bluuebunny/crossref_metadata_2025 huggingface dataset:
Ramipril Decreases Chlorthalidone‐Induced Loss of Magnesium and Potassium in Hypertensive Patients
Authors: Šimunić Miroslav , Rumboldt Zvonko , MD Dragan Ljutić , Sardelić Sanda
Published: March 2013

A double‐blind clinical trial was conducted to compare the efficacy of and electrolyte changes caused by ramipril‐chlorthalidone combination treatment (5 mg + 25 mg) and chlorthalidone monotherapy (25 mg daily) in patients with hypertension. After a 4‐week placebo period, 32 patients (mean age, 51 ± 9 years) with essential hypertension (average blood pressure of 181.4/104.5 ± 13.0/6.9 mmHg) were randomly assigned to receive combination therapy (group A, n = 17) or monotherapy (group B, n = 15). After 12 weeks of active treatment, systolic and diastolic blood pressure decreased by 16.1% and 13%, respectively, for patients taking combined therapy, and by 12.7% and 9.8%, respectively, for patients taking monotherapy. The difference was significant for between‐group comparisons. There were no changes in serum sodium concentration, but a significant similar increase in 24‐hour urinary sodium excretion was seen in both groups. Serum calcium levels increased slightly and 24‐hour urinary calcium excretion decreased significantly in both groups, probably due to chlorthalidone administration. Serum potassium levels increased slightly in group A (from 4.16 ± 0.39 mmol/L to 4.30 ± 0.42 mmol/L) and decreased slightly in group B (from 4.18 ± 0.32 mmol/L to 3.99 ± 0.49 mmol/L). Urinary potassium excretion did not change significantly in group A, but increased by ∼15% in group B. There was a decrease in 24‐hour urinary magnesium excretion (from 4.01 ± 1.24 mmol/24 hours to 3.50 ± 0.93 mmol/24 hours) in group A and an increase (from 3.49 ± 0.98 mmol/24 hours to 4.35 ± 1.12 mmol/24 hours) in group B. At the end of the trial these changes were significant in between‐group comparisons. Consistent with the previously shown amelioration by ramipril of thiazide‐induced metabolic side‐effects, ramipril appears to improve magnesium balance during cotreatment with chlorthalidone.
Variability in the Pharmacokinetics and Pharmacodynamics of Low Dose Aspirin in Healthy Male Volunteers
Authors: Benedek Irma H. , Joshi Amita S. , Pieniaszek Henry J. , King Shang‐Ying P. , Kornhauser David M.
Published: March 2013

Data describing the pharmacokinetics and pharmacodynamics of low dose aspirin (acetylsalicylic acid; ASA) are limited. This single‐center study was designed to determine the rate and extent of oral absorption of 80‐mg ASA tablets in healthy, young male subjects and to assess the intra‐ and inter‐subject variability of ASA pharmacokinetics and platelet aggregation effects. Ten subjects each received a single, open‐label, oral 80‐mg ASA dose on three separate days. Each dose was separated by a 2‐week washout interval. Blood samples for pharmacokinetic determinations of ASA and its metabolite, salicylic acid (SA) and platelet aggregation studies were obtained at scheduled timepoints before and up to 24 hours after each dose. Peak plasma ASA levels of 1 μg/mL were achieved within 30 minutes. Peak plasma SA levels of approximately 4 μg/mL were attained in 1 hour. The terminal half‐lives (t1/2) of ASA and SA were 0.4 and 2.1 hours, respectively. Both ASA and SA pharmacokinetics and the platelet aggregation response to ASA exhibited considerable intra‐ and inter‐subject variability. Inhibition of platelet aggregation was found to relate with ASA area under the plasma concentration versus time curve (AUC).
BOOK REVIEWS
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

EKG and EEG Multiphase Information Analysis. KC Feng.

Individualized Therapy of Hypertension. NM Kaplan, CVS Ram, Editors.

Neurochemistry in Clinical Application: Proceedings of the International Neuropharmacology Symposium, November 9–11, 1992, Guangzhou, China. LC Tang, SJ Tang, Editors

Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Volume 1: Principles and Practice. Manfred E Wolff, Editor.

Contributions to Nephrology: Cyclosporine in the Therapy of Renal Disease, Volume 114. A Teiani, Editor.

Reproductive Toxicology, Second Edition (Target Organ Series). RJ Witorsch, Editor.

Planning Pharmaceutical Clinical Trials: Basic Statistical Principles. WM Wooding, Editor.

Advances in Psychosomatic Medicine: Psychotropic Drug Use in the Medically Ill, Volume 21. PA Silver, Editor.
Tricenter Assessment of the Efficacy of the ACE Inhibitor, Moexipril, by Ambulatory Blood Pressure Monitoring
Authors: White William B. , Whelton Andrew , Fox Alanna A.L. , Stimpel Michael , Kaihlanen Paul M.
Published: March 2013

To assess the efficacy and time‐dependent effects of once‐daily moexipril, a nonsulfhydryl ester prodrug of the angiotensin‐converting enzyme (ACE) inhibitor, moexiprilat, we conducted a multicenter, double‐blind, placebo‐controlled trial in 51 hypertensive patients using both clinic and ambulatory blood pressure (BP) recordings. Patients were included in the trial based on a minimum of 40% of the daytime diastolic BPs of 90 mm Hg or more during a placebo baseline phase; and the primary endpoint was change in 24‐hour ambulatory diastolic BP. Patients were randomized to receive placebo, 7.5 mg of moexipril, or 15 mg of moexipril once daily. Clinic and ambulatory BPs were taken on the first day and after eight weeks of double‐blind therapy. After the 7.5‐mg dose, there were no significant changes in the acute or prolonged clinic BPs compared with placebo. Compared with adjusted mean changes for placebo, the 15‐mg moexipril dose lowered clinic systolic BP, but not diastolic BP. In contrast, acute (1 day) reductions in 24‐hour diastolic BPs were −2/−3 mm Hg, −6/−4 mm Hg, and −14/−9 mm Hg on placebo, 7.5 mg of moexipril, and 15 mg of moexipril, respectively (P < .01 for the 15−mg dose). Similarly, after long‐term dosing for 8 weeks, reductions in 24‐hour diastolic BPs were 1/‐2 mm Hg, −6/‐4 mm Hg, and −12/‐9 mm Hg for the respective treatment groups (P < .01 for the 15‐mg dose). Peak effects of the drug occurred approximately 6 hours post‐dosing, and duration of action based on ambulatory BP monitoring was less for the 7.5‐mg dose (approximately 12–14 hours) than for the 15‐mg dose (24 hours). These data show that ambulatory BP was a more sensitive tool in the assessment of the antihypertensive effects of moexipril; that prolonged 24‐hour efficacy of this ACE inhibitor was predicted by its acute effects; and that the duration of antihypertensive activity of moexipril appears to be extended by higher dosing.
Clinical Pharmacology of Estrogens: Cardiovascular Actions and Cardioprotective Benefits of Replacement Therapy in Postmenopausal Women
Authors: Schwartz Jill , Freeman Ruth , Frishman William
Published: March 2013

The use of estrogens in postmenopausal women has been the subject of much controversy regarding hormone formulation, dosage, use in combination with progestins, duration of treatment, and contraindications. Estrogens have been prescribed to relieve menopausal symptoms for more than three decades. The hormones reduce the gynecologic and psychologic changes associated with menopause while inhibiting bone resorption and possibly reducing the risk of cardiovascular disease. Their use however has been complicated by an increased risk of endometrial cancer and possibly breast cancer. The use of estrogens as cardioprotective agents is discussed and the clinical experiences and the possible mechanisms of action are reviewed. The clinical pharmacology of estrogens and the various formulations that are available as monotherapy or in combination with progestins will also be reviewed.
The Effect of Dosage Release Formulations on the Pharmacokinetics of Propranolol Stereoisomers in Humans
Authors: Bleske Barry E. , Welage Lynda S. , Rose Steve , Amidon Gordon L. , Shea Michael J.
Published: March 2013

Recent studies in dogs have suggested that the disposition of S‐ and R‐propranolol may depend on the input rate of drug delivered to the liver. Therefore, this study was designed to determine whether differences in the disposition of S‐ and R‐propranolol occur in humans when altering the input rate of propranolol by giving different dosage forms of the drug. Twelve healthy subjects were enrolled in a single‐dose, 4‐way crossover pharmacokinetic study in which racemic propranolol was given according to 1 of 4 treatments: one 80‐mg immediate‐release (IR) tablet, phase A; two 80‐mg IR tablets, phase B; a 160‐mg controlled‐release capsule, phase C; or a 10‐mg IV bolus, phase D. The results showed no significant differences in the ratios of S/R‐propranolol for AUC, clearance, or overall mean concentration among the oral dosage groups. Significant differences in these parameters including Cmax S/R ratio were seen between the oral phases and the IV phase. These differences appear to be related more to the route of administration than to the low input rate. However, at high concentrations there may be input‐rate alteration in S/R ratios. Specifically, for phase B, which had the highest Cmax concentrations, the Cmax S/R ratio was significantly lower than the other oral dosage groups A and C (Cmax S/R ratios: 1.44 versus 1.54 and 1.54, respectively; P < .05). These results suggest, as shown by the Cmax S/R ratio, that at high concentrations as seen after 160‐mg IR propranolol, the disposition of S‐ and R‐enantiomers may be different (i.e., input‐rate dependent) compared with dosage forms that result in lower drug concentrations. This may have important clinical implications, because the pharmacodynamic response may be altered.
Disposition of Misoprostol and its Active Metabolite in Patients With Normal and Impaired Renal Function
Authors: Foote Edward F. , Lee Daniel R. , Karim Aziz , Keane William F. , Halstenson Charles E.
Published: March 2013

The disposition of misoprostol acid, the active metabolite of misoprostol, was studied in 48 subjects with various degrees of renal function after administration of a single 400 μg oral dose of misoprostol. Subjects were assigned to one of four treatment groups: group 1, normal renal function with creatinine clearance (CLCR) 80–140 mL/min/1.73 m2; group 2, mild renal impairment with CLCR 50–79 mL/min/1.73 m2; group 3, moderate renal impairment with CLCR 20–49 mL/min/1.73 m2 or group 4, end stage renal disease (ESRD) patients maintained on hemodialysis. The maximum plasma concentration (Cmax) and time to reach Cmax (tmax) for misoprostol acid tended to be larger in group 4 subjects; however, it failed to reach statistical significance. Although not statistically significant, in group 4 subjects the terminal half‐life (t1/2) of misoprostol acid was almost twice as large (1.27 ± 0.77 h) as in groups 1, 2, and 3 (0.70 ± 0.72, 0.72 ± 0.67, and 0.73 ± 0.45 h, respectively). Misoprostol acid's total area under the plasma concentration curve (AUC0)∞ was larger in group 4 subjects (1173.5 ± 487.4 pg ∞ h/mL, as compared with groups 1, 2, and 3 (421.4 ± 263.1, 418.9 ± 114.5, and 377.0 ± 145.2 pg ∞ h/mL, respectively; P < .05). The apparent total body clearance (CL) of misoprostol acid was statistically significantly smaller in group 4 subjects (0.094 ± 0.044 L/kg/min) as compared only with group 3 subjects (0.284 ± 0.102 L/kg/min). The dose of misoprostol may need to be reduced in ESRD patients on prolonged hemodialysis to prevent unnecessary high plasma levels of misoprostol acid and to avoid possible dose‐related adverse effects.
Single‐ and Multiple‐Dose Pharmacokinetics of Dezocine in Patients With Acute or Chronic Pain
Authors: Wilson John M. , Cohen Robert I. , Kezer Edward A. , Schange Stephen J. , Smith Emil R.
Published: March 2013

The pharmacokinetic properties of dezocine were examined in 15 patients with acute or chronic pain. In 3 groups of 5 patients each, serum levels were determined at various intervals after single intravenous doses of 5, 10, and 20 mg. After these single doses, dezocine was very rapidly distributed (mean t1/2α less than 2 minutes), and then rather rapidly eliminated (mean t1/2β about 4 hours); the apparent volume of distribution was large (mean Vzβ about 6 L/kg) as was the total clearance (mean CL about 1.5 L/h/kg). In 2 groups of 5 patients each, serum levels were determined after the first and third of 3 intravenous doses of 5 or 20 mg given at 3‐hour intervals. The pharmacokinetic parameters after these multiple doses were consistent with those after the single doses. Although some observations were suggestive, there was no unequivocal evidence that the pharmacokinetics were dose‐related. In 7 serum samples containing dezocine at concentrations ranging from 12.8 to 522 ng/mL, the mean (±SE) proportion of dezocine bound to protein was 91.6 ± 0.8%.
The Pharmacokinetics of Venlafaxine When Given in a Twice‐Daily Regimen
Authors: Troy Steven M. , Parker Vernon D. , Fruncillo Richard J. , Chiang Soong T.
Published: March 2013

The comparative bioavailability of the novel antidepressant venlafaxine and its pharmacologically active metabolite O‐desmethylvenlafaxine was assessed when venlafaxine was given orally twice daily (75 mg bid) or 3 times daily (50 mg tid). Eighteen healthy subjects participated in an open‐label, randomized, two‐period, crossover study lasting 12 days. Each subject was randomly assigned to take venlafaxine according to a bid or a tid regimen through day 8 and was crossed over to the other regimen on days 9 to 12. The daily dose was titrated up to 150 mg/d and was held constant on days 5 to 12. Plasma samples for quantitation of venlafaxine and O‐desmethylvenlafaxine were obtained during a 24‐hour steady‐state interval on days 8 and 12. Analysis of variance showed no significant differences between the two venlafaxine regimens for peak concentration (Cmax), area under the curve during 24 hours (AUC0–24), trough concentration, or fluctuation ratio for venlafaxine or O‐desmethylvenlafaxine in plasma. The bioequivalence ratios for Cmax and AUC0–24 of both compounds were calculated to compare the bid regimen and the tid regimen. The mean value for each of the 4 ratios was between 96 and 100%, and the 90% confidence limits around each ratio were within 90 to 110%. These results indicate that dividing a daily 150‐mg venlafaxine dose into 2 or 3 doses provides equivalent total exposure and peak plasma concentrations of venlafaxine and O‐desmethylvenlafaxine, its active metabolite. Therefore, based on pharmacokinetic considerations, it appears that the same daily dose of venlafaxine can be given in either two or three divided doses without compromising efficacy.
Pharmacokinetic and Pharmacodynamic Evaluation of the Potential Drug Interaction Between Venlafaxine and Diazepam
Authors: Troy Steven M. , Lucki Irwin , Peirgies Antoni A. , Parker Vernon D. , Klockowski Patricia M. , Chiang Soong T.
Published: March 2013

To assess possible pharmacokinetic and pharmacodynamic interactions between the antidepressant venlafaxine and diazepam, a randomized, two‐period, crossover study was conducted in 18 men. Multiple‐dose venlafaxine (50 mg every 8 hours) or placebo (double‐blind) was given for 10 days; on day 4 a single placebo dose (same appearance as diazepam capsule, single‐blind) was given; and on day 5 a single dose of diazepam (10 mg) was given. Pharmacokinetic data indicated that diazepam had no significant effect on venlafaxine or O‐desmethylvenlafaxine disposition. Diazepam pharmacokinetics were minimally changed in the presence of venlafaxine. Diazepam oral clearance (CL/f) increased slightly (24 ± 8 versus 26 ± 6 mL/h/kg; P = .007), volume of distribution (Vz/f) increased (0.85 ± 0.28 versus 0.99 ± 0.34 L/kg; P = .02), and AUC decreased (5973 ± 2304 versus 5008 ± 1354 ng • h/mL; P = .02). Venlafaxine did not alter desmethyldiazepam pharmacokinetics. Pharmacodynamic data showed a statistically significant diazepam—venlafaxine interaction for only one of the eight psychometric tests given. Critical flicker fusion slightly decreased (P = .01) between placebo—diazepam (37.85 ± 3.28 Hz) and venlafaxine—diazepam (37.09 ± 4.13 Hz) treatments. The observed pharmacokinetic and pharmacodynamic interactions between diazepam and venlafaxine were small and probably clinically insignificant.
Chronic Effect of Oral Mexiletine Administration on Left Ventricular Contractility in Patients with Congestive Heart Failure: A Study Based on Mitral Regurgitant Flow Velocity Measured by Continuous‐Wave Doppler Echocardiography
Authors: Morita Hisaki , Hirabayashi Koichi , Nozaki Shiro , Ohmori Koji , Yoshikawa Kei , Matsuo Hirohide
Published: March 2013

The long‐term effect of mexiletine on left ventricular (LV) contractility in patients with congestive heart failure is not clear. The authors therefore measured LV contractility before and after continuous oral administration of mexiletine in patients with congestive heart failure accompanied by mitral regurgitation (MR) using Doppler echocardiography. The study population consisted of 8 patients with congestive heart failure (6 due to dilated cardiomyopathy and 2 due to old myocardial infarction) accompanied by significant functional MR who had more than 1000 ventricular premature contractions (VPCs) per day or Class IV Lown classification arrhythmias before mexiletine administration. The LV contractility was evaluated by calculating a Doppler‐derived index, the rate of increase in LV pressure during the isovolumic contraction time (ICT ΔP/Δt), which has been confirmed to be nearly equal to LV Max dP/dt. The increase in LV pressure (ΔP) between 1 and 3 m/sec of the MR flow velocity as measured by continuous‐wave Doppler echocardiography was calculated using the simplified Bernoulli's equation, and ICT ΔP/Δt was derived by dividing ΔP by the time required for this change. The left ventricular ejection fraction and the left ventricular and left atrial dimensions also were measured by echocardiography. These parameters were obtained before and after 2 to 4 weeks of daily oral administration of mexiletine 300 mg. Values of ICT ΔP/Δt were 640 ± 202 mm Hg/sec and 650 ± 210 mm Hg/sec before and after mexiletine administration, respectively, showing no change. The left ventricular ejection fraction and the left ventricular and left atrial dimensions also were unchanged. These findings indicate that continuous oral administration of mexiletine has no effect on LV contractility in patients with congestive heart failure.
A Multicenter Comparison of Adverse Reaction Profiles of Isradipine and Enalapril at Equipotent Doses in Patients with Essential Hypertension
Authors: Johnson Brian F. , Eisner Gilbert M. , McMahon F. Gilbert , Jain Adesh K. , Rudd Peter , Sowers James R.
Published: March 2013

A multicenter, randomized, double‐blind trial compared the safety and efficacy of the dihydropyridine isradipine with the angiotensin‐converting enzyme (ACE) inhibitor enalapril given twice daily for mild hypertension. 160 patients received either isradipine (starting at 1.25 mg twice daily) or enalapril (starting at 2.5 mg twice daily) for 10 weeks. The dosage was increased if the average sitting diastolic blood pressure was > 90 mm Hg. Significantly greater mean reductions in systolic blood pressure were seen after 2, 6, and 8 weeks of isradipine. However, by the end of the trial, 83% of patients receiving isradipine and 78% receiving enalapril showed a decrease of at least 5 mm Hg in sitting diastolic blood pressure to a level below 96 mm Hg. Possible or probable drug‐related adverse effects were reported in 36% of patients showing a good antihypertensive response to isradipine, and in 30% of those who responded to enalapril. There was a trend for a lower frequency of adverse effects in isradipine non‐responders (25%) and a higher frequency in enalapril non‐responders (43%). Pruritus, dizziness, edema, and fatigue were reported more often with isradipine, and cough and changed bowel habits were more common with enalapril. The relationship between the pattern of adverse effects and the extent of blood pressure reduction may be dependent on the mechanism of action of a drug. In responders, isradipine and enalapril showed differing patterns, but a similar overall incidence of adverse effects.
Effect of Timing of Food on Absorption of Cefpodoxime Proxetil
Authors: Borin Marie T. , Driver Mary R. , Forbes Kristi K.
Published: March 2013

The effect of a high‐fat meal and the timing of this meal on the absorption of a 400‐mg oral dose of cefpodoxime proxetil was evaluated in 20 healthy, adult, male volunteers in a four‐way crossover study. The area under the plasma concentration‐time curve, peak plasma concentration, and urinary recovery were significantly greater (P = .0001) after administration of cefpodoxime proxetil tablets with and 2 hours after a meal relative to dosing under fasted conditions or 1 hour before a meal. The time to peak concentration did not differ significantly among treatments, which suggests that food did not affect the rate of drug absorption. These results indicate that absorption of cefpodoxime proxetil is enhanced when tablets are taken with food or shortly after a meal.
Lack of Effect of Tacrine Administration on the Anticoagulant Activity of Warfarin
Authors: Reece Phillip A. , Garnett William R. , Rock William L. , Taylor John R. , Underwood Barbara , Sedman Allen J. , Rajagopalan Rukmini
Published: March 2013

The effect of tacrine administration on prothrombin time was studied in 13 patients receiving prolonged warfarin therapy. After a 3‐week baseline period and 5 days of placebo administration, patients received 20 mg tacrine four times daily for 5 days. Prothrombin times were determined during baseline, daily before the morning doses of placebo and tacrine, and 14 days after the last tacrine dose (closeout). Mean (±SD) prothrombin times were 16.2 ± 2.8 seconds at baseline, 15.1 ± 2.6 seconds during the placebo phase, 15.8 ± 3.6 seconds during the tacrine phase, and 15.3 ± 3.6 seconds at closeout, indicating that tacrine has no effect on the anticoagulant activity of warfarin. Alteration of warfarin dosage should not be required in patients receiving concurrent tacrine therapy.
Helicobacter pylori and Gastrointestinal Disease
Authors: Gibaldi Milo
Published: March 2013

New paradigms are few and far between. The discovery that peptic ulcer disease is the result of an infection by a previously unrecognized microorganism rather than the consequence of excess secretion of gastric acid aptly qualifies as a paradigm shift. Eradication of Helicobacter pylori from the stomach by antibacterial agents heals ulcers at least as effectively as H2‐blockers. Further, eradication of the organism results in long‐term cures of peptic ulcers. In contrast, the relapse rate in patients succesfully treated with H2‐blockers exceeds 50% in the first year after healing. Also of interest is the role of H. pylori in gastric cancer.
Steady‐State Pharmacokinetic Evaluation of a Novel, Controlled‐Release Morphine Suppository and Subcutaneous Morphine in Cancer Pain
Authors: Bruera Eduardo , Fainsinger Robin , Spachynski Kathy , Babul Najib , Harsanyi Zoltan , Darke Andrew C.
Published: March 2013

Although the oral route is the preferred method for morphine administration for cancer pain, many patients will require an alternate route of administration at some point during their illness. The authors studied the steady‐state pharmacokinetics of morphine after administration of a novel, controlled‐release suppository (MS‐CRS) and subcutaneous morphine in a randomized, double‐blind, two‐way crossover evaluation in 10 patients with cancer pain. When administered at a 2.5:1 analgesic ratio, MS‐CRS given every 12 hours showed an equivalent extent of absorption compared with subcutaneous morphine given every 4 hours (AUC0–12, 132.5 ± 30.1 versus 123.8 ± 27.3 ng•h•mL−1, P = not significant [NS]). Peak morphine concentrations were lower, time of peak was later, and percent fluctuation less after MS‐CRS than after subcutaneous morphine (Cmax, 14.7 ± 2.9 versus 29.9 ± 5.4 ng/mL, P = .0110; tmax, 3.33 ± 0.75 versus 2.22 ± 0.15 hours, P = .0160; fluctuation, 122 ± 71 versus 356 ± 123%, P = .00160). Relative bioavailability of MS‐CRS using the 2.5:1 analgesic ratio was 105%, and bioavailability from data dose normalized without regard to route specificity in metabolism was 42%. For both routes of administration there was a significant linear relationship between morphine dose and AUC (MS‐CRS, r = .8568, P = .0032; subcutaneous morphine, r = .8314, P = .0055). MS‐CRS morphine provides a pharmacokinetic profile consistent with dosing every 12 hours; at steady state, the extent of absorption is comparable with that of subcutaneous morphine when administered at a 2.5:1 dose ratio. MS‐CRS represents a reliable, noninvasive alternative method of morphine administration for patients unable to take oral morphine.
A Double‐Blind, Placebo‐Controlled, Dose‐Ranging Safety Evaluation of Single‐Dose Intravenous Dolasetron in Healthy Male Volunteers
Authors: Hunt Thomas L. , Cramer Michael , Shah Ajit , Stewart William , Benedict Claude R. , Hahne William F.
Published: March 2013

The safety and tolerability of dolasetron mesylate, a potent and selective 5‐HT3 receptor antagonist, were evaluated after single intravenous doses in healthy male volunteers. In this double‐blind, placebo‐controlled, randomized, phase I study, 80 subjects received either placebo or dolasetron in escalating doses (0.6 to 5.0 mg/k). Subjects were monitored for adverse events, vital sign and laboratory alterations, and changes in electrocardiographic (ECG) intervals and electroencephalographs (EEG) patterns. Overall, the percentage of subjects reporting adverse events was similar in those receiving dolasetron (44/64; 68.8%) or placebo (10/16; 62.5%); most adverse events were mild in severity. Subjects receiving dolasetron reported a higher incidence of central nervous system (headache and dizziness/lightheadedness), gastrointestinal (increased appetite and nausea), and visual adverse events and taste alterations. No clinically significant changes in laboratory variables were observed. Transient and asymptomatic ECG changes (small mean increases in PR interval and QRS complex duration versus baseline) were noted in several subjects at 1 to 2 hours after infusion at doses ≥ 3.0 mg/kg. Transient, mild blood pressure decreases were observed in five subjects, including one on placebo. Dolasetron mesylate was well tolerated in single intravenous doses up to 5.0 mg/kg in healthy male volunteers. Clinical studies of the drug are ongoing for antiemetic indications.
Oral and Intravenous Zidovudine Pharmacokinetics: The Effect of Granulocyte‐Macrophage Colony Stimulating Factor
Authors: Aweeka Francesca T. , Mak May , Al‐Uzri Amira , Peter Katrin , Dett Carmen , Franco Jose , Affrime Melton , Guerciolini Roberto , Cutler David L. , Kahn James , Gambertoglio John G.
Published: March 2013

Combination therapy with zidovudine and recombinant human granulocyte‐macrophage colony stimulating factor (rHu GM‐CSF) may be warranted, owing to the bone marrow suppressive effects of zidovudine. A study of 16 patients, 8 of whom had acquired immune deficiency syndrome (AIDS) and 8 of whom were infected with human immunodeficiency virus (HIV) but were asymptomatic, was conducted. The effect of 4 days of rHU GM‐CSF versus placebo on intermittent zidovudine therapy (200 mg every 8 hours) was evaluated using a randomized, cross‐over study design. Pharmacokinetics of oral and intravenous zidovudine were determined on days 1 (oral), 3 (oral), and 4 (intravenous) of rHu‐GM‐CSF (placebo) administration. After intravenous dosing, zidovudine plasma clearance for placebo and rHu GM‐CSF averaged 1.4 ± 0.2 and 1.3 ± 0.2 L/hr/kg, respectively (P = 0.017), mean residence time averaged 1.5 ± 0.5 and 1.9 ± 0.6 hours, respectively (P = 0.012), and the steady‐state volume of distribution was 2.0 ± 0.7 and 2.3 ± 0.7 L/kg, respectively (P = 0.027) for the two treatment arms. Stratified data for patients with AIDS and those with asymptomatic HIV infection revealed no significant difference in plasma clearance or mean residence time between the two patient groups. These pharmacokinetic results indicate that dosage adjustments for zidovudine are not warranted when administered with rHu GM‐CSF owing to the small changes observed. However, the statistically significant increase in Vss suggests the possibility of enhanced zidovudine cellular uptake in the presence of rHu GM‐CSF.
Steady‐State Pharmacokinetics of Hydromorphone and Hydromorphone‐3‐Glucuronide in Cancer Patients After Immediate and Controlled‐Release Hydromorphone
Authors: Hagen Neil , Thirlwell Michael P. , Dhaliwal H. S. , Babul Najib , Harsanyi Zoltan , Darke Andrew C.
Published: March 2013

Although the pharmacokinetics of oral hydromorphone has been evaluated in healthy volunteers after small single oral doses, data are not available regarding the disposition of hydromorphone and its principal metabolite, hydromorphone‐3‐glucuronide (H3G), at steady‐state and after large oral doses. The authors studied the pharmacokinetics of hydromorphone and H3G after oral administration of an immediate‐release (IR) and controlled‐release (CR) formulation of hydromorphone at a daily dose of 48 ± 11 mg (range 6–216 mg) in a randomized, double‐blind, steady‐state, two‐way crossover evaluation in 18 patients with chronic cancer pain. Controlled‐release hydromorphone demonstrated equivalent bioavailability and acceptable CR characteristics, when compared with IR hydromorphone (CR vs. IR: AUC0–12 123.10 ± 20.38 vs. 118.98 ± 20.92 ng · hr · mL−1, P = NS, Cmax 17.76 ± 3.07 vs. 19.70 ± 4.04 ng · mL−1, P = N.S., Cmin 6.04 ± 1.01 vs. 5.28 ± 1.00 ng · mL−1, P = NS, and Tmax 4.78 ± 0.78 vs. 1.47 ± 0.22 hr, P = 0.0008). A significant linear relationship existed between hydromorphone dose and hydromorphone AUC (r = 0.8315, P = 0.0001) and between hydromorphone AUC and H3G AUC (r = 0.8048, P = 0.0001) over a wide dose range. The steady‐state molar ratio of H3G to hydromorphone was 27:1. The authors conclude that CR hydromorphone provides a pharmacokinetic profile consistent with 12 hourly dosing and that at steady state, oral hydromorphone is extensively metabolized to H3G, although the pharmacologic activity of this metabolite remains unknown.
Efficacious Response with Lower Dose Indapamide Therapy in the Treatment of Elderly Patients with Mild to Moderate Hypertension
Authors: Weidler Donald , Jallad Nader S. , Curry Charles , Ferdinand Keith , Jain Adesh K. , Schnaper Harold W. , Toth Phillip D. , Codispoti Joseph , Stokes Arthur , McNally Charles
Published: March 2013

A low dose (1.25 mg) of indapamide (Lozol®, Rhône‐Poulenc Rorer Pharmaceuticals, Collegeville, PA) was evaluated in 222 elderly patients (≥50 years) with mild to moderate essential hypertension in a multicenter, randomized, double‐blind, parallel‐group clinical trial. A 4‐week single‐blind placebo washout period was followed by an 8‐week double‐blind treatment period. Patients were randomized to receive indapamide 1.25 mg/day or to receive placebo. The primary efficacy variable was the mean change in sitting diastolic blood pressure from baseline to week 8. Eighty‐one patients in the indapamide group (73%) and 87 patients in the placebo group (78%) completed the 8 weeks of double‐blind therapy. Therapy with 1.25 mg of indapamide produced greater reductions compared with placebo in sitting diastolic blood pressure after 8 weeks of therapy, with statistical significance (P ≤ 0.0015) seen after only 2 weeks of therapy and continuing throughout the 8 weeks. All secondary efficacy measures (sitting systolic blood pressure, standing systolic and diastolic blood pressures, and ≥ 10 mm Hg decrease or final value of ≤ 90 mm Hg in sitting diastolic blood pressure) also showed superior (P ≤ 0.0014) improvement in the indapamide group compared with placebo after 8 weeks of double‐blind treatment. During the 8‐week double‐blind treatment period, incidence rates for all adverse events and for drug‐related adverse events were similar between the two treatment groups. Among patients who received indapamide, the only drug‐related adverse events that occurred with an incidence of ≥ 2% were headache (4%), dizziness (4%), asthenia (2%), pain (2%), abnormal vision (2%), and impotence (2%). Similar incidence rates for these adverse events were seen in the placebo group. Among indapamide patients, mean changes in potassium (–0.27 mEq/L), uric acid (0.76 mg/dL), and BUN (1.42 mg/dL) were noted but not clinically significant.
Continuous Versus Intermittent Subcutaneous Infusion of Octreotide in the Treatment of Acromegaly
Authors: Harris Alan G. , Kokoris Sam P. , Ezzat Shereen
Published: March 2013

This review evaluates the efficacy, tolerability, and safety of continuous subcutaneous infusion (CSI) relative to intermittent subcutaneous injection (ISI) of the somatostatin analog, octreotide in the treatment of acromegaly. Data was extracted from five clinical series using CSI octreotide in acromegaly, six reports comparing CSI to ISI, and three studies comparing pulsatile subcutaneous infusion (PSI) to ISI. Effects of each drug regimen on the control of growth hormone (GH), insulin‐like growth factor (IGF‐1), clinical symptomatology, pituitary tumor size, and adverse effects were evaluated. Normalization of serum GH or IGF‐1 levels, as well as improvement in clinical symptoms was reported in the majority of the patients studied. Cases in which pituitary adenomas decreased in size were also documented during the study period. When the effects of CSI were compared with ISI, a more pronounced control of GH and IGF‐1 was observed. In addition, diurnal GH fluctuation during CSI was significantly reduced relative to ISI in two reports. Moreover, in two patients, CSI achieved similar clinical and biochemical effects at lower doses than when the drug was given by ISI. Finally, adverse effects with CSI may be less severe than with ISI. Continuous subcutaneous infusion of octreotide produced biochemical improvement in 67 of the 88 patients reviewed. When compared with ISI, CSI induced more pronounced biochemical control, often with less fluctuation in GH and IGF‐1 levels. Because of a lack of data, definite conclusions regarding the differences between regimens on clinical symptomatology and tolerability could not be discerned. A large prospective, long‐term randomized crossover study is recommended to make these determinations.
Hypertension in Diabetic Patients: An Update of Interventional Studies to Preserve Renal Function
Authors: Hoelscher David D. , Weir Matthew R. , Bakris George L.
Published: March 2013

Hypertension and diabetes mellitus are a malignant combination of diseases for the kidney. They markedly increase the risk for progressive renal injury and are the largest single cause of renal failure. Strategies to reduce the risk for renal injury in hypertensive diabetics are very important. Although Type I and Type II diabetes are different diseases, they may be associated with similar mechanisms of renal injury in hypertensive patients. Reduction of elevated systemic arterial pressure is of proven benefit in limiting progressive renal injury in diabetic hypertensives. However, converting enzyme inhibitors and possibly the nondihydropyridine calcium antagonists may possess antiproteinuric abilities independent of blood pressure reduction which, in addition to their antihypertensive effects, may be important in limiting the progression of human diabetic renal disease. Long‐term clinical trials have evaluated the impact of these and other agents on progression of diabetic renal disease. This paper reviews these trials and focuses on renal effects of antihypertensive agents independent of blood pressure reduction.
Selected Aspects of ACE Inhibitor Therapy for Patients with Renal Disease: Impact on Proteinuria, Lipids and Potassium
Authors: Keilani Taha , Schlueter William , Batlle Daniel
Published: March 2013

Overt proteinuria is often accompanied by hypercholesterolemia and is associated with increased lipoprotein(a) levels. These lipid abnormalities are probably involved in the high incidence of macrovascular complications associated with diabetic nephropathy and possibly other kinds of non‐diabetic proteinuric renal disease. Over the last decade many studies have shown that ACE inhibitors can reduce urinary protein excretion but little attention was paid to the impact of this form of therapeutic intervention on the lipid profile. In this article we review our recent data showing that fosinopril administration was associated with significant decreases in both urinary protein excretion, serum total cholesterol levels, and plasma lp(a) levels. The use of ACE inhibitors in patients with renal impairment can result in the development of hyperkalemia as a result of suppression of angiotensin II‐driven aldosterone secretion by the adrenal gland. Inhibition of aldosterone secretion may depend on the degree of inhibition of angiotensin II formation in the circulation and also locally in the adrenal gland. Because the various ACE inhibitors exhibit different degrees of ACE inhibition at the tissue level, we have postulated that angiotensin II‐dependent aldosterone production will be inhibited to a lesser degree by agents that have low tissue affinity for the adrenal gland. The implication of this theoretical concept for the development of hyperkalemia in patients with impaired renal function treated with ACE inhibitors is discussed.
Intra‐ and Interethnic Variability in Reduced Haloperidol to Haloperidol Ratios
Authors: Lam Y. W. Francis , Jann Michael W. , Chang Wen‐Ho , Yu Hing‐Sing , Lin Shih‐Ku , Chen Horng , Davis Chester M.
Published: March 2013

Steady‐state haloperidol and reduced haloperidol concentrations were measured in 250 schizophrenic patients from 4 ethnic groups: 39 Blacks, 66 Caucasians, 82 Chinese, and 63 Mexican Americans. The distribution of the reduced haloperidol to haloperidol concentration (RH/HL) ratios was bimodal in all ethnic groups, with the antimode determined by probit plot as 0.46, 0.51, 0.36, and 0.76, respectively. With these antimodes, the proportion of patients with low RH/HL ratios were 41%, 42%, 73%, and 57% in the four ethnic groups, respectively. Compared with the other three ethnic groups, in the Chinese patients the ratio was lower. The mean RH/HL ratio in the Chinese was 0.34 compared with 0.81 to 0.87 in the non‐Chinese groups. In 53 patients who were treated with two or more haloperidol dosage regimens, steady‐state haloperidol and reduced haloperidol drug concentrations obtained from the different regimens were positively correlated with the haloperidol dose (R = .79 and R = .62, respectively). Our data suggest not only the existence of a bimodal distribution in the RH/HL ratio, but also that the antimode separating the low and high ratio subgroups is different among the various ethnic groups.
Dose‐Ranging Study of a New, Once‐Daily Diltiazem Formulation for Patients with Stable Angina
Authors: Cutler Neal R. , Eff Jack , Fromell Gregg , Brass Eric P. , Archer Stephen , Chrysant Steven G. , Fiddes Robert
Published: March 2013

A double‐blind safety and efficacy dose‐ranging study was conducted with a new, once‐daily, extended‐release (XR) diltiazem hydrochloride formulation (Dilacor XR®, Rhǒne‐Poulenc Rorer, Collegeville, PA) in 189 patients with chronic stable angina pectoris. After a 2‐week placebo lead‐in phase, the patients were randomly assigned to 1 of 4 once‐daily, fixed‐dose treatment groups: placebo, XR diltiazem 120 mg, 240 mg, or 480 mg. Extended‐release diltiazem, at 240‐mg and 480‐mg once‐daily doses, significantly improved (P < .05) total exercise time during treadmill exercise tolerance testing after 2 weeks of treatment when assessed 24 hours after the previous dose. These increasing doses of XR diltiazem were associated with incremental improvements in exercise tolerance. Outpatient function, as assessed by frequency of anginal attacks, nitroglycerin use, and ambulatory electrocardiogram (Holter, Scole Engineering Culver City, CA) monitoring of ischemic events, was also improved by XR diltiazem. This extended‐release diltiazem formulation can be clinically titrated within the 120‐ to 480‐mg dosing range, permitting effective once‐daily administration for treating chronic stable angina.
Experience‐Based Teaching of Therapeutics and Clinical Pharmacology of Antiepileptic Drugs. Sudden Unexplained Death in Epilepsy: Do Antiepileptic Drugs Have a Role?
Authors: Lathers Claire M. , Schraeder Paul L.
Published: March 2013

The contents of this paper have been written to be used in a teaching program specifically designed for medical postgraduate education of resident physicians and fellows in training interested in the clinical pharmacology of antiepileptic drugs and their role in the treatment of epilepsy and/or in the prevention of sudden unexpected death associated with this disease. With some modifications, such as a specific lecture to provide an overview of the numerous concepts presented in the text, the article could be used when teaching fourth‐year medical students. The format of the paper is a combination of didactic review and eight case reports in a self‐learning format. A quiz for self‐assessment is included at the end of the article (see Appendix). This material was covered in part in the 1992 Board Review Course for Clinical Pharmacology sponsored by the American College of Clinical Pharmacology.

The format or setting of instruction for this material could include small learning groups composed of 10 to 15 students. When used in combination with other topics prepared in similar formats, this could become a take home course for those preparing to take the Boards in Clinical Pharmacology. Each instructor could select specific publications from the reference list for assigned readings depending upon the material emphasized by the instructor. The questions included at the end of the text could be used as either a closed or an open book quiz to assess student learning.
Is Quinine Effective and Safe in Leg Cramps?
Authors: Mandal Anil K. , Abernathy Teresa , Nelluri Satya N. , Stitzel Vincent
Published: March 2013

Muscle cramp is a recurrent and painful condition and a common complaint among elderly subjects and patients treated with hemodialysis. It is commonly nocturnal and can disturb a good night's sleep. No specific cause can be identified; therefore, therapy is mostly symptomatic. Quinine sulfate, an antimalarial drug, is widely used as an effective therapy for idiopathic leg cramps. Several double‐blind, randomized, placebo‐controlled studies have questioned the effectiveness of quinine in leg cramps; whereas other studies have shown significantly more benefit with use of quinine in reducing the frequency and severity of cramps compared with placebo or vitamin E. The mechanism of this beneficial effect is obscure, however. Quinine appears to decrease the excitability of the motor end plate, thereby reducing the muscle contractility. Most patients consider quinine beneficial for their leg cramps, which is difficult to refute by scientific data. More important, cramp is a subjective symptom, therefore difficult to measure objectively. Consequently, scientific studies designed to prove or disprove the effectiveness of quinine can be subject to flaws. Further, a dosage of 200 to 300 mg of quinine every night has not been shown to cause significant side effects. Nevertheless, quinine should be used in a small dose and cautiously, especially in the elderly and patients with renal failure, and should be avoided in patients with liver disease.
The Effect of Lovastatin on Early Restenosis
Authors: Beigel Y. , Zafrir N. , Teplitzky Y. , Neuman Y. , Gavish D. , Wurzel M. , Fainaru M.
Published: March 2013

The effect of lovastatin given before percutaneous coronary angioplasty (PTCA) on early restenosis was investigated in men with mild to moderate hypercholesterolemia. Thirty‐four hypercholesterolemia patients (serum LDL cholesterol 130–200 mg/dL) undergoing their first PTCA completed a 6‐month prospective, double‐blind, placebo‐controlled trial. Eighteen received lovastatin 20 mg/day (Lo group) and 16 placebo (P1 group), beginning 10 to 21 days before PTCA. All underwent a thallium‐201 quantitative exercise test 5 to 7 days after PTCA. Endpoints for restenosis were either 50% narrowing of the dilated artery on coronary angiography, performed in symptomatic patients or, in asymptomatic patients, the appearance of newly developed reversible filing defects in the vascular territory of the dilated artery on a second thallium scan done 6 months after PTCA. The hypocholesterolemic change observed in the Lo group was not accompanied by a reduction in early restenosis risk. The authors conclude that effective hypocholesterolemic therapy before PTCA does not affect early restenosis rate in men with mild to moderate hypercholesterolemia.
A Randomized, Double‐Blind, Placebo‐Controlled, Dose‐Response Study of the Analgesic Effect of Lornoxicam After Surgical Removal of Mandibular Third Molars
Authors: Nørholt Sven E. , Sindet‐Pedersen Steen , Bugge Christine , Branebjerg Poul E. , Ersbøll Bjarne K. , Bastian Henning L.
Published: March 2013

The aim of the present study was to investigate the dose‐effect relationship of single doses of 4 to 32 mg of lornoxicam (LNX), a new nonsteroidal antiinflammatory drug belonging to the oxicam group, compared with placebo and 10 mg ketorolac (KET) in the treatment of pain after oral surgery. Also, it was the aim of the study to evaluate the relationship between adverse events and different doses of LNX.

After the surgical removal of a mandibular third molar, test medication was taken when the patients experienced at least moderate pain. After medication, pain relief, pain intensity, and any discomfort from the medication were noted in a questionnaire. Paracetamol was used as rescue medication.

A total of 278 patients completed the study according to the protocol. The primary efficacy parameter was total pain relief after 6 hours, and all active treatments showed significantly better effect than placebo, with LNX 16 and 32 mg being significantly superior to LNX 4 mg. All other efficacy parameters showed the same dose‐effect relationship.

A total of 37 adverse events were reported evenly distributed in the 6 treatment groups; only 3 of these were considered severe, and all disappeared without treatment.

In conclusion, the study showed a dose‐effect relationship of LNX without a rise in adverse events. The effect of 10 mg KET seemed to be at the level of 8 to 16 mg LNX.
Doxorubicin Encapsulated in Liposomes Containing Surface‐Bound Polyethylene Glycol: Pharmacokinetics, Tumor Localization, and Safety in Patients with AIDS‐Related Kaposi's Sarcoma
Authors: Northfelt Donald W. , Martin Francis J. , Working Peter , Volberding Paul A. , Russell Julie , Newman Mary , Amantea Michael A. , Kaplan Lawrence D.
Published: March 2013

A study of the plasma pharmacokinetics, tumor localization, and safety of a single dose of doxorubicin encapsulated in liposomes containing surface‐bound polyethylene glycol (PEG‐liposomal doxorubicin) was conducted in patients with Kaposi's sarcoma (KS) as a manifestation of acquired immune deficiency syndrome (AIDS). Eighteen patients with AIDS‐KS diagnosed by examination of biopsy specimens were randomly assigned to receive either standard doxorubicin or PEG‐liposomal doxorubicin. Consecutive participants were entered at three dose levels (10, 20, and 40 mg/m2) in ascending fashion. Clearance of PEG‐liposomal doxorubicin was 0.034 L/h/m2 to 0.108 L/h/m2, volume of distribution (Vd) was 2.2 L/m2 to 4.4 L/m2, and half‐lives (t1/2) of the initial decline in the plasma concentration—time curve and of the terminal decline were 3.77 hours and 41.3 hours, respectively. Seventy‐two hours after administration, doxorubicin levels observed in lesions of patients receiving PEG‐liposomal doxorubicin were 5.2 to 11.4 times greater than those found in patients given comparable doses of standard doxorubicin. PEG‐liposomal doxorubicin and standard doxorubicin were roughly equipotent in producing toxicity. Encapsulation in liposomes containing surface‐bound PEG significantly limits the distribution and elimination of doxorubicin, results in greater accumulation of the drug in KS lesions 72 hours after dosing than does standard doxorubicin, and may improve drug efficacy and therapeutic index in the treatment of AIDS‐KS.