, 1.01). Eprosartan did not significantly alter the 24‐hour plasma glucose profile in patients with type II diabetes mellitus who were previously stabilized on glyburide.
Biotransformation of Mestranol to Ethinyl Estradiol In Vitro: The Role of Cytochrome P‐450 2C9 and Metabolic Inhibitors
Authors: Schmider Jürgen , Greenblatt David J. , von Moltke Lisa L. , Karsov Dmitri , Vena Richard , Friedman Hylar L. , Shader Richard I.
Published: March 2013

Mestranol, the estrogen component of some oral contraceptive formulations, must be demethylated to its active metabolite, 17α‐ethinyl estradiol, to produce estrogenic activity. To investigate the transformation of mestranol to ethinyl estradiol, an in vitro assay was used with human liver microsomes from four different donors. Incubation of a fixed concentration of mestranol (3 μmol/L) with varying concentrations of CYP inhibitors revealed strong inhibition of ethinyl estradiol formation by sulfaphenazole, a specific CYP2C9 inhibitor, with an average inhibitor concentration at one half of Emax (IC50) of 3.6 μmol/L (range, 1.8–8.3 μmol/L) and an average maximal inhibitory capacity (Emax) of 75% (range, 60–91%). Troleandomycin (a CYP3A3/4 inhibitor) and quinidine (a CYP2D6 inhibitor), however, produced no substantial inhibitory activity. α‐Naphthoflavone (a CYP1A1/2 inhibitor only at concentrations <2 μmol/L and a CYP2C9 inhibitor at higher concentrations) had a weak inhibitory effect on ethinyl estradiol formation (<20% decrease in mestranol demethylation activity). Of the three antifungal azoles tested, miconazole strongly inhibited mestranol demethylation, with an average IC50 of 1.5 μmol/L (range, 0.7–3.2 μmol/L) and an average Emax of 90% (range, 77–100%), whereas fluconazole displayed relatively weak inhibition only at the highest concentration of 50 μmol/L (mean reduction in demethylation activity was 29%). Itraconazole produced no meaningful inhibition. Strong inhibition of ethinyl estradiol formation by sulfaphenazole suggests a major contribution of CYP2C9 to this reaction.
Phase I Dose‐Escalation Pharmacokinetics of AZT‐P‐ddI (IVX‐E‐59) in Patients with Human Immunodeficiency Virus
Authors: Zhou Xiao‐Jian , Squires Kathleen , Pan‐Zhou Xin‐Ru , Bernhard Steve , Agrofoglio Luigi , Kirk Marion , Duchin Kenneth L. , Sommadossi Jean‐Pierre
Published: March 2013

3′‐Azido‐3′‐deoxythymidilyl‐(5′,5′)‐2′,3′‐dideoxy‐5′‐inosinic acid (AZT‐P‐ddI, IVX‐E‐59, Scriptene) is a heterodimer composed of one molecule of 3′‐azido‐3′‐deoxythymidine (zidovudine or AZT) and one molecule of 2′,3′‐dideoxyinosine (didanosine or ddI) linked through their 5′ positions by a phosphate bond. AZT‐P‐ddI exhibits enhanced antiviral activity and selectivity in vitro compared with AZT and ddI alone. The pharmacokinetics of AZT‐P‐ddI were studied in 12 patients with human immunodeficiency virus (HIV) who had CD4+ cell counts higher than 200 cells/mm3. Isotopic preparations of (14C)‐AZT‐P‐(3H)‐ddI were administered intravenously (50 mg and 100 mg) to eight patients; 1 month later these patients were crossed over to oral administration (100 mg and 200 mg). A second group of patients (n = 4) received only a 450‐mg oral dose of AZT‐P‐ddI. Plasma levels of unchanged AZT‐P‐ddI after intravenous infusion declined rapidly and were undetectable 0.75 hours after the end of infusion, whereas the parent compound was not detected after oral administration, indicative of a very rapid metabolism. The parent entity was enzymatically cleaved in vivo yielding the two constituent drugs AZT and ddI, which were subsequently subjected to their respective pharmacokinetic and metabolic processes. The β‐glucuronide derivative of AZT (GAZT) represented the major metabolite of AZT, but there were no detectable levels of the toxic metabolite 3′‐amino‐3′‐deoxythymidine (AMT). A major and previously unrecognized in vivo metabolite of ddI, referred as ddI‐M, was detected in plasma and urine. Analysis by high‐field proton nuclear magnetic resonance and mass spectrometry led to the identification of ddI‐M as being R(–)‐dihydro‐5‐(hydroxymethyl)‐2(3H)‐furanone. The formation of AZT and ddI metabolites was increased after oral administration of AZT‐P‐ddI compared with the intravenous infusion, with an area under the concentration—time curve (AUC) ratio of metabolite to AZT and metabolite to ddI being 7.7 and 5.7 (oral) and 3.8 and 1.1 (intravenous), respectively. The newly identified ddI‐M exhibited sustained plasma levels for extended time periods with an apparent elimination half‐life (t1/2) of approximately 10 hours after oral administration of AZT‐P‐ddI. Recovery of radioactivity associated with 3H and 14C in urine was essentially complete within 48 hours after oral and intravenous administration of AZT‐P‐ddI. The oral bioavailability of AZT (64.7–67.3%) and ddI (33.6–42.9%) and the other pharmacokinetic parameters were consistent with previous data reported with each nucleoside analog alone or in combination therapy.
Fenoldopam: A New Dopamine Agonist for the Treatment of Hypertensive Urgencies and Emergencies
Authors: Post James B. , Frishman William H.
Published: March 2013

Fenoldopam is a selective dopamine agonist that is being considered for the parenteral treatment of systemic hypertension. In both an oral and parenteral form, the drug causes peripheral vasodilation by stimulating dopamine‐1 adrenergic receptors. Its pharmacodynamics are reviewed in this article, along with the clinical experiences in patients with hypertensive urgencies and emergencies. Intravenous fenoldopam may provide advantages over sodium nitroprusside because it can induce both a diuresis and natriuresis, is not light sensitive, and is not associated with cyanide toxicity. There is no evidence for rebound hypertension after discontinuation of fenoldopam influsion. J Clin Pharmacol 1998;38:2–13.
The Effects of Renal Impairment on the Pharmacokinetics of Zalcitabine
Authors: Bazunga Munama , Tran Hieu T. , Kertland Heather , Chow Moses S. S. , Massarella Joseph
Published: March 2013

The pharmacokinetics of zalcitabine (ddC) were studied in three groups of subjects with varying degrees of renal function: group I (n = 5), creatinine clearance (Clcr) 0–10 mL/min; group II (n = 10), Clcr 11–50 mL/min; and group III (n = 8), Clcr >50 mL/min. Each patient received a single 0.75‐mg oral dose of zalcitabine, and multiple blood and urine samples were collected over a 10‐hour period after administration. Plasma and urine concentrations of zalcitabine were measured by high‐performance liquid chromatography. No statistically significant differences were observed between the three groups in maximum concentration (Cmax), time to Cmax (tmax), or volume of distribution (V/F). Also, elimination half‐life (t1/2), area under the concentration—time curve (AUC0–10), total body clearance (Cl/F), elimination rate constant (Ke), and renal clearance (Clr) did not differ significantly between the two groups with renal impairment (groups I and II). However, there was a significant difference in these parameters between groups with renal impairment (I and II) and group III. A linear correlation was observed between creatinine clearance (Clcr) and Clr, Ke, and Cl/F in all subjects. Clearance of zalcitabine is decreased after a single oral dose in patients with renal impairment. Dosage adjustment may be warranted in such patients, especially in those with severe renal impairment.
A Phase I Double‐Blind, Placebo‐Controlled, Single Rising Dose Study to Determine the Safety, Tolerability, and Pharmacokinetics of Oral YM934 in Healthy Male Volunteers
Authors: Burggraaf Jacobus , Schoemaker Rik C. , Terpstra Ido J. , Cohen Adam F.
Published: March 2013

In this phase I study a novel potassium channel opener (YM934) was administered to young healthy male volunteers to identify a dose with minimal cardiovascular effects. The study was carried out using a double‐blind, placebo‐controlled rising dose design with oral YM934 in single doses of 20 μg, 60 μg, and 180 μg. During each study day frequent blood samples were obtained for drug assay, measurements of cardiovascular parameters, and parasympathetic activity. The drug was well tolerated, with headache being the only significant adverse event. No relationship could be detected between dose or plasma concentration of YM934 and headache. No significant changes in routine laboratory and pharmacodynamic parameters occurred between placebo and active drug treatment. The pharmacokinetics of YM934 were characterized by a rapid oral absorption, an elimination half‐life of 30 hours, and an oral clearance of 1.7 L/h. The obtained data allow estimation of a YM934 dose regimen with minimal cardiovascular (side) effects to be used for future efficacy studies.
Short‐term Efficacy and Tolerability of Combination Therapy with Lovastatin and Acipimox in Chinese Patients with Type 2 Diabetes Mellitus and Mixed Dyslipidemia
Authors: Ko Gary T. C. , Mak Tony W. L. , Yeung Vincent T. F. , Chan Dick C. F. , Lam Christopher W. K. , Tsang Lynn W. W. , Chow Chun‐Chung , Cockram Clive S.
Published: March 2013

In type 2 diabetes, it is not uncommon to find an elevated serum triglyceride and/or reduced high‐density lipoprotein (HDL) cholesterol levels; elevated total cholesterol levels often occur as well. To evaluate the short‐term efficacy and tolerability of combination therapy with lovastatin and acipimox in Chinese patients with type 2 diabetes who have mixed dyslipidemia, an open‐label 6‐month trial was conducted. All patients had type 2 diabetes (n = 33) with total cholesterol ≥6.2 mmol/L and fasting triglyceride ≥2.8 mmol/L, which had been confirmed twice and persisted for at least 12 weeks after introduction of diet control. After a 4‐week run‐in period, they were given lovastatin 40 mg daily at night for 12 weeks. Acipimox 250 mg three times a day was then added for a further 12 weeks. After 12 weeks of treatment with lovastatin alone, improvement was observed in total cholesterol (21% reduction), triglyceride (32% reduction), low‐density lipoprotein (LDL) cholesterol (5.5% reduction), HDL cholesterol (11.6% elevation), apolipoprotein A‐I (4.6% elevation), and apolipoprotein B (20.5% reduction). The addition of acipimox to lovastatin for an additional 12 weeks further reduced serum total cholesterol, triglyceride, LDL cholesterol, and apolipoprotein B, but this additional decrease was not statistically significant. However, HDL cholesterol and apolipoprotein A‐I levels were significantly increased by the addition of acipimox (a 14.2% and 9.0% elevation, respectively). Serum creatine phosphokinase increased slightly after 12 weeks of lovastatin but decreased to a concentration similar to baseline after 12 weeks of combination treatment. No patients reported muscle pain or weakness or other side effects. Combination treatment with lovastatin and acipimox appears to be a safe and effective therapy in patients with type 2 diabetes and mixed dyslipidemia, and has particular benefit in elevating serum HDL cholesterol and apolipoprotein A‐I levels.
Accumulation of Fluconazole in Scalp Hair
Authors: Yeates Rodney , Laufen Heinrich , Zimmermann Torsten , Scharpf Friedrich
Published: March 2013

The accumulation in scalp hair of the antimycotic triazole, fluconazole, was studied during and after administration. Fluconazole 50 mg was administered to 12 healthy subjects as a single capsule each day for 28 days. The concentration of fluconazole 5 hours after administration was measured in different 1‐cm sections of scalp hair at intervals during treatment and for 6 months after the end of treatment. In each section of scalp hair the concentration of fluconazole increased during treatment and was consistently higher than values found in plasma. For example, the mean concentration in the first hair section on day 28, 19.8 μg/g, corresponded to a mean penetration ratio relative to plasma of 9.42. During administration, the maximal concentration of fluconazole was found in the first hair section. After cessation of administration, the measured concentrations of fluconazole decreased and greater concentrations were found in the distal hair sections, presumably as a result of hair growth. Fluconazole was detectable, however, in the hair of 9 of the 12 subjects even 6 months after treatment. The mean concentration of fluconazole in hair bulbs on day 28 was 12.1 μg/g (n = 6), corresponding to a mean penetration ratio of 5.99. In a second study, fluconazole was administered as a single oral 150‐mg capsule per week for 4 weeks to a group of 8 healthy subjects. The mean fluconazole concentration in whole scalp hair 5 hours after the last dose was 3.2 μg/g.
Pharmacokinetics of Multiple‐Dose Oral Cilostazol in Middle‐Age and Elderly Men and Women
Authors: Suri Ajit , Forbes William P. , Bramer Steven L.
Published: March 2013

Cilostazol is being developed for the treatment of intermittent claudication due to peripheral arterial disease (PAD). This study was conducted to investigate the effects of age and gender on the pharmacokinetics of cilostazol after multiple‐dose administration. It was an open label, multiple‐dose study of cilostazol administered to male and female subjects 50 years of age and older at a dose of 100 mg (oral tablet) twice daily for 7 days. Equal numbers of healthy male and female (7 per group), nonsmoking subjects stratified into age groups of 50 to 59 years, 60 to 69 years, and 70 years or older were enrolled. Serial plasma samples were obtained. Data were analyzed by model‐independent methods. Cilostazol was absorbed at a moderate rate, with peak plasma concentrations occurring at an overall mean of 2.4 hours after administration. Cilostazol is extensively bound (95%), primarily to albumin. A trend toward increasing cilostazol free fraction with age was observed in the male subjects, which was explained by a decrease in plasma albumin concentration with age. Differences in plasma protein binding between age and gender groups (less than 15%) are not expected to have any clinical significance. Plasma cilostazol concentrations reached steady state by day 4. The pharmacokinetic characteristics of cilostazol were not affected by age or gender.
Analgesic Efficacy and Safety of (R)‐ Ketoprofen in Postoperative Dental Pain
Authors: Cooper Stephen A. , Reynolds Donald C. , Reynolds Beverly , Hersh Elliot V.
Published: March 2013

This double‐blind, randomized, parallel‐group study compared the analgesic efficacy and safety of single doses of (R)‐ ketoprofen 25 mg and 100 mg to that of acetaminophen 1,000 mg and placebo in 177 patients experiencing moderate to severe pain after surgical removal of their impacted third molars. Both (R)‐ ketoprofen 100 mg and acetaminophen 1,000 mg were significantly (P < 0.05) more efficacious than placebo for all summary analgesic measures. Other than a more rapid analgesic onset (45 minutes versus 60 minutes) for acetaminophen 1,000 mg, (R)‐ ketoprofen 100 mg and acetaminophen 1,000 mg were statistically equivalent to each other. The 25 mg dose of (R)‐ ketoprofen appeared to approach the analgesic threshold dose, being numerically but not statistically superior to placebo for all summary measures. There were no serious adverse events observed in this study, with the overall incidence of side effects being somewhat less in the (R)‐ ketoprofen groups than in the acetaminophen 1,000 mg group. (R)‐ Ketoprofen possesses analgesic activity and an acceptable side‐effect profile in the oral surgery pain model. J Clin Pharmacol 1998;38:11S‐18S.
The Importance of Arterial Compliance in Cardiovascular Drug Therapy
Authors: Glasser Stephen P. , Arnett Donna K. , McVeigh Gary E. , Finkelstein Stanley M. , Bank Alan K. , Morgan Dennis J. , Cohn Jay N.
Published: March 2013

Arterial compliance, defined as a change in dimension in response to a given change in stress, is becoming an increasingly important clinical parameter. Related concepts, such as distensibility, elasticity, and stiffness, and more traditional concepts such as resistance, afterload, and impedance need to be differentiated from compliance, although they are frequently (inappropriately) used interchangably. Many studies cannot differentiate between compliance changes due to a drug's effect on blood pressure and those due to a drug's effect on vessel wall integrity. This differentiation is important because a more physiologic therapy, one that benefits pulsatile and nonpulsatile flow, should be of greater clinical benefit than a therapy that only lowers blood pressure. A number of methods have been used to estimate compliance, but to date there is no generally agreed‐on best method. There also are no longitudinal studies that relate abnormal compliance and drug effects to outcome. Nonetheless, patients at risk from a variety of disease states, such as hypertension, diabetes mellitus, and hypercholesterolemia, may benefit from earlier recognition of abnormal compliance. Earlier recognition may lead to interventions that would reduce their risk. This review includes a discussion of compliance and related estimates of blood vessel function and attempts to summarize the data currently available regarding the effects of cardioactive drugs on arterial compliance.
Stable Isotope Techniques in Early Drug Development: An Economic Evaluation
Authors: Browne Thomas R.
Published: March 2013

Stable isotope labeled (SIL) drug methods are compared with standard methods for performing early (phases I and IIa) drug development studies (mass balance, bioavailability, single‐dose volunteer and patient, multiple‐dose volunteer and patient). SIL methods offer considerable reduction in the cost (>50%) and number of subjects (67%) required for bioavailability and multiple‐dose patient studies. Moreover, a complete early drug development program is described for optimally combining SIL and standard studies, which can reduce cost by 23% and number of subjects by 36% compared with a program using standard methods. These reductions should result in development time savings of at least one year.
Pharmacokinetics of Mycophenolic Acid in Renal Transplant Patients with Delayed Graft Function
Authors: Shaw Leslie M. , Mick Rosemarie , Nowak Irena , Korecka Magdalena , Brayman Kenneth L.
Published: March 2013

The pharmacokinetics of mycophenolic acid (MPA), the immunosuppressant form of the prodrug mycophenolate mofetil (MMF), and the primary glucuronide metabolite, MPAG, were characterized in renal transplant patients with delayed graft function using random effects piecewise linear models. Eight patients were evaluated after receiving their first and subsequent daily oral doses of 1.5 g mycophenolate mofetil twice daily on study days 1 (n = 8), 7 (n = 8), 14 (n = 5), 21 (n = 2), and 28 (n = 7). The area under the concentration—time curve from zero to 12 hours (AUC0–12) for MPA, MPAG, MPA free fraction, and free MPA were analyzed in serial plasma samples using validated high‐performance liquid chromatography and ultrafiltration procedures. Random effects piecewise linear models, fit by maximum likelihood methods, were applied to AUC0–12 of MPA and MPAG, MPA free fraction, AUC0–12 of free MPA, and serum creatinine concentration, the index of renal function used in this study. Two hemodialysis sessions did not lower MPA plasma concentration, although some MPAG was removed. The AUC0–12 of MPA increased as a function of time, although it was not possible to fit a statistical model to the data due to considerable among‐patient variation in the pattern of increase with time. The AUC0–12 of MPAG, MPA free fraction, and AUC0–12 of free MPA reached maximal values on day 7; each of these parameters had unique day 1 to 7 positive slope values and unique day 7 to 28 negative slope values. The average creatinine concentration was maximal at day 1 and a unique negative slope was obtained between days 7 and 28. Thus, this study provides statistical models for the alteration of AUC0–12 of MPAG, MPA free fraction, AUC0–12 of free MPA, and serum creatinine in renal transplant patients with delayed graft function. These results provide evidence that renal dysfunction is associated with altered pharmacokinetics of MPA, particularly increased AUC0–12 of MPAG, MPA free fraction, and AUC0–12 of free MPA. The perturbed pharmacokinetics normalized with improving renal function.
Innovative Drug Treatments for Viral and Autoimmune Myocarditis
Authors: Anandasabapathy Sharmila , Frishman William H.
Published: March 2013

Myocarditis has been shown to be a common cause of cardiomyopathy and is believed to account for 25% of all cases in human beings. Unfortunately, the disease is difficult to detect before a myopathic process ensues. Treatment of myocarditis‐induced heart failure includes the standard regimen of diuretics, digoxin, angiotensin‐converting enzyme inhibitors, and currently, β‐adrenergic blockers. Treatment of myocarditis itself is dependent on the etiology of the illness. Treatments under investigation include immunosuppressants, nonsteroidal antiinflammatory agents, immunoglobulins, immunomodulation, antiadrenergics, calcium‐channel blockers, angiotensinconverting enzyme inhibitors, nitric oxide inhibition (e.g., aminoguanidine), and antiviral agents. Despite advances in treatment, more work needs to be done in the early detection of myocarditis. Additionally, better means need to be established for distinguishing between viral and autoimmune forms of the disease, so that appropriate treatment can be instituted.
Effects of Extensive and Poor Gastrointestinal Metabolism on the Pharmacodynamics of Pravastatin
Authors: Ito Matthew K.
Published: March 2013

The enhanced nonenzymatic isomerization of pravastatin to SQ 31,906, a relatively inactive metabolite, has been demonstrated to occur on exposure to gastric acidity in humans. However, the effect of gastric metabolism on the pharmacodynamics of pravastatin has not been studied. In addition, it was hypothesized that some individuals may be more extensive gastric metabolizers than others. Sixteen men received 4 weeks of oral therapy with pravastatin 10 mg after a 6‐week drug washout diet run‐in period. Pharmacokinetic and pharmacodynamic parameters were determined after 8 hours of serum sampling on the final day of therapy. Patients with a metabolic ratio for area under the concentration‐time curve (AUC0–8 of pravastatin/AUC0–8 of SQ 31,906) of less than 1.6 had a significantly lower reduction in total and low‐density lipoprotein (LDL) cholesterol compared with those with a ratio > 1.6. An enteric formulation of pravastatin should increase the bioavailability of pravastatin and enhanced lipid‐lowering efficacy.
Evaluating the Safety of Calcipotriene 30 g Per Day in Patients with Psoriasis: A Parallel Group, Vehicle‐Controlled Study
Authors: Blum Robert , Schwartzel Edmund , Siskin Stewart , Epinette Warren W.
Published: March 2013

Elevated blood and urine calcium levels have been reported with the use of high doses of calcipotriene ointment in patients with psoriasis. The objective of this study was to evaluate key measures of calcium metabolism in patients with psoriasis under supervised dosing conditions in a vehicle‐controlled study. Of the 24 patients enrolled, 12 each were administered 15 g of ointment containing calcipotriene or vehicle twice a day for 14 days. Blood and urine samples and 24‐hour urine collections were obtained at selected time points. All 24 patients completed the study with no significant differences between treatments in any of the laboratory parameters. Trend analysis failed to show any significant differences over time with the exception of calcium, which showed significant changes common to both the calcipotriene and vehicle groups, suggesting that these changes were unrelated to treatment. The results of this study show that the use of calcipotriene ointment at a dose of 30 g per day for 14 days did not produce any significant alterations in blood or urine calcium concentrations and was well tolerated.
Urine Drug Screening Results from Volunteers in Phase I Clinical Pharmacology Studies: Are We Being Misled?
Authors: Ramey Karen L. , Kovacs Steven f. , Martin David E. , Jorkasky Diane K.
Published: March 2013

The general intent of phase I clinical pharmacology studies is to demonstrate the safety and tolerability of investigational new drugs in healthy human volunteers. There is emerging evidence that people who volunteer for these studies are not always truthful with investigators during the screening process. All healthy volunteers who participate in studies at the SmithKline Beecham Clinical Pharmacology Unit in Philadelphia, Pennsylvania, are required to submit to urine drug testing. During 11 months of 1996, a total of 1,469 urine samples were collected and tested for eight different drugs or classes of drugs of abuse. The urine samples collected during the first five months of 1996 were all analyzed using EMIT (Syva Corporation) and interpreted according to the guidelines established by the National Institutes of Drug Abuse (NIDA). Of 534 samples, 12 (2.2%) were reported as positive. During the last 6 months of 1996, a new methodology using a fluorescence polarization immunoassay (FPIA) was used. This assay had lower limits of quantification than EMIT, and more stringent interpretation guidelines than those of the NIDA were used. Of 935 samples analyzed by FPIA, 89 (9.5%) were positive. Of the 89 positive test results, 59 were below the cut‐offs specified by the NIDA guidelines and would have been reported as negative. Interpretation of urine drug screen results according to the NIDA guidelines is not acceptable for clinical pharmacology investigations.
Absence of Effect of Terbinafine on the Activity of CYP1A2, NAT‐2, and Xanthine Oxidase
Authors: Trépanier Eric F. , Nafziger Anne N. , Kearns Gregory L. , Kashuba Angela D. M. , Amsden Guy W.
Published: March 2013

Terbinafine is an allylamine antifungal agent used for the treatment of onychomycosis. It has previously been reported to interact with caffeine and is metabolized in part by the cytochrome P450 systems. This open‐label, randomized, crossover study was conducted to examine the effect of terbinafine on the activity of cytochrome P450 1A2 (CYP1A2), N‐acetyltransferase (NAT‐2), and xanthine oxidase (XO). Twelve healthy nonsmoking adult volunteers were enrolled. Each received single doses of caffeine (100 mg), and urine was collected for a 16‐hour period with and without multiple‐dose oral administration of terbinafine (250 mg daily for 3 days). Study periods were separated by a 4‐week washout period. Urinary caffeine metabolite ratios were used to assess CYP1A2, NAT‐2 and XO activity. Comparison of mean metabolic ratios for treatment with and without terbinafine indicated that terbinafine did not appear to alter the activity of CYP1A2, NAT‐2, or XO, all of which regulate the biotransformation of caffeine.
Effect of Increasing Gastric pH with Famotidine on the Absorption and Oral Pharmacokinetics of the Inotropic Agent Vesnarinone
Authors: Koneru Brinda , Cowart Douglas T. , Noorisa Manizhe , Kisicki James , Bramer Steven L.
Published: March 2013

The effect of famotidine, an H2 receptor blocker, on the oral absorption and pharmacokinetics of the novel agent vesnarinone was investigated after oral administration of 60 mg vesnarinone with and without pretreatment with intravenous famotidine. The single‐blind, randomized, two‐way crossover study was conducted in 12 volunteers, with a washout period of 7 days between the two treatments. A pH monitor was used to ensure that gastric pH of the subjects was ≤ 3 in the absence of and ≤ 5 in the presence of famotidine. A significant decrease in maximum concentration (Cmax) and increase in time to Cmax (tmax) was observed for vesnarinone during treatment with famotidine, whereas area under the concentration‐time curve (AUC) was similar for both treatments. The physicochemical properties of the drug support the above observations. Therefore, therapies that increase gastric pH will affect the rate but not the extent of absorption of vesnarinone or the safety or efficacy profile of vesnarinone.
Double‐Blind, Single‐Dose Comparison of Bromfenac Sodium, Tramadol, and Placebo after Oral Surgery
Authors: Mehlisch Donald R.
Published: March 2013

This double‐blind, parallel‐group study was performed at a single site in patients with moderate or severe pain after oral surgery to remove one or more impacted third molars. Patients recorded their pain intensity at baseline and were then assigned to receive a single dose of bromfenac sodium (25 mg or 50 mg), tramadol (100 mg), or placebo, using a randomized double‐blind code. At regular intervals for up to 8 hours after study drug administration, pain intensity and pain relief were recorded and were used to derive the efficacy variables, total pain relief (TOTPAR), pain intensity difference (PID), and summed pain intensity difference (SPID). Both doses of bromfenac were superior to tramadol and placebo in terms of hourly and peak pain relief and PID. The 3‐hour and 8‐hour TOTPAR and SPID results for both doses of bromfenac also were significantly superior to those for tramadol and placebo, whereas the scores for tramadol did not show superiority to placebo. Similarly, both doses of bromfenac were superior to tramadol and placebo as measured by patient global assessment, time to meaningful pain relief, and duration of pain relief. Bromfenac was well tolerated and was equivalent to placebo with respect to treatment‐emergent study events. Overall, significantly more study events (total), digestive events (particularly nausea and vomiting), and nervous system events (particularly dizziness) occurred in patients treated with tramadol than in those in other treatment groups. Single oral doses of bromfenac were more effective, longer‐acting, and better tolerated than single doses of tramadol in providing pain relief after oral surgery.
Maximum Tolerated Dose and Pharmacodynamics of Eptastigmine in Elderly Healthy Volunteers
Authors: Mant Tim , Troetel William M. , Imbimbo Bruno P.
Published: March 2013

Eptastigmine is a new acetylcholinesterase (AChE) inhibitor currently under development for the symptomatic treatment of Alzheimer disease. This study was conducted to establish the maximum tolerated dose and the pharmacodynamics of eptastigmine in nine healthy elderly volunteers. Subjects received single oral doses of 8 mg, 20 mg, 32 mg, and 40 mg eptastigmine and placebo according to a double‐blind, randomized, rising‐dose, five‐way crossover design. Adverse events, blood pressure, heart rate, body temperature, forced expiratory volume, salivary flow, and pupilar activity were closely monitored during treatment. Pharmacodynamic activity of eptastigmine was evaluated with an assay of AChE activity in red blood cells. Eptastigmine doses of 8 mg, 20 mg, and 32 mg were well tolerated. Two of four subjects receiving the 40‐mg dose developed profound AChE inhibition (58–59%) and reported severe adverse events (nausea, vomiting, syncope, and bradycardia), precluding further administration in the remaining subjects. Eptastigmine administration produced a weak effect on supine heart rate, body temperature, and pupil diameter. There were no effects on blood pressure, forced expiratory volume, salivary flow, and near point of focus. Acetylcholinesterase activity was inhibited in a dose‐related fashion according to a sigmoidal (logistic) function. The mean (± SEM) maximum inhibition of AChE activity (Imax) was 14.5 ± 3.3%, 20.4 ± 2.3%, 28.7 ± 2.9%, 45.2 ± 1.3% and 53.6 ± 2.9% after placebo, 8 mg, 20 mg, 32 mg, and 40 mg of eptastigmine, respectively. The theoretical maximum response (Emax) was 72.9%, and the dose that produced half of the maximum response (ED50) was 29.5 mg. At 24 hours, residual AChE inhibition ranged from 9% to 15%, with a half‐life of recovery of the enzyme of approximately 10 hours. The maximum tolerated dose of eptastigmine after single‐dose oral administration in healthy elderly subjects is 32 mg. Single oral doses of eptastigmine produce sustained, dose‐related inhibition of AChE activity. Adverse events are related to the degree of AChE inhibition.
A Randomized, Placebo‐Controlled Study of Loop Diuretics in Patients with Essential Hypertension: The Bumetanide and Furosemide on Lipid Profile (BUFUL) Clinical Study Report
Authors: van der Heijden Marjon , Donders Servaes H. , Cleophas Ton J. , Niemeyer Menco G. , van der Meulen Jan , Bernink Peter J. , De Planque Ben A. , van der Wall Ernst E.
Published: March 2013

This study was conducted to determine whether loop diuretics are more effective than placebo in reducing blood pressure without raising serum lipid levels, and whether bumetanide is more effective than furosemide in this respect. In a double‐blind, 24‐week placebo‐controlled crossover study, 27 patients with essential hypertension were treated in four periods of 6 weeks each, including placebo twice, furosemide 40 mg daily, and bumetanide 1 mg daily. Several metabolic parameters, including serum lipid levels, and blood pressure were assessed. Overall levels of total cholesterol, triglycerides, and low‐density lipoprotein (LDL) cholesterol were 5%, 12.4%, and 4.8% higher, respectively, during loop diuretic therapy than during placebo treatment. Overall systolic and diastolic blood pressure measurements were 12 mmHg and 4 mmHg lower, respectively, during loop diuretic therapy than during placebo treatment. Any added effect of bumetanide on serum lipid levels and blood pressure compared with furosemide, however, could not be confirmed. Our results indicate that the loop diuretics bumetanide and furosemide are effective in reducing blood pressure, and influence serum lipid levels markedly less than do thiazide diuretics or chlorthalidone. In addition, these results indicate that differences in blood pressure reduction and serum lipid levels between the two compounds were small and nonsignificant.
The Relevance of T‐Type Calcium Antagonists: A Profile of Mibefradil
Authors: Glasser Stephen P.
Published: March 2013

L‐ and T‐type voltage‐dependent transmembrane calcium channels are important for normal functioning of the cardiovascular system. T‐type channels are a heterogeneous group, and have physiologic and pathophysiologic relevance in a number of organ systems, including the heart and central nervous system. They appear to be involved in the control of blood pressure in patients with essential hypertension and in protection from ischemic damage. Alterations of both L‐ and T‐type calcium channels are involved in the development of hypertension. Pharmacologic modulation of T‐type calcium channels appears to reduce membrane calcium flux and ameliorate hypertension. During early ischemic damage, T‐type calcium channels appear to remain functional whereas L‐type channels are already inactivated. T‐type calcium channels also appear to be involved in the development of supraventricular arrhythmias, some forms of arrhythmias in cardiomyopathy, and cardiac hypertrophy. The heterogeneity of T‐type calcium channels should make it possible to target drugs to specific subgroups of T‐type calcium channels. A new class of calcium antagonist, the benzimidazolyl‐substituted tetraline derivatives, has been shown to block both L‐ and T‐type calcium channels. The first member of this class approved for clinical use is mibefradil. Clinical studies have demonstrated the efficacy of mibefradil in lowering blood pressure and as an antianginal and antiischemic agent. At clinically recommended doses, mibefradil has a heart rate lowering effect without a negative inotropic effect, and a favorable side effect profile. Because it is metabolized by the cytochrome P450 pathway, it should be used cautiously with other agents similarly metabolized.
Pharmacokinetics of Torsemide in Patients with Decompensated and Compensated Congestive Heart Failure
Authors: Bleske Barry E. , Welage Lynda S. , Kramer William G. , Nicklas John M.
Published: March 2013

Plasma pharmacokinetics of oral furosemide have been shown to be influenced by degree of decompensation in patients with congestive heart failure (CHF). This open‐label, sequential comparison trial was conducted to determine whether CHF decompensation also alters the pharmacokinetics and pharmacodynamics of torsemide. Twelve patients with CHF, defined by either hemodynamic parameters or clinical signs and symptoms, were enrolled. On admission for treatment of their CHF, the patients were given 100 mg oral torsemide (phase A). A second dose of oral torsemide 100 mg was administered after hemodynamic parameters and clinical signs and symptoms of decompensated CHF resolved (phase B). Plasma and urine samples were collected over a 24‐hour period for determination of torsemide concentrations and urine sodium. Hemodynamic measurements and physical signs and symptoms also were evaluated. During phase A, patients had significantly greater urine output and fractional sodium excretion compared with phase B. A significant increase in the area under the plasma concentration‐time curve (AUC) was observed during phase B compared with phase A. However, no significant differences in maximal excretion rate of torsemide were noted between phase A and phase B. Heart failure status slightly affects the plasma pharmacokinetics of torsemide; however, this does not significantly alter the maximal urinary excretion rate of torsemide.
Silica Phenyl Sulfonic Acid as a Solid Acid Heterogeneous Catalyst for Chemoselective Thioacetalization of Carbonyl Compounds and Dethioacetalization under Mild Conditions
Authors: Veisi Hojat , Sedrpoushan Alireza , Zolfigol Mohammad Ali , Mohanazadeh Farajollah , Hemmati Saba
Published: March 2013

Silica phenyl sulfonic acid (SPSA) is an effective catalyst for chemoselective thioacetalization of aldehydes in the presence of ketones under neutral conditions. In addition, a simple and an efficient procedure for deprotection of 1,3‐dithianes and 1,3‐dithiolanes of aromatic, aliphatic, and α,β‐unsaturated aldehydes and ketones in the solvent‐free to the corresponding parent carbonyl compounds was successfully carried out with SPSA in excellent yields.
Polycyclic N‐Heterocyclic Compounds 73: Synthesis and Evaluation of 5‐Substituted 1,2‐Dihydrofuro[2,3‐c]isoquinolines as Inducers of Lipoprotein Lipase mRNA Expression
Authors: Okuda Kensuke , Yoshida Masahiko , Hirota Takashi , Sasaki Kenji
Published: March 2013

Several 5‐substituted 1,2‐dihydro[2,3‐c]isoquinoline derivatives were synthesized as part of our research to develop new diabetes drugs. Amines and sulfanyls were used as substituents at the 5th‐position. Evaluation of the effects of the newly synthesized compounds on lipoprotein lipase mRNA expression in 3T3‐L1 preadipocytes revealed one promising candidate with potency comparable to that of troglitazone.
One‐Pot Synthesis and Characterization of Some New Types of 5,5′‐Disubstituted Bis(imidazolidine‐2,4‐diones)
Authors: Khodaee Ziba , Yahyazadeh Asieh , Mahmoodi Nosrat O.
Published: March 2013

The synthesis and structural elucidation of some novel 5,5′‐disubstituted spiro and nonspiro‐bis‐hydantoins are reported. The Bucherer Burge's method has been modified for the preparation of some 5,5′‐substituted bis(imidazolidine‐2,4‐dione) derivatives starting with diketones (1–5) and dialdehydes (6, 7). In some cases, diastereoisomeric mixtures of compounds were obtained. The resulting bis‐hydantoins (8–11, 13, 14) have not to our knowledge been previously reported in the literature.
Synthesis, Characterization, and Antimicrobial Evolution of Bissydnone Based on Sulfonamide Derivatives
Authors: Asundaria Shahrukh T. , Patel Keshav C.
Published: March 2013

3,3′‐(Sulfonyldi‐1,4‐phenylene)bis(4‐substituted aminosulfonyl)sydnones (7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h, 7i, 7j) were synthesized from the starting material 4,4′‐diaminodiphenylsulfone. The synthesized compounds were characterized by IR, NMR, and elemental analysis. Some of the compounds were effectively active against Gram‐positive bacteria (Streptococcus pneumoniae and Staphylococcus aureus) and Gram‐negative bacteria (Escherichia coli and Pseudomonas aeruginosa).
Synthesis of Bis‐acridine Derivatives Exhibiting Anticancer and Anti‐inflammatory Activity
Authors: Sondhi Sham M. , Kumar Sandeep , Rani Reshma , Chakraborty Ajanta , Roy Partha
Published: March 2013

A series of bis‐acridine derivatives 3a–j and 5a–j have been synthesized by condensation of 9‐chloro‐2,4‐(un)substituted acridines (1a–e) and 9‐isothiocyanato‐2,4‐(un)substituted acridines (4a–e) with diamine 2a and 2b, respectively. These bis‐acridines were evaluated in vitro for activity against a panel of human cancer cell lines of lung (NCI H‐522), ovary (PA1), breast (T47D), colon (HCT‐15), and liver (HepG2). Several bis‐acridines were found to possess good anticancer activity against various cancer cell lines. Of these, compound 3h exhibited good anticancer activity against all cancer cell lines tested except liver (HepG2) cell line. In addition to this, these compounds were screened for anti‐inflammatory activity at a dose of 50 mg/kg p.o. Compound 3g exhibited 41% anti‐inflammatory activity, which is better than most commonly used standard drug ibuprofen, which showed 39% anti‐inflammatory (at 50 mg/kg p. o.) activity.