bluuebunny/crossref_metadata_2025 huggingface dataset:
The Correlation of Vinblastine Pharmacokinetics to Toxicity in Testicular Cancer Patients
Authors: Chong Clayton D. K. , Logothetis Christopher J. , Savaraj Niramol , Fritsche Herbert A. , Gietner Allene M. , Samuels Melvin L.
Published: March 2013

The clinical pharmacokinetics of vinblastine administered by continuous 5‐day infusion (3 mg/m2/day) was studied in 12 patients with primary testicular cancer. Serum vinblastine concentrations were determined by radioimmunoassay on serum collected over a 10‐day period. Steady‐state vinblastine concentrations were achieved within 60 to 108 hours (median, 72 hours). Vinblastine pharmacokinetics were analyzed and correlated to hematologic and nonhematologic toxicity. Hematologic toxicity was severe (granulocytopenia of less than 500/μL) in all patients; however, no correlation of vinblastine pharmacokinetics to duration of granulocytopenia or nadir was noted.

Nonhematologic toxicity, however, showed a direct correlation to steady‐state vinblastine concenations. Two distinct groups of patients were identified by a toxicity score evaluating nonhematologic toxicity: as low (group A) or high (group B). The toxicity score was calculated for each patient based on accumulated toxicity during the course of treatment. The mean toxicity score for all patients was 7.11 and for groups (A and B) it was 4.0 and 9.6, respectively (P = .02). Steady‐state vinblastine concentration for each patient was compared with toxicity where the mean steady‐state vinblastine concentration was 7.3 ng/mL for all patients, and 5.8 ng/mL and 8.5 ng/mL for groups A and B, respectively (P = .01). These steady‐state vinblastine concentrations correlated directly with the mean toxicity scores revealing that patients with high steady‐state vinblastine concentrations demonstrated more nonhematologic toxicity. Application of these data to pharmacokinetically directed studies are warranted to investigate this relationship and designate dosages of vinblastine to avoid excessive toxicity.
The Effect of Chronic Timolol in an Animal Model for Myocardial Infarction
Authors: Lathers Claire M. , Spivey William H. , Levin Robert M.
Published: March 2013

The effect of no drug or timolol (5 mg/kg, PO, for 1, 2, or 8 weeks on postganglionic cardiac sympathetic neural discharge, blood pressure, heart rate and beta‐receptor density after acute coronary occlusion of the left anterior descending artery was compared. Beta‐receptor density, determined by binding of3H‐dihydroalprenolol, was examined in the myocardium (LA = left atrium, RA = right atrium, LV1 = proximal and LV2 = distal left anterior descending artery distribution, LV3 = posterior left ventricle, S = septum, and RV = right ventricle). In control cats (no coronary occlusion or timolol) beta‐receptor density of LV2 and LV3 was greater (P <.05) than LA, RA, LV1, and RV. LV3 was greater (P <.05) than S and RA, and LA was less than S. Longer treatment with timolol increased beta‐receptor density. When compared with no timolol, beta‐receptor density was greater in RA after 8 weeks and in LV1 after 2 weeks and not different in LV2 and S. Beta‐receptor density and LV3 and RV were greater after 8 weeks than after 1 week or no timolol. Spearman rank correlation coefficients between dose and beta‐receptor density revealed an increase (P <.05) for all heart areas. Heart rate did not vary before timolol and was decreased after all doses of timolol. Timolol increased the mean times to coronary occlusion‐induced death although the increase was not statistically significant. Timolol did not prevent postganglionic cardiac sympathetic neural discharge associated with arrhythmia. Timolol may increase beta‐receptor density and decrease synaptic norepinephrine, causing a decreased release per cardiac sympathetic nerve impulse. Alternatively, molecules of timolol may accumulate in nerve endings and be released in greater concentrations at the receptors. This could explain the protection against coronary occlusion‐induced arrhythmia and death.
Efficacy of Esmolol in the Treatment and Transfer of Patients with Supraventricular Tachyarrhythmias to Alternate Oral Antiarrhythmic Agents
Authors: Das Gopal , Tschida Victor , Gray Richard , Dhurandhar Raja , Lester Robert , McGrew Frank , Askenazi Joseph , Kaplan Kerry , Emanuele Martin , Turlapaty Prasad , Hua T. A. , Hoff Julie , Allin Douglas , Laddu Atul
Published: March 2013

The efficacy and safety of esmolol, a titratable intravenous beta‐adrenergic blocking agent with a short elimination hall‐life (t1/2 = 9.0 min) was evaluated in a multicenter open‐label study for the treatment of supraventricular tachyarrhythmias (heart rate greater than 100 bpm). The study also investigated the feasibility of transferring patients from esmolol to alternate oral antiarrhythmic agents without loss of therapeutic response. Of the 113 patients studied, 95 (84%) achieved therapeutic response (reduction in heart rate of 15% or more or conversion to sinus rhythm). Most of these patients (93%) achieved the therapeutic response at esmolol doses of 200 μg/kg/min or lower. Transfer from esmolol to an oral antiarrhythmic agent(s) was studied in 76 patients. Alternate antiarrhythmic agents used in this study were digoxin (N = 25), propranolol (N = 21), verapamil (N = 10), metoprolol (N = 11), quinidine (N = 2), and a combination of two antiarrhythmic agents (N = 7). Sixty‐seven (88%) patients were successfully transferred to oral antiarrhythmic agents without loss of the therapeutic response obtained with esmolol. The most frequent adverse effect observed during the study was hypotension, which resolved quickly (16 ± 14 min) either by decreasing the dose or by discontinuation of esmolol infusion. This study supports previous observations concerning the safety and efficacy of esmolol in the treatment of supraventricular tachyarrhythmias. Furthermore, it demonstrates that the majority of patients successfully treated with esmolol can be safely and effectively transferred to oral therapy with alternate antiarrhythmic agents.
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

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
Pharmacologic Effects of A‐56234, a New High‐Ceiling Diuretic
Authors: Luther Robert R. , Ringham Gary L. , Thomas Elizabeth W. , Patterson Karen J. , Tolman Keith G.
Published: March 2013

The pharmacokinetic characteristics, the diuretic, saluretic, and uricosuric properties, and the safety of single, rising, oral doses of A‐56234, a new high‐ceiling diuretic, were evaluated in this double‐blind, placebo‐controlled, cross‐over study. Each of three groups of eight subjects received placebo and three different single doses of the diuretic at 1‐week intervals. Doses ranged from 0.5 to 80 mg. Significant, dose‐related increases in urine volume and in urinary excretion of sodium and chloride were produced during the 24 hours after administration of 20, 40, 60, and 80 mg of the drug. Uricosuria was not observed at any dose. The drug was rapidly absorbed and displayed linear pharmacokinetics within the dose range studied. The elimination‐phase plasma half‐life was approximately 6 hours. Hepatic clearance was the main route of excretion in humans; only 2 to 10% of the parent drug was excreted in the urine. The drug was well tolerated and no clinically important adverse events were noted.
Efficacy and Pharmacokinetics of Oral Pirmenol, A New Antiarrhythmic Drug
Authors: Garg Dyal C. , Jallad Nader S. , Singh Sharanjeet , Ng Kevin F. , Weidler Donald J.
Published: March 2013

Pirmenol is a new orally effective antiarrhythmic agent. Reported are the results of oral administration of pirmenol to six patients (age 48.5 ± 8.6 years, weight 83 ± 15 kg) with stable ventricular extrasystoles (PVCs)—average ectopy rate 1040 ± 630/hr (mean ± SD). Patients received oral doses of placebo or 200 mg of pirmenol in a double‐blind cross‐over fashion followed by a single‐blind rising‐dose administration of 250 mg and 300 mg of pirmenol. The time period between doses was 48 hours. Pirmenol was rapidly absorbed (time to peak plasma levels 1 to 1.5 hours) and the mean maximum plasma concentrations were 1.8, 2.7 and 3.4 μg/mL with 200‐mg, 250‐mg and 300‐mg doses, respectively. The elimination half‐life was 9.3 ± 3.0 hours and 31 ± 14% of the dose was recovered in urine. The response criterion (80% suppresion of PVCs of control for 8 hours) was met after the 300‐mg dose in three patients. In three patients >80% reduction occurred for up to 8 hours after the 200‐mg dose. Pirmenol administration was not associated with any significant changes in blood pressure, heart rate, hepatic and renal function, PR interval or QRS duration. LV ejection fraction determined echocardiographically decreased from 63.0 ± 6.9% predose to 59.7 ± 5.0% about 2 hours after the 300‐mg dose and QT interval increased by <10%. Two patients complained of transient bad taste sensation. Our results suggest that 250 mg to 300 mg of pirmenol, administered twice a day will suppress the PVCs effectively.
Epoprostenol (PGI2, Prostacyclin) During High‐Risk Hemodialysis: Preventing Further Bleeding Complications
Authors: Swartz Richard D. , Flamenbaum Walter , Dubrow Alan , MS Jane C. Hall , Crow James W. , Cato Alan
Published: March 2013

The frequency of hemodialysis‐associated hemorrhage was studied prospectively in two successive, parallel, heparin‐controlled studies using epoprostenol (PGI2; average dose, 4.1 ng/kg‐min) as the sole antithrombotic agent. Sixty‐three patients with active or recently active Weeding underwent 163 hemodialysis treatments in each of which prospective Weeding risk was assessed. PGI2 was associated with up to 50% overall reduction in the frequency of Weeding, particularly in the highest risk circumstances. PGI2 also allowed successful completion of the full, prospectively prescribed hemodialysis time in the most treatments (82% versus 93% with heparin). Furthermore, the efficiency of hemodialysis using PG12, as indicated by the reduction in concentration of blood urea nitrogen and serum creatinine, was equal to that using heparin, even though there was a tendency toward modest reduction in residual volume of the hollow fiber dialyzer and slightly more frequent early termination of treatment from dialyzer clotting with PGI2. No severe vasodilatory side effects of PGI2 were observed during these studies. Hypotension was equally frequent during hemodialysis with heparin as with PGI2. The current results suggest that PGI2 should be considered as a substitute for heparin during high‐risk hemodialysis because PGI2 may reduce the incidence of dialysis‐associated Weeding without severe adverse side effects.
Correlation Between Verapamil Plasma Concentration and P‐R Prolongation in Essential Hypertension
Authors: Zachariah Prince K. , Shub Clarence , Sheps Sheldon G. , Schirger Alexander , Wolf Mary K. , Carlson Christopher A.
Published: March 2013

Plasma verapamil concentration was correlated with serial electrocardiographic P‐R intervals in patients with essential hypertension receiving immediate‐release (80 to 120 mg three times a day) or sustained‐release (240 mg daily) verapamil. The mean P‐R interval in 22 patients taking placebo and immediate‐release verapamil was 0.18 second. The borderline first‐degree atrioventricular block of three patients did not change during treatment. Plasma verapamil concentrations of patients with a P‐R interval longer than 0.20 second and of those with a P‐R interval of 0.20 second or less were 169 ± 73 ng/mL and 63 ± 8 ng/mL, respectively. Six patients taking sustained‐release verapamil had a maximal mean P‐R interval of 0.19 ± 0.01 second during 24‐hour ambulatory electrocardiographic monitoring. P‐R intervals were 0.22 second or more in two patients, but they returned to normal by hour 7 for one and by hour 20 for the other patient. In summary, transient P‐R prolongation occurred with oral verapamil therapy, but no patient, regardless of baseline P‐R interval, developed high‐grade atrioventricular block.
Influence of Hypo and Hyperthermia on Disposition of Morphine
Authors: Bansinath Mylarrao , Turndorf Herman , Puig Margarita M.
Published: March 2013

Using morphine as a prototype opiate anesthetic, the dispositional changes and cardiovascular effects during hypothermia (30°C) and hyperthermia (40°C) in dogs under isoflurane anesthesia was assessed. Single intravenous bolus injection of 1 mg/kg morphine resulted in a significant and sustained decrease in mean arterial pressure in hypothermic, but not in hyperthermic or normothermic (37°C) conditions. Hypothermic dogs showed significantly higher levels of morphine both in plasma and in cerebrospinal fluid. In contrast, hyperthermia did not affect these levels. Body temperature did not affect the t1/2α, however t1/2β and mean residence time were significantly increased while volume of distribution at steady state and total body clearance were decreased during hypothermia. The results provide evidence that hypothermia is likely to be associated with a sustained increase in opiate levels and might be associated with a enhanced side effects. The results suggests the need for a controlled clinical trial to assess the dose of opiate anesthetics during hypothermia.
Blood Pressure and Blood Pressure Variability Following Withdrawal of Propranolol and Clonidine
Authors: Neusy Andre‐Jacques , Lowenstein Jerome
Published: March 2013

The effects of placebo, propranolol, and clonidine on blood pressure and blood pressure variability were examined in 14 subjects who had moderate essential hypertension. Hydrochlorothiazide was given throughout successive 4‐ to 5‐week periods of placebo, propranolol, and clonidine administration. During each treatment period, subjects were admitted twice to the clinical research unit for 24‐hour blood pressure monitoring performed during administration of placebo, propranolol and clonidine and repeated 1 to 2 weeks later during the first 24 hours after the abrupt cessation of placebo or drug administration. Blood pressure was recorded at 15‐minute intervals using an automated noninvasive recorder (Arteriosonde, Roche, New Jersey). Systolic and diastolic blood pressure readings were averaged and the standard deviation taken as the measure of long‐term variability (LTV). Systolic and diastolic blood pressure in sequential overlapping blocks of seven readings were averaged and the standard deviation calculated. Short‐term variability (STV) was estimated as the average of the standard deviations of the running means. During placebo administration and withdrawal, systolic and diastolic blood pressures as well as LTV and STV were unchanged. Systolic and diastolic pressures did not differ during propranolol administration from those during propranolol withdrawal or placebo withdrawal. Systolic and diastolic LTV and STV did not differ during propranolol administration and withdrawal from those observed during placebo administration or withdrawal. After clonidine withdrawal, both systolic and diastolic pressures increased to values significantly greater than during clonidine administration. These values were significantly greater than those observed after placebo withdrawal, thereby indicating rebound hypertension. After clonidine withdrawal, seven of fourteen subjects developed systolic pressure rebound; diastolic pressure rebound was observed in three patients. During clonidine withdrawal, LTV and STV of both systolic and diastolic pressures increased significantly compared with placebo withdrawal.
Effects of Coadministration of Propafenone on the Pharmacokinetics of Digoxin in Healthy Volunteer Subjects
Authors: Nolan Paul E. , Marcus Frank I. , Erstad Brian L. , Hoyer Gifford L. , Furman Carol , Kirsten Edward B.
Published: March 2013

Previous reports have suggested an interaction between propafenone and digoxin. We investigated the pharmacokinetics of IV digoxin when given alone (Phase I), after pretreatment with propafenone 150 mg every 8 hours for seven days (Phase II), and after propafenone 300 mg every 8 hours for 7 days (Phase III). The total body clearance of digoxin during Phase I was 2.45 ml/min/kg and was 2.17 ml/min/kg during Phase II (NS) and decreased to 1.92 ml/min/kg during Phase III (P < 0.05). The renal clearance and half‐life of digoxin were not significantly altered by propafenone. There was a trend towards a decrease in the volume of distribution of digoxin from 9.43 L/kg in Phase I, to 9.33 L/kg in Phase II, and 8.02 L/kg in Phase III. Similarly there was a trend towards a decreased nonrenal clearance of digoxin from 1.21 ml/min/kg during Phase I to 1.01 ml/min/kg during Phase II and to 0.75 ml/min/kg during Phase III. The changes in volume of distribution and nonrenal clearance parallel each other resulting in no change in the elimination half‐life of digoxin. It is postulated that the mechanism of this interaction is due to decreases in the volume of distribution and nonrenal elimination of digoxin by propafenone. The degree of this interaction was related to the dose of propafenone. The magnitude of this interaction may be greater in patients and, thus, may require a reduction in the digoxin dose.
Chronic Treatment with Fluvoxamine, Clovoxamine, and Placebo: Interaction with Digoxin and Effects on Sleep and Alertness
Authors: Ochs Hermann R. , Greenblatt David J. , Verburg‐Ochs Birgitt , Labedski Lothar
Published: March 2013

The influence of 17 days of administration of fluvoxamine or clovoxamine, two new antidepressant agents, on the kinetics of a single intravenous dose of digoxin, and on self‐rated parameters of sedation, mood, and sleep, was evaluated in a series of healthy volunteers. In the fluvoxamine study, subjects received fluvoxamine, 100 mg daily, or matching placebo for 17 consecutive days in a crossover design. For the clovoxamine study, subjects received clovoxamine, 150 mg daily, or placebo for 17 days. All treatments were double blind. At the end of each treatment, digoxin kinetics were evaluated following a single 1.25 mg intravenous dose. Compared to the placebo condition, fluvoxamine had no significant influence on digoxin elimination half‐life (57 vs 47 hours), volume of distribution (10.5 vs 10.3 liters/kg), total clearance (2.4 vs 3.0 ml/min/kg), or 72 hour urinary excretion (33 vs 37 percent of the dose). Likewise clovoxamine did not alter digoxin elimination half‐life (39 vs 40 hours), volume of distribution (10.7 vs 10.2 liters/kg), or total clearance 3.4 vs 3.4 ml/min/kg). 72 hour urinary excretion of digoxin was slightly increased by clovoxamine (41 vs 50 percent of the dose, P < .05). Self‐ratings indicated a sedating effect of fluvoxamine, with reports of difficulty attaining morning alertness. These effects were not reported with clovoxamine. Thus clovoxamine and fluvoxamine appear to have differential effects on sleep and alertness in healthy volunteers. However, neither have an important influence on the kinetics of digoxin.
BOOK REVIEWS
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

Biotechnologically Derived Medical Agents: The Scientific Basis of Their Regulation Edited by John L. Gueriguian

Hypercholesterolemia: Clinical and Therapeutic Implications (Atherosclerosis Reviews, Vol. 18) Edited by Joseph Stokes III, and Mario Mancini
Comparative Evaluation of the Effects of Labetalol, Verapamil and Diltiazem on Antipyrine and Indocyanine Green Clearances
Authors: Rocci Mario L. , Vlasses Peter H. , Lener Michelle E. , Fruncillo Richard A. , Sirgo Mark A.
Published: March 2013

The effects of labetalol, diltiazem and verapamil on antipyrine and indocyanine green clearance were evaluated in a placebo‐controlled, repeated measures evaluation. Twelve healthy subjects received either labetalol (200 mg every 12 hours), diltiazem (90 mg. every 8 hours), verapamil (80 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the morning of Day 3 immediately following their dose, the subjects assumed the supine position for 90 minutes, after which time a 0.5 mg/kg dose of indocyanine green was administered. Blood samples were obtained serially over a 20 minute period for indocyanine green plasma concentration determinations by HPLC. Ten minutes later, subjects ingested a 1.2 Gm. dose of antipyrine and blood samples were obtained over a 48 hour period for antipyrine plasma concentration determinations by HPLC. A 2 week washout period separated treatment sequences. Mean (SD) antipyrine clearance (L/hr/kg) following diltiazem [0.028 (0.010)] and verapamil [0.030 (0.012)] treatment was significantly lower than that observed following placebo [0.039 (0.012)]. Antipyrine clearance following labetalol administration [0.033 (0.010)] was not significantly different from that observed following placebo, diltiazem or verapamil administration. No effects of these drugs on indocyanine green clearance could be detected.
Pharmacokinetics and Efficacy of Digoxin Specific Fab Fragments in a Child Following Massive Digoxin Overdose
Authors: Kearns Gregory L. , Moss M. Michele , Clayton Bruce D. , Hewett Debra D.
Published: March 2013

The use of digoxin‐specific Fab fragments (d‐Fab) to treat life‐threatening digitalis intoxication has been widely substantiated in adults. This reports a case of a 2‐year‐old girl who ingested 90–92, 0.25 mg tablets of digoxin and within four hours, developed vomiting, lethargy, tachycardia and AV block (Mobitz type I and II). These symptoms were associated with total and free serum digoxin concentrations of 17.1 and 12.4 ng/ml, respectively. Following GI decontamination, a total dFab dose of 1280 mg (32 vials) was given with resolution of electrocardiographic abnormalities within 40 minutes and a concomitant reduction in the free serum digoxin concentration to 0.11 ng/ml. Repeated blood sampling over 19 days revealed an apparent elimination half‐life (t12) of 134.9 and 129.9 hr/or total and free digoxin, respectively. The long t1/2 for digoxin corresponded to a low apparent renal clearance of total digoxin which ranged from 0.56 to 0.82 ml/minute over four separate collection intervals. The free serum digoxin concentration never exceeded 3% of the total concentration and the patient did not develop a recurrence of toxic symptoms or any adverse effects (e.g. fever) attributable to dFab. Administration of an equimolar dFab dose to children following acute, massive digoxin intoxication represents safe, effective treatment which produces a prompt, sustained reversal of toxic effects. Digoxin specific Fab fragments should be promptly administered to any infant or child with significant, life‐threatening symptoms following acute digoxin intoxication.
Effect of Nifedipine on Urinary Concentrating Ability: A Placebo Controlled Study
Authors: Okaniwa Takashi , Ishizaki Takashi , MD Tetsuji Iizuka , Yasuda Kohtaro
Published: March 2013

A placebo‐controlled, randomized, crossover study was conducted to assess a possible effect of a dihydropyridine Ca‐entry blocker, nifedipine, on urinary concentration ability in nine healthy men under a water‐deprivated condition. Placebo and nifedipine (20 mg) were orally administered on two separate occasions, at least one week apart, after the urinary osmolarity was stabilized. Urinary osmolarity, osmolar clearance, negative free water clearance, urine volume, urinary solutes (Na, K and urea), creatinine clearance and plasma vasopressin (AVP) were measured during the postdose 3‐hour period and compared with those during the respective predose (baseline) period. Urinary osmolarity decreased by nifedipine from 1047.2 ± 34.4 to 873.0 ± 38.3 mOsm/kg (mean ± SEM) at 2 hours postdose (P < 0.05). Mean % decrease in urinary osmolarity at 1 to 3 hours after nifedipine was significantly (P < 0.01) greater than after placebo. Urine volume significantly (P < 0.01) increased from the baseline of 0.49 ± 0.06 to 1.1 ± 0.15 ml/min at 2 hours after nifedipine. Relationship between osmolar clearance and negative free water clearance relative to glomerular filtration rate observed during the postnifedipine phase was significantly (P < 0.01) shifted downward compared with that derived from the pooled data unrelated to nifedipine dosing. No significant drug effect was detected on plasma AVP. Both placebo and nifedipine dosed during the continued water deprivation and stabilized urinary osmolarity condition caused an increase in the urinary excretions of solutes. The results indicate that nifedipine inhibits urinary concentration. This does not appear to be due to the inhibition of AVP secretion from the hypophysis. However, the possibility that nifedipine might inhibit the action of AVP at renal collecting tubules cannot be negated. In addition, whether the observed natri‐ and kaliuresis would be due to placebo or water deprivation (or both) requires further studies.
Nizatidine Suppression of Basal Gastric Acid Output: A Comparison of Two Intravenous Dosage Regimens
Authors: Danziger Larry , Furmaga Kevin M. , Rodvold Keith A. , Bombeck C. Thomas , Fischer James H.
Published: March 2013

To study the pharmacokinetics and pharmacodynamics of two intravenous nizatidine dosing regimens, serial plasma concentrations and continuous intragastric pH were monitored simultaneously in 10 subjects with a documented history of duodenal or gastric ulcers. A 24‐hour gastric pH profile was characterized for a 300 mg daily dose of nizatidine randomly administered both as 100 mg every 8 hours and 150 mg every 12 hours. No significant differences were observed in the mean pharmacokinetic parameters between the two dosing regimens. Pharmacodynamic parameters for the 100 mg every 8 hours versus the 150 mg every 12 hours regimen were not significantly different except for percent of time during the 24‐hour study period that the pH was maintained >4 (43.6 ± 20.7 versus 34.7 ± 18.3, P < .05). A significant relationship was demonstrated for both regimens (P < .05) between the percent time pH > 4 and area under the plasma curve for the 24 hour study period. The lack of a significant difference in nizatidine pharmacokinetics between the two dosage regimens suggests a pharmacodynamic cause for the greater cumulative pH effect of the every 8 hour regimen.
The Effect of Food on the Bioavailability of Velnacrine (HP 029) in Healthy Elderly Men: A Potential Alzheimer Agent
Authors: Puri Surendra K. , Hsu Robert S. , Ho Irwin , Lassman Howard B.
Published: March 2013

Velnacrine (HP 029; 1,2,3,4‐tetrahydro‐9‐aminoacridin‐1‐ol‐maleate) is an investigational drug being studied in patients with Alzheimer's disease. In this open, randomized, crossover study, 24 healthy, elderly men were given 100 mg of velnacrine on two different study days to assess the influence of food on the bioavailability of velnacrine. On the first day, subjects received drug either after an overnight fast or 15 minutes after completing a standard breakfast. Seven days later, the treatments were crossed over. Blood and urine samples were collected at specific times and various intervals, respectively, from all subjects before and after drug administration for up to 24 hours. Plasma and urine concentrations of velnacrine were determined by an HPLC method. Administration of velnacrine with food resulted in slightly lower peak plasma levels of unconjugated velnacrine, (175 vs 213 ng/ml) and delayed times‐to‐peak plasma levels, (2.5 vs 1.5 h) without affecting the AUCs and the t1/2 of the drug. The amount of unconjugated velnacrine excreted in urine was slightly higher when the drug was taken with food (19 vs 17 mg), but renal clearance was not altered. These results indicate that food delayed the rate but not the extent of velnacrine absorption. The minor differences in Cmax and tmax may not be clinically meaningful. Therefore, velnacrine can be administered with or without food.
Differences in Oral Verapamil Absorption as a Function of Time of Day
Authors: Eldon Michael A. , Battle Michele M. , Voigtman Ronald E. , Colburn Wayne A.
Published: March 2013

As part of a multiple dose bioavailability study, 80‐mg verapamil hydrochloride tablets were administered to healthy subjects every 8 hours for 15 doses. Statistically significant successive decreases in verapamil maximum plasma concentrations (Cmax) and area under the concentration‐time curve (AUC) values were observed corresponding to dosing at 8 AM, 4 PM, and 12 AM. Mean Cmax and AUC values from the 12 AM dose were decreased 36% and 30%, respectively, relative to those from the 8 AM dose. Similar effects on norverapamil pharmacokinetics were observed. Decreased Cmax and AUC values show that verapamil absorption is influenced by the time of day when doses are administered. Pharmacokinetic simulation results suggest that the rate of absorption is reduced approximately by one half and two thirds during the 4 PM and 12 AM dosing intervals, respectively, relative to the 8 AM dosing interval. The reductions in verapamil absorption as a function of time of administration observed in this study may in part explain previous reports of reduced antihypertensive effect during evening and night hours as compared to daytime hours.
Dose Dependent Effect of Diltiazem on the Pharmacokinetics of Nifedipine
Authors: Tateishi T. , Ohashi K. , Sudo T. , Sakamoto K. , Toyosaki N. , Hosoda S. , Toyo‐oka T. , Kumagai Y. , Sugimoto K. , Fujimara A. , Ebihara A.
Published: March 2013

The effect of diltiazem pretreatment on the pharmacokinetics of nifedipine were determined in six healthy male volunteers. Placebo or diltiazem (30 mg and 90 mg) was given orally three times daily for 3 days in a double‐blind, Latin square method. On the fourth day, a 20‐mg nifedipine was given orally 1 hour after the last dose of placebo or diltiazem. The mean elimination half‐life of nifedipine prolonged significantly following diltiazem (2.54 hours on placebo vs 3.40 hours on 30 mg diltiazem and 3.47 on 90 mg diltiazem, both P < .01). The mean AUC of nifedipine increased during diltiazem (1726.6 nmol × hr/ml on placebo vs 3838.0 on 30 mg diltiazem, and 5370.0 on 90 mg diltiazem, both P < .05, 30 mg vs 90 mg, 0.1 < P < .05). The ratio of the AUC of primary metabolite (nitropyridine form) to the AUC of nifedipine was reduced by diltiazem pretreatment in a dose‐dependent manner. ICG clearance was not influenced following diltiazem. These results indicate that diltiazem dose‐dependently alters the pharmacokinetic profiles of nifedipine. The ICG clearance test showed that the liver blood flow did not decrease during diltiazem therapy, therefore, the reduction in the metabolic clearance of nifedipine might be caused by inhibiting effect of diltiazem on the activity of drug oxidizing enzymes.
The Efficacy and Tolerability of Nifedipine (NIF) and Nisoldipine (NIS) Both Alone and Combined with a Beta‐Blocker in Patients with Essential Hypertension: A Multicenter, Parallel‐Group Study
Authors: Rosenfeld J. B. , Zabludowski J.
Published: March 2013

We have assessed the efficacy and tolerance of Nifedipine twice daily and Nisoldipine once daily, both alone and in combination with a beta‐blocker in 171 essential hypertensives in a randomized parallel comparison fashion. Both drugs were equally effective in lowering blood pressure: 72.6% of the subjects on Nisoldipine and 80.5% of those on Nifedipine reached a supine diastolic blood pressure ≤ 90 mmHg. Spontaneously reported side effects were frequent but no biochemical, hematological or electrocardiographic abnormalities were detected.
Ibuprofen and Acetaminophen in the Relief of Acute Pain: A Randomized, Double‐Blind, Placebo‐Controlled Study
Authors: Cooper Stephen A. , Schachtel Bernard P. , Goldman Elliot , Gelb Sanford , Cohn Perry
Published: March 2013

To determine the relative analgesic efficacy of ibuprofen 400 mg and acetaminophen 1000 mg, we conducted a single‐dose, double‐blind, placebo‐controlled, randomized clinical trial using a standard assay for analgesic agents, the dental pain model. At regular intervals over 6 hours, 184 patients who had undergone dental impaction surgery rated pain intensity and relief on categorical scales and pain half‐gone on a dichotomous nominal scale; a categorical overall evaluation was completed at the end of 6 hours. Both active agents were effective compared to placebo. Ibuprofen 400 mg was more effective than acetaminophen 1000 mg for Sum Pain Intensity Difference (SPID), Total Pain Relief (TOTPAR), sum pain half‐gone, and overall evaluation (P < .05 to P < .001). The time‐effect curves demonstrated a greater peak effect and longer duration of action for ibuprofen 400 mg compared to acetaminophen 1000 mg. Side effects were reported in five ibuprofen patients, 11 acetaminophen‐treated patients, and seven placebo patients. Based on the results of this clinical study, we conclude that ibuprofen 400 mg is a safe and more effective analgesic than acetaminophen 1000 mg for patients with acute pain.
BOOK REVIEWS
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

Molecular Aspects of Human Disease Volume 1 Editor: J. W. Gorrod.

Pharmacological Issues in Alcohol and Substance Abuse Editor: Barry Stimmel, MD The Haworth Press, Inc. Binghamton, NY, 1989.

Alcohol Research from Bench to Bedside Editors: Enoch Gordis, MD, Boris Tabaoff, PhD, and Markku Linnoila, MD, PhD The Haworth Press, Inc. Binghamton, NY, 1989.

Journal of Pharmaceutical Marketing & Management Volume 3, No. 3 Editor: Mickey C. Smith, RPh, PhD The Haworth Press, Inc. Binghamton, NY, 1989.

Journal of Geriatric Drug Therapy Volume 3, No 3 Editor: James Cooper, PhD, FCP The Haworth Press, Inc. Binghamton, NY, 1989.

Journal of Research in Pharmaceutical Economics Volume 1, No. 1 Editor: Mickey C. Smith, RPh, PhD. The Haworth Press, Inc. Binghaton, NY, 1989.

Drugs and the Athlete—Contemporary Exercise and Sports Medicine Volume 2 Editor: Allan J. Ryan, MD. F. A. Davis Company.
Peripheral Hemodynamic and Humoral Effects of Oral Zofenopril Calcium (SQ. 26,991) in Patients with Congestive Heart Failure
Authors: Borghi Claudio , Magelli Carlo , Boschi Stefano , Costa Francesco V. , Capelli Maurizio , Varani Elisabetta , Magnani Bruno , Ambrosioni Ettore
Published: March 2013

In 14 patients with congestive heart failure (CHF) of various grade (NYHA class 2–4) the effects of zofenopril calcium (SQ 26,991) on blood pressure and forearm circulation were studied by venous occlusion pletismography. Changes in plasma renin activity (PRA), aldosterone, Atrial natriuretic factor (ANF) and arginine‐vasopressin (AVP) were also measured. Two hours after oral administration of 7.5 mg of zofenopril we observed a decrease in blood pressure, heart rate, and forearm vascular resistance along with an increase in venous distensibility. Zofenopril also decreased ANP levels in a manner directly related to peripheral venodilatation (r = .64; P < .05) and modified arginine‐vasopressin (AVP) proportionally to the fall in blood pressure observed in response to drug administration (%SBP/%AVP: r = .64, P < .05; % DBP/%AVP: r = .67, P < .05). Hemodynamic and humoral responses to zofenopril occurred without any significant unwanted adverse reaction, even in patients with greater pressor reduction. We conclude that oral acute zofenopril administration, in patients with congestive heart failure, causes an arterial and venous forearm vasodilatation which is probably involved in the acute changes in plasma levels of ANF and AVP observed after drug administration.
Comparison of Oral and Aerosol Ribavirin Regimens in the High Risk Elderly
Authors: Bernstein Jack M. , Liss Howard , Erk Stanley D.
Published: March 2013

A comparison of different regimens of ribavirin (R), administered either orally or by aerosol, was performed in 16 elderly subjects (13 men, 3 women, mean age 63 ± 8 years) considered to be in the “high‐risk” category for complications from influenza as defined by the Centers for Disease Control. The subjects were divided into four groups. Group O‐600 received 600 mg orally R every 8 hours for 48 hours followed by 200 mg every 8 hours for 72 hours for a total dose of 5.4 g (22.1 mmol). Group O‐800 received 800 mg oral R every 8 hours for 24 hours followed by 400 mg every 12 hours for 96 hours for a total dose of 4.1 g (22.9 mMoles). Group A‐40 received R (40 mg/ml) aerosolized through a small particle aerosol generator for 6 hours every 12 hours for 96 hours, yielding an average delivered dose of 6.2 g (25.4 mMoles) R. Group A‐60 received aerosolized R (60 mg/mL) for 2 hours every 8 hours for 96 hours, yielding an average delivered dose of 4.6 g (18.8 mMoles) R. No hematologic or other laboratory abnormalities were associated with any of the regimens. Group O‐800 and O‐600 reached mean peak plasma R levels of 11.8 μM and 5.3 μM, respectively, after 18 hours of therapy. Subsequent administration of 20 mg R every 8 hours was sufficient to maintain a plasma R level greater than 7 μM. Among the aerosol groups, group A‐40 approached steady state plasma R levels (8–10 μM) more quickly than group A‐60. Steady state levels could be maintained by administering 60 mg/ml aerosol R for 2 hours, every 8 hours. No adverse pulmonary effects were noted in any patient. Further trials evaluating the clinical efficacy of oral and aerosol ribavirin in the elderly should be carried out.
BOOK REVIEWS
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

Advances in Biotechnology of Membrane Ion Transport— Serono Symposia Publications Volume 51 Editors: P. L. Jorgensen and R. Verna.

Molecular Aspects of Human Disease Volume 2 Editor: J. W. Gorrod.

Nurse's Drug Reference—NDR 89 Editors: George R. Spratto and Adrienne L. Woods.
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 towards 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.
Propafenone Disposition in Renal Insufficiency and Renal Failure
Authors: Burgess Ellen , Duff Henry , Wilkes Peter
Published: March 2013

The pharmacokinetics of a single intravenous dose of propafenone were studied in subjects with normal renal function (n = 5), renal insufficiency (n = 5), and renal failure (n = 3). No difference in central volume of distribution, total systemic clearance or terminal half‐life existed. None of the pharmacokinetic parameters examined correlated to creatinine clearance. Within the confines of the small number of patients studied, there does not appear to be any effect of renal insufficiency or failure on single‐dose propafenone disposition.
Absolute Bioavailability and Noncompartmental Analysis of Intravenous and Intramuscular Cefotan® (Cefotetan) in Normal Volunteers
Authors: Zimmerman James , Cohen Albert , Thyrum Per
Published: March 2013

Cefotetan (1 g) was administered to 12 normal volunteers as a 30 minute intravenous infusion and as an intramuscular injection. The pharmacokinetic parameters were estimated using noncompartmental analysis. The mean ± SD maximum plasma concentration, terminal half‐life, and systemic clearance after intravenous infusion were 158 ± 21 μg/mL, 4.54 ± 1.05 hours, and 29.1 ± 3.8 mL/min/1.73 m2, respectively. Renal clearance and nonrenal clearance accounted for 63.1% and 36.9% of the systemic clearance, respectively. The mean ± SD maximum plasma concentration, time to maximum concentration, terminal half‐life, and absolute bioavailability after intramuscular injection were 75.5 ± 8.7 μg/mL, 1.33 ± 0.48 hours, 4.32 ± 0.77 hours, and 0.931 ± 0.193, respectively. Moment analysis gave average ± SD mean residence times (MRT) of 4.98 ± 0.75 and 5.86 ± 0.77 hours after intravenous and intramuscular administration, respectively. The average ± SD mean absorption time (MAT) after intramuscular injection was 1.11 ± 0.57 hours. The mean ± SD steady‐state volume of distribution after intravenous infusion was 0.129 ± 0.024 L/kg. The mean ± SD cumulative percentages of the dose excreted in the urine in 24 hours were 61.1 ± 11.4% and 50.4 ± 13.5% after intravenous and intramuscular dosing, respectively. The maximum urinary cefotetan concentrations occurred during the first 2 hours after dosing by both routes of administration. Cefotetan tautomer was detected in the plasma and urine of all subjects after both routes of administration, but the mean concentrations were only minimal compared to those for cefotetan. In conclusion, intramuscular cefotetan (1 g) is rapidly and almost completely absorbed. The near coincidence of plasma mean cefotetan concentrations starting at 2 hours after intramuscular and intravenous administration suggests that intramuscular cefotetan is a reasonable alternative to intravenous dosing in the treatment of infections due to susceptible bacteria.
Antihypertensive Therapy in the Geriatric Patient I: A Review of the Role of Calcium Channel Blockers
Authors: Piepho Robert W. , Sowers James R.
Published: March 2013

Animal and clinical studies have demonstrated the efficacy of calcium channel blockers in reducing blood pressure, especially in older patients whose hypertension is characterized by increased peripheral vascular resistance. Their chemical heterogeneity, which permits targeted therapy, as well as their minimal side effects, drug interactions, and clinical utility in numerous pathophysiologic states common to the elderly, enhance the suitability of calcium channel blockers in treating mild to moderate hypertension in this subgroup. This is particularly relevant for those patients who have concomitant conditions, such as diabetes, chronic obstructive pulmonary disease, or peripheral vascular disease, and for whom many of the more traditional antihypertensive drugs are either contraindicated or might cause a worsening of the disease.
Obesity and Beta‐Blockers: Influence of Body Fat on Their Kinetics and Cardiovascular Effects
Authors: Galletti Ferruccio , Fasano Maria Luisa , Ferrara Liberato Aldo , Groppi Angelo , Montagna Maria , Mancini Mario
Published: March 2013

Beta‐blockers are among the most widely used antihypertensive drugs. They differ from each other in regard to several factors such as: β‐agonist activity, β1‐selectivity and solubility. Aim of this work was to evaluate the influence of obesity on the kinetics and the antihypertensive effect of two Beta‐blockers with different solubility such as: the water‐soluble, atenolol and the liposoluble, metoprolol. The study was carried out according to an open randomized cross‐over design. Eight obese hypertensive patients, after a two week washout period, were randomly allocated to a four week treatment. After a two week intermediate washout period, each patient switched to the other treatment for an additional four week period. On the first and the last day of each treatment the subjects were hospitalized to collect blood samples for the assay of the two drugs and to measure cardiovascular parameters. Obesity does not exert any effect on the kinetics of the water‐soluble beta‐blocker, atenolol, while markedly interferes with that of the liposoluble, without any apparent influence on its anti‐hypertensive effect. These findings extend to obese hypertensives the concept that the plasma concentrations of beta‐blocking agents are not reliable predictors of their therapeutic effect.
Pharmacokinetics of Oral Nifedipine: Relevance of the Distribution Phase
Authors: Hoyo‐Vadillo C. , Castañeda‐Hernández G. , Herrera J. E. , Vidal‐Gárate J. , Salazar L. A. , Moreno‐Ramos A. , Chávez F. , Tena I. , Hong E.
Published: March 2013

Pharmacokinetics of oral Nifedipine was studied in 12 Mexican young healthy volunteers, six men and six women, who received a 10 mg capsule. Plasma levels were determined by a nifedipine specific HPLC assay. Experimental data were fitted and pharmacokinetic parameters were calculated using an open two compartment model. No statistically significant difference was detected between men and women, thus both sexes were considered as a single population. Nifedipine plasma levels rose rapidly (ka = 8.46 ± 1.96 h−1) reaching a maximum concentration of 145 ± 23 ng/ml in 0.61 ± 0.07 h. Plasma levels then decayed with a distribution phase (α = 1.98 ± 0.40 h−1 t1/2α = 0.46 ± 0.06 h) and a terminal elimination phase (β = 0.17 ± 0.03 h−1 t1/2β = 4.98 ± 0.55 h). AUC was 384 ± 41 ng h/ml. Values of AUC and t1/2β were higher than those reported by other authors. Differences in the AUC could be due to ethnic origin, environmental factors or nutritional habits. Ten subjects presented plasma concentration‐time curves in which the distribution phase was clearly distinguishable, having a ka/α relationship higher than 1.5. For the other two subjects, the distribution phase was not apparent and ka/α was lower than 1.5. The results show that an adequate characterization of the distribution phase is required if one pretends to use pharmacokinetic data for dosage regimen design.
Extension of the Serum Digoxin Concentration—Response Relationship to Patient Management
Authors: Kolibash Albert J. , Lewis Richard P. , Bourne David W. A. , Kramer William G. , Reuning Richard H.
Published: March 2013

The purposes of this investigation were to demonstrate how computer simulations may be employed to extrapolate data obtained from a single intravenous digoxin dose to multiple oral dosing patterns and how these simulations may apply to clinical situations. The intravenous data were obtained from a previous study of the pharmacokinetics of serum digoxin and its inotropic response (derived from systolic intervals) in 12 normal male volunteers. The simulations were applied to various clinical situations including variations in oral dosing, alternate loading doses, no loading versus loading dose, and intravenous versus oral dosing. A nonlinear relationship was found between response and the post‐distribution serum digoxin concentration in the therapeutic range. Thus, the increase in inotropic response is less than proportional to the increase in digoxin concentration in serum. This nonlinear relationship has several important clinical implications for loading and maintenance dosing protocols. Such concepts may be important relative to more rational clinical use of digoxin and to decreasing digoxin toxicity.