bluuebunny/crossref_metadata_2025 huggingface dataset:
Alteration of Pentoxifylline Pharmacokinetics by Cimetidine
Authors: Mauro Vincent F. , Mauro Laurie S. , Hageman John H.
Published: March 2013

Pentoxifylline, recently approved for the treatment of intermittent claudication, is hepatically cleared with a high degree of first‐pass metabolism. Subsequently, the effect of cimetidine on pentoxifylline pharmacokinetics was studied in humans. Ten healthy subjects received, in random cross‐over fashion, pentoxifylline 400 mg as a controlled‐release tablet every 8 hours with and without cimetidine 300 mg four times a day for 7 days. Pentoxifylline and metabolite plasma concentrations over one dosing interval were measured on day 7 of each phase. The unavailability of an immediate‐release pentoxifylline dosage form prevented a single dose trial. Cimetidine significantly increased (P < .05) pentoxifylline area under the curve at steady state 26.2% from 675 ± 97 (mean ± SEM) to 852 ±108 ng. hr/mL. The average steady‐state plasma concentration increased 27.4% from 84 ± 12 to 107 ± 14 ng/mL (P < .05). Apparent oral clearance decreased 21.5% from 1309 ± 304 to 1027 ± 244 mL/min (P < .02). Significant alterations in pentoxifylline metabolite concentrations were also observed. The results of this trial suggest cimetidine elevates pentoxifylline plasma concentrations, presumably by decreasing apparent oral clearance, although a reduction in total body clearance or an increase in gastric absorption could not be ruled out.
BOOK REVIEWS
Authors: Cavaliere M. Beth
Published: March 2013

Book reviewed in this article:

Mild Hypertension: From Drug Trials to Practice Edited by T. Strasser and D. Ganten

The Role of Pharmacology in Pediatric Oncology Edited by D. G. Poplack, L. Maseimo, and P. Cornaglia‐Ferraris

The Cytoskeleton: A Target for Toxic Agents Edited by T. W. Clarkson, P. R. Sager, and T. L. M. Syverson

Amyotrophic Lateral Sclerosis: Therapeutic, Psychological and Research Aspects Edited by V. Cosi, A. C. Kato, W. Parletti
The Absorption and Disposition of Enoxacin in Healthy Subjects
Authors: Somogyi Andrew A. , Bochner Felix
Published: March 2013

Enoxacin is a new orally active, synthetic broad‐spectrum antibacterial drug of the fluorinated quinolone class. The pharmacokinetics and renal handling of this drug have not been thoroughly investigated, in particular, with specific analytical methodology. Sixteen healthy, young subjects received a single 400‐mg oral dose of enoxacin after an overnight fast and multiple blood samples and all urine were collected for 33 hours. Enoxacin in plasma and urine and oxo‐enoxacin in urine were determined by a high‐performance liquid chromatographic method. Enoxacin was absorbed rapidly, with tmax values ranging from 0.5 to 2.5 hours. The variability in the AUC values of 35% was reduced to 23% when variations in body weight were taken into consideration. The terminal half‐life ranged from 4.2 to 6.8 hours and the unbound fraction in plasma was 0.33 ± 0.07. In urine, 44 ± 9% of the dose was recovered as unchanged enoxacin and 5.4 ± 3.9% as oxo‐enoxacin; there was no evidence of conjugates of enoxacin in urine. Renal clearance of enoxacin was 230 ± 92 mL/min, with 17 ± 8% of this being due to glomerular filtration and 83 ± 8% being due to tubular secretion. These data indicate that the major potential drug interactions affecting enoxacin disposition are likely with drugs competing for renal proximal tubular secretion and hepatic elimination. These conclusions regarding enoxacin are likely to be applicable to the fluorinated quinolones in general.
Pharmacokinetic Profile of OPC‐8212 in Humans: A New, Nonglycosidic, Inotropic Agent
Authors: Ohnishi Akihiro , Ishizaki Takashi
Published: March 2013

OPC‐8212, a new inotropic agent, was administered orally as a single 7.5‐, 15‐, 30‐, 60‐, 120‐, or 240‐mg dose in a sequentially ascending order to 21 male healthy volunteers to determine the pharmacokinetic profile. Each volunteer received one of the six doses after an overnight fast. After the single‐dose study was completed and the safety and tolera‐bility were ascertained, 3 of the 21 volunteers participated in a 15‐day repeated‐dose (30 mg once daily) study to determine the steady‐state kinetic profile. The AUC0‐∞ and Cmax values were proportional to doses (mg or mg/kg, P <.001). The mean elimination t1/2, apparent oral clearance (CL/FJ and percentage fraction of dose excreted unchanged in urine up to 336 hours postdose (fe0–336) appeared to be comparable among the six single doses examined. The overall mean (±SEM) kinetic parameters obtained from the 21 subjects were: 44.7 ± 1.2 hours for t1/2, 0.284 ± 0.018 L/hv or 4.49 ± 0.28 mL/hr/kg for CL/F, and 17.7 ± 0.9% for fe0–336. A steady state of the drug appeared to be attained by about day 9 after the initiation of the repeated dosing: the mean postdose 2‐ and 24‐hour plasma drug concentrations observed during days 9 to 15 ranged from 6.3 ± 0.5 μg/ig/mL to 6.9 ± 0.6 fig/ml and from 3.6 ± 0.7 μg/mL to 4.0 ± 0.6 μg/mL, respectively. The mean fraction of the daily dose excreted unchanged in urine over the dosing interval (fe0‐r) during days 9 to 15 ranged from 19.2 ± 1.4% to 25.6 ± 0.6%. The mean elimination t1/2 and CL/F observed after the final dose were comparable not only to the overall mean but also to that from the same 30 mg in the single‐dose study. The results suggest that the elimination of OPC‐8212 is dose independent and the plasma concentrations attained are proportional to doses. The drug appears neither to inhibit nor to induce its own metabolism during the repeated doses. This new, nonglycosidic, inotropic agent may be given on a once‐daily basis (like digoxin) to treat patients with congestive heart failure.
Red Blood Cell Sorbitol Lowering Effects and Tolerance of Single Doses of AL 1576 (HOE 843) in Diabetic Patients
Authors: Averbuch Mordechai , Weintraub Michael , Liao J. C. , Brazzell R. Kim , Dobbs Richard E.
Published: March 2013

The safety and biochemical effects of AL 1576 (HOE 483), a recently developed aldose reductase inhibitor, were evaluated. In a double‐blind, placebo‐controlled, clinical trial, AL 1576 (HOE 483) was administered to diabetic patients for the first time. Four single, orally administered dose levels were tested, (2, 5,10, and 20 mg). No clinically important adverse effects were seen in any of the patients. AL 1576 (HOE 433) suppressed red blood cell (RBC) sorbitol concentrations in a dose‐related fashion. Also found were statistically significant inverse correlations between the plasma drug concentration and both RBC sorbitol concentrations as well as RBC sorbitol/serum glucose ratios. In single doses up to 20 mg, AL 1576 (HOE 433) is well tolerated and decreases BBC sorbitol, a biochemical marker of pharmacologic activity, in diabetic patients.
Drug Regulation in South Africa
Authors: Folb P. I. , Haus M. , Schlebusch J.
Published: March 2013

South Africa has a population of approximately 30 million people. The country has a mixture of advanced industrial and rural economies, but the medicine control system is consistent with similar systems established in the major industrial countries of Western Europe and North America. Because most of South Africa's population lives in conditions more closely akin to the developing world than to the Western nations, it is important to examine whether the country is optimally served by this drug regulation model and to define critically the strengths and limitations of the established system. The conclusions might be relevant for other countries at a comparable stage of development.
The Effect of Encapsulated, Low‐Dose Colestipol in Patients with Hyperlipidemia
Authors: Linet Otto I. , Grzegorczyk Cynthia R. , Demke Donald M.
Published: March 2013

Colestipol is an effective cholesterol (C)‐loivering agent, but it must be taken in large doses and the palatability is poor. In an open‐label study, the effects of low doses (2–10 g) of encapsulated colestipol (size: 1 g or 0.65 g) were investigated. There were 16 men and 16 women with an average age of 59 ± 11 years and with hyperlipidemias IIA, IIB, or IV. Patients were on AHA I diet and stayed in the study for up to 2 years with regular follow‐up every 3 to 4 months. Colestipol was started after several months of dietary baseline; it was tolerated well with only two patients reporting mild constipation. A group mean for total cholesterol (T‐C), LDL‐C, HDL‐C, VLDL‐C and triglycerides (TG) was calculated at each of four daily dose intervals, i.e., 2 to 4 g, 4 to 6 g, 6 to 8 g and 8 to 10 g. Each patient usually received more than one of the four dosage intervals. A paired t test and a rank sum test were performed to test for significant (P ≤ .05) differences between baseline and drug treatment. With the exception of the lowest dose, total C was significantly decreased by all dosage ranges and LDL‐C changes were similar. There was no significant effect on HDL‐C and VLDL‐C whereas TG levels increased at 4 to 6 g and 8 to 10 g dose. The use of diet and low colestipol doses may be considered in patients with moderate hypercholesterolemia who do not respond to diet alone.
Pharmacokinetics of Iothalamate in Endstage Renal Disease
Authors: Evans J. Robert , Cutler Ralph E. , Forland Steven C.
Published: March 2013

Some nephrologists make alterations in routine peritoneal and hemodialysis schedules after diagnostic studies that use radiographic contrast agents. A study to determine the pharmacokinetics of one contrast agent, iothalamate, is reported. The plasma (total body) clearance of iothalamate was measured in seven patients who had endstage renal disease (ESRD) and who received maintenance hemodialysis. During an interdialytic period, plasma clearance of iothalamate varied from 0.7 to 5.2 mL/min (3.1 ± 1.8 mL/min, mean ± SD) with an elimination rate constant (beta) of 0.0164 ± 0.01 hr−1, a terminal half‐life of 61 ± 42 hours, and an estimated distribution volume of 11 ± 3.9 L. Hemodialysis clearance of iothalamate was 104 ± 54 mL/min. With the assumption that iothalamate is mainly distributed in the extracellular fluid (ECF) compartment, the theoretical fluid shift from the intracellular fluid (ICF) compartment to the ECF compartment was 323 mL after administration of the largest dose (2.1 mL/kg or 1.6 mmol/kg of body weight) of 60% meglumine iothalamate solution. The average maximum serum osmolarity change was less than expected, suggesting some type of internal buffering of meglumine iothalamate. In the first few hours after radiocontrast administration in four patients, the average change in serum osmolarity was 5 mmol/L; the average change in serum sodium concentration during this same time was a decrease of 0.5 mmol/L. The minor increase in ECF volume induced by hyperosmolar contrast agents does not require immediate dialysis in most patients. When needed, however, for contrast‐related adverse effects, hemodialysis is efficient in rapidly removing iothalamate.
Effects of Food on the Bioavailability of CGS 16617, an Angiotensin‐Converting Enzyme Inhibitor, in Healthy Subjects
Authors: Choi R. Leslie , Kochak Gregory M. , Reydel‐Bax Patricia , Nelson Edward B.
Published: March 2013

CGS 16617, a direct‐acting angiotensin‐converting‐enzyme inhibitor, was administered as a single dose of 20 mg in aqueous solution to 12 healthy male volunteers on two occasions in a randomized, cross‐over design study. On one occasion, the dose was administered after an overnight fast; on the other occasion, it was administered after subjects ate a standard breakfast. Administration of CGS 16617 after food was associated with statistically significant decreases in peak plasma concentrations (58%) and areas under the plasma concentration‐time curves (23%) compared with drug administration in the fasted state. Also, the time to peak plasma concentration was increased (57%) in a statistically significant manner when CGS 16617 was administered after food. Thus, the ingestion of food decreased both the rate and extent of absorption of this drug, but the mechanism of the interaction is unknown at present.
Desmethyldiazepam Pharmacokinetics: Studies Following Intravenous and Oral Desmethyldiazepam, Oral Clorazepate, and Intravenous Diazepam
Authors: Greenblatt David J. , Divoll Marcia K. , Soong May H. , Boxenbaum Harold G. , Harmatz Jerold S. , Shader Richard I.
Published: March 2013

After single 10‐mg intravenous (IV) doses of desmethyldiazepam (DMDZ) to 12 healthy human volunteers, (mean age, 62 years) blood samples were obtained over the next 14 or more days. Mean kinetic variables were volume of distribution (Vd), 90 liters; elimination half‐life (t1/2), 93 hours; and clearance, 12.3 mL/min. Vd was significantly correlated with body weight (r = .73, P <.01) and with percent ideal body weight (r = .91, P <.001). Eleven of the same subjects also received 5‐ to 15‐mg doses of IV diazepam (DZ). Mean kinetic variables were Vd, 180 liters; t1/2, 83 hours; and clearance, 28 mL/min. Clearances of DZ and DMDZ were significantly correlated (r = .73, P <.02). Based on area analysis, the extent of conversion of DZ to systemic DMDZ averaged 53%. After oral administration of DMDZ in tablet form (10 mg), or of clorazepate dipotassium in capsule form (15 mg), systemic availability of DMDZ from each of the oral dosage forms was not significantly different from 100%.
Clinical Pharmacokinetics of Pinacidil, A Potassium Channel Opener, in Hypertension
Authors: Goldberg Michael R. , Rockhold Frank W. , Thompson W. Leigh , DeSante Karl A.
Published: March 2013

Pinacidil is a potassium channel opener that decreases blood pressure by reducing peripheral arterial resistance. In two multicenter trials, we studied the concentrations and apparent clearance of pinacidil (406 patients) and concentrations of its pyridyl‐N‐oxide metabolite (147 patients). Responding patients had plasma samples collected hourly for 12 hours on 2 occasions after weeks to months of treatment. Pinacidil dose was titrated from 12.5 to 75 mg b.i.d. The peak concentration of pinacidil and N‐oxide and the area under the concentration‐time curve (AUC) were proportional to the dose of pinacidil, with an average pinacidil concentration of 268 μg/L (1.02 μM) and N‐oxide concentration of 172 μg/L (0.65 μM) for every 1 mg/kg pinacidil administered. Clearance of pinacidil (Clp = Dose/AUC) was 31 L/hr in patients younger than 45 years and 27 L/hr in those older than 60. Clp was significantly smaller in white patients compared with other races (Clp = 28 vs. 34 L/hr). Clp was significantly less in patients taking hydrochlorothiazide (27 vs. 31 L/hr) and greater in smokers (33 vs. 29 L/hr). Concomitant propranolol use did not influence Clp.
Delayed Elimination of Digoxin Antidotum Determined by Radioimmunoassay
Authors: Nollet Herman , Verhaaren Henri , Stroobandt Roland , Belpaire Frans
Published: March 2013

An observation of a treatment with digitalis antibodies (Fab‐fragments) in a young child is presented. The elimination of this antidotum proved to be much slower than normally expected. In the patient's history, the disappearance of the Fab‐fragments out of the blood lasted 142 days with a half‐life of 15.6 days, whereas an elimination with a T½ of 28 hours is accepted. Probably there has been intracellular penetration of the antibodies into the liver, caused by concomitant diseases (Hepatitis A and B infections). An “in vitro” experiment is reported. It demonstrates the equimolar binding of the Fab‐fragments for digoxin and shows that the elimination of the Fab‐fragments can be established by a routine radioimmunoassay of digoxin, in an indirect way.
Hemodynamic and Endocrine Effects of Acute and Chronic Administration of Nifedipine
Authors: Parent R. , Chiasson J. L. , Larochelle P.
Published: March 2013

Although it is well known that calcium channel blockers can influence contraction of vascular smooth muscle, there is less knowledge on its effect on excitation contraction coupling in the endocrine glands and more specifically on insulin and glucagon release. In this study, nifedipine was administered in doses of 40 to 80 mg/day to 14 patients with essential hypertension, and its hemodynamic effects were evaluated by non‐invasive methods, and its effect on glucose metabolism by an arginine infusion test Nifedipine produced a significant reduction in systolic and diastolic blood pressure, both after the first dose (30/12 mm Hg) and after 8 weeks of administration (19/12 mm Hg). There were no significant changes in cardiac output (5.1 to 4.9 L/min), muscle (2.4 to 3.2 mL/sec/min) or cutaneous basal flow (9.8 to 8.6 mL/100 mL) as measured non‐invasively by echocardiogram and by plethysmography. Insulin and glucagon release were evaluated by the arginine infusion test. Nifedipine produced a tendency toward an increase in glucagon release and a reduction in insulin release although these changes did not reach statistical significance. In this group of patients, nifedipine produced a significant reduction in systolic and diastolic pressure, but no significant changes in insulin or glucagon plasma levels.
FDA Advisory Committees and the New Drug Approval Process
Authors: Kaitin Kenneth I. , Melville Ann , Morris Betsy
Published: March 2013

To determine the impact of FDA advisory committee review on the approval time of new drug applications (NDAs) approved during the five‐year period 1983 through 1987, we compared NDA phase lengths of reviewed new chemical entities (NCEs) with those that were not reviewed and examined the elapsed time from final committee recommendation for approval to NDA approval. Of the 95 drugs approved during the study period that met the Center for the Study of Drug Development's definition of an NCE, 40 (42%) were submitted for review—mean NDA phase length was 36.9 months versus 32.4 months for unreviewed drugs. Reviewed drugs in the neuropharmacologic division had a longer NDA phase, while those in the metabolic/endocrine and oncology/radiopharmaceutical divisions had shorter NDA phases, than unreviewed drugs in those divisions. For NCEs grouped by therapeutic rating, reviewed drugs in each category had longer NDA phases than unreviewed drugs; the difference was largest for 1‐B rated drugs. The elapsed time from committee recommendation for approval to NDA approval as a percent of the total NDA phase was greatest for drugs submitted by the metabolic/endocrine division (83.0% of NDA phase) and for drugs rated 1‐A (63.2%). Results indicate that advisory committee review is associated with a small overall delay in NDA approval when compared with the regulatory fate of drugs not submitted for review.
Chronopharmacological Study of Nitrendipine in Healthy Subjects
Authors: Fujimura Akio , Ohashi Kyo‐ichi , Sugimoto Kouichi , Kumagai Yuji , Ebihara Akio
Published: March 2013

Nitrendipine 20 mg or placebo was given orally to eight healthy subjects in a cross‐over design separated by 1 or 2 weeks. Drug was given at 9:00 AM (morning dosage) or at 9:00 PM (evening dosage). Systolic and diastolic blood pressure (SBP, DBP) were measured just before and 1, 2, 3, 4, 5, 7, 9, 12 and 24 hrs after treatment. Plasma nitrendipine concentrations were determined at 0.5, 1, 2, 3, 4, 5, 7, 9, 12 and 24 hrs and plasma catecholamines were measured at 2 and 5 hrs following drug administration. SBP did not decrease significantly after nitrendipine compared to after placebo at 9:00 AM or at 9:00 PM. DBP decreased significantly at 2, 3, 4 and 5 hrs after nitrendipine at 9:00 AM, but only at 4 hours after the 9:00 PM dose. Mean plasma nitrendipine concentrations during the absorption phase were lower after the evening dosage compared to the morning interval. Maximum plasma concentration (Cmax) was significantly lower and time to maximum concentration (tmax) tended to be longer after the evening dosage. Area under the plasma concentration‐time curve from 0 to 24 hours (AUC0–24) and half‐life of the terminal elimination phase (t1/2β) of the morning and evening dosages did not differ. A significant correlation was observed between plasma nitrendipine concentrations and changes in DBP during the drug treatment. Plasma noradrenaline concentrations were significantly higher 5 hours after nitrendipine compared to after placebo at 9:00 AM, but not at 9:00 PM. These results suggest 1) that BP responsiveness to nitrendipine is relatively smaller after the evening dosage when compared to after the morning dosage, 2) that nitrendipine is absorbed more slowly from the gastrointestinal tract after the evening dosage than after the morning dosage, and 3) that the diurnal changes in the effects of nitrendipine are in part dependent on the time of administration and its subsequent effect on plasma concentrations of the drug.
Urinary Excretion of Prednisolone Following Intravenous Administration in Humans
Authors: Al‐Habet Sayed M. H. , Rogers Howard J.
Published: March 2013

The urinary excretion of prednisolone was studied in eight normal human volunteers (two women and six men) following intravenous (16, 32, 48 and 64 mg) doses. Urine prednisolone concentrations were determined by a high performance thin layer chromatographic method (HPTLC). The overall mean prednisolone elimination half life in urine following all the intravenous doses as determined by the rate and sigma minus plots was 1.13 ± 0.25 hour. This was independent of dose and shorter than that found in plasma (4.10 ± 1.00 s.d. hour). The overall mean percentage of dose excreted unchanged in urine was 16.7 ± 5.8% following all intravenous and oral doses respectively. About 80% of this amount was excreted within the first 4 hours of the intravenous administration. Renal clearance of prednisolone decreased with time by the first order kinetic (r = 0.790) and its overall value following all IV doses was 0.0183 ± 0.0103 (s.d.) 1/h/kg. The metabolic clearance remained constant with increasing doses from 16 to 64 mg (0.0883 ± 0.0306 s.d. 1/h/kg). From this study it was concluded that a definitive account of the renal elimination of prednisolone and its possible metabolites warrant further investigation. The fraction of the dose excreted unchanged was relatively small and variable suggesting that prednisolone elimination occurs mainly by metabolism.
Acute Effects of Combination of IB and IC Antiarrhythmics for the Treatment of Ventricular Tachycardia
Authors: Bleske Barry E. , Kluger Jeffrey , Fisher Jane , Chow Moses S. S.
Published: March 2013

There are limited data on the effects of Class IB and IC antiarrhythmic drug combination for the treatment of ventricular tachycardia. The present study evaluated this combination in 12 patients who had sustained ventricular tachycardia (SuVT) during programmed electrical stimulation (PES) and failed IC antiarrhythmic therapy. Following combination of lidocaine and a IC agent (7 with encainide and 5 with flecainide), two had no inducible ventricular tachycardia (VT) and one had nonsustained VT (NSVT). In seven of nine patients who still had SuVT, the mean VT cycle length increased 40 ± 25 msec post combination compared to IC antiarrhythmic therapy. Seven patients who had a favorable response to the initial combination (<10 beats of NSVT, or ≥ 10 beats of VT with a > 100 msec increase in cycle length compared to baseline and no hemodynamic compromise) were then placed on IC + oral IB agent (5 with mexiletine, 2 with tocainide). Similar effects on VT inducibility and cycle length were observed following the oral combination. In conclusion, the addition of lidocaine to IC therapy produced favorable effects on induced ventricular tachycardia in 58% of patients compared to IC agent alone. Also, a positive PES response to lidocaine and IC therapy corresponded to a similar positive response when either mexiletine or tocainide was substituted for lidocaine.
The Relationship of Dose to the Antihypertensive Response of Verapamil‐Sustained Release in Patients with Mild to Moderate Essential Hypertension
Authors: Mcmahon F. Gilbert , Reder Robert F. ,   For the Verapamil‐SR Study Group
Published: March 2013

The dose‐response relationship of verapamil‐SR was studied in 221 hypertensive patients. This double‐blind, parallel‐group, placebo‐controlled study compared placebo to 60 mg, 120 mg, 240 mg and 480 mg doily of verapamil‐SR. After 6 weeks of therapy, peak diastolic blood pressure was similar in the placebo group and the verapamil‐SR 60 mg group, 93.0 and 92.0 mmHg, respectively. The 120 mg, 240 mg and 480 mg verapamil‐SR groups produced significantly lower diastolic blood pressure, 89.8, 85.3 and 83.7 mmHg (P < 0.01), respectively. At trough, placebo and verapamil‐SR 60 mg groups and 120 mg groups had diastolic blood pressures of 96.6, 97.0 and 97.1 mmHg, respectively. Diastolic blood pressure with the 240 mg dose (92.4 mmHg) was significantly lower than with the 120 mg dose (P < 0.01). The 480 mg dose resulted in a diastolic blood pressure of 88.6 mmHg, which was significantly lower than the 240 mg dose (P < 0.01). The responder rate with 240 mg at peak was 82%. The trough to peak ratio was 0.58. Plasma concentrations were highly correlated with dose (r > 0.8; P < 0.01); but not with diastolic blood pressure (r > 0.4; P < 0.01). Headache and constipation, although not significantly different from placebo, were the most commonly reported adverse reactions in the verapamil‐SR groups, 6.3% (placebo—6.7%) and 5.1% (placebo—4.4%), respectively. Graded doses of verapamil‐SR produced a dose‐response curve in hypertensive patients with a greater than 80% responder rate at the 240 mg dose. Therefore, 240 mg of verapamil‐SR is effective monotherapy in the majority of patients.
Glipizide Pharmacokinetics: Effects of Age, Diabetes, and Multiple Dosing
Authors: Kradjan Wayne A. , Kobayashi Kelly A. , Bauer Larry A. , Horn John R. , Opheim Kent E. , Wood Francis J.
Published: March 2013

Aging and disease may contribute to alterations in drug pharmacokinetics. The purpose of this study was to determine the effects of aging, the presence of NIDDM, and multiple dosing on the pharmacokinetics of glipizide, an oral hypoglycemic drug. Ten healthy young men (under age 25), ten healthy older men (over age 65) and 15 older diabetic men ingested a single 5 mg tablet of glipizide after an overnight fast. Blood samples for measurement of serum glipizide were obtained over the next 24 hours. The study was repeated in the diabetics after 2 weeks of daily therapy. The mean values for Tmax (range 2.0–2.5 hours), Cmax (385–465 μg/l), and t1/2 (4.0–4.2 hours) were not significantly different in the three populations after single doses of glipizide. Several subjects in each population had slow absorption, with peak concentrations delayed for up to 12 hours. Only one elderly diabetic subject had evidence of drug accumulation at steady state. AUC, CI, Vgs and Varea were not significantly different in the three populations or at steady state, but there was a trend for AUC to be smaller and each of the other parameters to be increased in the older diabetics. The young subjects had a significantly higher fp (0.83%) than either of the two elderly groups (0.55–0.64%), but Clint did not differ between groups. Age, diabetes, and multiple dosing appear to have little effect on the pharmacokinetics of glipizide and should have little influence on the clinical response to this drug.
An Interindividual Variability in the Sensitivity of Atrioventricular Node to Diltiazem in Patients with Paroxysmal Supraventricular Tachycardia
Authors: Fukuhara Shunichi , Echizen Hirotoshi , Naito Masahito , Ishikawa Shinichiro , Toyama Masako , Nagoshi Hideki , Honda Masasada , Ishizaki Takashi
Published: March 2013

To study the sensitivity of atrioventricular (AV) node to diltiazem in seven patients with paroxysmal supraventricular tachycardia (PSVT), we analyzed the plasma concentration‐response relationship of this Ca‐antagonist using AH interval as an index for assessing its Ca channel blocking effect on the AV node after an IV infusion (0.4 mg/kg). The postdose AH intervals were prolonged compared with the baseline, and their percentage changes correlated significantly (P < 0.01) with log‐diltiazem concentrations in all patients. However, drug concentrations associated with a 20% prolongation of AH interval differed considerably among the patients (range; 65 to 260 ng/ml), indicating a large interindividual variability in the sensitivity of AV node to diltiazem. These results suggest that the interindividual difference in the responsiveness of AV node to diltiazem‐induced Ca channel blocking effect may be one of the possible explanations for the therapeutic failure of this Ca‐antagonist for terminating PSVT or preventing its recurrences in certain patients.
Alpha‐1 Adrenoceptor Blockade with Doxazosin in Hypertension: Effects on Blood Pressure and Lipoproteins
Authors: Ames Richard P. , Kiyasu John Y.
Published: March 2013

The effects of doxazosin, a long‐acting alpha‐1 adrenoreceptor blocking drug, were observed upon blood pressure and serum lipoproteins. Thirty patients with supine diastolic blood pressure between 90 and 114 mm Hg during single‐blind placebo therapy were randomized to double‐blind treatment with either doxazosin or further placebo in a parallel‐design protocol. Starting at one mg, dosage was doubled every 2 weeks during a 10‐week treatment period to a maximum dose of 16 mg once daily. Blood was sampled in the fasting state before and during double‐blind therapy for measurement of total cholesterol and triglycerides, cholesterol in the lipoprotein fractions, and apolipoproteins A and B. At the end of 10 weeks of titration, systolic and diastolic blood pressure were each reduced by 14 mm Hg in the standing position when measured 24 hours following the previous dose. Supine pressure was lowered by 6 mm Hg systolic and by 5 mm Hg diastolic at the same time point. Measured hourly for 12 hours following the ingestion of doxazosin, blood pressure was lowered maximally at 4–5 hours when an additional decline of 14/6 mm Hg (systolic/diastolic) was observed in the standing position and 13/6 in the supine posture. Postural dizziness, the most frequent symptomatic complaint, was reported in 4 patients during doxazosin treatment. After brief interruption of treatment in one and dosage adjustment in another, titration was continued in all four and no patient was withdrawn because of side effects. Concerning lipoproteins, the ratio of total cholesterol to HDL cholesterol and of LDL to HDL cholesterol both improved during treatment with doxazosin. Although these changes did not differ from those in the placebo group, the findings indicate that both blood pressure and lipoprotein concentrations respond favorably during treatment with doxazosin. This favorable combination of effects on CHD risk factors is matched by few other classes of antihypertensive drugs. In this way doxazosin offers a distinct advantage as first‐line therapy of hypertension.
Disposition of Guanadrel in Subjects with Normal and Impaired Renal Function
Authors: Halstenson Charles E. , Opsahl John A. , Abraham Paul A. , Schwenk Michael H. , Andreadis N. A. , Antal Edward J. , Matzke Gary R.
Published: March 2013

The disposition of a single 25 mg oral dose of guanadrel was evaluated in 22 subjects with various degrees of renal function. The terminal elimination half‐life was significantly prolonged in subjects with a creatinine clearance (ClCr) < 30 mL/min/1.73 m2 (19.2 ± 16.8 h) compared to 3.7 ± 1.9 h in subjects with a ClCr > 80 mL/min/1.73 m.2 Apparent total body clearance (Clp/F) was also progressively lower in the patients with decreased renal function and the decline was significantly correlated with ClCr (Clp/F = 0.0294 + 0.0236 ClCr, r = 0.74, P = 0.002). Renal clearance and apparent nonrenal clearance also declined as creatinine clearance decreased and both were significantly correlated with the observed ClCr. Apparent volume of distribution averaged 11.5 ± 8.9 L/kg and did not differ in patients with decreased renal function compared to those with normal renal function. Thus, the disposition of guanadrel is significantly altered in the presence of renal insufficiency and dosage adjustments may be necessary, especially in patients with ClCr < 50 ml/min.
Transdermal Clonidine Compared with Hydrochlorothiazide as Monotherapy in Elderly Hypertensive Males
Authors: Schmidt Gary R. , Schuna Arthur A. , Goodfriend Theodore L.
Published: March 2013

Sixteen of 22 elderly male patients (aged 60–74 years) who had previously taken only hydrochlorothiazide 50 mg completed a study evaluating the safety, efficacy, and tolerability of 12–20 weeks of transdermal clonidine (Catapres TTSR) as monotherapy for mild hypertension. Thirteen of the sixteen patients (81%) responded to transdermal clonidine which was begun after 28 days of placebo. Five patients discontinued transdermal clonidine therapy because of intolerable skin irritation, and one because of daytime fatigue. Clonidine caused none of the metabolic effects we observed with hydrochlorothiazide: no change in serum potassium, uric acid, cholesterol, or triglyceride. Eleven of the 22 patients (50%) who began the study experienced a skin reaction under the transdermal clonidine patch. The incidence of dry mouth and fatigue in patients using transdermal clonidine was dose‐related and similar to reports of dry mouth and fatigue in patients taking oral clonidine tablets. Rebound hypertension occurred in one patient upon withdrawal of transdermal clonidine. There was no effect of transdermal clonidine or hydrochlorothiazide on cognitive function or emotional state tested with three questionnaires. Overall, transdermal clonidine, in various doses, was as effective as hydrochlorothiazide in elderly male hypertensive patients. The effectiveness of both was inversely proportional to the level of untreated blood pressure. The high incidence of skin reactions limited prolonged use of transdermal clonidine in our patients.
Dosing Regimen of Gentamicin During Intermittent Peritoneal Dialysis
Authors: Kaojarern Sming , Arkaravichien Wiwat , Indraprasit Suchati , Pummangura Chalermsri
Published: March 2013

The peritoneal clearance of gentamicin was studied in 11 chronic uremic patients who undergoing intermittent peritoneal dialysis. Gentamicin was significantly removed by peritoneal dialysis with a clearance value of 9.75 ± 3.78 ml/min. The serum half life was 14.08 ± 3.57 hr, a value significantly less than that of non dialysed end stage renal disease patients. The mean apparent volume of distribution of the drug in these patient was about 27% of body weight. The derived value for gentamicin peritoneal clearance and volume of distribution can be used to calculate maintenance dose during intermittent peritoneal dialysis. In order to achieve the peak level of 8 ug/ml, supplementary dose compensated for the loss during peritoneal dialysis is approximately 40% of loading dose 0.8 mg/kg every 12 hours.
Phase I Study of E1040, a New Parenteral Cephem Antibiotic
Authors: Nakashima M. , Uematsu T. , Kanamaru M. , Ueno K. , Setoyama T. , Tomono Y. , Ohno T. , Okano K. , Morishita N.
Published: March 2013

The safety and pharmacokinetics of E1040, a new injectable cephem antibiotic, were evaluated in healthy volunteers. In single‐dose studies, 125, 250, 500, 1000 and 2000 mg of E1040 were administered by I.V. infusion over 1 hour. Results of 5 minute I.V. infusions of 500, 1000 and 2000 mg of the drug were also studied. Plasma concentration‐time profiles were well suited to a two‐compartment open model. The half‐life of elimination from plasma was 1.85 ± 0.16 hours, and the Cmax and AUC paralleled the doses given. The mean urinary recovery within the first 24 hours was 85.7 ± 6.43% of the dose. In a multiple‐dose study, 2000 mg of E1040 (I.V. over 1 hour) was administered every 12 hours (total 9 times) and no abnormal accumulation of the drug in plasma was observed. There were no significant differences in plasma levels or in urinary recoveries between single‐ and multiple‐dose regimens. There were no subjective or objective abnormal findings definitely attributable to the drug except that one subject given 250 mg over 1 hour reported diarrhea, and another complained of nausea during the infusion of 2000 mg over 5 minutes. From these results E1040 was concluded to be safe and well tolerated.
Development of a Computer‐Based Instructional System in Pharmacokinetics: Efficacy in Clinical Pharmacology Teaching for Senior Medical Students
Authors: Feldman R. D. , Schoenwald R. , Kane Janet
Published: March 2013

The teaching of pharmacokinetics is acknowledged to be a key aspect of the core curriculum in clinical pharmacology and therapeutics, but is also widely acknowledged to be a very difficult part of the curriculum to teach. In order to assess the potential efficacy of interactive computer instruction in clinical pharmacokinetics we have developed a prototype computer‐based instructional package. The courseware contains a comprehensive learning system including tutorial, simulation, and problem solving components. To determine the efficacy of this approach we randomly assigned senior medical student volunteers enrolled in the fourth year clinical pharmacology and therapeutics course to receive conventional teaching in clinical pharmacokinetics and/or adjuctive teaching using the computer‐based instructional system.

There was a high degree of acceptance of the program and over the short term of the trial those students using the computer program scored significantly higher [35%, P< 0.05] on the mid‐term pharmacokinetics quiz. The data suggests that a computerized instructional system in pharmacokinetics may significantly improve the teaching of clinical pharmacokinetics to medical students.
Flurbiprofen in Post‐Partum Women: Plasma and Breast Milk Disposition
Authors: Smith Iain J. , Hinson James L. , Johnson Virginia A. , Brown R. Don , Cook Sally M. , Whitt Robert T. , Wilson John T.
Published: March 2013

The plasma and milk disposition of flurbiprofen (FB) was assessed in healthy women during the early post‐partum period after multiple doses of FB. The results confirmed that a pragmatic study design is an attainable requirement for definitive statements about the excretion of FB in transitional milk. Nine doses of FB (50 mg per dose) were administered during three days. Paired milk and plasma samples were obtained during this period of dosing as well as after the last dose. The plasma data were used to derive an equation, which was then used to simulate cumulative plasma profiles for multiple doses given at unequal time intervals. The observed data corresponded to the simulated cumulative profiles of FB in plasma. The plasma elimination half‐life of FB during early lactation was slightly prolonged (mean 4.8 hrs) as compared to reported values for normal adult men. The peak plasma concentrations of FB were comparable to those reported for healthy volunteers. In 10 of 12 women (3–5 days post‐partum) the FB concentration in breast milk was less than 0.050 μg/ml. In two women the milk concentrations of FB were 0.06, 0.07 and 0.07 μg/ml as found in only three samples. We conclude that, on the basis of dose found in milk, FB is safe for women breast feeding their infants in the early post‐partum period.
Effects of Liver Disease on the Disposition of Ciramadol in Humans
Authors: Hoyumpa Anastacio M. , Brown Michael W. , Johnson Raymond , Troxell Rebecca , Snowdy Pam , Schenker Steven
Published: March 2013

To determine the effects of liver disease on the disposition of ciramadol, an analgesic that undergoes ether glucuronidation, we studied its plasma pharmacokinetics in 10 patients with stable cirrhosis, 8 with acute viral hepatitis, and 16 age‐matched healthy controls. Renal excretion of the glucuronides was also determined. In healthy controls given a single intravenous dose of the drug the t1/2 was 3.4 ± 0.3 hrs and the systemic clearance was 668 ± 109 ml/min of which renal clearance was 320 ± 73 ml/min and non‐renal clearance 349 ± 74 ml/min. The corresponding values after an oral dose were similar. Renal clearance was related directly to the estimated creatinine clearance. Moreover, the renal clearance of ciramadol exceeded creatinine clearance, suggesting that the drug was excreted not only by glomerular filtration but also by tubular secretion. The systemic clearance of intravenous ciramadol was diminished by 40% in cirrhosis, P < 0.05, due to a reduction in renal clearance, while non‐renal clearance remained normal. Renal clearance of the inactive glucuronides, on the other hand, was not affected. In patients with acute viral hepatitis, systemic clearance was unchanged, but renal clearance of ciramadol tended to increase during the acute phase of the disease and to return toward normal after recovery. Renal excretion of the inactive glucuronides was decreased by 48% (P < .05). These findings suggest that the non‐renal ether glucuronidation of ciramadol remains intact in patients with stable cirrhosis or acute viral hepatitis. However, the renal clearance of the drug may be impaired in cirrhosis, but tends to be enhanced in acute hepatitis. Finally, the renal excretion of the parent compound may differ from that of its metabolites. Thus, ciramadol may be a suitable analgesic in patients with stable liver disease provided the kidneys are functioning normally.
Comparative Gastrointestinal Blood Loss Associated with Placebo, Aspirin, and Nabumetone as Assessed by Radiochromium (51Cr)
Authors: Lussier André , Davis Alan , Lussier Yves , LeBel Etienne
Published: March 2013

Nabumetone differs from most other nonsteroidal anti‐inflammatory drugs. It is presented to the gut as a nonacidic prodrug, and is metabolized to its active form after absorption. Studies in animals and humans suggest it is less irritating to the gastrointestinal mucosa. This study compared the gastrointestinal microbleeding induced by nabumetone to aspirin (acetylsalicylic acid, ASA), and placebo in a double blind parallel study using chromium 51Cr labelled red cells to quantitate fecal blood loss (FBL) in healthy volunteers. Thirty subjects were randomized to treatment with nabumetone (2000 mg), ASA (3.6 g) or placebo for 21 days following a 7 day placebo period. Six subjects served as untreated controls. FBL in nabumetone treated subjects was not significantly different to placebo or untreated subjects. In contrast, ASA‐treated subjects exhibited significantly increased FBL than the other 3 groups (P < .0001).
Effects of H2‐Receptor Antagonists on Plasma Aldosterone Response to Angiotensin II in Healthy Subjects; (II) Comparison of Cimetidine and Ranitidine
Authors: Fujimura Akio , Ohashi Kyoichi , Sudo Toshiaki , Sakamoto Koichi , Oka Taichi , Ebihara Akio
Published: March 2013

The effects of H2‐receptor antagonists, cimetidine and ranitidine, on plasma aldosterone response to angiotensin II (AII) were examined in six healthy subjects. The study was carried out on three different occasions with a two week interval. Cimetidine (400 mg), ranitidine (150 mg) or a placebo was given orally every 12 hours for 3 days in a double‐blind, cross‐over, double‐dummy design. On the fourth day, 1 hour after the final (seventh) administration of the same agent, furosemide (20 mg) was injected intravenously. The plasma levels of renin activity (PRA), AII and aldosterone (PA) were determined for a 120 minute period after furosemide. PRA, AII and PA increased after furosemide with as well as without H2‐receptor antagonist. The basal and stimulated levels of these parameters were not significantly different at any observation point among the three regimen groups. A significant correlation was observed between AII and PA with placebo (P < 0.01) and ranitidine (P < 0.01), but not with cimetidine (P > 0.05). The slope of the regression line with ranitidine was not significantly different from that of the placebo.
Saturable First‐Pass Kinetics of Propranolol
Authors: Keller Frieder , Kunzendorf Ulrich , Walz Gerd , Haller Hermann , Offermann Gerd
Published: March 2013

Reduced bioavailability (F) due to hepatic first‐pass extraction of an oral dose (D) is a well‐known pharmacokinetic phenomenon. An integrated solution for Michaelis‐Menten kinetics of the first‐pass effect is derived from the maximal metabolic rate (Vm), volume of distribution (Vd), first order absorption rate constant (ka), Michaelis constant (Km), and liver blood flow (Q).

This equation for single dosage can also be extended to steady state kinetics after multiple dosing in which the amount of a drug present in the hepatic circulation is considered. According to the literature, the bioavailability of a single 80 mg oral dose of propranolol (F = 0.22) increases after multiple doses (Fss = 0.36). Based on the first pass equations for single dosage and multiple dosing, the maximal metabolic rate (Vm = 0.043 mg l−1 h−1) corresponding to 310 mg per day and the Michaelis constant (Km = 0.10 mg/l) were calculated for propranolol. Incorporation of nonlinear plasma protein binding in this concept may explain the lack of threshold phenomenon for a single dose of less than 40 mg propranolol. Zero order absorption kinetics could explain why cumulation kinetics seem linear even at an excessive dosage of 960 mg propranolol per day.

From these derivations it may be concluded that multiple dosing, increase in plasma protein binding, high absorption rate, and increased portal venous blood flow will increase bioavailability, whereas slow release formulations, fractional drug dosage, and saturable absorption kinetics will decrease bioavailability of first‐pass drugs like propranolol.
Influence of Demographic Factors on Cyclosporine Pharmacokinetics in Adult Uremic Patients
Authors: Grevel Joachim , Reynolds Kimberley L. , Rutzky Lynn P. , Kahan Barry D.
Published: March 2013

The causes of variability in cyclosporine (CS) clearance (CL) are mostly unknown. The pharmacokinetics of CS were studied in 30 adult uremic patients after single intravenous and oral doses by analyzing serial concentrations in serum by radioimmunoassay (SR) and in whole blood by radioimmunoassay (WR) and high pressure liquid chromatography (WH). Bioavailability (F) and CL were calculated by noncompartmental models and were significantly different depending upon the assay method except for FSR = FWR: FSR = 43.2 ± 21.7%; FWR = 43.5 ± 18.5%; FWH = 36.4 ± 17.3%; CLSR = 849 ± 363 ml/min; CLWR = 380 ± 156 ml/min; CLWH = 559 ± 174 ml/min. The age of the patients and parameters describing body size such as weight, surface area and percent of ideal weight were not correlated with CL. The height of the patients correlated with CLWH but not CLSR or CLWR. Parameters responsible for CS binding in blood such as cholesterol, triglyceride, hemoglobin concentration or hematocrit did not explain variability in CL. Of the factors indicative of liver function alanine transaminase activity but not aspartate transaminase, lactate dehydrogenase, alkaline phosphatase activity nor total bilirubin concentration in serum was correlated with CL. F was not correlated with any of the demographic factors except for alanine transaminase. None of the significant correlations explained enough of the variability to afford a reliable prediction of CL or F.