bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of sulbenicillin, a new broad‐spectrum semisynthetic penicillin
Authors: Hansen Ib , Jacobsen Erik , Weis Jan
Published: January 2016

In a pharmacokinetic study on a new semisynthetic penicillin, α‐sulfobenzylpenicillin, sulbenicillin, serum level, serum half‐life, apparent distribution volume, renal clearance, urinary excretion, and metabolism were determined after a 4‐gm intravenous dose and compared to that of carbenicillin in 5 patients with normal renal function. In the case of sulbenicillin, the mean serum concentration at 1 hr was 157 ± 25 µg/ml, the mean serum half‐life was 70 ± 10 min, the renal clearance was 95 ± 25 ml/min, and the total urinary recovery after 24 hr was about 80% of the dose. The only metabolite detected in the urine was the penicilloic acid derivative, in an amount usually less than 5% of the dose. Serum values, serum half‐life, renal clearances, and excretion pattern did not differ significantly from that of carbenicillin. In 8 patients with decreased renal function (creatinine clearance < 50 ml/min) there was an inverse correlation between creatinine clearance and serum half‐life.
Iodine absorption in burn patients treated topically with povidone‐iodine
Authors: Lavelle Kevin J. , Doedens David J. , Kleit Stuart A. , Forney Robert B.
Published: January 2016

Povidone‐iodine is used as a topical antimicrobial in burn patients. Although absorption of iodine has been thought to be negligible, several patients have recently.been noted with substantial elevations of serum free iodide. Unexplained abnormalities occurred in several of these patients, renal failure, metabolic acidosis, and elevation of serum glutamic oxaloacetic transaminase. It is conceivable that the large iodide loads noted were at least in part responsible for these abnormalities.
Plasma levels and effects of metoprolol on blood pressure and heart rate in hypertensive patients after an acute dose and between two doses during long‐term treatment
Authors: Bengtsson C. , Johnsson G. , Regårdh C.‐G.
Published: January 2016

Plasma levels and the effect of orally administered metoprolol on the resting arterial blood press ure and heart rate have been studied during acute and steady‐state conditions in patients with mild hypertension. The patients receiving an 80‐mg dose had a mean maximum plasma level of about 100 ng/ml plasma in single‐dose studies and about 140 ng/ml plasma during steady‐state conditions. The corresponding values for the patients on the 50‐mg dose were about 60 and 100 ng/ml plasma, respectively. The maximum concentrations were reached 1 hr after administration. After the single dose the elimination half‐life of metoprolol in plasma was 4.3 ± 0.7 hr in the patients receiving the 80‐mg dose and 3.8 ± 0.3 hr in the other group. The difference was not statistically significant. The elimination half‐life in the plasma was about the same in the single‐dose study and during steady state in both groups. The morning dose induced a decrease of the systolic blood pressure whereas the diastolic blood pressure was not significantly different from that recorded immediately before administration of metoprolol. For the 80‐mg dose the systolic pressure droppedfrom 167 ± 4 to 146 ± 4 mm Hg in the single dose study andfrom 160 ± 8 to 140 ± 4 mm Hg at steady state. The corresponding values for the 50‐mg dose were 150 ± 3 to 135 ± 3 mm Hg and 144 ± 3 to 138 ± 3 mm Hg, respectively. In experiments with placebo the systolic blood pressure was not significantly changed. There was no correlation between the plasma levels and the effect on the systolic blood pressure . Both doses of metoprolol markedly reduced the heart rate after the single dose as weil as at steady state. The effect was linearly related to the logarithm of the plasma concentration, and the relationship was virtually the same as obtained previously for the effect on exercise heart rate in healthy volunteers.
Pharmacokinetics of procainamide intravenously and orally as conventional and slow‐release tablets
Authors: Graffner Christina , Johnsson Gillis , Sjögren John
Published: January 2016

Pharmacokinetics of procainamide were studied in healthy volunteers after single doses intravenously and orally as conventional and slow‐release tablets and after repeated oral doses to steady state. The initial distribution after intravenous administration was rapid and the overall elimination in the ß‐phase corresponded to tÛ of 2.7 hr. The mean volume of the central compartment was small and only 4% of Vd(ß), which was 2.3 l/kg body weight. About 65% was excreted unchanged after intravenous administration and about 55% after a single oral dose of 500 mg. The recovery of the metabolite N‐acetylprocainamide was 12% after both routes of administration. Procainamide was completely absorbed from the gastrointestinal tract and the first‐pass elimination was very limited. The rates of absorption from the tablet compositions were weil correlated to the in vitro dissolution properties. Administration of slow‐release tablets every 8 hr gave about the same mean plasma level at steady state as ordinary tablets given every 4 hr, and the availability was the same from both preparations. The occasional high plasma concentration peaks after ordinary tablets were not observed after the slow‐release tablets. Renal clearance was about 500 ml/min, indicating an active secretion in the tubules.
Effects of high dosage delta‐9‐tetrahydrocannabinol on sleep patterns in man
Authors: Feinberg Irwin , Jones Reese , Walker James M. , Cavness Cleve , March Jonathan
Published: January 2016

Electroencephalographic readings and eye movement were recorded in experienced marijuana users under placebo and tetrahydrocannabinol (THC). Four subjects were studied for 3 baseline nights, 3 nights under initial dosage of 70 mg/day, the last 3 nights of a 2‐wk period of 210 mg/day, and thefirst 3 nights of withdrawal. Three other subjects were studied only during the latter 2 conditions. Administration of THC significantly reduced eye movement activity during sleep with rapid eye movements (REM) and, to a lesser extent, the duration of REM itself. Withdrawal led to increases above baseline in both measures but the “rebound” effect was greater for eye movement. Stage 4 sleep tended to increase on drug, but this effect was not statistically significant. On withdrawal, stage 4 sleep decreased significantly; this change was marked only on the first withdrawal night. The functional or biological significance of these changes is unclear. Nevertheless, these are the most marked effects of THC on brain electrical activity demonstrated thus far. Since its pattern of effects on sleep appears unique to THC, this drug may prove to be a valuable tool in the elucidation of the pharmacology of sleep. Possible relations between effects on sleep pattern and on behavior are discussed.
Influence of diet and fluid on bioavailability of theophylline
Authors: Welling P. G. , Lyons L. L. , Craig W. A. , Trochta G. A.
Published: January 2016

The influence of various test meals, and of fluid volumes, on the bioavailability of theophylline from asolid dosage form has been studied in healthy male volunteers. Absorption of drug was faster after dosing immediately following a high protein meal than after a high fat or a high carbohydrate meal. Absorption from a solution was faster than from asolid dosage form in all treatments; areas under serum level time curves after dosing were also significantly higher up to 12 hr. Areas up to 12 hr after dosing also tended to be higher after the high protein meal and after dosing with 500 ml water on an empty stomach than after other solid dose treatments.
Diphenylhydantoin elimination kinetics in overdosed children
Authors: Garrettson L. K. , Jusko W. J.
Published: January 2016

Diphenylhydantoin (DPH) elimination was studied in 4 overdosed children who presented with serum concentrations ranging from 44 to 76 mg/l. Serum was assayed for DPH and urine was assayed for both DPH and 5‐(p‐hydroxyphenyl)‐5‐phenylhydantoin (HPPH). The serum and urine data were subjected to simultaneous computer nonlinear regression analysis using a one‐compartment pharmacokinetic model, which accounts for much of the known disposition kinetics of DPH. Computed va lues for the apparent in vivo Michaelis‐Menten constants, KM and V max, were compared with values derived from data in the literature for normal adult subjects. A trend toward relatively lower KM and higher V max/KM values was seen in children. Patients with higher Vmax values had greater urinary excretion rates of HPPH which, at high serum levels of DP H, were relatively constant except jor an apparent diurnal rhythm. The time of onset of DPH toxicity in the children was related to the magnitude by which the rate of DPH administration exceeded the Vmax values.
Pharmacokinetics of carbamazepine in normal man
Authors: Levy R. H. , Pitlick W. H. , Troupin A. S. , Green J. R. , Neal J. M.
Published: January 2016

The bioavailability of commercial carbamazepine tablets with and without meals was compared to a propylene glycol solution with respect to extent of absorption in 6 normal humans after a dose of 6 mg/kg. The presence of dose‐dependent kinetics within a clinically significant range was also investigated. Serum and urine samples were assayed by gas‐liquid chromatography (GLC). Carbamazepine is rapidly absorbed from the propylene glycol solution. Eight per cent of the dose was absorbed from the commercial tablet, resulting in therapeutic serum concentrations (3 to 6 mcg/ml). The data were consistent with dissolution rate‐limited absorption. Mean half‐lives ranged from 31 to 35 hr. No dose‐dependent kinetics were observed following administration of doses of 3, 6, or 9 mg/kg. The fraction of dose absorbed, the fraction excreted unchanged in urine, the time of maximum serum concentration, and absorption and elimination half‐lives appear to be independent of dose. The time course of side effects could not be correlated with serum carbamazepine levels, suggesting that metabolites contributed to side effects.
Influence of acute viral hepatitis on phenytoin kinetics and protein binding
Authors: Blaschke Terrence F. , Meffin Peter J. , Melmon Kenneth L. , Rowland Malcolm
Published: January 2016

Patients with liver disease are thought to have abnormal responses to drugs metabolized by the liver. although supportive evidence is sparse. The influence of acute viral hepatitis on the pharmacokinetics and protein binding of phenytoin (DPH) was examined in 5 patients. A longitudinal study design was used so that each patient acted as his own control. DPH clearance was unaffected by acute viral hepatitis over the concentration range studied. but the percentage of un bound DPH increased by an average of nearly one‐third during acute viral hepatitis. A small decline in serum albumin concentration and elevated serum bilirubin levels may be responsible for the alterations in protein binding. These results indicate that acute inflammatory liver disease has complex and perhaps paradoxical effects on drug disposition. Clinical and laboratory observations including plasma drug concentrations. still provide the best means for adjusting dosage regimens in patients with fluctuating hepatic function.
Comparative effects of tolamolol and propranolol on cardiac and peripheral circulatory function in patients with coronary artery disease
Authors: Miller Richard R. , Vismara Louis A. , Mason Dean T.
Published: January 2016

In a clinical study comparing the cardiocirculatory effects of intravenous tolamolol to those of propranolol, tolamolol, 16 mg, induced similar reduction in resting heart rate as 8 mg propranolol in 16 coronary patients. Tolamolol did not disturb cardiac pump performance and exerted less negative inotropic action than propranolol as assessed by mechanical contractility indices. Myocardial beta‐one chronotropic and inotropic stimulation by exogenous epinephrine was blocked equally by tolamolol and propranolol. Tolamolol exerted less systemic vascular beta‐two blockade than propranolol as assessed by the peripheral resistance and vasopressor responses to epinephrine irifusion. Tolamolol is a potent cardioselective beta antagonist with relatively less inotropic depressant action than propranolol and is thereby suitable for careful extension of beta blockade therapy to certain patients with pulmonary and ventricular dysfunction.
A method for achieving blood pressure control expeditiously with oral minoxidil
Authors: O'Malley Kevin , McNay John L.
Published: January 2016

Twelve patients with essential hypertension were treated aggressively with oral minoxidil in order to achieve blood pressure control as expeditiously as possible. Pretreatment blood pressure ranged from 159/109 to 238/161 mm Hg. Following an initial dose of 5 mg, subsequent dosage increments were administered every 6 hr until a fall in blood pressure was observed. The size of additional doses was determined by the magnitude of, and response to, the lowest effective dose and the therapeutic objective. Over a time interval of 24 to 42 hr, the blood pressure was reduced to normal or near normal in each case. Untoward hypotension was uniformly avoided. Analysis of the relationship between blood pressure response and cumulative dose indicates that at suboptimal blood pressure responses, it is safe and efficacious to give half the antecedent cumulative dose as a single dose in arriving at the therapeutic objective. The use of such a regimen should be considered as an alternative to parenteral drug administration in severe hypertension when immediate control of blood pressure is not required.
Disposition of acetylmethadol in relation to pharmacologic action
Authors: Kaiko Robert F. , Inturrisi Charles E.
Published: January 2016

The levels of acetylmethadol and its active biotransformation products were quantitated in the plasma and urine of subjects on acetylmethadol maintenance by the use of solvent extraction and gas‐liquid chromatography. The time‐course of plasma acetylmethadol. noracetylmethadol. and dinoracetylmethadol over 48 hr was determined concurrently with the time‐action of pupillary constriction in 8 subjects receiving an average oral maintenance dose of 50 mg. The plasma level of acetylmethadol reached a peak at 4 hr and had nearly disappeared by 24 hr. The mean apparent half‐life was 7 hr. The plasma level of noracetylmethadol peaked at 4 to 8 hr and slowly declined over the next 40 hr. The mean apparent half‐life of noracetylmethadol was 48 hr. Dinoracetylmethadol plasma levels remained relatively constant throughout the dosing interval. The miotic effect reached a peak at 8 hr and decayed at a rate slower than that of plasma elimination of acetylmethadol but more rapidly than that of noracetylmethadol and dinoracetylmethadol. Substantial variation in the plasma levels of the compounds was observed in subjects after the same doses. The study indicates that the relatively long duration of opiate effects of acetylmethadol results from biotransformation to active and persistent metabolites.
Antihypertensive effect of a dopamine beta hydroxylase inhibitor, bupicomide: A comparison with hydralazine
Authors: Velasco M. , Gilbert C. A. , Rutledge C. O. , McNay J. L. , McNay J. L.
Published: January 2016

The cardiovascular effects of a new antihypertensive drug, bupicomide, were compared with those of hydralazine in 6 patients with mild to moderate hypertension. The mean supine arterial pressure of patients was reduced 15.2 mm Hg by bupicomide (900 to 2,000 mg/day) and 15.7 mm Hg by hydralaslne (300 to 600 mg/day). Heart rate increased an average of 11.3 bpm during bupicomide and 14.5 bpm by hydralaine. Neither drug was associated with a postural decrease in mean arterial pressure. The heart rate response during maximum tolerated treadmill exercise was not diminished by either drug. Cardiac index was increased during administration of both drugs. Bupicomide and hydralazine reduced forearm vascular resistance, while renal blood flow and renal vascular resistance were not significantly modified. Evidence of equivalent augmentation of sympathetic nervous activity during administration of both drugs consisted of equal and significant increases in heart rate and urinary norepinephrine excretion, and decreases in duration of the pre‐ejection period. The absolute values of these parameters were correlated with mean arterial pressure, which may indicate that the increase in sympathetic nervous activity was mediated by baroreceptor reflexes. Although bupicomide inhibits dopamine ß‐hydroxylase, our results suggest that it is acting as a direct vasodilator.
Respiratory effects of lorazepam, pentobarbital, and pentazocine
Authors: Gasser J. Conrad , Kaufman Robert D. , Bellville J. Weldon
Published: January 2016

The respiratory effects of a new benzodiarepine, lorazepam, were compared to those of pentobarbital and pentazocine. Pentobarbital, 50 and 150 mg, produced respiratory depression, as did pentazocine, 30 mg intramuscularly. Lorazepam at 1.33 and 4 mg intramuscularly produced none.
Methadone in man: Pharmacokinetic and excretion studies in acute and chronic treatment
Authors: Verebely Karl , Volavka Jan , Mulé Salvatore , Resnick Richard
Published: January 2016

The biologic disposition of methadone in acute and during chronic administration was studied in 12 human volunteers. In the acute study a biexponential methadone plasma level deeay was observed. The acute primary half‐life (t½) of 14.3 hr in combination witn the acute seeondary t½ of 54.8 hr were longer than the single exponential chronic t½ of 22.2 hr determined in the same subjeets. The urinary and feeal excretion of methadone and its mono‐Nvdemethylated metabolite increased from 22.2% in the acute to 62.0% in the ehronic phase of the study. The urinary metabolite 1 to methadone ratio tripled from the acute to the ehronie phase. The pupillary effeets of methadone monitored throughout 24 hr were nearly the same in magnitude in the acute and the chronic studies, whereas the plasma levels increased 3‐ to 8‐fold following chronic methadone administration, These findings suggest that both dispositional and pharmacologic toleranee are involved in the development of toleranee following chronic administration of methadone.
Effects of tricyclic antidepressants on drug metabolism
Authors: Pond Susan M. , Graham Garry G. , Birkett Donald J. , Wade Denis N.
Published: January 2016

The effects of chronic treatment with amitriptyline and nortriptyline on the elimination from plasma of warfarin, dicumarol, phenytoin, and tolbutamide were examined in man. No alteration of plasma half‐life of warfarin, phenytoin, or tolbutamide was observed following dosage with the tricyclic antidepressants used. There was no consistent effect on the metabolism of dicumarol following treatment with amitriptyline or nortriptyline although the bioavailability of dicumarol appeared to be increased. In some subjects, this increased bioavailability was associated with significant prolongation of the plasma half‐life of dicumarol due to its dose‐dependent kinetics.
Folie acid dosage for chronic hemodialysis patients
Authors: Skoutakis Vasilios A. , Acchiardo Sergio R. , Meyer Marvin C. , Hateh Fred E.
Published: January 2016

The doses of folic acid, neeessary to avoid folic acid deficiency in patients being maintained on hemodialysis, have been estimated to be between land 5 mg daily. To more precisely define an adequate dose of folic acid, 6 anephric patients were studied. The patients were maintained on hemodialysis and received, in a crossover fashion, 1 mg and 5 mg of folic acid for 3 wk. In a second crossover study, 3 anephric patients were first maintained on 0 and then on 1 mg of folic acid after each dialysis for 3‐wk periods. Pre‐ and postdialysis folic acid blood levels were measured and dialyzer clearances of folic acid were determined. The results of this study support the conclusion of the Food and Drug Administration report suggesting that daily doses of 1 mg of folic acid are adequate to sustain therapeutic folate levels. The data further indicate that the administration of 1 mg of folic acid after each dialysis, rather than 1 mg of folic acid daily, can provide adequate folate.
Distribution of salicylate between neonatal and maternal serum at diffusion equilibrium
Authors: Levy Gerhard , Procknal Josephine A. , Garrettson Lorne K.
Published: January 2016

The post‐distributive neonatal: maternal plasma salicylate concentration ratio following salicylate administration to the mother before delivery is appreciably higher than unity. The protein binding of salicylate and the albumin concentration in one such plasma pair were considerably higher in the neonatal than in the maternal plasma. Equilibrium dialysis of neonatal plasma or serum from 6 newborn infants against that of their mothers produced a neonatal: maternal salicylate concentration ratio above unity in alt cases even if the albumin concentration in the neonatal serum did not exceed that in the maternal serum. However, there was a strong correlation between the neonatal: maternal concentration ratios of salicylate and albumin. These observations demonstrate that conclusions concerning the distribution of a drug across the placenta in relation to its plasma protein binding characteristics must be based on the results of binding studies witti plasma or serum from neonates and their mothers, and not from other adult subjects.
PTG, a new antineoplastic epipodophyllotoxin
Authors: Creaven Patrick J. , Allen Larry M.
Published: January 2016

The pharmacology of 4'‐demethylepipodophyllotoxin 9‐(4, 6‐0‐thenylidene‐β‐Dglucopyranoside) PTG, a new anticancer drug, is reported. Six patients with advanced cancer were treated witli PTG (67 mg/m2 of body surface area intravenously) specifically labeled with tritium as the first dose of a weekly × 6 course. Recovery of drug in the urine was 44.49 ± 8.2% ofthe administered dose in 72 hr, of which 78.7 ± 5.1% was metabolite. Recovery in thefeces was 0 to 10.05% in 4 patients. Plasma decay fitted the equation Cp = Ae‐αt + Be‐βt + Ce‐yt by nonlinear least‐squares regression. Mean values for the parameters (after infusion) were A 14.3 ± 5.5, B 9.66 ± 3.98, C 2.44 ± 1.33 µg/ml; α 2.05 ± 1.25, β0.26 ± 0.15, σ 0.038 ± 0.016 hr‐1, Levels of drug in the cerebrospinal fluid (CSF) were <1 % of plasma levels in 3 patients at 24 hr after treatment and 27% in 1 patient who had had brain surgery and brain radiotherapy. Four of 4 patients considered evaluable for toxicity (>2 consecutive weekly doses) developed leukopenia (WBC <5,000/mm3). Mean nadir of WBC was 3,600/mm3. The most marked leukopenia (WBC, 2,300/mm3) was seen in the patient with the longest terminal phase plasma half‐life (38.5 hr). Two of 5 patients evaluable for response received clinical benefit (1 laryngeal carcinoma, 1 histiocytic lymphoma). It is concluded that PTG has a long terminal phase half‐life (11‐38.5 hr), is largely metabolized, and does not penetrate the normal blood‐brain barrier.
Depression and antidepressant drugs
Authors: Berger Frank M.
Published: January 2016

During the past two decades several new classes of drugs were discovered that proved of value in the treatment of depression. Although these discoveries were made fortuitously by clinical observers, they greatly stimulated both laboratory and clinical research and added importantly to our knowledge of the etiology, pathogenesis, and treatment of depression. The purpose of this paper is to review the advances that have been made and to speculate how this new knowledge may lead to a better understanding of the biochemical substrates of depression and in doing so facilitate the development of new and different drugs for the treatment of this common disease.
Studies on the disposition of antipyrine, aminopyrine, and phenacetin using plasma, saliva, and urine
Authors: Vesell Elliot S. , Passananti G. Thomas , Glenwright Patricia A. , Dvorchik Barry H.
Published: January 2016

In normal male subjects, the half‐lives of antipyrine, aminopyrine, or phenacetin were not significantly different from the half‐lives of each drug in saliva. Apparent volumes of distribution (aVd) in plasma and saliva differed by the extent to which each drug has been reported to bind to plasma proteins. Thus, the aVd of antipyrine in plasma and saliva was similar; there were significant differences in aVdfor aminopyrine; even greater differences were observed for penacetin. The expression 1 − aVd (p)/aVd (s) equals the fraction of the drug bound to plasma proteins. Rates of appearance in the urine of metabolites of antipyrine and aminopyrine were measured. General equations were used to show the relationship between half‐life for elimination of the parent drug from the body and rate of excretion of metabolites. There were significant correlations between the half‐life for elimination of antipyrine from the body and the half‐life for production of 4‐0H antipyrine (r = 0.90), as well as between the plasma half‐life of aminopyrine and the half‐life of 4‐aminoantipyrine (r = 0.95). No significant correlation was observed in the same individual between the plasma half‐lives of antipyrine and phenacetin (r = 0.05, p < 0.05), of aminopyrine and phenacetin (r = 0.11, p < 0.05), or of antipyrine and aminopyrine (r = 0.50, p < 0.05).
Effects of marihuana combined with secobarbital
Authors: Dalton William S. , Martz Robert , Lemberger Louis , Rodda Bruce E. , Forney Robert B.
Published: January 2016

Twelve male volunteers smoked a marihuana cigarette prepared to deliver 0 or 25 µ/kg tetrahydrocannabinol (THC) 50 min after ingesting a capsule containing either placebo or 150 mgl70 kg sodium secobarbital. Drugs were administered in a double‐blind manner, and all treatments were assigned to each subject in a randomized complete block design. Objective and subjective tests designed to measure mental and motor performance indicated that marihuana impaired stability, hand‐eye coordination, and mental performance. Secobarbital affected motor performance, manual coordination, and mental performance. In combination, marihuana and secobarbital had an additive effect on subjective responses and impairment in certain psychomotor performance tests.
First‐pass metabolism of nortriptyline in man
Authors: Gram Lars F. , Overø Kerstin Fredricson
Published: January 2016

The kinetics of nortriptyline were studied after oral and intravenous (iv) administration of test doses of 50 mg 14C‐nortriptyline. The systemic availability of orally administered nortriptyline varied from 0.46 to 0.59 in 6 subjects. The decrease in availability was due to metabolism after administration. Systemic clearance varied from 0.31 to 0.66 Llmin. From these measurements indirect estimates of the hepatic blood flow could be made, and a variation from 0.6 to 1.5 L/min was found. Quantitative measurements of first‐pass metabolism could also be obtained from urinary metabolite excretion data when the kinetics of metabolite formation and elimination were taken into account. From the second or third day after the test dose, the urinary excretion rate of total radioactivity declined monoexponentially with half‐lives closely corresponding to the plasma half‐lives of unchanged nortriptyline. Analysis of the data from the iv test according to a 2‐compartment open model showed that there was a close correlation between the rate constant of distribution from central to peripheral compartment (k12 and the elimination rate constant in the central compartment (ke1). Still, there was some variation in the kp1lk 12‐ratio, and this variation corresponded to the variation of the estimated hepatic blood flow.
Bioavailability of dexamethasone; II. Dexamethasone phosphate
Authors: Hare L. E. , Yeh K. C. , Ditzler C. A. , McMahon F. G. , Duggan D. E.
Published: January 2016

Plasma levels of dexamethasone phosphate (DP) and dexamethasone free alcohol (DA) were determined by a modification of existing radioimmunoassay methodology following intravenous administration of DP in man. Areas under DA plasma profiles were a linear function of DP dosage over the 40‐fold range 0.05 to 2.0 mg/kg, and, by comparison with values obtained after DA was intravenously administered, indicated an overall conversion of DP to DA of90%. The first‐order rate constant for the conversion, 4.03 hr‐1, was approximately 25 times that for hydrolysis in whole blood incubated in vitro. This relationship as well as disposition kinetics suggested that the major component of DP hydrolysis occurs within highly perfused organ(s) comprising the central kinetic compartment. Eighteen subjects were studied in a crossover experiment, and no significant differences were observed in best‐fit parameters for the 4 mg/ml parenteral solution of DP in current use and an experimental high potency preparation of 24 mg Iml.
Effect of hydrochlorothiazide on phosphorus during treatment with diphosphonate
Authors: Recker Robert R.
Published: January 2016

The effects of probenecid and hydrochlorothiazide on renal handling of phosphorus during hyperphosphatemia induced by diphosphonate (ethane‐l‐hydroxy‐l, l‐diphosphonate, EHDP) was studied. Measurements of calcium, phosphorus, and creatinine clearance were performed in 2 sessions on each of 3 consecutive days in 10 normal fasting volunteers during the morning hours from 8 A.M. to 12 noon. During 2 to 3 wk thereafter, each subject was treated with EHDP, 30 mg/kg/day. The second group of studies were performed in the same manner as the first except that EHDP administration was continued throughout. EHDP caused elevation of serum phosphorus in all cases. Probenecid did not affect urine phosphorus. Hydrochlorothiazide caused a transient phosphaturia of similar magnitude in the EHDP treated and untreated states. Creatinine clearance was not affected by any of the treatments and urine calcium was decreased by EHDP. It was concluded that hydrochlorothiazide inhibits tubular reabsorption of phosphorus but that it does not affect the mechanism whereby EHDP causes increased tubular reabsorption of phosphorus. Chronic administration of hydrochlorothiazide along with EHDP may inhibit hyperphosphatemia and may change the bone effects of EHDP.
Europeanization of American drug discovery
Authors: McMahon F. Gilbert
Published: January 2016

Therapeutic progress is directly dependent upon the continued support and encouragement of both basic and clinical research. The support must be both economic and moral. Ultimately, moral support must come from the general public who must understand that, for their own future benefit, proper conduct of research must be not simply tolerated but encouraged.
A physiological approach to hepatic drug clearance
Authors: Wilkinson Grant R. , Shand David G.
Published: January 2016

A physiological approach has been developed recognizing that hepatic blood flow, the activity of the overall elimination process (intrinsic clearance), drug binding in the blood, and the anatomical arrangement of the hepatic circulation are the major biological determinants of hepatic drug clearance. This approach permits quantitative prediction of both the unbound and total drug concentration/time relationships in the blood after intravenous and oral administration, and any changes that may occur as a result of alterations in the above biological parameters. These considerations have led to a classification of drug metabolism based on the hepatic extraction ratio. The proposed classification allows prediction and interpretation of the effects of individual variations in drug‐metabolizing activity, route of administration, pharmacokinetic interactions, and disease states on hepatic drug elimination.
Effect of intravenous diazepam on renal function
Authors: Guignard J. P. , Filloux B. , Lavoie J. , Pelet J. , Torrado A.
Published: January 2016

The effect of intravenous diazepam on glomerular filtration rate (inulin clearance) and effective renal plasma flow (PAH clearance) was investigated in 6 children and 12 anesthetized rabbits. A transient decrease in inulin and P AH clearances was observed in 6 children given 4 mg of diazepam intravenously, without measurable change in blood pressure. A similar renal effect was observed in anesthetized rabbits, together with a transient drop in systemic arterial pressure. Continuous infusion of diazepam (5 mg/kg/hr) did not affect renal function in rabbits. We suggest that this effect of diazepam should be borne in mind when the drug is administered to patients undergoing renal clearance studies or to patients with preexistent renal insufficiency.
Total body potassium and 24‐hour creatinine excretion in healthy males
Authors: Turner William J. , Cohn Stanton
Published: January 2016

Total body potassium may be predicted from height, weight, and age by TBKmmol = 30.83 Hem + 18.05 Wkg − 11 (ageYr − 20) − 3034. This equation, based on measurements of 31 men, has been compared with others in the literature. Prediction of 24‐hr creatinine (CR), excretion derived from 33 control adults whose excretion rates gave a coefficient of variation less than 13%, may be made from the equation: CRgm = 0.0143 Hem + 0.00975 Wkg − 0.00734 (ageYr −20) −1.391. For 31 chronic schizophrenics, the corresponding equation CRgm = 0.0122 Hem + 0.0145 Wkg − 1.611 contained no age correction. The relationship between CR and TBK is expressed by CRgm = 0.000403 TBKmmol + 0.278. Discussion of significance of these equations in the light of extensive literature suggests that about half of the error variance in predicting CR may be explained by the lack of suitable data on somatotype and much of the residual variance, including the day‐to‐day variation in CR, relate to factors altering basal O2 consumption. The predictors given should prove generally satisfactory for many metabolic and drug studies.
Pharmacokinetics of hexobarbital in acute hepatitis and after apparent recovery
Authors: Breimer D. D. , Zilly W. , Richter E.
Published: January 2016

The pharmacokinetics of hexobarbital were studied in 13 patients with acute hepatitis. Hexobarbital sodium was administered by zero order intravenous (iv) infusion, and plasma concentrations were determined regularly by gas chromatography. For each patient the data were fitted according to 2‐compartment kinetics. The results were compared to those obtained for 14 healthy volunteers. The elimination half‐life of hexobarbital was 490 ± 186 min in the hepatitis patients and 261 ± 69 min in the control group. Clearance was significantly reduced in the hepatitis group, whereas the volume of distribution at steady state was not significantly altered. For some patients the initial distribution volume was reduced. In 6 patients the experiment with hexobarbital was repeated after apparent recovery from hepatitis as judged by normal transaminase and bilirubin levels. Generally the half‐life of hexobarbital was shorter and the clearance value was higher than during the acute illness, but the values had not yet returned to normal. Clinical recovery from liver disease is not accompanied by corresponding recovery of drug‐metabolizing capability.
In vitro and in vivo transport of lithium by human erythrocytes
Authors: Mallinger Alan G. , Kupfer David J. , Poust Rolland I. , Hanin Israel
Published: January 2016

An in vitro system that can be used to measure both uptake and efflux of lithium by erythrocytes (RBCs) is described. Using this system, RBC lithium accumulation in vitro was compared with in vivo RBC lithium concentrations observed in 6 normal volunteers. A significant correlation was demonstrated between in vitro RBC lithium accumulation after 48‐hr incubation and in vivo RBC lithium concentration at 24, 48, 72, and 96 hr following the beginning of lithium ingestion. In addition, when efflux of lithium from RBCs in vitro was studied, a significant correlation was observed between residual lithium in RBCs and in vitro RBC lithium accumulation. Finally, it has been demonstrated that storage of blood in ice for 5 hr prior to incubation with lithium results in increased RBC lithium accumulation. A potential role for this in vitro incubation system as a model for in vivo RBC lithium accumulation is suggested.
Patient package inserts. I. Nature, notions, and needs
Authors: Joubert Pieter , Lasagna Louis
Published: January 2016

A total of 137 completed questionnaires were obtained from several population samples in an attempt to assess drug knowledge, information sources, and views on drug information with particular attention to the possible role of a patient‐oriented package insert. The results indicated that the study population was variably informed and could make fairly accurate assessments of this knowledge. Responders placed great importance on the doctor and pharmacist as preferred and actual drug information sources. The mass media were accorded little prominence. Great emphasis was placed on the adequate provision of information, and this appears to be a crucial function in an adequate doctor‐patient relationship. The results appear to indicate a favorable climate for establishing a patient‐oriented package insert that should have summarized as well as detailed information to complement the doctor and pharmacist as primary information sources.
Butorphanol and pentazocine in patients with severe postoperative pain
Authors: Dobkin Allen B. , Eamkaow Sooky , Caruso Frank S.
Published: January 2016

Either butorphanol tartrate (1, 2, or 4 mg) or pentazocine (30 or 60 mg) was given intramuscularly (5 dose groups) to 262 patients, who were scheduled for major operations, if they had severe pain after full awakening in the recovery room, postoperatively under double‐blind conditions. There were at least 50 patients in each of the five dosage groups. Pain intensity and relief were scored numerically for each treated patient at ½, 1, 2, 3, and 4 hr, while under direct surveillance, and the patients were seen again for follow‐ups during the first 24 hr postoperatively. Appreciable pain relief developed within 30 min at all dose levels, with a peak analgesic effect apparent at about 1 hr. Satisfactory relief persisted for 4 hr in the majority of patients in each group. With the lowest dose of butorphanol tartrate (1 mg), which gave good pain relief for only 2 to 4 hr, approximately 60% of the patients had to be remedicated within 4 hr. Vital signs were not appreciably affected, but the patients who received the high dose of analgesics (butorphanol tartrate 4 mg or pentazocine lactate 60 mg) were often quite drowsy. The incidence of other side effects was negligible. The relative potency assay showed that butorphanol was approximately 20 times as potent as pentazocine for up to 4 hr.
Oral benzquinamide in the treatment of nausea and vomiting
Authors: Moertel C. G. , Schutt A. J. , Hahn R. G. , O'Fallon J. R.
Published: January 2016

The clinical antiemetic effect of benzquinamide by oral route at a dosage of 100 mg 3 times daily was evaluated by a controlled double‐blind method in 183 studies of patients treated with 5‐fiuorouracil. The incidence of nausea and vomiting in benzquinamide‐treated patients was equal to that in placebo‐treated patients and significantly higher than that in patients treated with prochlorperazine, 10 mg 3 times daily. Sedation was the only significant side effect observed. and this occurred at essentially equal rates in benzquinamide‐ and prochlorperazine‐treated patients.
Salivary excretion of amobarbital in man
Authors: Inaba T. , Kalow W.
Published: January 2016

The concentrations of amobarbital in saliva and serum were determined in 5 normal adults following ingestion of 120 mg of sodium amobarbital. There was excellent linear relationship between amobarbital concentrations in saliva and serum (r = 0.993); salivary levels were 36.1% of serum levels. Since the pH of saliva was generally lower than that of blood in man. the degree of ionization of amobarbital in serum and saliva had to be taken into consideration. Estimation of the protein binding of amobarbital in serum from concentrations of amobarbital in saliva and serum was in good agreement with the in vitro data of equilibrium dialysis.
Effect of acidosis on patients with myocardial ischemia
Authors: Holsinger J. W. , Miscia V. F.
Published: January 2016

Reduction in pH is known to decrease O2 affinity (Bohr effect) and increase the rate of O2 release from blood. It provides a potential mechanism for increasing O2 transport to the myocardium. Fifteen patients with refractory, chronic angina were studied by treadmill exercise tolerance tests and whole blood‐oxygen release rate measurements before and 4 days after beginning treatment with oral acetazolamide (10 to 20 mg/kg body weight). Positive treadmill exercise test or myocardial necrosis was present in each case. There was a correlation between an increased O2 release rate from blood and relief of symptoms. The major side effect in 2 patients was pathologic fatigue believed to result from acidosis. Of the 7 patients who obtained relief from angina, in each there was a 27% increase in the rate of release of O2 from their whole blood. Seven patients did not obtain relief; they showed no change in the rate of release. In the 4 patients who became worse the rate of deoxygenation decreased by 22%. All changes in deoxygenation rate coincided with the clinical findings. The treatment of ischemic heart disease with acetazolamide or other acidifying agents should not, however, be attempted until further investigation establishes their clinical value.
Propranolol in hypertensive dialysis patients: Efficacy and compliance
Authors: Briggs William A. , Lowenthal David T. , Cirksena William J. , Price William E. , Gibson Thomas P. , Flamenbaum Walter
Published: January 2016

The effect of propranolol therapy on plasma renin activity and blood pressure control was evaluated in 35 uremic patients receiving intermittent center‐based outpatient hemodialysis. Patients were determined to be either compliant or noncompliant with therapy based on the steady‐state predialysis plasma propranolol concentration. Noncompliance occurred with remarkable frequency and was associated with persistent hyperreninemia and poorly controlled hypertension. Blood pressure control was significantly better in compliant patients, in whom plasma renin activity was generally, but not universally, suppressed. Propranolol can be effectively used in the management of hypertensive dialysis patients, but steady‐state plasma propranolol levels should be measured to assess compliance in patients apparently refractory to treatment.
Electrophysiologic properties of perhexiline
Authors: Vera Zakauddin , Gray Don R. , Harter Kyle W. , Janze David A. , Massumi Rashid A. , Mason Dean T.
Published: January 2016

Perhexiline maleate (Pexid), a promising clinical antiarrhythmic and antianginal drug, was evaluated for its electrophysiologic effects on the entire conduction system of the intact canine heart throughout a wide range of therapeutic and potentially toxic doses. Intracardiac conduction times were measured by bipolar intramyocardial and transvenous endocardial electrodes before and following the intravenous administration of each dose of perhexiline maleate, 3 mg/kg every 30 min for a total of 4 doses in 7 open‐chest anesthetized dogs. Eight animals served as controls in which similar operative technique and electrophysiologic variables were recorded after infusion of the maleate diluent. In addition, the effects of perhexiline on atrial and ventricular thresholds to electrical stimulation were recorded, as well as the QRS and QT intervals, sinus rate, and rhythm disorders. It was observed that perhexiline did not significantly (p > .05) alter sinus rate, QT interval, QRS duration, PR interval, intra‐atrial conduction time, atrioventricular nodal conduction time, and His‐Purkinje conduction velocity. The drug did not affect the cardiac threshold to electrical stimulation of <0.1 mao No ectopic atrial or ventricular activity emerged during the accumulated influence of the agent. From this study, it is concluded that perhexiline does not exert deleterious actions on the conduction system of the intact canine heart. In view of the negligible toxic effects and its efficacy in treating ventricular tachyarrhythmias in patients, the drug deserves further clinical evaluation.
Effect of oral contraceptives on plasma clearance
Authors: Carter Dean E. , Bressler Rubin , Hughes Mark R. , Haussler Mark R. , Christian C. Donald , Heine M. Wayne
Published: January 2016

The effects of chronic steroid contraceptive therapy on drug clearance from plasma were studied by using plasma antipyrine, phenylbutazone, and cholecalciferol half‐lives in women. After 3 mo of oral steroid therapy (Norinyl, 2 mg; norethindrone + mestranol), the antipyrine half‐life was increased in 3 of 6 subjects, phenylbutazone half‐life was not consistently altered, and vitamin Da half‐life was increased in 3 of 4 patients. After 1 to 7 yr of oral steroid therapy, the antipyrine half‐life was longer while taking the contraceptive than when the contraceptive treatment was discontinued in 4 of 6 subjects, whereas that of phenylbutazone was not consistently altered.
Effects of repeated doses of scopolamine on the electroencephalographic stages of sleep in normal volunteers
Authors: Sagalés T. , Erin S. , Domino E. F.
Published: January 2016

Single doses of scopolamine markedly alter sleep patterns in man. This study intended to evaluate the persistence of these changes during continued administration. The design consisted of a sequence of habituation, no‐medication, saline (control), scopolamine (0.006 mg/kg intramuscularly 3 consecutive nights), and saline. The first dose of scopolamine markedly retarded the onset of stage rapid eye movement (REM) sleep (p < 0.005) and diminished the total amount of REM sleep during the night (p < 0.025). A decrease in total number of eye movements (p < 0.05) and an increase in body movements (p < 0.025) were also observed. Changes after the second dose of scopolamine were less marked but still significant. The third dose of scopolamine produced less marked changes than the preceding two. When compared with the first scopolamine night, the onset of stage REM was retarded to a lesser extent (p < 0.05) and the total amount of REM sleep was increased (p < 0.05). An increase in the duration of the first REM period was also observed. Rebound effects on the appearance of the first REM period (p < 0.01), number of eye movements (p < 0.001), total amount of REM sleep (p < 0.01), and body movements were observed in the last saline night.
Studies in porphyria; v. Drug oxidation rates in hereditary hepatic porphyria
Authors: Anderson Karl E. , Alvares Alvito P. , Sassa Shigeru , Kappas Attallah
Published: January 2016

The mean plasma half‐life (T½) of antipyrine was prolonged (21.69 ± 1.92 hr) in a group of 10 patients with hereditary hepatic porphyria, 8 of whom had acute intermittent porphyria (AIP) confirmed by decreased erythrocyte uroporphyrinogen‐1‐synthetase (URO‐S) activities and 2 of whom had mixed hepatic porphyria, in comparison to the mean of 20 normal control subjects (12.65 ± 0.86 hr, p < 0.01). Antipyrine T½ was especially prolonged in patients with a history of more severe symptoms, but there was no correlation with the degree of elevation in urinary excretion of the porphyrin precursors δ‐aminolevulinic acid (ALA) and porphobilinogen (PBG). In 7 completely latent carriers of the AIP gene deJect who had normal urinary ALA and PBG levels, the elimination rates of antipyrine from plasma were entirely normal. Phenylbutazone T½ were normal in 10 porphyric patients tested. These results demonstrate that the cytochrome P‐450‐dependent enzyme system for oxidizing antipyrine, but not that for phenylbutazone, is impaired in some AIP individuals in whom the gene defect for the disorder is clinically expressed and that this impairment may be related to the severity of the disease. The partial decrease in URO‐S activity characteristic of AIP does not result in a proJound or generalized decrease in hepatic cytochrome P‐450 Junction, however, even when there is sufficient derangement in the hepatic heme biosynthetic pathway to lead to excessive excretion of chemical intermediates in the pathway.