bluuebunny/crossref_metadata_2025 huggingface dataset:
Monoamine metabolites in cerebrospinal fluid and serotonin uptake inhibition during treatment with chlorimipramine
Authors: Åsberg Marie , Ringberger Vivi-Ann , Sjöqvist Folke , Thorén Peter , Träskman Lil , Tuck J. Richard
Published: January 2016

The effects of chlorimipramine on the concentrations of the main metabolites of serotonin (5‐HT) norepinephrine (NE), and dopamine, i.e. 5‐hydroxyindoleacetic acid (5‐HIAA), 4‐hydroxy‐3‐methoxyphenyl glycol (HMPG), and homovanillic acid (HVA), respectively, were studied in cerebrospinal fluid from 14 depressed patients, and related to the serotonin‐ and NE uptake inhibiting activity in vitro of plasma drawnfrom the patients. Chlorimipramine inhibited the uptake of both transmitter amines in all patients. During treatment, the levels of 5‐HIAA and HMPG in cerebrospinal fluid (CSF) were significantly reduced. HVA levels were reduced in 6 patients and increased in 8 patients; there was no mean change. The decrease in 5‐HIAA level in CSF was correlated to the uptake inhibition of 5‐HT but there was no corresponding relationship between NE uptake and HMPG levels. The changes in HVA levels were also correlated to the uptake of 5‐HT despite the absence of a unidirectional change of this metabolite.
Metolazone and spironolactone in cirrhosis and the nephrotic syndrome
Authors: Lang Gordon R. , Westenfelder Christof , Nascimento Luiz , Dhupelia Virendra B. , Arruda Jose A. L. , Kane Robert E.
Published: January 2016

Eighteen patients with hepatic cirrhosis or nephrotic syndrome and having edema and/or ascites were treated during successive periods with metolazone 5 to 40 mg/day, spironolactone 100 mg/day, and with both diuretics concurrently. Metolazone alone produced a marked diuresis, natriuresis, and weight loss in 8 patients. Spironolactone alone had little effect, but the addition of metolazone renewed diuresis and natriuresis and resulted in additional substantial weight losses in all patients responsive to metolazone alone. Concurrent spironolactone and metolazone also induced moderate diuretic effects in some patients who failed to respond to either drug alone. The drugs were well tolerated; the administration of spironolactone with metolazone prevented decreases in serum potassium, which had occurred during treatment with metolazone alone.
Toward the operational identification of adverse drug reactions
Authors: Karch Fred E. , Lasagna Louis
Published: January 2016

The evaluation of adverse drug reactions in clinical practice is somewhat arbitrary and is characterized by considerable differences of opinion. This report presents a decision table algorithm approach toward the development of an operational system for the identification of adverse drug reactions. The algorithm incorporates an estimate of the certainty of the link between the untoward clinical event and the suspect drug, and examines the underlying causes of the identified drug reactions. Use of such a system is a first step toward reducing ambiguity in the evaluation of adverse drug reactions.
Guanabenz in essential hypertension
Authors: McMahon F. Gilbert , Ryan Jerome R. , Jain Adesh K. , Vargas Ramon , Vanov Svetislav K.
Published: January 2016

Fifty‐five patients with mild to moderately severe essential hypertension were treated with guanabenz (2,6‐dichlorobenzylidene aminoguanidine acetate) in doses from 4 to 16 mg twice daily in a randomized, placebo‐controlled study. The patients treated with placebo in the initial phase of the study were subsequently treated with guanabenz. The mean arterial pressure in the guanabenz group decreased from 130.6 to 107.6; that in the placebo group decreased from 129.6 to 126.6 standing and from 126.6 to 109.9 and 128.8 to 120.5, respectively, supine. The principle adverse effects included sedation, dry mouth, weakness, and tiredness. Of the guanabenz‐treated patients 84% had sustained decrease in supine diastolic blood pressure of 10 mm Hg or more, whereas in the placebo‐treated patients only 32% had such a response. There was no signijicant orthostatic hypotension. Guanabenz thus appears to be an effective antihypertensive drug in patients with mild to moderately severe hypertension.
Theophylline kinetics in acute pulmonary edema
Authors: Piafsky K. M. , Sitar D. S. , Rangno R. E. , Ogilvie R. I.
Published: January 2016

Nine patients with acute cardiogenic pulmonary edema were given theophylline intravenously, and its disposition was observed over the next 24 hr. Compared to that in 19 normal subjects, these patients had prolonged plasma half‐lifes (mean, 22.9 from 6.7 hr) and decreased plasma clearances of theophylline (mean, 0.041 from 0.062 L [kg−1] hr−1). The intersubject variation in these parameters was 20‐fold in patients with pulmonary edema and 4‐fold in normal subjects. Since the peak plasma concentrations attained and the apparent volumes of distribution were not different in the two groups, a suitable initial dose can be calculated. A loading dose of 4.5 to 5 mg/kg theophylline (6 mg/kg aminophylline) given over 20 min appears sale. Because of the great variability in the plasma clearance of this drug in patients with heart failure, plasma concentrations and toxicity would be unpredictable after repeated doses or constant infusions.
Toxicity of high‐dose flurazepam in the elderly
Authors: Greenblatt David J. , Allen Marcia D. , Shader Richard I.
Published: January 2016

To assess the potential hazards of flurazepam (Dalmane) therapy of insomnia in the elderly, the relation of dosage and patient age to the frequency of flurazepam‐attributed adverse reactions was studied in 2,542 hospitalized medical patients. Adverse reactions, predominantly unwanted residual drowsiness, were reported in 78 flurazepam recipients (3.1%). None of the adverse reactions were serious. The frequency of reported toxicity increased with average daily dose, ranging from 1.3% among those receiving less than 15 mg/day to 12.3% at doses of 30 mg/day or more (p < 0.001). Toxicity increased with age, progressively from 1.9% among those under 60 to 7.1 % among those 80 or over (p < 0.001). Unwanted effects of high‐dose flurazepam were observed much more commonly in the elderly. Only 2.0% of those 70 years of age or older experienced adverse reactions at doses under 15 mg/day, as opposed to 39.0% at 30 mg or more per day. Low doses of flurazepam appear to be safe for elderly individuals, but they are susceptible to unwanted central nervous system depression at high doses.
Absorption of rifampin from various preparations and pharmaceutic forms
Authors: Männistö Pekka
Published: January 2016

The absorption of 9 rifampin preparations was measured in two separate crossover studies on 10 healthy female volunteers. In the first set of experiments, one of the three capsule preparations was absorbed more slowly than the other ones. The absorption of two syrup preparations was nearly twice that of the best capsule preparation. In the second set, the absorption of the commercial tablets appeared to be somewhat faster than that of the reference capsule preparation. One tablet dissolved slowly in vitro and yielded very low serum concentrations. On the basis of these results the equiactive dose of rifampin in syrup form may be 25% to 50% lower than that of the other forms.
The central hypotensive effect of clonidine; Studies in tetraplegie subjcets
Authors: Reid J. L. , Wing L. M. H. , Mathias C. J. , Franker H. L. , Neill E.
Published: January 2016

A single oral dose of 300 µg of clonidine lowered systolic blood pressure by 20 ± 4 mm Hg and diastolic blood pressure by 13 ± 4 mm Hg in five healthy normotensive subjects (controls). Heart rate fell from 56 ± 2 to 52 ± 2 beats/min. In six tetraplegie subjects with physiologically complete chronic cervical spinal cord transection above the level of the sympathetic outfiow, the same dose of clonidine did not significantly lower either systolic or diastolic blood pressure. Heart rate fell from 67 ± 4 to 53 ± 2 beats/min. Peak plasma coneentrations of clonidine, measured by mass fragmentography, and elimination of the drug from plasma were similar in tetraplegic and control subjects and there was no difference in the incidence of the principal side effects of clonidine‐sedation and dry mouth. Although the number of subjects studied is small, the absence of a fall in blood pressure after clonidine in the tetraplegic subjects suggests that the hypotensive action of clonidine in man is dependent on intact descending bulbospinal pathways and is mediated by withdrawal of sympathetic tone and provides direct evidence that some antihypertensive drugs may lower blood pressure in man by a direct action on the brain.
Effects of levodopa on the renin‐aldosterone system
Authors: Katz Fred H. , Hoehn Margaret M.
Published: January 2016

Plasma renin activity and plasma aldosterone, supine and erect, and urinary aldosterone levels were measured in 18 patients on normal sodium diets and in 11 patients on low sodium diets, all of whom also were on long‐term levodopa therapy. Of the 230 hormone measurements, 185 were normal, 11 were high, and 34 were low. Most of the low levels were in 3 patients who had recently received fludrocortisone for orthostatic hypotension, and the renin‐aldosterone systems might have been suppressed by it. In another phase of this study, 4 subjects were maintained on a constant diet for 6 wk, while the effect of gradualty increasing dosages of levodopa on mineral balance and renin‐aldosterone was determined. In 3 of the 4 patients there was a mild natriuretic effect of levodopa (previously demonstrated for acute levodopa therapy). There were no significant consistent changes in renin or aldosterone levels while levodopa was being administered. These studies indicate that levodopa does not usualty suppress the elements of the renin‐aldosterone system and that such a mechanism is unlikely to be the cause of orthostatic hypotension during the course of levodopa therapy. Since levodopa may induce natriuresis, in this situation unchanged levels of renin and aldosterone may, however, represent an inappropriately low set of this hormonal system.
Cigarette smoking and plasma nortriptyline levels
Authors: Norman Trevor R. , Burrows Graham D. , Maguire Kay P. , Rubinstein Gertrude , Scoggins Bruce A. , Davies Brian
Published: January 2016

Cigarette smoking was found to have no effect on the steady‐state plasma levels of nortriptyline in a group of 22 smokers and 31 nonsmokers. Smokers achieved a mean steady‐state nortriptyline concentration oi 191.2 ± 141.3 ng/ml; nonsmokers had a level of 169.3 ± 92.4 ng/ml. Age, sex, and number of cigarettes smoked had no effect on the plasma concentrations achieved.
Influence of rifampicin on drug metabolism: Differences between hexobarbital and antipyrine
Authors: Breimer D. D. , Zilly W. , Richter E.
Published: January 2016

Six healthy volunteers were treated with 1,200 mg of rifampicin daily for 8 days. Before and immediately afterward each received indocyanine green, hexobarbital, galactose, and antipyrine by intravenous infusion on 3 consecutive days. The plasma concentrations of the drugs were determined several times after infusion. The average elimination half‐life of hexobarbital had decreased from 407 to 171 min and its metabolie clearance had increased almost threefold. In contrast, the average elimination half‐life of antipyrine was virtually the same on both occasions (6.9 and 7.2 hr) and there was no change in metabolie clearance. In a tuberculous patient treated with rifampicin the antipyrine elimination rate was unaffected. Rifampicin did not infiuence indocyanine green clearance or galactose elimination capacity. Serum gamma glutamyl transferase was not affected but urinary D‐glucaric acid excretion was increased during rifampicin treatment. The experiment with hexobarbital was repeated after 2 weeks in all subjects; half‐lives and clearance values had returned to near control values. It appears that rifampicin is a selective inducer of oxidative drug metabolism in man.
Acute overdosage with benzodiazepine derivatives
Authors: Greenblatt David J. , Allen Marcia D. , Noel Barbara J. , Shader Richard I.
Published: January 2016

A total of 773 admissions to Massachusetts General Hospital between 1962 and 1975 were due to acute overdosage with one or more psychotropic drugs. Benzodiazepine derivatives were involved in 99 of these cases (13%), and the frequency of benzodiazepine overdosage, particularly with diazepam, increased relative to other psychotropic drugs over the years. Only 12 admissions were due to benzodiazepine overdosage alone, and none of these patients were seriously ill or had significant complications. Multiple drugs were ingested in the other 87 cases, and the jrequency and severity of complications among these individuals depended upon the type and quantity of other nonbenzodiazepines taken. For example, 21 of 31 patients who ingested benzodiazepines together with barbiturates experienced severe central nervous system (CNS) depression, and 14 of 31 required assisted ventilation. However, the irequency of such complications was nearly identical in a group of patients who ingested barbiturates alone. This report and a review of the literature suggest that serious intoxication iollowing overdosage with a benzodiazepine derivative alone is unusual. Ingestion of benzodiazepines together with other drugs appears to be considerably more common than benzodiazepine overdosage alone as a cause of intoxication. The severity of intoxication in such cases of multiple drug ingestion probably depends largely on the type and quantity of nonbenzodiazepines.
Pharmacokinetics and concentration‐effect relationships of intravenous and oral clonidine
Authors: Davies D. S. , Wing L. M. H. , Reid J. L. , Neill E. , Tippett P. , Dollery C. T.
Published: January 2016

The kinetics of the disposition of intravenous and oral clonidine in five normotensive subjects have been determined. It is proposed that a two‐compartment model adequately describes the disposition of the drug. The drug is rapidly distributed (tllza = 10.8 ± 4.7 min) but slowly eliminated (t½β = 8.5 ± 0.9 hr). The bioavailability of oral clonidine in the tablets tested averaged 75.2% and 40 to 50% of the bioavailable dose is excreted unchanged in urine. Renal clearance of the drug showed considerable intersubject variation (1.82 ± 0.34 ml/min/kg) and exceed the calculated glomerular filtration rate in some subjects. Oral and intravenous clonidine induced significant falls in blood pressure (>20/15 mm Hg) in our normotensive subjects and consistently caused marked sedation and dryness of the mouth. Sedation and salivary flow correlated with plasma clonidine concentration over the range 0 to 4 ng/ml. Falls in blood pressure were related to plasma concentration to 1.5 to 2 nglml but at higher concentrations the hypotensive effect was attenuated.
Relationship between blood level of atenolol and pharmacologic effect
Authors: Amery Antoon , De Plaen Jean-Francois , Lijnen Paul , McAinsh James , Reybrouck Tony
Published: January 2016

Thirty‐five hypertensive patients were treated with atenolol in weekly increasing doses (25, 50, 100, and 200 mg thrice daily). Factors determining the blood level of the drug were studied along with the relationship between blood level, the degree of cardiac beta blockade, and the antihypertensive effect of the drug. The blood level obtained varied with the daily dose, the time of blood sampling during the day, the body weight, and the creatinine clearance. The degree of beta blockade was assessed by measuring maximum‐exercise tachycardia and was correlated with the blood level of atenolol. The reduction of the maximum exercise heart rate was independent of age. The hypotensive effect was not closely correlated with the blood level. Three days after the termination of long‐term atenolol treatment, blood levels and beta blockade were still detectable.
Interruption of the enterohepatic circulation of phenprocoumon by cholestyramine
Authors: Meinertz Thomas , Gilfrich Hans-Joachim , Groth Ulrich , Jonen Hans Georg , Jähnchen Eberhard
Published: January 2016

The effect of cholestyramine (12 gm/day divided into 3 doses) on the pharmacokinetics and pharmacodynamics of a single intravenous dose (30 mg) of phenprocoumon was studied in 6 normal subjects. Cholestyramine treatment led to an increase in the rate of elimination of phenprocoumon in all. Total clearance increased 1.5‐ to 2‐fold. The total anticoagulant effect per dose was considerably reduced during treatment with cholestyramine. Binding studies in vitro showed that phenprocoumon is strongly bound to cholestyramine and that at a given cholestyramine concentration the percentage of phenprocoumon bound remained constant over a large concentration range of phenprocoumon. The results suggest that phenprocoumon undergoes extensive enterohepatic recycling in man which can be effectively interrupted by cholestyramine.
Pharmacokinetics of cytosine arabinoside in acute myeloid leukemia
Authors: van Prooijen Rix , van der Kleijn Eppo , Haanen Clemens
Published: January 2016

In 14 patients with acute myeloid leukemia (AML) the plasma concentration of cytosine arabinoside (Ara‐C) was determined at the start of the first course of treatment at various intervals after a bolus injection. In 10 patients plasma concentration/time data were fitted to a biexponential equation and pharmacokinetic parameters were estimated from the coefficient and exponents of such equations. The plasma half‐life (t½) of Ara‐C of the first phase varied from 1.2 to 1.9 min (mean 1.6). The t½ of the second phase varied from 8.8 to 18.9 min. All patients were treated with Ara‐C alone in a dose of 100 mg/m2 for 10 or 14 days. There was poor treatment response in five patients with second‐phase t½ of Ara‐C ranging from 6.6 to 10.7 min whereas there was complete remission in nine patients with t½ exceeding 12.7 min. In three patients plasma Ara‐C concentrations were measured during constant‐rate infusion of different amounts of drug. It appeared that the plateau concentrations were directly proportional to the dose, which indicated that in the therapeutic range no enzyme capacity‐limited elimination occurs.
Enhancement of the bioavailability of propranolol and metoprolol by food
Authors: Melander A. , Danielson K. , Scherstén B. , Wåhlin E.
Published: January 2016

The possible influence of food intake on the bioavailability of one nonselective and one cardioselective beta adrenoceptor antagonist, propranolol and metoprolol, was examined by serial determinations of the drug concentrations in blood of healthy subjects, taking single doses of the drugs both on an empty stomach and together with a standardized breakfast. The results indicate that food enhances the bioavailability of both propranolol and metoprolol. They also confirm that there is extensive interindividual variation in the bioavailability of these drugs.
Digoxin toxicity in patients with normokalemic potassium depletion
Authors: Brater D. Craig , Morrelli Howard F.
Published: January 2016

Reviews of large series of patients with digitalis‐induced arrhythmias create a seeming paradox: Hypokalemia is infrequently associated with digitalis‐induced arrhythmias but the clinical benefit of supplementation of potassium for most digitalis‐induced arrhythmias is obvious. Examination of the electrophysiologic abnormalities induced by digitalis coupled with the electrophysiologic effects dependent on the ratio of intracellular to extracellular concentrations of potassium clarifies the issue. We present evidence that supports additive effects ol the toxicity of digitalis and abnormal ratios of concentrations of potassium inside and outside the cardiac cell. We provide guidelines for assessing this aucial ratio of intracellular to extracellular concentrations of potassium to aid the clinician in the diagnosis and effective treatment of digitalis‐induced arrhythmias.
Response optimization of drug dosage: Antiarrhythmie studies with tocainide
Authors: Meffin Peter J. , Winkle Roger A. , Blaschke Terrence F. , Fitzgerald John , Harrison Donald C. , Harapat Sandra R. , Bell Patricia A.
Published: January 2016

The benefits of using antiarrhythmic response to optimize dosage regimens of antiarrhythmic drugs in individual patients have been examined. Graded antiarrhythmic response and simultaneously measured plasma drug concentrations have been obtained in 15 patients receiving multiple oral doses of a new antiarrhythmic, tocainide. Plasma drug concentration‐antiarrhythmic response data from each of 11 subjects responding to the drug have been fitted by a generalized concentration effect function which is valid over the entire range of response. With the use of experimentally determined pharmacokinetic parameters to define the dose‐plasma concentration relations hip and plasma drug concentration‐response parameters estimated for individual patients, simulations were carried out to show the effect of various dosage regimens on antiarrhythmic response in individual patients. Such simulations provide a means of assessing antiarrhythmic effect in the range of clinical interest (80% to 100% of maximum effect), where the antiarrhythmic effect is a non linear function of dose, plasma drug concentration, or their logarithms. The simulations also demonstrate that for identical daily doses and dosing intervals patients show marked variability in antiarrhythmic response.
Amelioration of bendrofluazide‐induced hypokalemia by timolol
Authors: Hettiarachchi J. , Ramsay L. E. , Davies D. L. , Fraser R. , Watson W. S.
Published: January 2016

The beta adrenergic blocking drug, timolol, tended to correct the hypokalemia of short‐term bendrofiuazide treatment in 6 healthy male subjects and although the effect was small it was significant. Timolol also reduced the rise in plasma aldosterone and urine potassium excretion following bendrofiuazide and increased the urine sodium/potassium ratio. There was no evidence of a shift of potassium from the intracellular to the extracellular space.
Digoxin kinetics in patients with thyroid dysfunction
Authors: Lawrence James R. , Sumner David J. , Kalk William J. , Ratcliffe Wendy A. , Whiting Brian , Gray Kay , Lindsay Margaret
Published: January 2016

The disposition of intravenously administered (3H)‐digoxin has been studied in 9 hyperthyroid and 4 hypothyroid patients. In 9 of these subjects the handling of simultaneously administered oral digoxin was assessed from serum digoxin levels determined by radioimmunoassay. Glomerular filtration rate was measured in each individual at the end of the period of study. There was a close correlation (p < 0.001) between digoxin renal clearance and glomerular filtration rate. Considerable overlap was observed when estimates of digoxin renal clearance in hyperthyroid persons were compared with those obtained in normal control subjects and hypothyroid patients, and there was no correlation between the severity of thyrotoxicosis and digoxin renal clearance; in fact, 3 thyrotoxic patients with established or paroxysmal atrial fibrillation showed impaired digoxin renal clearance. No consistent abnormality of digoxin extrarenal clearance was observed in this group of patients with thyroid disease and digoxin absorption was normal in 9 subjects in whom measurement of this parameter was possible (percent absorption, 71 ± 15). Analysis of the ratio of digoxin concentration in the “deep” compartment to digoxin concentration in the “central” compartment was made by means of a three‐compartment open kinetic model; this revealed a significantly greater “tissue” concentration of digoxin in thyrotoxic patients when compared with hypothyroid patients. These results suggest that the well‐recognized insensitivity of thyrotoxic patients to cardiac glycosides is inexplicable on pharmacokinetic grounds.
Effects of prazosin on forearm resistance and capacitance vessels
Authors: Awan Najam A. , Miller Richard R. , Maxwell Kevin , Mason Dean T.
Published: January 2016

The effects of oral prazosin on the peripheral circulation were evaluated in 10 subjects, including 7 patients with chronic congestive failure due to coronary heart disease. To achieve this purpose the actions of 30 to 50 µg/kg body weight prazosin were assessed on both the forearm arteriolar and venous beds simultaneously with the use of the limb plethysmographic technique. Prazosin produced marked decline of forearm venous tone (FVT) from 44.5 ± 12.3 to 14.3 ± 3.1 mm Hg/ml (p < 0.01) concomitant with marked decrease in forearm vascular resistance (FVR) from 70.2 ± 11.4 to 48.4 ± 4.9 mm Hg/ml/100 gm/min (p < 0.05) which persisted for at least 60 mins without change in heart rate. These findings, demonstrating that prazosin induces systemic venodilation and peripheral arteriolodilation, indicate potential benefits of the oral drug for relief of pulmonary congestion and elevations of cardiac output in patients with chronic congestive heart failure.
Effects of clofibrate on cholesterol metabolism
Authors: Kudchodkar B. J. , Sodhi H. S. , Horlick L. , Mason Dean T.
Published: January 2016

The effects of clofibrate on cholesterol metabolism were studied in one normolipidemic and 5 hyperlipidemic patients by sterol balance methods. In 2 patients, the effects of discontinuation of treatment were also assessed. Clofibrate reduced all classes of plasma lipids. The percentage reduction in triglycerides correlated weil (r = 0.99) with pretreatment levels. On the other hand, percentage reductions in plasma cholesterol, free fatty acids, and phospholipids did not correlate with pretreatment levels but correlated significantly with the fall in plasma triglycerides. In 3 patients, in whom plasma cholesterol was labeled by intravenous infusion of radioactive cholesterol, the specific activity (SA) of plasma cholesterol was determined at frequent intervals. Clofibrate reduced the rate offall ofplasma cholesterol SA while discontinuation of clofibrate increased rate of decline of plasma cholesterol SA. Since clofibrate did not affect the absorption of dietary cholesterol, the changes in plasma cholesterol SA were in all probability related to changes in endogenous synthesis of cholesterol. In addition to the above changes in the specific activity slopes, there were acute increases in plasma cholesterol specific activity which could be explained only by mobilization of tissue cholesterol from the slowly exchangeable pool immediately after the beginning of treatment. The effect of clofibrate on the excretion offecal neutral and acidic steroids was variable and was probably dependent on the balance of its effect on the turnover of plasma lipoproteins on one hand and the mobilization of tissue cholesterol on the other.
Clonidine and the vasodilating beta blocker antihypertensive drug interaction
Authors: Pettinger William A. , MitcheII Helen C. , Güllner Hans-Georg
Published: January 2016

Because propranolol is contraindicated in some patients and since clonidine can decrease heart rate and renin release, clonidine was substituted for propranolol in 14 severely hypertensive minoxidil‐treated outpatients. Clonidine induced weight loss which, since plasma concentrations were not suppressed, was not due to inhibition of release of antidiuretic hormone or renin. These endocrine interrelations were confirmed by later administration of clonidine to 4 of the subjects under controlled circumstances in our General Clinical Research Center. When substituted for propranolol, clonidine controlled blood pressure and heart rate in 8 of the 9 outpatients whose blood pressure had been previously weil controlled. Clonidine and propranolol had additive antihypertensive effects in the other 5 patients . Thus, clonidine can substitute for propranolol or when added to the propranolol‐vasodilator combination supply an additional blood pressure‐lowering effect. This substitution or addition results in an increase in side effects. In addition, clonidine has a diuretic action under these circumstances byan unknown mechanism .
Kinetics of intravenous theophylline
Authors: Chrzanowski Francis A. , Niebergall Paul J. , Mayock Robert L. , Taubin Joel M. , Sugita Edwin T.
Published: January 2016

The pharmacokinetics of theophylline was studied in 6 normal, nonsmoking, adult male volunteers. A constant‐rate intravenous infusion of 3.84 to 4.98 mglkg oftheophylline (as the ethylenediamine salt, aminophylline} was administered over 40 min, Serum theophylline concentrations were measured for 24 hr by means of agas chromatographic method specific for theophylline . Within 30 min of an average intravenous dose of 4.4 mglkg oj theophylline, serum levels reached 10 uglml, The highest serum level at the end of the infusion was 17 ug/ml. The serum concentration‐time data were fitted to a two‐compartment open model and yielded a mean serum half‐life (1½) of 11.02 hr, a value longer than those previously reported. Dur results indicated that after the original loading dose of 4.4 mglkg was infused for 40 min, an immediate infusion rate of 1.40 mglkglhr (1 .65 mgIkgIhr aminophylline) would be necessary to maintain a serum level of 10 ug/ml.
Phentolamine testing for alpha adrenergic participation in hypertensive patients: Independence from renin profiles
Authors: Drayer J. I. M. , Weber M. A. , Atlas S. A. , Laragh J. H.
Published: January 2016

To evaluate alpha adrenergic participation in sustaining blood pressure levels in hypertension. phentolanine. I mglmin for 20 min. was infUsed into 30 seated hypertensive patients. An average fall in diastolic blood pressure of 13.9 ± 9.2 (SD) mm Hg was induced: 21 of the 30 patients (70%) experienced a fall of at least 10%. Systolic blood pressure fell by 7.8 ± 15.7 mm H g. a decrement less (p < 0.05) than that for diastolic pressure. Heart rate increased by 36.2 ± 19.8 bpm and plasma renin activity increased by 1.5 ± 2.6 ng Iml Ihr during infusion. These increases did not correlate with the induced blood pressure changes and. thus. presumably reflected either the alpha blocking or perhaps beta agonistic properties of phentolamine. When patients were subdivided according to their renin‐sodium indices. there were no differences between the high. normal. and low renin subgroups in response to phentolamine and there was no correlation between control plasma renin activity and induced changes in systolic or diastolic blood pressure. Furthermore. in 24 patients who separately received an angiotensin‐converting enzyme inhibitor. teprotide. there was no relationship between the blood pressure decrements induced by it and those induced by phentolamine. In 13 patients in whom renin levels were stimulated by a restricted sodium diet. the blood pressure response to phentolamine was the same as that when they were studied on an unrestricted sodium diet. The results suggest that alpha adrenergic factors may often participate in sustaining blood pressure in hypertensive patients. This role is independent of the renin‐angiotensin system and of the state of sodium balance.
Metabolism of pentaerythritol trinitrate
Authors: Carlo Frederick J. Di , Crew Malcolm C. , Brusco Linda S. , Davidson Ivan W. F.
Published: January 2016

The absorption, excretion, and biotransformation of 14C‐labeled pentaerythritol (PE) trinitrate was studied in man. The administration of a single sublingual dose was followed by rapid absorption and extensive biotransformation. Six drug metabolites were identified. Final excretion of the drug and its metabolites was almost totally through the kidney. Low levels of unchanged drug were present in plasma and urine. PE mononitrate was the major drug metabolite in plasma and urine. Glucuronides of PE trinitrate, dinitrate, and mononitrate were identified for the first time in man. PE trinitrate glucuronide appeared in plasma rapidly and about 8% of the dose was excreted in urine. Reversible and irreversible pathways are proposed for the formation of the metabolites. The reconversion of PE trinitrate glucuronide to PE trinitrate is postulated to explain the duration of drug activity and excretion.
Effect of pentobarbital on the disposition of alprenolol
Authors: Alvan Gunnar , Piafsky Kenneth , Lind Margareta , von Bahr Christer
Published: January 2016

Alprenolol was administered orally and intravenously to 5 healthy subjects before and after IO to 14 daily doses of 0.1 gm pentobarbital. The area under the plasma concentration time curve after an oral 200‐mg dose decreased from 706 ± 277 to 154 ± 48 ng/ml . hr (mean and SD) with the barbiturate treatment, but there was no significant change in elimination rate. The change in area corresponded to an increase in extraction by the liver from 0.72 ± 0.13 to 0.93 ± 0.01. The disposition ofa 5.0‐mg intravenous dose of alprenolol did not change significantly after pentobarbital treatment. There was no indication of a marked change in hepatic blood flow estimated from the clearance of alprenolol after intravenous administration. It is concluded that pentobarbital administration induces the metabolism ()f alprenolol in man and that the pharmacokinetic theories derived for hepatic extraction of drugs subject to a high metabolic clearance can be successfully applied.
Pharmacologic studies of continuous infusion of arabinosylcytosine by liquid infusion system
Authors: Ho O. H. W. , Brown N. S. , Benvenuto J. , McCredie K. B. , Buckel D. , Freireich E. J
Published: January 2016

Arabinosylcytosine (ara‐C) was administered by prolonged intravenous infusion with a portable liquid infusion system (LIS) to patients with acute myelogenous leukemia. With the use of tritiated ara‐C and this portable system, pharmacologic studies were performed in 8 patients. Most of the plasma radioactivity is in the deaminated product, arabinosyluracil (ara‐U). After continuous intravenous irifusion, a constant ara‐C level is achieved slowly in the plasma. Unless a loading (priming) dose is administered immediately before beginning the irifusion, a steady‐state ara‐C level cannot be achieved until 8 to 24 hr after the infusion. The infusion system has two mechanisms‐one for giving a loading dose (3 mllmin) and the other for regular infusion at a rate of 0.5 to 2.0 m!lhr. If a loading dose is given before continuous infusion, a steady‐state ara‐C level is achieved within an hour. The plasma ara‐C disappearance curves are biphasic with a terminal half‐life of 104 min, which is the same as that of a single injection. The cumulative urinary excretion after approximately 23 hr of infusion varied from 14% to 35% in different patients; more than 90% is ara‐U and the remainder is ara‐C. Our results have demonstrated that LIS can be used conveniently to sustain a constant plasma level of ara‐C. The LIS increases mobility of both inpatients and outpatients and is particularly convenient for ambulatory patients.
Effects of furosemide on glomerular filtration rate and clearance of practolol, digoxin, cephaloridine, and gentamicin
Authors: Tilstone W. J. , Semple P. F. , Lawson D. H. , Boyle J. A.
Published: January 2016

Furosemide was shown to decrease inulin clearance in 20 of 27 normal subjects. The depression in inulin clearance occurred in both water‐loaded and non‐water‐loaded subjects. The renal clearance of practolol, but not digoxin, was reduced when furosemide was given. The average total plasma clearances of gentamicin and of cephaloridine over a 6‐hr period were decreased after furosemide. The reduced clearances of the antibiotics were associated with higher plasma levels, the increase in antibiotic concentration being as much as 100% at 1 hr after an intravenous bolus injection.
Influence of probenecid and spironolactone on furosemide kinetics and dynamics in man
Authors: Homeida M. , Roberts C. , Branch R. A.
Published: January 2016

The pharmacokinetics and pharmacodynamics following administration of furosemide (40 mg intravenously) have been studied before and after treatment with probenecid (0.5 gm orally every 6 hr for 3 days) and spironolactone (200‐mg initial oral dose followed by 50 mg every 6 hr for 3 days) in 6 normal male subjects. Urine losses during each study period were replaced with saline‐dextrose‐KCI intravenously. The study was performed with the use of a Latin‐square design. Probenecid pretreatment induced significant reductions in renal clearance of furosemide by 78%, the extrarenal clearance by 56%, and the volume of distribution by 52%. As a consequence, furosemide half‐life was increased by 54%. Probenecid sign(ficantly reduced the rate of sodium excretion at all plasma concentrations of furosemide, but the ratio between urinary furosemide concentration and urinary sodium concentration was not altered. Since the proportion of furosemide excreted unchanged in the urine was not markedly changed, total diuretic response was not influenced by probenecid. There was no evidence of any pharmacokinetic interaction between spironolactone and furosemide. The relationship ~f furosemide kinetics to dynamics observed in these studies confirms that, in man, the diuretic response is determined by drug that reaches the renal tubule rather than the drug level in plasma.
Codeine kinetics as determined by radioimmunoassay
Authors: Findlay John W. A. , Butz Robert F. , Welch Richard M.
Published: January 2016

Radioimmunoassay (RIA) was used to determine several pharmacokinetic parameters of codeine in man, including the relative bioavailability after oral and intramuscular administration. The study followed a crossover design in 6 healthy, young (18 to 21 yr), male volunteers. Three subjects received 65 mg codeine phosphate orally in an analgesic mixture which also contained aspirin, phenacetin, and caffeine. At the same time a similar group received an equivalent dose of codeine phosphate in a single intramuscular injection. Two weeks later the study was repeated so that each group received the alternate treatment. Plasma samples were collected at various times after drug administration, and codeine concentrations were determined by a specific RIA procedure. The procedure can detect less than 50 pg of codeine. Following intramuscular administration, peak plasma concentrations (194 to 340 nglm!) were observed between 0.25 to 1 hr; after oral dosing, peak codeine plasma concentrations (102 to 140 nglmt) appeared within 0.75 to I hr. The mean plasma t1;2 and volume of distribution of codeine following intramuscular injection were 3.32 hr and 5. I Llkg, respectively. Oral, relative to intramuscular, bioavailability qf codeine, based on areas under the codeine plasma curves, was 42% to 71% (mean, 53%).
Glutethimide and 4‐0H glutethimide: Pharmacokinetics and effect on performance in man
Authors: Crow James W. , Lain Pedro , Bochner Felix , Shoeman Don W. , Azarnoff Daniel L.
Published: January 2016

The relationship between the plasma concentration of glutethimide (G) and the change from baseline of the standard error of the mean (ΔSDE) of a tracking test was determined in 7 volunteers. There was excellent positive correlation (r = 0.9/) between log G and log ΔSDE and good correlation between log G and ΔSDE (r = 0.77). The metabolite, 4 hydroxyglutethimide, did not contribute significantly to the effect of G administered in therapeutic doses. No trend in performance versus level was found with 5 other tests (finger tapping, card sorting, digit substitution, subtraction, and subjective perception of drowsiness). Although the numbers were small, when the volunteers were divided into smokers (3) and nonsmokers (4) G decreased tracking ability to a greater extent in smokers than in nonsmokers.
Pindolol availability in hypertensive patients with normal and impaired renal function
Authors: Chau Nguyen Ph. , Weiss Yves A. , Safar Michel E. , Lavene Daniele E. , Georges Daniel R. , Milliez Paul L.
Published: January 2016

Intravenous and oral pharmacokinetics of pindolol were studied in 18 hypertensive patients‐9 with normal renal function and 9 with impaired renal function. Analysis of data showed that a linear two‐compartment model was suitable to describe the pindolol kinetics. Compared with patients with normal renal junction, patients with chronic renal failure exhibited: (1) unchanged transfer rate constants and distribution volumes and (2) decreased total body clearance with decreased renal clearance and unchanged nonrenal clearance. Analysis of oral data by the Loo‐Riegelman method showed that the pindolol absorption kinetic was not first order. Compared with patients with normal renal function, patients with chronic renal failure exhibited decreased fraction of dose effectively absorbed and increased initial rate of absorption. The initial rate of absorption was inversely correlated with the creatinine clearance. The study disclosed evidence that absorption was modified in chronic renal failure.
Acebutolol disposition after intravenous administration
Authors: Meffin Peter J. , Winkle Roger A. , Peters Flora A. , Harrison Donald C.
Published: January 2016

The disposition of acebutolol has been studied following intravenous doses of 0.25 to 1.0 mg/kg in 9 healthy subjects using a specific chromatographic assay to determine concentrations of drug in blood. The mean blood clearance was 6.55 mllmin/kg and the mean renal clearance, 2.68 mllmin/kg. Blood clearance was found to have a coefficient of variation of 14% for the group, to be independent of dose, and to remain essentially constant over approximately 3 wk. The fraction of the dose excreted in the urine unchanged was 0.405. Data were fitted to an equation for a two‐compartment model. The mean fast and slow half‐lives were 6.08 and 156.8 min, respectively. The volume of the central compartment was 0.223 L/kg, and the volume of distribution at steady‐state was 1.165 L/kg. The fraction of acebutolol unbound to plasma proteins was 0.743 and was independent of drug concentration in the range examined. Data obtained from 15‐min infusions were used to predict plateau blood concentrations with good accuracy during an 8‐hr dosage regimen.
Uricosuric effects of niridazole
Authors: Weintraub Michael , Nash Theodore E. , Ottesen Eric , Becker Michael A.
Published: January 2016

Niridazole, an antischistosomal drug, caused a 44% decrease in the serum uric acid (SUA) concentration in II patients with schistosomiasis. The mean SUA (±SE) was 6.3 ± 1.4 mglIOO ml at baseline and 3.5 ± 1.5 mglIOO ml (p < 0.01) on day 7 of treatment. There was a significant increase in the urinary uric acid/creatinine ratio, from 0.446 ± 0.165 at baseline to 0.550 ± 0.145 on day 3. There was no significant difference on day 7. The fractional clearance of uric acid rose from 7.2 ± 6.8% to 13.9 ± 17.3% (p < 0.01), indicating a uricosuric effect. Oxypurine excretion was unchanged. In a separate study on 7 other patients, the SUA remained low for 4 to 7 days after the last dose. Niridazole, although not an organic acid, has uricosuric effects.
Metabolism of procainamide and p‐aminobenzoic acid in patients with chronic liver disease
Authors: Souich P. du , Erill S.
Published: January 2016

Procainamide acetylation and hydrolysis. procainamide‐derived p‐amino‐benzoic acid acetylation. and plasma hydrolysis of procaine were studied in normal volunteers and in 20 patients with chronic liver disease. Impairment of procainamide acetylation was evident in the patients. but no correlations were demonstrable between the degree of impairment and the severity of the disease. On the other hand. procainamide hydrolysis was diminished in liver disease. and as indicated by depression of serum albumin levels and plasma prothrombin activity this alteration did correlate with the degree of impairment of liver function. Procaine hydrolysis in plasma was also affected. the mean in vitro plasma half‐life being prolonged in the patients with liver disease and correlating with the degree of hepatic impairment. A correlation of procainamide hydrolysis with procaine hydrolysis was also observed. Finally. acetylation of procainamide‐derived p‐aminobenzoic acid appeared to increase in patients with liver disease. the degree of acetylation increasing with decreasing procainamide hydrolysis capacity.
Plasma concentration of pyridostigmine and effects in myasthenia gravis
Authors: Chan K. , Calvey T. N.
Published: January 2016

The relation between the plasma concentration of pyridostigmine and its effects was studied in 5 patients with myasthenia gravis. In 4 patients with typical electromyographic decrement in the adductor pollicis, there was a positive correlation between the concentration of pyridostigmine in plasma and the effect on neuromuscular transmission. The plasma concentration of pyridostigmine required to restore transmission to normal (as calculated from the regression line relating plasma concentration to neuromuscular function) varied over a 5‐fold range, reflecting the variable severity of the disease. In another myasthenic patient with purely ocular symptoms, there was a significant correlation between the plasma concentration of the drug and the diameter of the palpebral fissure. It is suggested that the routine measurement of the plasma concentration of pyridostigmine may be of value in the management of myasthenia gravis. A method to calculate the optimal daily dose of pyridostigmine in individual myasthenic patients is described.
Kinetics of oral ethambutol in the normal subject
Authors: Lee Ching S. , Gambertoglio John G. , Brater D. Craig , Benet Leslie Z.
Published: January 2016

Six normal adult volunteers received 15 mg/kg of ethambutol (EMB) by mouth, once as an aqueous solution and again as the commercial tablet preparation. Each dose was separated by at least 7 days. Plasma and urine samples were collected at regular intervals for up to 24 and 72 hr, respectively. Peak plasma concentrations ranged from 3.25 to 5.62 mcg/ml, 2 to 4 hr after tablet dosing. Earlier peak times were found after administering the solution. For plasma concentrations up to 12 hr there was a distinct distribution phase followed by an apparent elimination phase with a mean half‐life (t½) (±SD) of 4.06 ± 0.53 and 4.78 ± 0.41 hr for the tablet and the solution, respectively. Excretion rate plots exhibited similar t½values for the apparent elimination phase. An even longer tV2 of approximately 10 hr was evident from 24‐hr plasma samples and urinary excretion measurements up to 72 hr. Unchanged drug excreted in the urine averaged 61.1 ± 3.8 % of the dose for the tablet and 63.4 ± 2.6 % for the solution. Plasma protein binding for ethambutol determined by equilibrium dialysis and ultrafiltration was approximately 20% to 30%. The concentration ratio of ethambutol in erythrocytes to plasma ranged from 1.1 to 1.6.
Naturally occurring toxic substances in foods
Authors: Gross Robert l. , Newberne Paul M.
Published: January 2016

Numerous chemical toxins, including normal components of natural foods, e.g., mycotoxins, and toxic chemicals as contaminants such as pesticides, fertilizers, food additives, and preservatives, which are potentially toxic to humans, are discussed. Potential toxiciiy, the hazard to man represented by most of these chemicals, may be low because the concentration in food may be low. The gap in our knowledge of long‐term effects makes rational decisions as to allowable levels of these substances a major problem. On the other hand, nitrosamines and afiatoxins are toxins for which there exists a voluminous literature documenting extreme biologic activity in experimental animals and indirect evidence for activity in man. Epidemiologic evidence has linked them to human cancers, and because of increasing evidence of long‐term human exposure to these toxins either as inadvertent contaminants during food preparation or as the metabolites of mycotic infestation this possible hazard demands intensive investigation. An exhaustive review of data from epidemiologic surveys in various parts of the world, as well as from long‐term laboratory studies, represents an impressive start in this direction.