bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiologic and pharmacologic influences on adrenergic regulation of renin release
Authors: Levy Steven B. , Holle Rolf , Hsu Larry , Lilley John J. , Stone Richard A.
Published: January 2016

Changes in hemodynamic variables and plasma renin activity (PRA) induced by short‐term alteration of blood pressure and sympathetic nervous system activity were studied in normotensive and hypertensive men on high‐sodium and low‐sodium intake. Blood pressure and heart rate alterations caused by standard cold pressor tests, amyl nitrite inhalation, phentolamine infusion, and phenylephrine infusion were recorded. PRA was measured at time 0,5, 15, and 30 min. No change in PRA occurred in either group following cold pressor test and amyl nitrite inhalation. Phenylephrine suppressed PRA in normal but not hypertensive subjects, and phentolamine elevated PRA in normotensive and hypertensive subjects regardless of diet. Short‐term stimulation of the sympathetic nervous system does not appear to elevate PRA in man. Suppression of PRA by an alpha agonist was not observed in hypertensives and may reflect barorecptor insensitivity in this group of subjects.
Digoxin in hyperthyroidism
Authors: Huffman D. H. , Klaassen C. D. , Hartman C. R.
Published: January 2016

A patient with chronic atrial fibrillation developed hyperthyroidism. Increasing doses of digoxin were required to maintain satisfactory ventricular rate control. The systemic availability of oral digoxin was decreased in this patient. The metabolism of digoxin was studied in hyperthyroid rats. The plasma digoxin concentrations were significantly decreased in the hyperthyroid rats. A threefold increase in digoxin excretion in the bile of the hyperthyroid rats was associated with these changes in plasma digoxin concentrations. Conversely. hypothyroid rats excreted less digoxin in the bile when compared with control and hyperthyroid rats. Thus, changes in digoxin absorption and its biliary excretion result, in part, in a decreased therapeutic effect of digoxin based on dose in hyperthyroidism.
Error dependent on renal function when monoexponential equation assumed
Authors: MacKichan Janis J. , , Michael R. Dobrinsk , Welling Peter G. , Wagner John G.
Published: January 2016

An example from the literature has been used to demonstrate errors involved in calculating drug clearance by inappropriate use of the apparent drug distribution volume V dext. The V dext is always an overestimate of the true volume of distribution in a multicompartment system, and the degree of overestimation in using it to calculate clearance for such a system will increase as renal function increases. Drug dosages calculated on the basis of overestimated clearance values may give rise to overdosage in normal individuals, or therapeutic failure in severely uremic patients. Problems associated with the use of an oversimplified pharmacokinetic model for clearance calculations are discussed, together with the concept of model‐independent calculations.
Nutrition and drug‐metabolizing enzymes
Authors: Campbell T. Colin
Published: January 2016

The role played by nutrition and nutritional status in drug metabolism, as distinct from the effects of diet plus nonnutrient components on these reactions, is discussed. The cytochrome P‐450‐dependent mixed‐function oxidation (MFO) activity, primarily located in the liver, and such other reactions involving the transferases and hydrases which, on theoretic grounds, may become rate limiting during nutritional alteration determine the degree of the biologic response. This is exemplified by the relationship between dietary protein deficiency which decreases MFO activity and increases the duration of action of barbiturates by decreasing their rates of metabolism and tissue clearance. Male Sprague‐Dawley weanling rats were fed on a deficient diet of 5% protein and compared with controls on 20% protein. In the protein‐deficient animals, the liver cells were larger, there were fewer per liver weight as demonstrated by DNA content, the cells were higher in lipid content, and the liver contained less protein per unit weight than that of control animals. Preliminary experiments to examine a possible relationship between protein intake and certain types of cancer were undertaken. The effect of protein deficiency on the proportion of a 3H‐AFB1 dose which binds critical macromolecules in liver nuclei was studied. An important finding was that protein‐deficient diets depressed the binding to DNA by 70%. If, indeed, as recently postulated, 80 to 90% of human cancers are due to environmental chemicals and chemical carcinogens require metabolic activation, the question is posed whether nutritional manipUlation, particularly of the amount of dietary protein, may modify carcinogenic susceptibility. Similarly, nutritional status could also significantly affect pharmacologic response and environmental chemical insult.
Nutrition and chemical biotransformations in man
Authors: Conney A. H. , Pantuck E. J. , Kuntzman R. , Kappas A. , Anderson K. E. , Alvares A. P.
Published: January 2016

Nutritional factors are important in the regulation of drug metabolism in animals and in man. The average plasma half‐life of antipyrine decreased 41% and the plasma half‐life of theophylline decreased 36% when the diets of normal volunteers were changed from their customary home diets to diets that contained high protein and low carbohydrate. When the subjects were shifted from this high protein‐low carbohydrate diet to a high carbohydrate‐low protein diet. the average antipyrine and theophylline half‐lives increased 63% and 46%. respectively. Feeding a charcoal‐broiled beef‐containing diet to human volunteers for 4 days significantly decreased the plasma half‐life of antipyrine. This diet also decreased the plasma levels of orally administered phenacetin without influencing the plasma concentrations of phenacetin's principal metabolite. N‐acetyl‐p‐aminophenol. or the plasma half‐life of phenacetin. which suggests that feeding charcoal‐broiled beef enhances the metabolism of phenacetin in the gastrointestinal tract and/or during its first pass through the liver. This effect of charcoal‐broiled beef was not caused by a change in dietary protein but was probably caused by polycyclic hydrocarbon enzyme inducers in the charcoal‐broiled beef. Some subjects had large changes in drug metabolism when their diets were changed. whereas other subjects had little or no response to altered dietary regimens. which indicates marked individuality in the responsiveness of different people to changes in the diet. The intestinal metabolism of phenacetin was stimulated in rats fed a diet that contained charcoal‐broiled beef. Brussels sprouts. or cabbage. Feeding Brussels sprouts or cabbage to rats also enhanced the intestinal metabolism of 7‐ethoxycoumarin. benzo[a] pyrene. and hexobarbital. Pretreatment of rats with several indoles that are present in cabbage and Brussels sprouts stimulated the intestinal metabolism of phenacetin. 7‐ethoxycoumarin. benzo[a] pyrene. and hexobarbital. Additional studies are needed to more fully explore the effects of dietary factors on the action of drugs. environmental pollutants. and normal body constituents in humans.
Regulation of cytochrome P‐450‐dependent microsomal drug‐metabolizing enzymes by nickel, cobalt, and iron
Authors: Maines Mahin D. , Kappas Attallah
Published: January 2016

The effects of metals as modifiers of the activity of microsomal drug‐metabolizing enzymes were studied with the use of nickel, cobalt, and iron. These metals were found to impair cellular heme‐dependent metabolism by affecting both the heme biosynthetic and heme degradative pathways, inhibiting the former and inducing the latter. As powerful cellular toxins, metals depress respiratory activity and indirectly reduce drug‐detoxifying ability of cells. Metals also perturb cellular glutathione content and thus may alter the activity of glutathione‐dependent enzymes. The toxicity of metals is cumulative depending on concentration and degree of cellular exposure to one or to several closely related metals. On the other hand, these metal effects on cellular heme metabolism could also have selective therapeutic application in circumstances in which it may be desirable to suppress heme synthesis in order to decrease drug biotransformation, i.e., when a certain drug metabolite is more toxic than the parent compound.
Insecticides: Effect on drug metabolism
Authors: Azarnoff Daniel L.
Published: January 2016

The effects of chlorinated organic insecticides on the half‐life and rate of elimination of a variety of drugs were studied in laboratory animals; observations were made in humans occupationally exposed and in birds environmentally exposed to pesticides. Species differences are reported depending on the insecticide tested: DDT decreased hexobarbital sleep time of rats but had no effect in mice, which did respond similarly when treated with chlordane. All isomers of DDT as well as their metabolites were potent inducers of hepatic microsomal drug‐metabolizing enzymes in rats. In treated dogs, plasma elimination half‐life of hexobarbital was shortened, but the half‐life of pentobarbital was lengthened. Exterminators exposed to a mixture of chlorinated organic pesticides, showed significantly shorter antipyrine plasma elimination half‐lives as contrasted to office personnel from the same company. Similar observations were made on workers in a DDT factory, with decreasing plasma half‐lives of phenylbutazone as compared with findings in a control group. Induction of mixed Junction oxidase (MFO) activity by chlorinated insecticides was associated with frequency of eggshell breakage and decreased eggshell weight in breeding birds, e.g., falcon, sparrow hawks, and others with a declining population. It was postulated that the eggshell defects resulted from altered metabolism due to excess steroid inactivation secondary to induction of MFO activity.
Concluding remarks
Authors: Dollery Colin T.
Published: January 2016

Instead of attempting to review individually the 20 papers read at this conference, I intend to address myself to only one question. And that is: What does it all mean?
Temporal variations of antipyrine half‐life in man
Authors: Vesell Elliot S. , Shively Carol A. , Passananti G. Thomas
Published: January 2016

Temporal variations in antipyrine disposition were studied in 19 normal male volunteers using salivary antipyrine half‐lives determined after a single oral dose of antipyrine (18 mg Ikg) given at 7:00 A.M. Specimens of saliva obtained at half‐hour intervals from 10:30 A.M. to 2:00 P.M. and also from 10:30 P.M. to 2:00 A.M. were designated the noon and midnight periods, respectively. In these 19 volunteers there were no significant differences between the mean antipyrine half‐lives calculated using only the noon period (12.8 ± 3.0 hr SD), those calculated using only the midnight period (13.2 ± 3.6 hr SD), and those determined using the whole 24‐hr period (13.0 ± 2.5 hr SD); neither were there significant differences among these periods for mean antipyrine metabolic clearance rates and mean apparent volumes of distribution. However, between the noon and midnight periods, 12 of the 19 subjects changed antipyrine half‐life by more than 10%. In the 12 subjects in whom the change exceeded 10%, there were 7 increases and 5 decreases in antipyrine half‐life. The range of extremes was more than 2‐fold, from an increase in half‐life of 173% in one individual to a decrease of 42% in another. That these temporal changes were not random fluctuation is suggested by repeated studies performed in the 5 subjects who exhibited the largest alterations; when the temporal change exceeded 10%, values were reproducible with respect to direction as well as magnitude. The observation that neither the direction nor the magnitude of temporal variation was altered by antipyrine administration at 7:00 P.M., rather than 7:00 A.M., also supports the concept that an endogenous circadian rhythm affects drug metabolism. Another rhythm, noted over a much shorter period of time, was a waver in the curves for both saliva and plasma antipyrine concentrations of all subjects. Since the same rhythm was also observed when antipyrine was measured in numerous aliquots of a single sample, the waver appeared to be artifactual in nature arising from random variability in the assay.
Effectiveness of prednisolone during phenytoin therapy
Authors: Petereit Lillie B. , Meikle A. Wayne
Published: January 2016

The effects of diphenylhydantoin (DPH) on the clearance of prednisolone from plasma, its bioavailability, and its biologic effectiveness were studied in 5 persons before and after daily DPH therapy for more than 3 wk. DPH decreased the mean half‐time of disappearance of prednisolone from plasma by 45% and increased its metabolic clearance rate by an average of 77%. The gastrointestinal absorption of prednisolone and its first‐pass clearance through splanchnic tissues were not significantly altered by DPH. The mean oral midnight dose of prednisolone required to suppress the 8 A.M. plasma level of cortisol to 5 p,g/dl was doubled following treatment of DPH. The increment in dose of prednisolone varied from 58% to 260% in the five individuals.
Serum digoxin and empiric methods in identification of digitoxicity
Authors: Waldorff Stig , Buch Jan
Published: January 2016

A prospective study of consecutive patients admitted to a medical service was undertaken to evaluate the prevalence of cardiac digitalis toxicity and the relative diagnostic values of serum digoxin versus an empiric method, based on calculations of digoxin dose in relation to kidney function and body weight. Of 711 patients admitted, 109 were treated with digitalis on admission. Sixteen of the patients developed cardiac arrhythmias consistent with digitalis intoxication. Five of these, none with serum digoxin above 1.6 ng/ml, were not toxic. The remaining eleven patients, all with serum digoxin levels above 1.6 ng/ml, were either definitely or possibly toxic. A similar borderline between intoxicated and nonintoxicated patients could not be established on the basis of calculations based on body weight and renal function. In all eases in which suspicion of digitalis intoxication was raised, serum digoxin measurements could discriminate between the toxic and the nontoxic patients.
Determination of procainamide acetylator status
Authors: Lima John J. , Jusko William J.
Published: January 2016

Variation in renal function can obscure the measurement of acetylator status for compounds such as procainamide in which appreciable active drug or acetyl metabolite is excreted in urine. Computer simulations and patient studies were used to compare two common metabolite/drug ratio methods and a proposed clearance technique for phenotyping acetylation rate. The calculation of apparent acetylation clearance from steady‐state serum concentrations of procainamide and urinary excretion rates of N‐acetyl‐procainamide provides the most definitive discrimination between fast and slow acetylators.
Pharmacokinetic studies on tolerance to sedative‐hypnotics in a poly‐drug abuse population; I. Secobarbital
Authors: Faulkner Thomas P. , McGinity James W. , Hayden James H. , Martinez Maria , Comstock Eric G.
Published: January 2016

Patients from a poly‐drug abuse treatment program with a history of sedative‐hypnotic abuse were titrated with secobarbital, their alleged drug of choice, to a minimal state of toxicity consisting of nystagmus, drowsiness, ataxia, and slurred speech. Volunteer control subjects underwent the same titration procedure. Blood level determinations were made, and several pharmacokinetic parameters were estimated in order to determine the nature and degree of tolerance in the patient population. The patients tolerated a titration dose which was slightly, but significantly. higher than that tolerated by the control group. Cellular tolerance could be demonstrated in terms of higher blood levels determined at 7.0 hr after the last dose but not at the onset of toxicity. A significantly greater β‐phase disposition constant and significantly smaller area under the curve per dose in the patient population suggested the contribution of drug disposition tolerance. Statistical comparisons of these parameters were made between several subgroups of the patient population. The patients indicating a higher frequency of sedative abuse did not differ from their patient counterparts. Those patients presenting with positive screens for barbiturates on admission provided similar results except for an apparently higher volume of distribution. Patients indicating concurrent alcohol use did not differ from the overall patient population; those also using amphetamines showed no sign of tolerance or increased elimination and were indistinguishable from control subjects.
Hand‐washing degerming: A comparison of povidone‐iodine and chlorhexidine
Authors: Dineen Peter
Published: January 2016

Two antiseptic preparations for hand washing were compared by the glove‐juice method in a crossover study on 10 volunteers. The reference preparation was 7.5% povidone‐iodine (Betadine Surgical Scrub); the test agent was 4% chlorhexidine gluconate combined with 4% isopropyl alcohol (Hibiclens). The experimental model included inoculation of the hands with a mixture of Serratia marcescens, Escherichia coli, Providentia stuartii, and Pseudomonas aeruginosa. The reference preparation achieved a reduction ratio in colony counts of 695 to 1 under the conditions of this study: The average postwash. colony count after use of 7.5% povidone‐iodine was significantly less than the preinoculation colony count. Logarithmic values, and the paired t test applied to them, showed a highly significant difference (p = < 0.001) in favor of the degerming ability of the reference agent compared to the test agent. These data are of value in the selection of preparations for hand washing and may point the way to quantitative methods for other degerming studies.
XLII. The architecture of cross‐sectional research (Part I)
Authors: Feinstein Alvan R.
Published: January 2016

Despite the many mathematical ‘models’ that have been developed for the statistical analysis of a research project, relatively little attention has been given to the basic scientific ‘models’ on which the work depends. For most people who have learned about science and the ‘scientific method’, the fundamental ‘model’ of scientific research is an experiment. This ‘model’ has many obvious advantages, but it is not applicable for many types of research that appear in clinical and epidemiologic journals. The investigator may be interested in studying observer variability or diagnostic test procedures for which an experimental model is inappropriate. Alternatively, the investigator may want to explore etiologic possibilities or therapeutic events for which an experimental model is unfeasible.
A message from the President—Come to Atlanta March 29–31, 1978
Authors: Aagaard George N.
Published: January 2016

It is time to make plans to attend the annual meeting of the American Society for Clinical Pharmacology and Therapeutics at the Peachtree Plaza Hotel, March 29 to 31, 1978. Once again the number of excellent abstracts submitted to Arthur Hayes, Jr., Program Committee Chairman, has demanded two and one‐half days of multiple scientific sessions. This will guarantee that there will never be a dull moment scientifically. Of course, all of the papers will be of interest to clinical pharmacologists.
Absorption of nicotine from small cigars
Authors: Armitage Alan , Dollery Colin , Houseman Terry , Kohner Eva , Lewis Peter J. , Turner David
Published: January 2016

The absorption of nicotine from cigars was measured in 7 male subjects who each smoked a single small cigar containing 14C‐nicotine. The proportion of nicotine in the mainstream smoke delivered to the smoker's mouth was greater than that observed for cigarettes, but the proportion of nicotine in the cigar smoke which was retained by the smoker was about the same. The total dose of nicotine retained varied between 1 and 4.5 mg. Arterial plasma concentrations of nicotine were as high as those achieved by cigarette smoking but rose more slowly. Some nicotine from small cigars is absorbed by inhalation of the smoke into the lungs and some by buccal absorption.
Pharmacokinetics of fentanyl as determined by radioimmunoassay
Authors: Schleimer Robert , Benjamini Eliezer , Eisele John , Henderson Gary
Published: January 2016

The pharmacokinetics of fentanyl were determined in human surgical patients using radioimmunoassay. Fentanyl was measured in the serum, cerebrospinal fluid (CSF). and urine of patients receiving 0.1, 0.5. or 1.0 mg/m2 of fentanyl intravenously. The kinetics of the disappearance of fentanyl from the serum were very similar at the three administered doses. At all doses. levels fell rapidly in the first five minutes to approximately 20% of the peak value. Thereafter, serum levels fell more slowly with an observed half‐life (t½) of approximately 10 to 20 min, depending on dose. By 2 hr serum levels had stabilized at low values (1, 5, and 8 ng/ml) and continued to decrease very slowly thereafter. with an observed t½ of 1 to 2 hr at the low dose (0.1 mg/m2) and greater than 4 hr at 0.5 and 1.0 mg/m2. The serum elimination curves were dissected and described mathematically in terms (if a three‐compartment model. Urinary excretion of fentanyl accounted for 15% to 20% of the administered dose. Urinary excretion was very low during the first 2 hr, suggesting that this route of elimination is not important in terminating the actions of fentanyl in man. Fentanyl levels in the CSF of patients given the high dose (1 mg/m2) were low. and never exceeded 4 ng/ml. Peak levels of fentanyl in the CSF were not seen until at least 15 min after administration.
Increase in diuretic effect of chlorothiazide by probenecid
Authors: Brater D. Craig
Published: January 2016

Thiazide diuretics reach their presumed intraluminal site of action by active transport at the organic acid secretory site of the proximal tubule. Probenecid competes for this transport and might therefore affect the diuresis induced by thiazide at that site. Doses of 500 mg and 1 gm of chlorothiazide (CTZ) intravenously to 5 volunteers with probenecid pretreatment increased 8‐hr rates of excretion of sodium and urine over that without probenecid. Eight‐hour excretion of sodium after administering 500 mg of CTZ was 147 ± 7.5 mEq and 257.9 ± 16.4 mEq after CTZ with probenecid (p < 0.0005). The volume of urine after CTZ was 728 ± 37 ml and 1,886 ± 301 ml after CTZ with probenecid (p < 0.001). This increase was associated with prolongation of cn diuresis rather than increase in intensity. These results are consistent with cn reaching its site of action from the peritubular side or that prolonged exposure of the lumen to lesser amounts of filtered CTZ causes a greater overall effect.
Disposition of meperidine in pregnancy
Authors: Morgan Denis , Moore George , Thomas Jack , Triggs Edward
Published: January 2016

Plasma concentration‐time profiles of meperidine after intravenous administration to 7 pregnant women during labor were investigated. There was considerable interpatient variation in initial plasma concentrations of meperidine and its volume of distribution. When the data in the literature on the disposition of meperidine in nonpregnant subjects were used for comparison, it was found that the initial dilution volume (V1), the volume of distribution at steady‐state (Vss), and the apparent volume of distribution during the terminal exponential phase of drug elimination (Vβ) were less (p < 0.05) in pregnant subjects than in healthy nonpregnant control subjects but were not significantly different in pregnant subjects and nonpregnant surgical patients. Mean total systemic blood clearance was also significantly less in the pregnant subjects (843 ml/min) than previously reported for healthy nonpregnant control subjects (1,465 ml/min). The blood/plasma concentration ratio of meperidine in pregnant women (0.940) was higher than that in control subjects (0.768; p < 0.01). Placental transfer of meperidine was investigated in 4 of the patients; in 2 the concentration of the drug was greater in cord plasma than in maternal plasma. Further study is indicated.
Failure of hydrocortisone to alter acutely antipyrine disposition
Authors: Shively Carol A. , Gagliardi Carol L. , Hartshorn Rodney D. , Vesell Elliot S.
Published: January 2016

The disposition of intravenously administered antipyrine in single doses of 40 mg/kg was studied in 3 dogs at 7:00 a.m. and 3 wk later at 7:00 p.m. Our purpose was to determine whether hydrocortisone differentially affected antipyrine disposition according to a circadian pattern. After each intravenous dose of antipyrine, saline was infused for 3 hr followed by intravenous hydrocortisone (2 mg/15 kg loading dose; 2 mg/15 mg/hr infusion for 3 hr). This regimen of hydrocortisone failed at either 7:00 a.m. or 7:00 p.m. to alter acutely antipyrine decay curves. Furthermore, in 4 normal male volunteers, no inflection in the salivary antipyrine decay curve occurred when hydrocortisone was injected 8 hr after antipyrine. In the human volunteers an intravenous injection of 3 mg was followed immediately by an additional 6 hr of continuous hydrocortisone infusion at 3 mg/hr. These experiments show that hydrocortisone alters the pharmacokinetics of previously administered antipyrine in neither dogs nor man.
Fluoxetine, a selective serotonin uptake inhibitor
Authors: Lemberger Louis , Rowe Howard , Carmichael Ralph , Crabtree Ross , Horng J. S. , Bymaster Frank , Wong David
Published: January 2016

Fluoxetine is a selective serotonin uptake inhibitor in man. Platelets harvested from subjects to whom fluoxetine was administered (30 mg daily for 1 wk) had a diminished ability to accumulate 3H‐serotonin. The inhibition of uptake was positively correlated with the plasma concentrations of fluoxetine. Plasma from fluoxetine‐treated subjects also inhibited the uptake of 3H‐serotonin by platelets obtained from nontreated subjects. Fluoxetine was without effect on the noradrenergic nerve endings; pressor effects induced after the administration of norepinephrine or tyramine were similar whether subjects were receiving fluoxetine or placebo. Fluoxetine administration for 30 days produced similar pharmacologic effects as after the 7‐day study and included: (1) no change in sensitivity to the pressor effects of tyramine and norepinephrine and (2) marked inhibition in the uptake of 3H‐serotonin by platelets harvested from subjects on this regimen. In addition, fluoxetine caused a diminution of the concentration of endogenous serotonin in platelets, resulting in serotonin levels of only 20% of control. Fluoxetine was well absorbed and achieved peak plasma concentration at 6 hr after administration. Fluoxetine and the major metabolite, norfluoxetine, appeared to reach a steady state within 12 to 14 days. Fluoxetine, administered in single doses of 1 to 90 mg produced no behavioral or adverse effects. Similarly, after 1 wk of fluoxetine administration, no behavioral or adverse effects were observed.
Rise in serum and urine creatinine after phenacemide
Authors: Richards Richard K. , Bjornsson Thorir D. , Waterbury L. David
Published: January 2016

Three patients undder treatment with phenacemide for uncontrollable psychomotor epilepsy were found to have greatly increased serum creatinine levels in the absence of elevated blood urea nitrogen (BUN) values or any other evidence of renal disease. Serum creatinine returned promptly to normal after omission of the phenacemide and rose quickly again on resumption. Experiments in rabbits and rats fully reproduced these clinical observations. In vivo and in vitro studies with the drug and its metabolites excluded these as a cause for a spurious analytical finding. Rabbits given phenacemide have a fall in serum and urine creatine, while the corresponding creatinine values rise. With the use of a creatininase degradation procedure, it could be proved that the markedly elevated serum level and the increased excretion consist of true creatinine and not of any other substance. An effect of phenacemide on the conversion rate of creatinine to creatinine in the body is a speculative possibility.
The effects of new Federal regulations on clinical investigation
Authors: McMahon F. Gilbert
Published: January 2016

On September 27, 1977, The Federal Register published the first of a series of proposed new regulations by the Food and Drug Administration on bio‐research monitoring. The purpose of these new proposals is stated to be the improvement of the quality of the clinical (and preclinical) research data and the promotion of safeguards for the patients and volunteers. The impetus for these new proposals is stated to be:
Calcitriol in dialysis patients
Authors: Maxwell Douglas R. , Benjamin David M. , Donahay Sherry L. , Allen M. Kathy , Hamburger Richard J. , Luft Friedrich C.
Published: January 2016

We conducted a 7‐month randomized, single, double, single‐blind comparison of calcitriol (1,25(OH)2D3) with vitamin D3 in 22 hemodialysis patients to study the effects on the biochemical abnormalities associated with osteodystrophy. Calcitriol was given for 3 mo. All patients had initial pre study calcium values ≤9.5 mg/100 ml, and phosphate values ≤4.5 mg/100 ml. Data were analyzed using the Normalized Trend Index (NTI). Calcitriol induced a rise in calcium (8.7 to 10.25 mg/100 ml) (p < 0.001) and a fall in alkaline phosphatase (p < 0.005), while D3 had no appreciable effect. The mean dose of calcitriol during treatment was 0.579 µg/day while that for D3 was 706 IU/day. The effect on serum phosphate concentration was variable. Hypercalcemia as high as 13.2 mg/100 ml occurred in 2 of 13 patients on 1,25(OH)2D3, but in every instance promptly returned to normal with dose reduction. No other adverse effects were noted with therapy. We conclude that calcitriol reverses the biochemical abnormalities of osteodystrophy. Since its effects are rapidly reversed with discontinuation, the drug is probably safe as well as effective.
Absorption of oral and intramuscular chlordiazepoxide by alcoholics
Authors: Perry Paul J. , Wilding David C. , Fowler Richard C. , Hepler Charles D. , Caputo James F.
Published: January 2016

The effect of chronic alcoholism on oral and intramuscular plasma levels of chlordiazepoxide (CDX) was assessed. A 50‐mg oral dose of CDX resulted in significantly higher plasma levels in the 2 hr following CDX than a 50‐mg intramuscular dose administered to acute withdrawing alcoholic subjects. The same CDX dose was administered 7 days later and the same differences were observed between the mean oral and intramuscular plasma levels during the first 2 hr after administration of CDX. Peak concentration occurred significantly sooner after the oral than intramuscular dose of CDX in both the initial dose and the dose given a week later. It was also observed that the areas under the curve for CDX were significantly greater initially than 1 wk later. It is suggested this effect may be at least partially the result of the longer CDX half‐lives initially than a week later. The active metabolite, N‐desmethylchlordiazepoxide, peaked significantly earlier with the oral dose than with the intramuscular dose after the patient was alcohol free for a week.
Doxepin kinetics
Authors: Ziegler Vincent E. , Biggs John T. , Wylie Laurence T. , Rosen Samuel H. , Hawf Donald J. , Coryell William H.
Published: January 2016

The kinetics of doxepin (DOX) hydrochloride were studied in 7 volunteers after the oral administration of 75 mg. Peak plasma concentrations of DOX ranged from 8.8 to 45.8 ng/ml and were reached within 4 hr. The disappearance of DOX was biphasic and followed first‐order kinetics. The mean DOX half life (t½) was 16.8 hr and in individuals ranged from 8.2 to 24.5 hr. The mean apparent volume of distribution was 20.2 L/kg and ranged from 9.1 to 33.3 L/kg. The estimated first‐pass metabolism of DOX ranged from 55% to 87% of the oral dose assuming complete absorption. Significant quantities of the metabolite desmethyldoxepin (DMD) were produced. Peak levels of DMD ranged from 4.8 to 14.5 ng/ml and were reached between 2 and 10 hr after administration. The mean tl½ of DMD was 51.3 hr and in individuals ranged from 33.2 to 80.7 hr. There was no correlation between the DOX and DMD t½s. The amount of DMD produced correlated with the plasma concentration of DOX and appears to explain the correlation between the steady‐state concentrations of DOX and DMD in patients given DOX.
Gentisuric acid: Metabolic formation in animals and identification as a metabolite of aspirin in man
Authors: Wilson John T. , Howell Randall L. , Holladay Mark W. , Brilis George M. , Chrastil Josef , Watson J. Throck , Taber Douglass F.
Published: January 2016

Gentisuric acid was synthesized from gentisic acid and glycine ethyl ester. NMR, mass spectrometric and elemental analysis confirmed the product as GU, and physicochemical characteristics were determined. A TLC‐densitometric technique was developed to estimate GU and other metabolites of aspirin. Conjugation of gentisic acid with glycine to form GU was catalyzed by a mitochondrial fraction of rat and beef liver. GU was also formed by the rat liver microsomal hydroxylation of salicyluric acid, and phenobarbital pretreatment increased this formation. A random survey showed GU in 76% of SA‐positive urines from aspirin‐treated patients. Identity of GU in urine from two aspirin‐treated patients was confirmed by TLC and mass spectrometric analysis, and hydrolysis of the compound from one patient yielded glycine and gentisic acid. Urine from controls or post‐aspirin treatment patients did not show GU by TLC analysis. These results demonstrate for the first time the metabolic formation of GU in animals and its occurrence as a metabolite of aspirin in man.
Ticrynafen and hydrochlorothiazide in hypertension
Authors: Okun Ronald , Beg Mirza
Published: January 2016

In a double‐blind study, 28 patients having mild to moderate essential hypertension were randomly assigned to a 6‐week regimen of ticrynafen, hydrochlorothiazide, or placebo. Blood pressure fell after ticrynafen and hydrochlorothiazide. Serum uric acid fell strikingly with ticrynafen whereas it rose with hydrochlorothiazide. Serum potassium declined very little with ticrynafen; much less than with hydrochlorothiazide. Serum creatinine and blood urea nitrogen rose slightly more with ticrynafen than with hydrochlorothiazide. There were no clinical adverse effects to either of the medications. Ticrynafen appears to be an effective antihypertensive with a substantial hypouricemic effect.
President's report on annual meeting
Authors: McMahon Gil
Published: January 2016

The Seventy‐ninth Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, held in Atlanta, Georgia, March 29 to 31, 1978, was an all‐time success for our Society. A record number of registrants (778), a record number of abstracts submitted (200), and papers accepted for presentation (110) were achieved. It is important to analyze why this meeting was such a success so that we can build on these strengths for our next meeting in Kansas City, March 21 to 23, 1979.
Automated monitoring of drug‐test interactions
Authors: Friedman Richard B. , Young Donald S. , Beatty Ellouise S.
Published: January 2016

A computer‐based file of the effects of drugs on clinical laboratory tests was used in a university hospital to generate reports of all potential interactions between the drugs administered to a patient and the laboratory tests ordered on his body fluids. More than 13,000 patient days were monitored in four different nursing units. The physician users of the system indicated that automatic reporting of possible drug‐test interactions had both educational and clinical value. A critical review of patient charts suggested that automatic reporting of drug‐test interactions caused physicians to alter therapy in about 0.1% of instances in which a report was generated. The users themselves indicated that they altered treatment as a result of the reports in a substantially greater number of cases.
Is phenytoin metabolism dose‐dependent by enzyme saturation or by feedback inhibition?
Authors: Perucca Emilio , Makki Khalil , Richens Alan
Published: January 2016

The suggestion from animal experiments that phenytoin metabolism may be dose‐dependent in man due to feedback inhibition by the major metabolite, 5‐(p‐hydroxyphenyl)‐5‐ phenylhydantoin, was examined in 3 normal subjects by measuring phenytoin clearance during an intravenous infusion of the metabolite and during a control infusion of solvent. Clearance was measured using both carbon‐labeled and unlabeled phenytoin. The infusion of metabolite did not produce any consistent change of phenytoin clearance, suggesting that feedback inhibition does not occur in man.
Clinically significant adverse effects in a Phase 1 testing program
Authors: Zarafonetis Chris J. D. , Riley Philip A. , Willis Park W. , Power Lawrence H. , Werbelow Judson , Farhat Leo , Beckwith Wendall , Marks Bernard H.
Published: January 2016

Twelve years' experience with a Phase I drug testing program in normal prison volunteers is reported. lnvolved in 805 protocol studies were 29,162 participants over 614,534 subject days. During this period there were 64 significant medical events ofwhich 58 were adverse drug reactions and 6 were complications. One subject has residual hip changes due to an infectious complication, another on placebo died from cerebrovascular hemorrhage while asleep. There was complete recovery from all adverse drug reactions and the other 4 complications encountered. Thus a clinically significant medical event occurred once every 9,602 days ofsubject exposure or about once every 26.3 years of individual subjeet participation.
Methodology tor analyzing clinical neurological data: ACTH in multiple sclerosis
Authors: Henderson William G. , Tourtellotte Wallace W. , Potvin Alfred R. , Rose Augustus S.
Published: January 2016

From 1965 to 1968 a multicenter (USA) clinical trial was conducted to compare ACTH with placebo for the treatment of multiple sclerosis patients in a stage of acute exacerbation. Of seven evaluation systems which were used, one was a quantitative neurological examination. In this report, the quantitative neurological data have been re‐evaluated using a transformation of the data which express patient scores in terms of a percentage of age‐ and sex‐matched normal function followed by a reduction of the data into composite neurological functions vs time. The results support the positive findings of previous reports. In addition, the methodology helps to simplify the therapists' task of interpreting results by enabling him to determine how near normal function the patient came following the treatment trial.
Spironolactone‐induced changes in digoxin kinetics
Authors: Waldorff Stig , Andersen Jens Damgaard , Heebøll-Nielsen Niels , Nielsen Ole Gamborg , Moltke Erik , Sørensen Ulla , Steiness Eva
Published: January 2016

Plasma clearance, volumes of distribution, and renal and extrarenal clearances of digoxin were calculated from plasma digoxin concentrations and urinary excretion of digoxin after intravenous injection of digoxin in 8 subjects. The investigation was repeated in the same subjects during long‐term treatment with spironolactone. Increased plasma concentration of digoxin was detected during spironolactone treatment. Calculated plasma and renal clearances of digoxin and the volumes of distribution decreased statistically significant. Near maximal capacity for the tubular secretion of digoxin was found when normal digoxin dosage was used. It is suggested that unless spironolactone decreases the myocardial sensitivity for digoxin, the loading dose as weil as the maintenance dose of digoxin should be reduced during treatment with spironolactone.
Pamatolol: Phase I evaluation of the pharmacodynamics of a cardioselective beta adrenoceptor blocking drug
Authors: Carruthers S. George , Hosler James P. , Pentikainen Pertti , Azarnoff Daniel L.
Published: January 2016

A Phase I evaluation of a new beta adrenoceptor blocker, pamatolol, was performed in 10 healthy male volunteers, Minor reductions in standing and exercise and isoproterenol‐induced increases in heart rate were observed with the 10‐mg oral dose and appeared maximal with the 400–600 mg dose. The rate of decline of effect averaged 1.5% of the exercise heart rate/hr. Neither resting systolic time intervals nor post‐exercise pulmonary function was affected by this dose range of pamatolol. Based on the latter responses and the isoproterenol dose response curve, we tentatively conclude that pamatolol is relatively cardioselective in man.
Salmon calcitonin in hypercalcemia
Authors: Wisneski Leonard A. , Croom William P. , Silva Omega L. , Becker Kenneth L.
Published: January 2016

We have undertaken a study of 24 hypercalcemic patients with the use of salmon calcitonin as a therapeutic agent. Seventy‐five percent of the patients exhibited a clinically significant decrease in serum calcium and approximately half became normocalcemic within 2 hr. Throughout salmon calcitonin administration, the mean serum calcium of the patients was lower than the pretreatment values. Although the drug did not always lower the calcium level to normal, it often brought the hypercalcemia to more tolerable levels. During the course of calcitonin therapy, the number of patients with normal or near‐normal serum calcium ranged from 31.3% (at 96 hr) to 82.4% (at 30 hr). Many of the patients improved symptomatically. The only significant side effects were nausea and vomiting in 12.5% of the patients, which necessitated cessation of therapy in only one. The drug was well tolerated in patients with azotemia. Calcitonin‐induced hypocalcemia was not encountered. Salmon calcitonin can be used safely alone or in conjunction with other hypocalcemic therapies.
Effect of oral aspirin on “ecto‐ATPase” activity of washed human platelets
Authors: Vue Kenneth T. N. , Davis James W.
Published: January 2016

Aspirin is a potent inhibitor of the platelet release reaction and the accompanying second phase of platelet aggregation. The platelet release reaction is an active, energy‐dependent process which appears to require ATP. Eight men ingested 0.32 gm of aspirin daily for 7 days. Although the second phase of 1.7 µM ADP‐induced platelet aggregation was absent after aspirin ingestion, the “ecto‐ATPase” activities of washed human platelet suspensions were not significantly different before and after ingestion of aspirin. This suggests that the effect of aspirin on the second phase of platelet aggregation is not mediated through inhibition of “ecto‐ATPase.”
Effect of procainamide on induced ventricular tachycardia
Authors: Engel Toby R. , Gonzalez Ana del C. , Meister Steven G. , Frankl William S.
Published: January 2016

Ventricular extrastimulation was performed in 11 patients evaluated for chronic recurrent ventricular tachycardia, before and after a 1‐gm procainamide infusion. Extrastimulation caused only nonsustained extra beats (<4) in 3 patients. Sustained tachycardia was induced in 7 patients in the basal state, of which 6 continued to have inducible tachycardia after procainamide was given (5.2 to 9.8 mg/L). The zone of coupling intervals that initiated tachycardia was unchanged or widened in these 6 patients because ventricular refractoriness was unchanged or because the tachycardia zone shifted to later diastole by an interval at least equivalent to the prolongation of ventricular refractoriness. Post‐procainamide tachycardia cycle length was prolonged in all patients, by an average 51 msec. The one patient who responded to procainamide had a shartened ventricular refractory period, but the greatest slowing of tachycardia. Finally, sustained ventricular tachycardia could be induced in the eleventh patient only following procainamide administration, consistent with his clinical history. These results suggest that procainamide often may be ineffective in preventing sustained ventricular tachycardia, and that slowed conduction, rather than prolonged refractoriness, is the basis for the procainamide antiarrhythmie effect. Our data emphasize that antiarrhythmie drug effectiveness be evaluated in terms of effect on sustained arrhythmia rather than suppression of isolated ectopic beats.
Steady‐state kinetics of valproic acid in epileptic patients
Authors: Bruni J. , Wilder B. J. , Willmore L. J. , Perchalski R. J. , Villarreal H. J.
Published: January 2016

Pharmacokinetic evaluation and prediction were carried out in 20 epileptic patients. Using conventional pharmacokinetic techniques and a one‐compartment model, predicted and observed valproic acid plasma concentrations were compared. Valproic acid assay was performed by gas‐liquid chromatography. There was good agreement between predicted and observed plasma concentrations. Most patients had predicted half‐lives (t½s) of 6 to 8 hr, independent of the plasma concentration of valproic acid. Five patients had predicted t½s of 12 hr. The correlation between dose and plasma level was poor. Most patients had valproic acid plasma levels between 55 and 100 µg/ml. Administration ofvalproic acid three times a day with determination of individual plasma concentrations offers a reliable method of monitoring. Constant levels are maintained in individual patients, but there is substantial intersubject variation.
Flucytosine kinetics in subjects with normal and impaired renal function
Authors: Cutler Ralph E. , Blair Andrew D. , Kelly Michael R.
Published: January 2016

Kinetics and bioavailability of flucytosine were studied in 5 subjects with normal renalfunction. Kinetic parameters and absorption were compared after a 500‐mg dose administered in the following manner: intravenously, aqueous solution, and capsules while fasting; capsules after meals; and capsules with antacid. Encapsulation, food, and antacid decreased the absorption rate constant but the total amount absorbed orally did not differ significantly. Bioavailability assessed by the urinary recovery or comparison of the AUCo to AUCiv on the average showed 76% to 89% oral absorption. In 3 patients on hemodialysis, the serum concentrations in the β‐phase following oral flucytosine in capsules during fasting were in the same range as those after a comparable intravenous dose. The mean steady‐state distribution volume (Vdss) was 0.679 L/kg in normal subjects and ranged between 0.413 and 0.706 L/kg in 9 patients with renal failure. The mean t½β was 4.2 hr in normal subjects and the renal clearance was comparable to creatinine clearance. In renal failure, a linear regression analysis showed the t½β (hr) to be numerically about 5 times the steady‐state serum creatinine concentration (mg/dl). Under the conditions of the study, hemodialyzer clearance of flucytosine was rapid and similar to creatinine hemodialyzer clearance. Computer simulation based on the measured pharmacokinetic parameters demonstrated that a loading dose (20 mg/kg) after dialysis should result in therapeutic plasma concentrations for susceptible organisms and avoid toxic levels.