bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Size and Shape of Tablets on Their Esophageal Transit
Authors: Channer Kevin S. , Virjee James P.
Published: March 2013

The esophageal transit times of small‐ and medium‐sized barium sulfate tablets were measured using x‐ray fluoroscopy in 50 patients after swallowing while in both erect and supine positions with a 15‐mL drink, and the esophageal transit times of large round and oval barium sulfate tablets were similarly measured in 25 patients. When tablets were swallowed by subjects who were standing, no difference was found between the transit times of small and medium tablets, but large oval tablets had significantly shorter times than did large round tablets (P < .04). The transit times of both small and medium tablets were significantly shorter than those of oval (P < .05) and large round tablets (P < .02). Retention of large oval and round tablets in the esophagus occurred in 20% of patients after swallowing while in the standing position. No medium‐sized tablet was retained, but in 4% of patients, a small tablet remained in the esophagus. Tablets that were retained in the esophagus remained there for five minutes, when they were washed down by a further drink. When tablets were swallowed in the lying position, no significant differences in transit times were found between any of the four tablets. Retention of tablets within the esophagus occurred in over 60% of patients with all four tablets after ingestion while in the supine position. Tablets stuck mainly in the lower esophagus above the lower esophageal sphincter, but after swallowing in the standing position, a significant proportion (33% [P < .01]) stuck in the upper esophagus. In conclusion, size and shape of tablets affected esophageal transit time after swallowing while in the standing but not in the supine position. Patients should be advised to swallow all tablets whatever their size or shape with a large drink while standing. Changing the shape of tablets from round to oval may aid esophageal transit.
Postburn Serum Drug Binding and Serum Protein Concentrations
Authors: Bloedow Duane C. , Hansbrough John F. , Hardin Thomas , Simons Michael
Published: March 2013

The free fractions of diazepam, imipramine, lidocaine, meperidine, phenytoin, propranolol, and salicylic acid were determined in the serum of seven burn patients (25% to 80% of their skin surface burned) about one week after the burn and in three of the patients at about four weeks following the injury. Serum protein fractions were measured by electrophoresis, and alpha‐1 acid glycoprotein levels were determined. For the drugs that bind predominantly to albumin, the serum free fractions were greater in patients one week after the burn incident than in control subjects (diazepam, 0.055 vs. 0.017; phenytoin, 0.24 vs. 0.16; and salicylic acid, 0.69 vs. 0.32). The increase in free fraction for these drugs was attributed to the postburn decrease in serum albumin levels (2.2 vs. 4.4 g/dL, control). Imipramine, lidocaine, meperidine, and propranolol bind primarily to alpha‐1 acid glycoprotein. The free fractions for these drugs decreased one week following the burn (imipramine, 0.074 vs. 0.095; lidocaine, 0.17 vs. 0.35; meperidine, 0.37 vs. 0.48; and propranolol, 0.045 vs. 0.107), presumably in response to the increased alpha‐1 acid glycoprotein concentration (222 vs. 83 mg/dL, control). Diazepam, lidocaine, propranolol, and salicylic acid free fractions were still different from control values at four weeks after the accident.
Book Reviews
Authors: Cavaliere M. Beth
Published: March 2013

Book reviewed in this article:

Variability in Drug Therapy: Description, Estimation, and Control edited by Malcolm Rowland, Lewis B. Sheiner, and Jean‐Louis Steimer

Chronic Treatments in Neuropsychiatry (Advances in Biochemical Psychopharmacology, Volume 40), Edited by Dargut Kemali and Giorgio Racagni
Pharmacokinetics and Pharmacodynamics of Pentopril, a New Angiotensin‐Converting‐Enzyme Inhibitor in Humans
Authors: Rakhit Ashok , Hurley Margaret E. , Tipnis Vijay , Coleman Jean , Rommel Alan , Brunner Hans R.
Published: March 2013

In a single, ascending‐dose tolerance study, nine healthy volunteers were given oral pentopril 50 to 750 mg (CGS 13945) in groups of three each. Disposition characteristics of pentopril and its active metabolite (CGS 13934) were determined using plasma concentration and urinary excretion data. The drug was absorbed rapidly following zero‐order kinetics. The drug has an apparent volume of distribution of 0.83 L/kg and an oral clearance of about 0.79 L/hr/kg. Urinary excretions, calculated after 125‐ and 250‐mg doses, showed a dose proportional urinary recovery of 21% (±5%) for pentopril and 40% (±5%) for CGS 13934. In the multiple‐dose study of 125 mg orally q12h in six healthy subjects, the plasma concentrations for both drug and metabolite showed no appreciable accumulation of either compound, which was expected from their short pharmacokinetic half‐lives (pentopril, <1 hr; CGS 13934, ∼2 hr). In a separate pharmacodynamic study, drug and metabolite concentrations were evaluated against angiotensin‐I (AI)‐induced changes in blood pressure and plasma angiotensin‐converting‐enzyme (ACE) activity in healthy volunteers after single oral doses (range, 10–500 mg). The pharmacodynamic half‐life for plasma ACE inhibition increased with the dose (10 mg, 1.5 hr; 500 mg, 9.8 hr). There was a close relationship between the plasma level of the metabolite and the inhibition of plasma ACE activity and AI‐induced pressor response. A hyperbolic function adequately described the dependence of plasma ACE activity on plasma metabolite concentration with a concentration at half‐maximal inhibition of 53 ng/mL.
Influence of Cardiopulmonary Bypass on Nitroglycerin Clearance
Authors: Dasta Joseph F. , Weber Robert J. , Wu Lei Shu , Sokoloski Theodore D. , Kakos Gerard S. , Smith Douglas F. , Howie Michael B.
Published: March 2013

The effect of cardiopulmonary bypass on the clearance of nitroglycerin (NTG) was studied in seven patients scheduled for coronary artery bypass graft surgery. Intravenous NTG was administered through nonadsorbing tubing at a starting dosage of 5–10 μg/min and was adjusted as needed. Blood samples were obtained from the radial artery and antecubital vein before bypass and from the arterial outlet of the oxygenator during bypass at least 30 minutes apart during a constant dosage or at least 30 minutes after a dosage change. Serum concentrations were analyzed for NTG by gas chromatography. Venous NTG concentrations were always lower than concurrent arterial concentrations, with an average arteriovenous extraction of 67.2%. Serum concentrations of NTG were generally within the range associated with a therapeutic response in congestive heart failure patients. Consistent with other reports, NTG concentrations varied widely among patients and considerable intrasubject fluctuations in drug concentrations were seen. The mean ± SD apparent clearance of NTG before bypass of 0.044 ± 0.02 L/kg/min increased 20% to 0.052 ± 0.02 L/kg/min during bypass (P = .05). These results suggest that cardiopulmonary bypass increases the clearance of NTG; however, the magnitude appears to be small and only partially explains the reported increased dosage needed during cardiopulmonary bypass.
Effects of Esmolol on Airway Function in Patients with Asthma
Authors: Sheppard Dean , DiStefano Sandra , Byrd Randolph C. , Eschenbacher William L. , Bell Valerie , Steck James , Laddu Atul
Published: March 2013

In a double‐blind, randomized, crossover study in ten patients with asthma, the effects on specific airway resistance of esmolol, a new ultra‐short‐acting beta1‐selective adrenoceptor blocker, were compared with those of placebo. Specific airway resistance was measured during increasing doses of esmolol infusion, during dry air provocation tests, and following isoproterenol inhalation. These same studies were later carried out on six of ten patients following intravenous propranolol infusion. All patients were able to tolerate the maximum dose of esmolol (300 μg/kg/min); treatment differences between esmolol and placebo were not found. In contrast, intravenous propranolol produced marked symptomatic bronchoconstriction after the lowest dose (1 mg) in two of six patients. Esmolol produced slight but statistically significant enhancement of patients' sensitivity to dry air provocation. Similarly, a slight but significant inhibition of bronchomotor sensitivity to isoproterenol was noted during esmolol infusion. After infusion of 5 mg of intravenous propranolol, one of four patients had a clinically significant increase in sensitivity to dry air. It is concluded that esmolol, because of its short duration of action and relative lack of effect on airway resistance, may be preferred over propranolol in patients with asthma who require treatment with an intravenous beta‐blocking agent.
Pharmacologic Support of the Myocardium Following Aortocoronary Bypass Surgery: A Comparative Study
Authors: Balderman Samuel C. , Aldridge Janerio
Published: March 2013

To evaluate the hemodynamic effects of simultaneous nitroglycerin and epinephrine infusion following aortocoronary bypass surgery, 16 patients were monitored and studied in the early postoperative period. All patients were given intravenous nitroglycerin, epinephrine, epinephrine combined with nitroglycerin, and dobutamine in a randomized manner. The dose of pharmacologic agent was gradually increased to achieve the required circulatory response. The measured variables included heart rate (HR), central venous pressure (CVP), arterial blood pressure (BP), pulmonary artery pressure (PA), pulmonary artery wedge pressure (PAWP), cardiac output, and arterial and venous oxygen saturations. A nitroglycerin infusion at 1.1 ± 2 μg/kg/min caused the PAWP to decrease by 37% (P .005). All other parameters were not significantly different from control. Epinephrine at a dose of 0.06 ± 0.02 μg/kg/min increased the mean blood pressure by 21% (P .005). The rate‐pressure product (RPP) and PAWP were elevated by 18% and 12%, respectively (P .005). Cardiac index, however, was not increased. When nitroglycerin was added to the epinephrine infusion, a PAWP increase was not seen. Also, the right ventricular stroke work index was increased by 23% (P .01), and the left ventricular stroke work index increased by 21% (P .01). Dobutamine 4.8 ± 1.0 μg/kg/min caused ventricular stroke work indexes to increase significantly (P .005). The CVP and PAWP were unchanged with this mode of therapy. Therefore, nitroglycerin is a drug of choice in patients with normotensive heart failure, since cardiac index can be maintained at lower filling pressures without increasing the myocardial oxygen consumption as reflected by the constant RPP. In the presence of hypotension, dobutamine, possibly combined with a vasodilator, or epinephrine and nitroglycerin combined are effective in improving function. Epinephrine infusion alone should be avoided in the presence of ischemic heart disease.
The Influence of Hemodialysis on the Pharmacokinetics of Ibuprofen and Its Major Metabolites
Authors: Antal E.J. , Wright C.E. , Brown B.L. , Albert K.S. , Aman L.C. , Levin N.W.
Published: March 2013

The pharmacokinetics of ibuprofen and its two major metabolites, the hydroxy and carboxy derivatives, were studied in seven functionally anephric subjects undergoing hemodialysis therapy. Subjects received ibuprofen 800 mg tid for 14 days. Hemodialysis was performed three times weekly during this period. Arterial and venous blood samples were collected before dialysis and along with dialysate, and during the final dosing interval and dialysis session. No accumulation of ibuprofen plasma concentrations and an absence of intact ibuprofen in dialysate indicated clearance through metabolic pathways. The metabolites did accumulate significantly (mean plasma levels, carboxy 249 μg/mL and hydroxy 57 μ/mL); however, both were detected in dialysate. Mean extraction efficiencies were 0.16 (hydroxy) and 0.15 (carboxy). Dialysis clearance calculated by arterial‐venous difference was found to agree with actual recovery in dialysate for both metabolites. Side effects were not observed in any subject.
Correlation Between Thiopental Induction Dose and the Volume of Distribution of Caffeine in Human Subjects
Authors: DeLaRocha Alvaro , Inchiosa Mario A. , Milliken Ralph A. , Schmahai Theodore J. , Bizzarri Dante V.
Published: March 2013

The correlation between the apparent volume of distribution (aVd) of caffeine and the induction dose of thiopental was studied in 23 patients. Caffeine, which has an effective partition coefficient that approaches that of thiopental, was used as an indicator substance to estimate the immediate volume of distribution of thiopental. The immediate volume of distribution is critical in determining thiopental induction dose. The aVd of caffeine was determined noninvasively from serial saliva samples after consumption of caffeine, which was given to the patients as coffee. A strong correlation (r = .69; P < .01) was found between the aVd of caffeine and the anesthetic induction dose of thiopental when the loss of eyelid reflex was used as the end point. The correlation between thiopental induction dose and body weight for the same individuals (r = .188) was not statistically significant.
Minimum Effective Dose of Etodolac for the Treatment of Rheumatoid Arthritis
Authors: Jacob Ginette , Messina Marianne , Kennedy Jacqueline , Epstein Carol , Sanda Marie , MD John Mullane
Published: March 2013

Etodolac was compared with aspirin and placebo for efficacy and safety, and a minimum effective dose was established in 264 patients with adult‐onset, active rheumatoid arthritis. In this six‐week, 14‐center, double‐blind, parallel‐group investigation, preceded by a washout period of up to two weeks, patients received daily doses of etodolac at 50, 100, or 200 mg/d; aspirin at 3,900 mg/d; or placebo. Both etodolac at the highest dose and aspirin produced statistically significant improvement from baseline in all disease activity assessments measured at four‐ and six‐week end points and were superior to placebo in the majority of assessments. A greater number of patient complaints occurred with aspirin, especially in regard to gastrointestinal‐related and otologic side effects. A significant therapeutic dose response was evident among the etodolac groups without an increase in side effects. Although the 100‐mg/d dose was effective in many of the efficacy parameters measured, the 200‐mg/d dose, which is comparably efficacious to aspirin 3.9 g/d, was suggested as the minimum effective dose for the relief of the signs and symptoms of active rheumatoid arthritis.
Voluntary Respiratory Effects of Butorphanol and Fentanyl Following Barbiturate Induction: A Double‐Blind Study
Authors: Dryden Gale E.
Published: March 2013

Thirty‐one healthy women undergoing outpatient gynecologic surgery were given either butorphanol or fentanyl following barbiturate induction, and various respiratory parameters were measured at intervals after administration of the study drugs. Both fentanyl and butorphanol caused comparable decrements in tidal volume and other respiratory parameters. However, seven of the 15 patients receiving fentanyl had significant respiratory depression that required assisted ventilation. One of the butorphanol patients experienced a 45‐second self‐limited respiratory depression. One of three butorphanol patients experiencing side effects required treatment for these effects, compared with seven of nine fentanyl patients who experienced adverse effects. It is concluded that butorphanol and fentanyl have comparable anesthetic effects, but butorphanol is safer in terms of respiratory and adverse effects.
Enhanced Bioavailability of Triazolam Following Sublingual Versus Oral Administration
Authors: Scavone Joseph M. , Greenblatt David J. , Friedman H. , Shader Richard I.
Published: March 2013

The rate and extent of the absorption of triazolam following sublingual and oral administration were evaluated in this study. Eight healthy volunteers received triazolam 0.5 mg in a commercially available tablet, by sublingual and oral routes on two occasions in random sequence. Plasma triazolam concentrations during 24 hours after each dose were measured by electron‐capture gas‐liquid chromatography. The mean total area under the curve for sublingual administration was significantly larger than that following oral dosage (28.9 vs 22.6 ng‐hr/mL, P < .025). The peak plasma concentration after sublingual dosage was also higher than after oral administration (4.7 vs 3.9 ng/mL, P < .1). No significant differences between sublingual and oral administration were found for the elimination half‐life of triazolam (4.1 vs 3.7 hr) and the time of peak concentration (1.22 vs 1.25 hr) after dose. Thus, the bioavailability of triazolam after sublingual administration is increased by an average of 28% compared with oral administration of the same dose, possibly because first‐pass extraction is bypassed. Clinical effects of triazolam may likewise be enhanced by sublingual dosage.
Treatment of Depression in Chronic Cocaine and Phencyclidine Abuse With Desipramine
Authors: Giannini A. James , Malone Donald A. , Giannini Matthew C. , Price William A. , Loiselle Robert H.
Published: March 2013

An open field trial was conducted comparing desipramine and an active placebo in separate populations of chronic cocaine and phencyclidine (PCP) abusers, who discontinued their abuse. Subjects who received desipramine showed a decrease in depressive symptoms after a 20–40 day period regardless of whether they abused PCP or cocaine.
Serum Protein Binding of Valproic Acid in Fetus‐Mother Pairs Throughout Pregnancy: Correlation With Oxytocin Administration and Albumin and Free Fatty Acid Concentrations
Authors: Nau Heinz , Krauer Béatrice
Published: March 2013

The protein binding (expressed as percent free drug fraction) of the antiepileptic drug valproic acid (VPA) was studied in 65 fetus‐mother pairs from weeks 13 to week 41 of gestation. The fetal free fractions (expressed as percent of total concentrations) of VPA were exceedingly high (>50%) during weeks 13 to 16 of gestation; these values decreased to 20% by week 20 and further decreased gradually to 10% at term. There was a highly significant negative correlation between free VPA fractions and fetal albumin concentrations. Maternal free fractions of VPA gradually increased from 10% during early pregnancy to 20% at term. The free fractions of VPA were significantly higher in mothers who had received oxytoxin. Thus, protein binding in the fetus exceeded that of the mother at term, whereas the converse was true during early gestation. These results agree with previous in vivo findings. It is likely that the free concentrations in the mother determine the drug effects and toxicity in both the mother and the fetus. Intermittent drug administration—particularly of large single doses—could result in a transient increase of the free concentrations of VPA, particularly because of the strong concentration dependence of VPA protein binding. Increased free fractions can also be expected from increased concentrations of displacing agents of endogeneous or exogeneous origin (other drugs).
Single‐Dose Pharmacokinetics of Oral Ciprofloxacin in Patients With Cystic Fibrosis
Authors: Goldfarb Johanna , Wormser Gary P. , Inchiosa Mario A. , Guideri Giancarlo , Diaz Magaly , Gandhi Ruta , Goltzman Carey , Mascia Armond V.
Published: March 2013

The singie‐dose pharmacokinetics of oral ciprofloxacin were studied in ten patients with cystic fibrosis aged 18 to 34 years. Each patient received three different drug doses (500 mg, 750 mg, and 1,000 mg) at successive one‐week intervals. Dosing and drug assays were double blinded. Blood and urine were assayed over the 48 hours following each dose. Ciprofloxacin was absorbed from the gastrointestinal tract. Peak serum concentrations averaged 2.8, 4.5, and 4.6 μg/mL respectively at the three doses, well above the mean inhibitory concentrations of most isolates of Pseudomonas aeruginosa. Time to peak concentration was approximately two hours. The range of sputum levels in three patients was 1.1–2.1 μg/mL at four hours after the three doses. The serum elimination half‐life was 3.7 hours and was independent of dose. Urinary recovery was 26%; greater than 90% of urinary excretion occurred within the first 12 hours. The results of this study indicate that ciprofloxacin has potential for use in the treatment of P aeruginosa infections in patients with cystic fibrosis.
Intrarenal Concentration‐Time Profile of Ampicillin After Administration of Bacampicillin to Patients Before Nephrectomy
Authors: Seppänen J. , Hällström O. , Sjövall J. , Vaalasti T.
Published: March 2013

Nineteen patients with renal cancer who were to undergo nephrectomy received a single oral dose of bacampicillin 800 mg at approximately three (N = 5), six (N = 7), or nine (N = 7) hours before nephrectomy. Serum samples were taken at 30, 60, and 90 minutes after administration and at nephrectomy. Urine was collected immediately before operation. Samples of medulla and cortex tissues were immediately and carefully dissected from a healthy part of the removed kidney and homogenized with a buffer solution. All concentrations were determined by bioassay. Bacampicillin was well absorbed, with a mean ± SD serum concentration of 16.0 ± 11.4 mg/L at one hour. The concentrations in renal tissues were higher than the serum levels taken at the same time, and the highest concentrations were found in the urine. The mean ampicillin elimination half‐life was approximately the same in the cortex, medulla, and urine, (2.7, 2.3, and 2.4 hr, respectively) but it was shorter in the serum (1.4 hr). Bacampicillin 800 mg produced concentrations in the renal tissues that were higher and more sustained than in the serum and were well above the minimum inhibitory concentrations for common urinary pathogens even ten hours after the dose.
Phase I and II Agents in Cancer Therapy: I. Anthracyclines and Related Compounds
Authors: Wadler Scott , Fuks Joachim Z. , Wiernik Peter H.
Published: March 2013

Anthracycline antibiotics remain among the most potent anticancer drugs, but their efficacy is limited by the development of a dose‐dependent irreversible cardiomyopathy and by the emergence of clones of tumor cells resistant to the effects of the drug. Modifications of the basic anthracycline structure have resulted in molecules that may share the activity of the parent compound, with amelioration of some toxicities, absence of cross‐resistance, or activity against tumors insensitive to the parent drug. Epirubicin has a unique metabolic pathway, glucuronidation, that may result in more rapid plasma clearance and reduced toxicity as compared with doxorubicin. Epirubicin has demonstrated comparable activity to doxorubicin in breast cancer, with possibly reduced toxicity. Idarubicin is of interest because of its cytotoxic activity when given orally. Idarubicin has prolonged retention in the plasma and has equal cytotoxic activity to the parent compound. Idarubicin has demonstrated activity against acute leukemia and breast cancer; in the latter tumor category, some doxorubicin‐resistant tumors have responded. Esorubicin is of interest because of its nearly absent cardiac toxicity. This agent has some activity against solid tumors and is currently being clinically tested. Aclacinomycin A is an anthracycline in which a trisaccharide is substituted for the aminosugar. Aclacinomycin A and the related compound marcellomycin are of interest as both cytotoxic and differentiating agents. Menogaril is an anthracycline with the aminosugar on the D ring; it does not exhibit cross‐resistance with doxorubicin or cardiotoxicity. Mitoxantrone is a compound that is related to the anthracyclines but has a different mechanism of action. This agent has significant activity against acute leukemia and breast cancer and is currently being compared with doxorubicin. Amsacrine is another compound related to the anthracyclines that possesses major activity against acute leukemias. Minor modifications of the anthracycline molecule have had major impact on the biologic activity of these drugs. New anthracycline analogues with up to 100 times the potency of currently available anthracyclines are being developed for clinical testing, and these complex molecules retain a nearly unlimited potential for structural modification.
Graphic Methods in Pharmacokinetics: The Basics
Authors: Welling Peter G.
Published: March 2013

A considerable amount of information regarding the kinetics of drug absorption, distribution, metabolism, and excretion can be obtained by graphic analysis of plasma concentration and/or urinary excretion data. The simplest pharmacokinetic model is used to describe the analysis of drug concentration profiles in plasma after administration intravenous or nonvascular routes. Methods to calculate pharmacokinetic and pharmacologic parameters include urinary excretion rate, cumulative excretion, and the construction and analysis of Sigma‐minus plots. The treatment for this simple pharmacokinetic model provides a basis for graphic analysis of more complex models.
The Effect of C1 Spinal Cord Transection or Bilateral Adrenal Vein Ligation on Thioridazine‐Induced Arrhythmia and Death in the Cat
Authors: Lathers Claire M. , Flax Ronald F. , Lipka Leslie J.
Published: March 2013

The phenothiazine thioridazine 1 mg/kg/min was infused intravenously into three groups of cats: (1) thioridazine alone (N = 5), (2) after bilateral adrenal ligation (N = 4), and (3) after spinal cord section at the atlanto‐occipital junction (C1; N = 6). The times to arrhythmia and death with thioridazine alone were 47.8 ± 7.8 and 72.8 ± 5.6 minutes respectively. After bilateral adrenal ligation, arrhythmia and death occurred at 41.1 ± 5.2 and 53.1 ± 5.8 minutes, respectively, which showed no increase (P > .05) from thioridazine alone. After spinal cord section, thioridazine‐induced arrhythmia and death occurred at 74.0 ± 13.7 and 85.7 ± 13.8 minutes, respectively, which were not increased (P > .05) when compared with thioridazine alone. The results of this study suggest that neither adrenomedullary catecholamines nor the central sympathetic component above C1 plays a significant role in acute thioridazine‐induced arrhythmia. The action of thioridazine to induce arrhythmia in spite of transection of the spinal cord or bilateral adrenal vein ligation suggests that its cardiotoxicity is a result of a direct myocardial effect. Thioridazine depressed blood pressure without producing the sustained reflex tachycardia normally seen with hypotension. This suggests that the agent may modify the baroreceptor reflex arc.
Prophylaxis of Migraine Attacks With a Calcium‐Channel Blocker: Flunarizine Versus Methysergide
Authors: Steardo Luca , Marano Enrico , Barone Paolo , Denman Daniel W. , Monteleone Palmiero , Cardone Gennaro
Published: March 2013

In this study, flunarizine, a selective calcium‐channel blocker, was employed in the prophylactic treatment of headache and was compared with methysergide in terms of efficacy. The trial was conducted with 104 patients (53 treated with flunarizine and 51 treated with methysergide) and lasted six months—one month of pretreatment and five months of therapy. Patients in both groups experienced a highly significant reduction in the number and duration of migraine attacks. Unlike those in the methysergide group, patients treated with flunarizine achieved a significant reduction in the intensity of attacks with very negligible side effects.
Pharmacokinetics of Diphenhydramine and a Demethylated Metabolite Following Intravenous And Oral Administration
Authors: Blyden Gershwin T. , Greenblatt David J. , Scavone Joseph M. , Shader Richard I.
Published: March 2013

Ten healthy volunteers received a single 50‐mg dose of diphenhydramine (DP) hydrochloride intravenously and orally on two separate occasions. Kinetics of DP and a major demethylated metabolite (DMDP) were determined from multiple plasma samples drawn during a 24‐ to 48‐hour period after dosage. Modification of a gas chromatographic (GC) technique allowed simultaneous quantitation of DP and DMDP. Mean kinetic variables for DP after intravenous (IV) dosage were: volume of distribution, 4.5 L/kg; elimination half‐life, 8.4 hours; clearance, 6.2 mL/min/kg. After oral DP administration, a peak plasma level of 66 ng/mL was reached 2.3 hours after dosage. Systemic availability was 72%, nearly identical to the predicted estimate (71%) based on clearance of IV DP relative to hepatic blood flow. Appearance of the metabolite, DMDP, mirrored disappearance of DP; the area under the plasma concentration‐time curve (AUC) for DMDP was highly correlated (r = .79, P < .05) with clearance of IV DP. However, metabolite AUC was significantly higher after oral as opposed to IV DP (218 vs 145 hr‐ng/mL, P < .05). Because DP and DMDP elute nearly identically on standard GC systems, methodologic modifications are needed to resolve them. Coelution of the two compounds could bias kinetic data based on plasma concentration presumed to be specific for intact DP.
The Effect of Once‐Daily Minoxidil on Blood Pressure and Plasma Lipids
Authors: Johnson Brian F. , Errichetti Ann , Urbach David , Hoch Kathleen , Johnson Johanna
Published: March 2013

Once‐daily minoxidil administration was added to the treatment regimen of 11 patients with hypertension that was inadequately controlled by nadolol 160 mg and chlorthalidone 50 mg given once daily. Additional diuretic therapy was needed by five patients. During treatment without minoxidil and at three and six months of maintenance minoxidil therapy, respectively, 24‐hour postdose supine blood pressure fell significantly (P <.01) from 142 ± 19/96 ± 6 mm Hg to 132 ± 16/87 ± 4 and 131 ± 12/87 ± 4 mm Hg, and home recordings showed that minoxidil induced a mean increase of about 5 beats/min in heart rate. Resting plasma renin activity was not significantly altered. High‐density lipoprotein (HDL) cholesterol increased from 31.6 ± 9.9 to 35.2 ± 10.9 mg/dL (P <.05) and to 34.4 ± 11.3 mg/dL (NS), and low‐density lipoprotein (LDL) cholesterol decreased from 146 ± 36 to 136 ± 32 mg/dL (P <.05) and to 126 ± 35 mg/dL (P <.01) over the same periods. At six months, approximately 20% changes in ratios of HDL cholesterol to either LDL or total cholesterol were seen. These changes occurred despite a three‐pound mean increase in body weight (P <.05); these alterations are potentially beneficial in terms of reducing the estimated risk of coronary artery disease.
Drug Distribution and Binding
Authors: Øie Svein
Published: March 2013

The distribution of drugs in the body depends on their lipophilicity and protein binding. Low plasma binding or high tissue binding or high lipophilicity usually means an extensive tissue distribution. In pharmacokinetics, the distribution is described by the parameter V, the apparent volume of distribution. This parameter measures the relative distribution of drugs between tissue and plasma and depends on the plasma and tissue binding and the lipophilicity of the drug. If the distribution of drug throughout the body is slow, V in the terminal phase will also depend on the clearance of the drug. At equilibrium, V will theoretically not be lower than 7 L in a 70‐kg person, but it has no upper limit. The extent to which a drug distributes affects the half‐life of the drug and the fluctuation of the concentration at steady state on multiple dosing, but not the average steady‐state concentration.
Pharmacokinetics and Pharmacodynamics of Nifedipine in Patients at Steady State
Authors: Gutierrez L. M. , Lesko L. J. , Whipps R. , Carliner N. , Fisher M.
Published: March 2013

The pharmacokinetics and associated pharmacodynamics of nifedipine were studied at steady state in 12 patients with angina pectoris who were receiving nifedipine 10–40 mg tid. After dosing, serum nifedipine concentrations rose rapidly and decayed in a log‐linear fashion. The mean (± SEM) maximum serum concentration (Cmax) after dose normalization, and the time to Cmax (tmax) were 115 ± 7 ng/mL and 0.72 ± 0.13 hr, respectively. The mean area under the plasma concentration‐time curve per 10‐mg dose was 304 ± 34 hr‐ng/mL. The average elimination rate constant was 0.205 ± 0.016 hr, and the harmonic mean elimination half‐life was 3.4 hr (range, 2.5‐4.9 hr). Heart rate increased (5–6 beats/min, P < .05) from baseline for up to one hour after dose, while mean diastolic blood pressure decreased (6–15 mm Hg, P < .05) for up to four hours. Cardiac output was increased (1.1–2.8 L/min, P < .05), and calculated total systemic resistance (3.6‐6.3 mm Hg/L/min, P < .05) was decreased for the entire dosing interval after nifedipine dosing. Hysteresis plots for heart rate and mean diastolic blood pressure showed a time lag between changes in serum nifedipine concentrations and heart rate, but not between serum nifedipine concentrations and blood pressure. Changes in cardiac output did not correlate with serum nifedipine concentrations. The steady‐state kinetic and dynamic parameter values in patients with angina pectoris in this study were similar to those found in healthy volunteers or hypertensive patients after acute nifedipine administration. Interpatient variability in pharmacokinetics and hemodynamic responses to nifedipine, rather than the underlying cardiovascular disease, would require titration of nifedipine doses to patient response.
Effectiveness of a New Calcium Antagonist in Severe Hypertension
Authors: Burris James F. , Santangelo Robert P. , Mroczek William J.
Published: March 2013

Nitrendipine is a new nifedipine‐like calcium antagonist antihypertensive agent. In this study, nitrendipine 5–40 mg orally bid was administered for up to three months to 16 patients with severe essential hypertension (untreated supine diastolic blood pressure 115 mm Hg). Hydrochlorothiazide or propranolol or both were also given to patients who did not achieve goal blood pressure with nitrendipine alone. Five patients achieved goal blood pressure (supine 90 mm Hg) with nitrendipine alone and six more after the addition of a second drug, and only four required triple‐drug therapy. One patient was terminated from the study because of headaches, a common nitrendipine side effect. This study demonstrates that nitrendipine is an effective and well‐tolerated agent in the treatment of severe hypertension.
Comparison of Sustained‐Release Quinidines Given Twice Daily to Patients With Ventricular Ectopy
Authors: Lehmann Craig R. , Boran Kevin J. , Kruyer William B. , VAN Reet Richard E. , Scoville George S. , Pierson Wayne P. , Melikian Armen P. , Crowe James T. , Wright George J.
Published: March 2013

To compare the steady‐state kinetic profiles and ectopy‐suppression rates of two sustained‐release forms of quinidine with those of a conventional quinidine preparation, 18 patients with ventricular ectopy were studied in randomized crossover fashion. The drugs were conventional quinidine sulfate 300 mg q6h, sustained‐release quinidine sulfate 600 mg q12h, and sustained‐release quinidine gluconate 648 mg q12h. Following baseline electrocardiographic ambulatory monitoring, each drug was given for three days, with repeat ambulatory monitoring and serial plasma drug level determinations performed on the third day. There were no washout periods between treatments. Plasma quinidine levels were assayed by both enzyme multiplied immunoassay technique (EMIT) and quinidine‐specific high‐performance liquid chromatography (HPLC) methods. Using actual steady‐state HPLC values, there were no differences in the area under the plasma concentration‐time curve (AUC) among the three treatments; the dose‐corrected AUC was greater for quinidine gluconate than for the other two preparations. Using EMIT values, mean plasma quinidine levels from the conventional quinidine sulfate regimen were greater during the last five hours of the 12‐hour study interval. A consistently strong inverse relationship between EMIT plasma quinidine levels and hourly ectopy rates was present in only one of eight (13%) responders. Diurnal variation of quinidine kinetics was observed after two days of each treatment; trough values at midnight were slightly lower than trough values at noon. Among patients demonstrating at least 70% suppression of premature ventricular contractions (PVCs), there were no differences in ectopy rates or ectopy‐suppression rates among treatments. Dosing sustained‐release quinidine sulfate 600 mg or quinidine gluconate 648 mg q12h was clinically acceptable in the small number of responders studied.
Whole‐Body Composition in Patients With Angina Pectoris Receiving Long‐Term Treatment With the Nonselective Beta‐Receptor Blocking Drug Nadolol
Authors: Gray J. M. B. , East B. W. , Robertson I. , Preston T. , Lawson D. H.
Published: March 2013

Nadolol is a nonselective beta‐adrenergic receptor antagonist used on a long‐term basis for therapy of angina and hypertension. It has been reported to increase renal blood flow in humans. Theoretically, this could lead to an increase in glomerular filtration rate and improved renal sodium handling. The present study was designed to test whether patients receiving long‐term nadolol therapy exhibited changes in whole‐body composition that might arise as a consequence. Nine nadolol recipients with angina were followed for up to one year, and serial assessments were made of glomerular filtration rates and whole‐body composition using in vivo neutron activation analysis to assess nitrogen, oxygen, sodium, potassium, chlorine, phosphorous, and calcium. No significant changes in these elements were observed. We conclude that any effect of nadolol on renal blood flow in short‐term studies is not associated with significant changes in body composition measured over a period of one year.
Gastric and Intestinal Absorption of Oxprenolol in Humans
Authors: Vidon N. , Palma R. , Godbillon J. , Franchisseur C. , Gosset G. , Bernier J.J. , Hirtz J.
Published: March 2013

The gastrointestinal absorption of the beta blocker oxprenolol was investigated in four healthy subjects by an intubation technique. Oxprenolol was introduced into the stomach, dissolved in a homogenized meal containing the marker 14C‐polyethylene glycol (PEG) 4000. Unlabeled PEG 4000 was perfused during the whole experiment into the duodenum at the ampulla of Vater. Samples of luminal contents were collected at regular intervals over four hours in the stomach, at the angle of Treitz, and 30 cm below this point. Blood was also collected. Oxprenolol was not absorbed in the stomach. About 80% of the drug emptied from the stomach was absorbed in the duodenum, and 80% of that released from the duodenum was absorbed in a 30‐cm segment of the jejunum. The amounts absorbed in these two intestinal segments were directly proportional to the amounts delivered. The areas under the plasma concentration‐time curves were not related to the amounts absorbed. A single dose of oxprenolol taken with an homogenized meal did not modify the gastric emptying and secretory response.
Basic Pharmacokinetics of Bisoprolol, a New Highly Beta1‐selective Adrenoceptor Antagonist
Authors: Leopold Götz , Pabst Joachim , Ungethüm Wolfram , Bühring Karl‐Ulrich
Published: March 2013

The basic pharmacokinetics of bisoprolol were investigated in three independent studies involving 23 healthy volunteers. After administering 20 mg of 14C‐bisoprolol orally, mean elimination half‐lives of 11 hours for the unchanged drug and 12 hours for total radioactivity were observed. The enteral absorption of bisoprolol was nearly complete. Fifty percent of the dose was eliminated renally as unchanged bisoprolol and the other 50% metabolically, with subsequent renal excretion of the metabolites. Less than 2% of the dose was recovered from the feces. Intraindividual comparison of the pharmacokinetic data measured after oral and intravenous administration of 10 mg bisoprolol to 12 subjects yielded an absolute bioavailability of 90%. Total and renal clearance were calculated as 15.6 L/hr and 9.6 L/hr, respectively. The volume of distribution was 226 L. Concomitant food intake did not influence the bioavailability of bisoprolol.
Effect of Sucralfate on the Absorption and Pharmacokinetics of Chlorpropamide
Authors: Letendre Peter W. , Carlson James D. , Seifert Randall D. , Dietz Albert J. , Dimmit Dan
Published: March 2013

This study compared the pharmacokinetics of chlorpropamide (C) when administered alone, or in combination with sucralfate (S) to evaluate whether a drug‐drug interaction exists between these two agents in vivo. A two‐way, randomized, cross‐over study was performed in 12 healthy male volunteers who received 250 mg C alone or were pretreated with S qid for two days and then received a single 250‐mg dose of C with S on day 3 and continued to take sucralfate throughout the day while serial blood samples were drawn. High‐performance liquid chromatography determination of plasma concentrations found there to be no statistically significant differences in maximum concentration, time to maximum concentration, elimination rate constant, or area under the concentration‐time curve from 0 to 96 hours. However, there was a statistically significant difference in the area under the curve from 0 to infinity data (P < .05). The authors conclude that there appears to be no drug interaction between sucralfate and chlorpropamide when given concurrently; however, a trend towards less drug availability was seen that may warrant a future multiple‐dose study to further evaluate the significance of this finding.
The Effect of Pirenzepine on Gallbladder Emptying in Humans
Authors: Keshavarzian A. , Fitzpatrick M. L. , Anagnostides A. , Chadwick V. S.
Published: March 2013

The effect of the selective antimuscarinic agent, pirenzepine, on gallbladder function was studied in six healthy volunteers, using 99mTc HIDA (N‐[2,6‐diethylthenyl] carbamoylmethyl iminodiacetic acid) hepatobiliary scanning. Pirenzepine, in doses that inhibit gastric acid secretion, did not alter gallbladder emptying responses to sham feeding stimulation or to a test meal.
Pharmacokinetics and Dose Proportionality of Domperidone in Healthy Volunteers
Authors: Huang Yih‐Chain , Colaizzi John L. , Bierman Robert H. , Woestenborghs Robert , Heykants Joseph J. P.
Published: March 2013

Domperidone is a potent gastrokinetic agent and antinauseant currently undergoing clinical trials in the United States. The bioequivalence of 20 mg of domperidone given as free‐base tablets and maleate salt tablets, and the bioavailability of base and maleate tablets relative to a solution, were studied in 21 fasting men using a crossover design. Plasma samples collected for up to 48 hours were analyzed for domperidone levels, using a sensitive and specific radioimmunoassay (RIA). The absorption of domperidone was very rapid, with mean peak plasma concentration (Cmax) values of 18.8, 15.0, and 20.7 ng/mL attained at 0.9, 1.2, and 0.6 hours after the administration of base tablet, maleate tablet, and solution, respectively. The mean elimination half‐life (t1/2) ranged from 12.6 to 16.0 hours. The mean oral clearance (CL/F) after the solution dose was 4,735 ± 2,017 mL/min and the mean apparent volume of distribution (Vd/F) was 6,272 ± 5,100 L, indicating an extensive distribution of domperidone in the body. The area under the plasma concentration‐time curve (AUC) data demonstrated bioequivalence of base and maleate tablets. The relative bioavailability for base tablet and maleate tablet was 107 ± 50% and 116 ± 47%, respectively, of that of the solution. Dose proportionality of domperidone was also studied in 12 subjects at solution doses of 10, 20, and 40 mg. Linear correlations between the dose and Cmax and AUC values were observed. Mean CL/F remained relatively constant after doses of 10, 20, and 40 mg (5,255 ± 3,159, 4,842 ± 1,774, and 4,380 ± 1,289 mL/min, respectively), indicating linear pharmacokinetics of domperidone over the dose range studied.
Outpatient Drug‐Induced Parenchymal Liver Disease Requiring Hospitalization
Authors: Beard Keith , Belic Lanie , Aselton Pamela , Perera David R. , Jick Hershel
Published: March 2013

A case‐history study of drug‐induced liver disorders requiring hospitalization was carried out at the Group Health Cooperative of Puget Sound, a health maintenance organization with about 280,000 members, for the five‐year period from January 1, 1977 to December 31, 1981. During this time, there were 12 instances of hospitalization for liver disorders judged to be probably (nine cases) or possibly (three cases) attributable to outpatient drug ingestion (other than antitumor agents). The rate was on the order of one per 100,000 person‐years at risk. Drugs implicated as probable causes were ampicillin (two cases), carbamazepine (one case), erythromycin (one case), methyldopa (one case), sulfasalazine (one case), quinidine (one case), trimethoprim/sulfamethoxazole (one case), and multiple drugs (one case).
Evaluation of the Effect of Food on the Absorption of Sustained‐Release Theophylline and Comparison of Two Methods for Serum Theophylline Analysis
Authors: Boner A. L. , Bennati D. , Valletta E. A. , Plebani M. , Stevens M. T. , Scott J. C. V.
Published: March 2013

Fifteen healthy volunteers took part in a study to investigate the effect of food on the bioavailability of a slow‐release formulation of theophylline. Serum theophylline levels were measured every two hours for ten hours after a single oral dose of 500 mg of theophylline. Serum levels were significantly higher after the dose was taken on an empty stomach; however, serum levels were significantly higher 10 hours later when the dose was taken after a standard meal. Despite these differences, eating had no overall effect on theophylline bioavailability. Two analytic methods for measuring serum levels of theophylline were compared, and it was found that fluorometry could measure lower levels and was therefore more precise than an enzyme immunoassay method, which is probably due to the complete automation and reduced interference of bilirubin and hemoglobin.
Multiple‐Dose Albuterol Kinetics
Authors: Powell M. L. , Chung M. , Weisberger M. , Gural R. , Radwanski E. , Symchowicz S. , Patrick J. E.
Published: March 2013

Albuterol a beta‐adrenergic agonist bronchodilator, was studied in 12 healthy male volunteers to evaluate the steady‐state pharmacokinetics following oral administration of 4‐mg tablets, given every six hours for five days. The kinetics of albuterol were best described by a two‐compartment open model with first‐order absorption kinetics. Steady‐state plasma levels were predictable from the kinetic data and were reached by the third day of dosing (ninth and tenth dose). Small accumulation ratios of approximately two were seen based on area under the plasma concentration‐time curve and maximal and minimal concentration data. The elimination phase half‐life was determined to be 6.5 hours, which is similar to the values reported following single‐dose administration.