bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of the gastrointestinal absorption of p‐ aminosalicylate (PAS) in rats and humans by diphenhydramine
Authors: Lavigne Jean‐Guy , Marchand Claude
Published: January 2016

Injection of diphenhydramine, 25 mg per kilogram, intraperitoneally, decreased the blood concentration of sodium p‐aminosalicylate (PAS), 200 mg per kilogram, administered per os. This effect was observed 10,20,30,45, and 60 minutes after administration of PAS. A dose‐response study (2 to 25 mg per kilogram) revealed that the effect was proportional to the dose of diphenhydramine. The decrease in blood concentration of PAS was associated with a similar decrease in the PAS levels in brain, lung, liver, lipids, muscle, and kidney of animals treated with diphenhydramine. PAS levels in the stomach after diphenhydramine, revealed that more than 20% of the PAS remained in the stomach 45 minutes after oral administration but only 3% remained in the stomach in the control animals. Study of the gastrointestinal peristalsis with 51Cr indicated that, 45 minutes after injection of diphenhydramine, 60% of the radioactive marker was found in the stomach, whereas less than 10% was recovered in the stomach of control rats in which most of 51Cr was located in the first segment of the ileum. Human volunteers treated with diphenhydramine, 50 mg intramuscularly, 10 minutes before ingestion of PAS, 2 gm, had significantly less PAS in the blood 10 minutes after ingestion. These observations indicate the importance of the gastrointestinal tract as a site of drug interaction.
Cireadian rhythm of therapeutie effectiveness of oxymetholone in paraplegie patients
Authors: Ede Martin C. Moore , Burr Robert G.
Published: January 2016

Extensive hone demineralization and hypercalciuria occur in paraplegie patients during the first few months of immobilization. During this time, urinary calcium excretion has been shown to have a circadian rhythm with a maximal excretion at midday. Oxymetholone (Anapolon, Anadrol) timed to cover the period of maximum calcium loss resulted in a flattened urinary calcium rhythm and reduction in the 24 hour calcium excretion in 2 of 4 paraplegie subjects. The effectiveness of a single 10 mg dose given at various times of day was then compared in 29 acute paraplegie patients. Ten milligrams of oxymetholone given at 6 AM, before the peak in calcium excretion, produced a significant fall in the 24 hour calcium excretion, but similar doses at other times of day were ineffective. The findings are consistent with known circadian rhythms of bone metabolism and provide another example of a circadian rhythm in drug effectiveness.
Disposition of propranolol V. Drug accumulation and steady‐state concentrations during chronic oral administration in man
Authors: Evans Gwyn H. , Shand David G.
Published: January 2016

In 6 normal volunteers, a twofold accumulation of propranolol in the blood was observed during chronic oral administration of 80 mg every 6 hours that was unpredicted on the basis of the drug's half‐life. No accumulation occurred in 2 subjects given 20 mg intravenously every 6 hours. The observed drug accumulation resulted from two mechanisms. During administration of the first dose an avid hepatic extraction process became saturated after removal of about 30 mg and remained saturated during the dosage interval. This resulted in a 60% increase in the amount of drug reaching the systemic circulation at steady state compared to that after a single dose. It is suggested that the avid hepatic extraction is a result of high‐affinity drug binding and that the increase in availability is due to saturation of this binding site. In addition, the increase in drug availability was sufficient to partially saturate drug metabolism and decrease systemiC drug clearance, resulting in a 44% increase in drug half‐life. These data were supported by the finding that during steady state folloWing 6 hourly oral propranolol administration to 7 subjects, plasma levels were proportional to the dose up to 160 mg per day, suggesting first‐order drug elimination in the presence of a saturated high affinity binding site in the liver. An average of between 160 and 320 mg per day metabolism becomes nonlinear, resulting in a disproportionate increase in plasma concentrations. These studies indicate that saturable hepatic tissue binding, as well as safurable metabolism, can result in nonlinear kinetics of drug disposition.
Disposition of propranolol VI. Independent variation in steady‐state circulating drug concentrations and half‐life as a result of plasma drug binding in man
Authors: Evans Gwyn H , Shand David G.
Published: January 2016

Plasma binding of propranolol has been measured at therapeutic concentrations in 6 subjects in whom steady‐state blood concentrations and half‐life had been measured during chronic oral administration of 80 mg every 6 hours. Neither steady‐state blood concentrations nor drug clearance (Cl**) was related to binding of drug in the blood. Volume of distribution (Vdβ), however, increased as the fraction of free drug in the blood (fb) increased, such that the volume of distribution of free drug (Vdp/fb) was relatively constant. Drug half‐life was proportional to fb/Cl** since it was a function of both Vdp and clearance that varied independently. These data show that propranolol can be classified as a drug whose hepatic elimination is not restricted to the free drug in the circulation, so that binding to elements in the blood accelerates its elimination rate by acting as a carrier system from the tissues to its site of elimination and that this occurs without alteration drug clearance or steady‐state total blood concentrations.
Continuous electrocardiographic monitoring during marihuana intoxication
Authors: Roth Walton T. , Tinklenberg Jared R. , Kopell Bert S. , Hollister Leo E.
Published: January 2016

The EKG was continuously recorded in 10 normal subjects during marihuana and placebo administration. NIMH marihuana was administered in cigarettes calibrated to a delta‐9‐tetrahydrocannabinol content of 20 mg. Automated methods of data analysis were used to scan the EKG records for cardiac arrhythmias and to plot graphs of pulse rate and average T wave amplitude computed every 20 seconds over sessions lasting from 2 to 4 hours. Only 5 ventricular premature contractions occurred in all of the sessions; they were not related to marihuana intoxication. The marihuana‐induced tachycardia had a mean of 127.6 beats per minute with a latency of 17.8 minutes from the onset of smoking to maximum tachycardia. T wave changes were slight and did not correspond to other effects of marihuana. We suggest that syncopal episodes associated with marihuana intoxication are not associated with cardiac arrhythmias, but rather with orthostatic or vasovagal reactions combined with inhibition of compensatory vascular reflexes.
Introductory remarks
Authors: McCrory W. W.
Published: January 2016

On behalf of the Planning Committee I wish to welcome all of you to this conference on drugs and the unborn child.
Use of fetal cell culture as an experimental system for predicting drug metabolism in the intact animal
Authors: Nebert Daniel W.
Published: January 2016

The extent of aryl hydrocarbon (benzo[a]pyrene) hydroxylase induction in various tissues of ten inbred strains of mice by aromatic hydrocarbon administration in vivo is correlated (0.02 < p < 0.05) with the magnitude of hydroxylase induction in fetal cell cultures derived from that strain. The enzyme causes the formation of highly reactive and therefore toxic polycycliC hydrocarbon epoxides and phenols. The toxicity of aromatic hydrocarbons in vivo and in cell culture is greater for the C57BL/6N mouse strain, in which the hydroxylase is inducible, than for the DBA/2N strain, in which the enzyme is virtually noninducible. Therefore, the degree of toxicity of aromatic hydrocarbons in fetal cell culture reflects in large part the toxicity of polycylic hydrocarbons in the intact animal and in turn reflects the genetically regulated response of the individual to the foreign compound. It is speculated that the teratogenicity of various drugs or other xenobiotics in a certain strain or species of animal may likewise be predicted, if one is able to quantitate certain parameters of a compound's metabolism in fetal cell cultures from that particular strain or species.
Concluding remarks
Authors: Fuchs Fritz
Published: January 2016

Of all the medical disciplines, obstetrics in my opinion is the most gratifying. To help a young woman through pregnancy and deliver her child usually will establish a unique relationship. A mother will never forget the man who delivered her babies, that is, if all goes well. Pregnancy and delivery are fraught with many dangers, and drugs represent only one category of hazards. The obstetrician must know them all and must guard his patient against them all. Yet he cannot and must not alert his patient to all, lest she be scared of all the gruesome things that can happen. If pregnancy required informed consent, the birth rate would drop catastrophically. So the obstetrician must carry the burden, and this meeting is chiefly aimed at him. But an infonned public who have some idea of the hazards can make life easier for him, and that is why this meeting has been opened to the press. To the science writers and reporters in the audience, I would like to say that you are faced with a delicate task, to inform without scaring. Leave the specifics out and keep in mind what our distinguished keynote speaker, Dr. Hellman, said. What counts in regard to the drugs of today is the ratio between benefit and safety. The epileptic patient does need anticonvulsants during pregnancy. Without them she might expose the fetus to other hazards such as oxygen deprivation and traumas during seizures. As Dr. Stern said, the fetus is the recipient of unwanted drugs; true—but its welfare may well depend on the mother receiving those drugs. The uterus is still the best test tube for producing babies, even if it does pennit the transfer of drugs and other potentially harmful agents.
Elimination of tritiated gentamicin in normal human subjects and in patients with severely impaired renal function
Authors: Wilson T. W. , Mahon W. A. , Inaba T. , Johnson G. E. , Kadar D.
Published: January 2016

The excretion of gentamicin, a widely used broad‐spectrum antibiotic complex, is reduced in renal failure. In order to prevent the cumulation of the drug to toxic serum concentrations, several investigators have produced nomograms relating gentamicin dosage to the level of renal function. Evidence is presented that the one‐component kinetic model upon which these nomograms are based is inadequate to describe the disposition of gentamicin. Pharmacokinetic considerations indicate that usage of such nomograms in patients with moderately reduced or normal renal function may lead to inadequate serum concentrations of the drug. In addition, evidence is presented that a certain amount of intravenously administered gentamiCin is excreted as a coniugated metabolite.
Oxandrolone disposition and metabolism in man
Authors: Karim A. , Ranney R. E. , Zagarella J. , Maibach H. I.
Published: January 2016

The disposition and metabolic fate of 14C‐oxandrolone (17α‐methyl‐17β‐hydroxy‐2‐oxa‐5α‐androstan‐3‐one) has been studied in 6 healthy male subiects. After administration of a single oral dose (10 mg containing 20 p.Ci of 14C in ethanolic solution), the peak concentration of 14C‐oxandrolone in the plasma was 417 (mean) µg per milliliter at 0.50 to 1.50 hours. Its level then declined in two phases: from 1.5 to 4.0 hours with a half‐life of 0.55 hour and from 4.0 to 48 hours with a half‐life of 9.4 hours. The ingested 14C was eliminated predominantly by urinary excretion. In the urine, 43.6% of the administered 14C was excreted in 24 hours and 60.4% in 96 hours. Recovery of 14C in the feces accounted for only 2.8% of the dose. The chloroform extractable urinary radioactivity was largely composed of the unchanged drug, which accounted for 46.1 % of urinary 14C or 28.7% of the illgested 14C. Enzyme hydrolysis of the urinary coniugated fraction, which accounted for 31.3% of the urinary 14C, gave two major aglycones in the approximate ratio of 2:7. These aglycones were tentatively identified as oxandrolone and 16β‐hydroxyoxandrolone, respectively.
Effect of trimepranol, a beta blocker, on plasma levels of growth hormone, insulin, glucose, and free fatty acids
Authors: Nedvídková J. , Felt V.
Published: January 2016

The effect of oral administration of a new beta blocker trimepranol (1‐[3,5,6‐trimethyl‐4‐acetoxyphenoxyl‐3‐isopropylamino‐2‐propanol]) on serum levels of growth hormone (GH), immunoreactive insulin (IRI), glucose, and free fatty acids (FFA) has been studied in normal persons. Fasting levels of GH, IRI, glucose, and FFA after trimepranol were not changed. The concentration of glucose and secretory response of IRI during oral glucose tolerance test decreased after trimepranol. The insulinogenic index was not changed. The total secretory response of GH during glucose tolerance test after trimepranol was enhanced. The levels of FFA during glucose tolerance test were not changed.
Bioavailability of digoxin tablets
Authors: Steiness Eva , Christensen Vinni , Johansen Hans
Published: January 2016

The absorption of a commercial digoxin tablet preparation of low and one of high therapeutic potency and of digoxin dissolved in alcohol was studied in digitalized patients and compared with the dissolution rates of the tablets. Biologic availability was estimated by measuring the area beneath the plasma digoxin curve. The bioavailability of the “low potency” tablet was markedly inferior to that of the “high potency” tablet, which did not differ significantly from that of digoxin in alcoholic solution. A significant correlation between bioavailability and the dissolution rate was found (p < 0.001). lt is suggested that measurement of the dissolution rate might be used as a guide to the biologic availability of a particular digoxin tablet preparation.
Kinetics of warfarin absorption in man
Authors: Breckenridge A. , Orme M.
Published: January 2016

The percentage of an oral dose of warfarin absorbed has been measured by two methods. Using the urine excretion of radioactivity following oral administration of HC warfarin in 4 subjects, between 61 % and 92% of an oral dose was recovered. This variation is due to differences in the duration of urine collection. Using a comparison of the area under the plasma concentration‐time curve in 8 subjects, between 77.6% and 100% of an oral dose was apparently absorbed. The rate of warfarin absorption was rapid as ;udged by a consideration of the oral plasma concentration time curve in 8 subjects; peak drug concentrations in plasma were reached by 25 to 60 minutes after oral dosing. Rapid absorption was confirmed by measurements using two different pharmacokinetic models. Absorption was complete by 120 minutes in 4 subjects.
Amoxicillin therapy of infections
Authors: Vallejos Carlos , Rodriguez Victorio , Gottlieb Jeffrey A. , Bodey Gerald P.
Published: January 2016

Amoxicillin was used in the treatment of 36 infections in 35 patients with adequate gmnulocyte counts. The antibiotic was effective against 61 % of all infections, against 90% of infections caused by gram‐positive organisms, and against 77% of infections caused by Escherichia coli, and Proteus mirabilis. Superinfection with Pseudomonas, Klebsiella, and Proteus vulgaris occurred in 8% of the cases. Transient side effects attributed to amoxicillin were abdominal cramps (1 patient) and erythematous skin rash (2 patients).
Effects of mode of management on plasma chlorpromazine in psychiatric patients
Authors: Rivera-Calimlim Leonor , Castañeda Lina , Lasagna Louis
Published: January 2016

Gas liquid chromatography (GLC) assay for plasma chlorpromazine was developed to maximize recovery, accuracy, sensitivity, and reproducibility. Plasma levels of chlorpromazine were monitored in psychiatric patients weekly for 6 weeks, at 0, 2, 3, and 4 hours after a prescribed dose of chlorpromazine. Weekly clinical evaluation was made with the Brief Psychiatric Rating Scale. The study suggests that schizophrenic patients with negligible plasma levels of chlorpromazine (less than 30 ng per milliliter) are not likely to improve clinically. Most patients who showed significant clinical improvement achieved high plasma levels (150 to 300 ng per milliliter or greater). Those who manifested toxiCity in the form of tremors and convulsicYns were shown to have very high plasma levels (750 to 1,000 ng per milliliter). A factor in patients who did not achieve adequate plasma levels despite moderate doses of chlorpromazine was the administration of trihexyphenidyl. Interpatient and intrapatient data suggest that trihexyphenidyl tends to lower plasma levels of chlorpromazine.
Spironolactone and plasma cortisol
Authors: Dumlao Juliet S. , Kannan Chakhavarthy , Krauss Thomas , Brooks Marion H.
Published: January 2016

Spironolactone has been shown to interfere with the determination of corticosteroids in plasma and urine. In the present study the fluorimetric method of Mattingly was used to determine how rapidly the spurious elevation of plasma cortisol develops after spironolactone administration and to define the rate of disappearance of the artifact from plasma. In normal subjects plasma cortisol levels increased by more than 100% 60 minutes after a single 50 mg oral dose of spironolactone. The maximal concentration of plasma cortisol was observed at 2 hours and the level slowly declined thereafter, reaching pretreatment values 72 hours after administration of the drug.
Phase II multiclinic study of elantrine in parkinsonism
Authors: Blonsky E. Richard , Ericsson Arthur Dale , McKinney Alexander S. , Rix Alvin , Wang Richard I. H. , Rimm Alfred A.
Published: January 2016

A cooperative controlled study comparing elantrine with trihexyphenidyl and a baseline placebo period demonstrates definite lessening of tremor severity during elan trine treatment and a statistically significantly greater reduction in tremor compared to trihexyphenidyl. Effectiveness in alleviating rigidity and akinesia was less but similar to trihexyphenidyl.
Arterial blood levels of fluorocarbons in asthmatic patients following use of pressurized aerosols
Authors: Dollery C. T. , Williams Faith M. , Draffan G. H. , Wise G. , Sahyoun H. , Paterson J. W. , Walker S. R.
Published: January 2016

The levels of fluorocarbon‐11 and fluorocarbon‐12 (F‐11, CCl3F; F‐12, CCl2F2) have been measured in arterial blood of 8 asthmatics after using an aerosol inhaler. Following two puffs with a 30 second interval, peak arterial plasma levels ranged from 0.53 to 3.1 µg per milliliter (F‐11) and 0.2 to 3.13 µg per milliliter (F‐12); folloWing a single puff peak levels were 0.26 to 2.0 J.lg per milliliter (F‐11) and 0 to 2.3 J.lg per milliliter (F‐12). The peak level was achieved 10 to 20 seconds after the inhalation, followed by a rapid fall in arterial level. The measured levels have been compared with predicted values using a computer model. This model has been used to predict the myocardial concentration in man from the measured arterial levels. Except with grossly excessive use of an aerosol inhaler in a short period of time, the predicted myocardial concentrations of fluorocarbon in man are much less than the levels shown to sensitize the heart of conscious normal dogs to epinephrine.
Effect of cigarette smoking on phenacetin metabolism
Authors: Pantuck E. J. , Hsiao K.‐C. , Maggio A. , Nakamura K. , Kuntzman R. , Conney A. H.
Published: January 2016

Nine nonsmokers and nine individuals who smoked more than 15 Cigarettes per day were administered 900 mg of phenacetin orally, and the concentration of phenacetin in plasma was measured 1, 2, 3.5, and 5 hours after the dose. The plasma levels of phenacetin in the smokers were markedly lower than in the nonsmokers. The plasma levels of unconiugated or total N‐acetyl‐p‐aminophenol in the smokers were the same or only slightly lower than in the nonsmokers, and the ratios of the plasma concentration of total N‐acetyl‐p‐aminophenol to phenacetin were increased severalfold in the smokers. These results indicated that cigarette smoking stimulated the metabolism of phenacetin. To learn whether polycyclic hydrocarbons in cigarette smoke could influence the gastrointestinal metaboli5m of phenacetin, we studied the effects of 3,4‐benzpyrene administration on the metabolism of CILphenacetin by enzymes in the intestinal mucosa of the rat. The data indicated that O‐dealkylation of phenacetin did occur—to a small extent—by an enzyme system in the small intestine, and that the activity of this enzyme system was stimulated by treatment of rats with 3,4‐benzpyrene.
Use of subjective responses to evaluate efficacy of mild analgesic‐sedative combinations
Authors: Smith Gene M. , Coletta Cesare G. , McBride Susan , McPeek Bucknam
Published: January 2016

Effects of mild analgesic‐sedative combinations on sleep and pain were studied in 420 hospitalized patients, most of whom were young postpartum patients with mild or moderate evening pain who expected to have difficulty sleeping. Each patient took an analgesic‐sedative or a placebo at bedtime, on a double‐blind, random basis, and evaluated its effects the following morning. Two dose levels of chloral hydrate (250 and 500 mg), each given with aspirin (650 mg), were compared with placebo and with each other. Three other analgesic‐sedative combinations, containing methapyrilene fumarate (42 or 50 mg) combined with aspirin and/or aspirin‐like analgesics, were also studied. The combinations containing methapyrilene are similar to ones sold over the counter and are not as subiect to abuse as are medications usually prescribed to induce and maintain sleep. The patient's estimate of number of hours slept significantly differentiated each experimental treatment from each other treatment with which it was compared; other subiective criteria did not differentiate as successfully. The influence of question format, response options, and other such methodological details is illustrated and discussed in this report.
Evaluation of hypnotics in outpatients with insomnia using a questionnaire and a self‐rating technique
Authors: Wolff B. Berthold
Published: January 2016

A brief, forced‐choice daily questionnaire was developed to quantitatively evaluate the efficacy of hypnotics over an extended period in outpatients with insomnia. The usefulness of this questionnaire, combined with the patients' ranking of successive weeks, was tested in two studies. The first, involVing 44 patients during three weeks, used a relatively potent hypnotic, 100 mg sodium pentobarbital, while the second, involVing 36 patients during four weeks, used a mild hypnotic, 2 Excedrin‐PM tablets. Both studies indicated the two subjective measures to be appropriate; the potent and the mild hypnotic were significantly discriminated from placebo under double‐blind conditions. The first study also included a magnetic pillow‐insert that was not differentiated from a placebo pillow‐insert, but that, nevertheless, appeared to have some central nervous system effects related to a greater frequency and more vividness of recall of dreams. It was concluded that these subjective measures are valuable for chronic hypnotic assays under “normal” (i.e., home) conditions where more objective laboratory techniques are not applicable.
Amitriptyline in man: Decreased formation of central 5‐hydroxyindoleacetic acid
Authors: Bowers Malcolm B.
Published: January 2016

5HIAA, HV A, l‐tryptophan, and probenecid were measured following a probenecid‐tryptophan tolerance test in lumbar CSF of unipolar depressive patients before and during successful treatment with ami. CSF 5HIAA levels were lower during this treatment despite high CSF l‐tryptophan levels. Probenecid values were comparable before and during treatment. The results suggest that during clinical treatment with ami, central 5HT turnover is decreased by a mechanism that does not involve decreased central availability of l‐tryptophan.
Effects of in vitro aspirin on blood platelets of gastrointestinal bleeders
Authors: Donald G. Mills , Ivan T. Borda , Richard B. Philp , Cheryl Eldridge
Published: January 2016

Collagen and adenosine diphosphate (ADP)‐induced platelet aggregation and the inhibitory effects of in vitro aspirin were studied in 11 subjects (Group I) having gastrointestinal hemorrhage within 96 hours at taking aspirin, II (Group II) with similar hemorrhage not associated with recent aspirin ingestion, and 11 hospitalized control subjects (Group III). Platelets at Groups I and II were significantly more sensitive to ADP aggregation than those of Group III (p < 0.005). Aspirin caused significantly greater inhibition of collagen aggregation in Group I than in either Group II (p < 0.005) or Group III (p < 0.02). Three of the II nonaspirin bleeders lacked the second phase of ADP aggregation. These data support the contention that individuals with defective platelet function are more susceptible to hemorrhage following mucosal erosion of the gastrointestinal tract and suggest that some individuals may have platelets that are intrinsically more sensitive to aspirin.
DifFerences in serum digoxin concentrations between outpatients and inpatients: An effect of compliance?
Authors: Sheiner Lewis B. , Rosenberg Barr , Marathe Vinay V. , Peck Carl
Published: January 2016

Concentrations of digoxin in serum were assayed at serial weekly visits (2 to 8) of outpatients receiving the drug (163 assays in 43 patients). A data analysis technique that models individual pharmacokinetics using routine clinical, laboratory, and drug concentration data was used to estimate mean pharmacokinetic parameters, the between‐individual variation in these, and average within‐individual serum digoxin concentration variation. Outpatient serum digoxin concentrations averaged only 72% of the amount expected after size, renal function, and stated dose were taken into account in a manner determined by inpatient data previously obtained. The 95% confidence region for mean steady‐state serum digoxin concentrations in individualoutpatients ranges from 40% to 104% of the concentrations expected. These findings may be explained by variable outpatient compliance with prescribed doses. Although highly variable between individuals, it seems remarkably constant for each individual over a 2 to 8 week period. If additional studies confirm these results, outpatient compliance may be a graded and predictable phenomenon. Using the technique of data analysis suggested in this paper and periodic measurement of serum digoxin concentrations, individual compliance and its consistency over time can be assessed. Such information may assist in patient management.
Glucaric acid as an indicator of use of enzyme‐inducing drugs
Authors: Sotaniemi Eero A. , Medzihradsky Fedor , Eliasson Gudmundur
Published: January 2016

The usefulness of urinary glucaric acid determinations to measure enzyme induction by drugs was investigated by correlating its excretion rate with the daily drug regimen of 100 hospitalized patients. The urinary excretion of glucaric acid was higher in patients than in normal controls. Patients treated with enzyme inducers excreted more glucaric acid than patients not getting them, as well as more than normal controls. In patients on multiple‐drug therapy, the effect of small doses of known enzyme inducers was masked, but even here relatively high doses of potent inducers significantly increased glucaric acid excretion. The results also suggest that urinary excretion of glucaric acid may have value as an indicator of the use of certain drugs by patients when such information is not revealed by the history.
Salicylamide metabolism in acute intermittent porphyria
Authors: Song Chull S. , Bonkowsky Herbert L. , Tschudy Donald P.
Published: January 2016

Salicylamide is metabolized in man by glucuronidation, sulfation, and hydroxylation. It was used to examine these three drug‐metaboliZing pathways in patients with acute intermittent porphyria (AIP). The over‐all rate of metabolism of salicylamide was significantly reduced in porphyric subjects, with a mean half‐life of 103 minutes in comparison to 72 minutes in normals. This was due largely to the reduced rate of conversion to the sulfate and hydroxyl derivatives. Glucuronidation was not significantly different although there was greater individual variation among porphyric subjects. Consequently, subjects with AIP excreted a larger fraction of salicylamide as its glucuronide. This reduction in the rate of hydroxylation may be related to clinical exacerbations precipitated in patients with AIP by drugs metabolized primarily by hydroxylation.
Relationship between theophylline concentration in plasma and saliva of man
Authors: Koysooko Renu , Ellis Elliot F. , Levy Gerhard
Published: January 2016

The concentration of theophylline in the plasma and saliva of 7 normal adults receiving single oral doses of 200 mg theophylline per square meter of body surface area (BSA) was determined spectrophotometrically over 8 hours. There was an excellent linear relationship between theophylline concentrations in plasma and saliva, over a plasma concentration range of 4 to 14 µg per milliliter. Theophylline concentrations in the saliva were about 48% lower than in the plasma and are similar to the concentration of free (not protein‐bound) drug in the plasma. There is very little intersubiect and intrasubiect variation of theophylline blank values in plasma and saliva, in the recovery of theophylline from plasma and saliva, and in the proportionality factor that relates saliva to plasma concentrations of the drug. These observations suggest that theophylline determination in saliva may be a convenient, painless, and noninvasive method for routine monitoring of theophylline levels.
Effect of practolol on blood pressure and renin release in man
Authors: Esler Murray D.
Published: January 2016

The effect of the β‐adrenergic receptor‐blocking drug, practolol, on plasma renin activity at rest and on the renin response to a graded isoproterenol (isoprenaline) infusion has been studied in man. Plasma renin activity at rest was not significantly changed by parenteral practolol. With isoproterenol, a dose of practolol that produced 50% to 60% reduction in the heart rate response to isoproterenol was without effect on the renin response. With chronic oral dosage of practolol, in 11 patients with essential hypertension, there was no significant change in plasma renin activity. The fall in blood pressure in these patients was unrelated to the pretreatment plasma renin level. Practolol, a “cardioselective” β‐adrenergic blocking drug, appears to lower blood pressure by a mechanism unrelated to inhibition of renin release.
Intravenous digoxin as a bioavailability standard: Slow infusion and rapid injection
Authors: Greenblatt David J. , Duhme David W. , Koch‐Weser Jan , Smith Thomas W.
Published: January 2016

Eight healthy male subjects received intravenous digoxin (0.75 mg) by rapid infection and by 1 hour infusion in a single‐dose crossover study. Multiple serum concentrations and 6 day urinary excretion of digoxin were determined by radioimmunoassay. Mean 6 day cumulative urinary excretion of digoxin after infusion (0.57 mg) was significantly greater than after rapid injection (0.52 mg). Between‐subject variability in urinary excretion after infusion was significantly less than that after rapid injection. Thus, administration of digoxin by slow infusion is preferable as an intravenous standard in bioavailability testing.
Dose‐effect relations of mariiuana smoking on various physiological parameters in experienced male users Observations on limits of self‐titration of intake
Authors: Domino Edward F. , Rennick Phillip , Pearl Joseph H.
Published: January 2016

The effects of smoking three different grades of marijuana (0, 0.5, and 2.9% Δ9 tetrahydrocannabinol [THC]) were determined on various physiological subjective end pOints in experienced users tested blind at intervals of at least one week. The largest amount of Δ9 THC equivalent taken by self‐titration was 31 mg. After 2.9% Δ9 THC marijuana, clear thinking was significantly reduced, dizziness increased, palpebral fissures narrowed, and pupils slightly decreased. There was dose‐related increase in the amplitude of the patellar reflex and heart rate, significant at both dose levels. The 2.9% Δ9 THC‐containing marijuana also slightly elevated systolic and diastolic blood pressure. Pulse rate changes were found to be correlated with subjective estimates of the marijuana “high.” Of the 18 subjects smoking the strongest material, 2 had panic reactions and 3 visual distortions and hallucinations. One subject became semicomatose. The majonty of subjects found their experience satisfying and reinforcing. One extremely heavy marijuana user tendea to show less effects than one less experienced user taking the same dose.
Propranolol and behavior of alcohol addicts after acute alcohol ingestion
Authors: Mendelson Jack H. , Rossi A. Michael , Bernstein Jerrold G. , Kuehnle John
Published: January 2016

Sixty‐four adult male chronic alcoholic addicts were studied to assess the effects of propranolol pretreatment on behavioral changes induced by acute ingestion of alcohol. The study was carried out under controlled research ward conditions with a double‐blind technique. Pretreatment with 10, 20, and 40 mg of propranolol 4 times a day for 3 consecutive days prior to alcohol administration failed to block or attenuate cognitive, perceptual, motor, and affective changes induced by acute alcohol intoxication.
Pharmacokinetics of furosemide in normal subjects and functionally anephric patients
Authors: Cutler Ralph E. , Forrey Arden W. , Christopher T. Graham , Kimpel Barbara M.
Published: January 2016

Furosemide pharmacokinetics were studied on 3 separate occasions in 4 hydropenic normal subjects. Single intravenous doses of approximately 0.5, 1.0, and 1.5 mg/kg were administered. The apparent volume of drug distribution was not affected by the dose and averaged 11.4 % of body weight. Mean plasma half‐life was 29.5 minutes with a clearance of 162 ml per minute. Renal excretion was the main route of elimination in these sub;ects and averaged 92% of the administered dose with a mean renal clearance of 149 ml per minute. This exceeded the glomerular filtration rate and suggested tubular secretion even though furosemide was 95% bound to plas'ma proteins. There was marked diuresis in all subjects, with a peak flow rate between 20 and 60 minutes after injection. Extracellular volume depletion was prevented by Ringer's lactate infusions. There was no significant difference in the peak fractional excretion of sodium with different doses. There was free water clearance during peak diuresis in all subjects, suggesting that furosemide does not affect the diluting segment of the nephron. In 5 functionally anephric patients, the distribution volume averaged 17.8% body weight, plasma half‐life was 80.7 minutes, and plasma clearance was 105 ml per minute. The data suggest a greater rate of nonrenal elimination than in normal subjects.
Human brain, cerebrospinal fluid, and plasma concentrations of diphenylhydantoin and phenobarbital
Authors: Vajda F. , Williams Faith M. , Davidson S. , Falconer M. A. , Breckenridge A.
Published: January 2016

The concentrations of diphellylhydantoin (DPH) alld phenoharhital have been measured in plasma, lumbar cerebrospinal fluid (CSF), and samples of temporal lobe in 12 epileptic patients undergoing temporal lobectomy. The brain:plasma ratio of DPH was 0.75 ± 0.19:1 and the CSF: plasma ratio 0.12 ± 0.04:1. For phenobarhital, the mean hrain:plasma ratio was 0.59 ± 0.21:1 and the CSF: plasma ratio 0.46 ± 0.12:1. The significant correlation (p < 0.01) between brain and plasma drug concentrations supports the value of monitoring plasma concentrations of anticonvulsant drugs in patients with epilepsy.
Bioequivalency of generic and brand‐named chlorpromazine
Authors: Simpson George M. , Varga Ervin , Reiss Martin , Cooper Thomas B. , Bergner Per-Erik E. , Lee J. Hillary
Published: January 2016

Fifty chronic schizophrenic patients were included in a double‐blind, crossover clinical and metabolite comparison of generic and Thorazine brand forms of chlorpromazine. Improvement was similar in quality and degree with the two compounds; there was no difference in frequency or severity of side effects or in incidence of laboratory abnormalities. Side effects consisted mainly of extrapyramidal reactions, drowsiness, and hypotension; the most serious were grand mal seizures that occurred in 2 patients, one on each compound. Weight changes and neuroleptic threshold were similar. Kinetic studies were carried out during the drug‐free intervals. Chlorpromazine, chlorpromazine nor1 + 2, and chlorpromazine sulfoxide nor1 + 2 were measured over a 24 hour period. The characteristics of the mean curves were similar, although there were marked interindividual differences. The urinary recovery over the same period also demonstrated wide individual variability although the results from the same patients were similar. Because of the consistent similarites between generic and brand‐named chlorpromazine on the wide range of dimensions evaluated, we concluded that the two compounds were bioequivalent. The results suggest that the methodology used by us for examining bioequivalency is practicable and adequate.
The additive effect of probucol on diet in hyperlipidemia
Authors: Brown Helen B. , deWolfe Victor G.
Published: January 2016

The effect of probucol, a hypocholesteremic drug, in reducing blood lipids below the level achieved with diet alone, was studied in 19 free‐living hyperlipidemic patients (13 type IIA, 4 type VI [IIB], 1 type III, 1 type V). Diet prescriptions were a4justed to lipid type. The study consisted of a 4 week adjustment period with patients on their usual diet, a 3 month period with fat‐modified diet and placebo, and a 3 month period with the same diet and 500 mg probucol twice a day. The mean serum cholesterol level of type IIA patients was the same for the placebo and probucol periods, but there were large differences among individual patients. One type IIA patient had an increase of 19.2% with probucol, 5 had no change, and 7 had an additional reduction of 8.1 %. There was a mean reduction of serum cholesterol level of 8.8% in 4 type VI, 1 type III, and 1 type V patient; serum triglyceride levels in these 6 patients were reduced by 22%. Lipoprotein patterns were unchanged. There were no side effects from probucol.
Lidocaine disposition kinetics in monkey and man; I. Prediction by a perfusion model
Authors: Benowitz Neal , Forsyth Ralph P. , Melmon Kenneth L. , Rowland Malcolm
Published: January 2016

Lidocaine pharmacokinetics are described in the unanesthetized restrained rhesus monkey after bolus and steady infusion. Simultaneous measurements of systemic and regional blood flows and tissue masses were made in the same animals. Physiologic data are combined in a perfusion model that is predictive of kinetics of lidocaine in the mankey. The model uses eight tissue compartments. Concentrations of lidocaine are described in various tissues at various times. In the first seconds after an intravenous bolus, much at the lidocaine is sequestered by the lungs; then by heart and kidneys and other rapidly perfused tissues. Redistribution then occurs into skeletal muscle and adipose tissue, which accounts for the long observed half‐life of lidocaine. Blood flow and tissue composition data from monkeys can be applied to man to predict blood levels of lidocaine after intravenous injection. The perfusion model is therefore potentially useful in describing and predicting blood levels in states of cardiovascular disease in both monkey and man.
Concentration‐effect relationships with major and minor tranquilizers
Authors: Curry Stephen H.
Published: January 2016

Relationships between the effects of centrally acting drugs and concentrations of the pharmacologically active moleeules in plasma can take a wide variety of forms, ranging from simple direct relationships, for instance, those involving effects on reaction time, to extremely complex relationships, for instance, those involving clinical rating of psychopathology. A number of forms of relationships have been revealed with glutethimide, nordiazepam, and chlorpromazine, and a brief review is presented of the current status of studies of the relationship between concentration and effect for these compounds.
Antihypertensive efficacy of metolazone
Authors: Fotiu Socrates , Mroczek William J. , Davidov Michael , Finnerty Frank A.
Published: January 2016

The antihypertensive etfects of metolazone and chlorthalidone were compared in 57 nonedematous hypertensive patients using a double‐blind technique. Metolazone was followed by significant reductions in arterial blood pressure at all doses (1.0, 2.5, and 5.0 mg daily), which were comparable to those of chlorthalidone, 100 mg daily. Although the chlorthalidone‐treated patients lost an average of 8.7 pounds after 24 weeks of therapy, there was no change in body weight after metolazone. Side etfects were similar after both; hypokalemia was equally frequent. It was concluded that metolazone in doses of 1.0, 2.5, and 5.0 mg daily was as etfective as chlorthalidone, 100 mg daily, and that 1.0 mg was probably a ceiling dose in patients without frank edema. M etolazone appeared to otfer no advantage over chlorthalidone.
Absorption and clearance of secobarbital, heptabarbital, methaqualone, and ethinamate
Authors: Clifford John M. , Cookson James H. , Wickham Phyllis E.
Published: January 2016

The absorption and clearance of secobarbital, heptabarbital, methaqualone, and ethinamate were studied by measurements of blood and plasma drug levels after single oral dosage in the therapeutic range to nonfasting sub;ects. Determinations of blood and plasma levels were carried out to the limits of sensitivity of the gas‐liquid chromatographic determination steps. The mean maximum plasma level of ethinamate was observed after 1 hour; that of methaqualone occurred after 2 hours; the mean maximum blood level of secobarbital was found after 3 hours, whereas that of heptabarbital was not observed until the sixth hour. Secobarbital was cleared slowly from the blood (the calculated half‐life was 28.9 hours); heptabarbital was faster (half‐life, 9.7 hours), and the half‐life of ethinamate was calculated as 2.3 hours. Methaqualone plasma levels decayed in a biphasic manner; the half‐life of the fast component was calculated as 0.9 hour and the slow one as 16 hours. Secobarbital, heptabarbital, and methaqualone could all be detected in the body 24 hours after they had been given.
Current trends in the introduction of new drugs
Authors: de Haen Paul
Published: January 2016

Trends in life are governed by internal stresses and outside influences. New drugs are subject to the same pressures. Innovation in a therapeutic field is usually followed by the synthesis of a number of derivatives of the original compound which is eventually exhausted, and this has influence on the number of “single new drugs” introduced annually. Such exhaustion has not occurred with cardiovascular drugs because new ideas have also been introduced. For this reason, drugs in this category available in other countries but not in the United States are here described in detail. This analysis will also show that there is a “drug lag𠇟 in transferring a new drug from one country to another in Europe and that this is not purely an American phenomenon.
Plasma digoxin after parenteral administration Local reaction after intramuscular injection
Authors: Steiness Eva , Svendsen Ove , Rasmussen Folke
Published: January 2016

Concentrations of digoxin in plasma after intravenous or intramuscular administration were measured in 8 sub;ects. Two hours after intramuscular in;ection concentrations were higher than after intravenous in;ection. A similar difference between the concentrations of digoxin in plasma was observed after intravenous and intramuscular administration to pigs. The shape of the curves was also similar to that of curves in man. Postmortem examination of the iniection sites in pigs revealed large necrotic areas after intramuscular in;ection of digoxin. The size of the necrotic area increased with the volume iniected. Necrotic areas were also demonstrated after intramuscular in;ection of the vehicle without digoxin, but they were smaller.
Myocardial distribution of digoxin and renal function
Authors: Jusko William J. , Weintraub Michael
Published: January 2016

Digoxin concentmtions in serum and left ventricular tissue were measured at autopsy and related to estimated antemortem creatinine clearances in 15 patients. A significant correlation teas found between myocardium:serum concentmtion ratio of digoxin and creatinine clearance. This phenomenon partly explains the large variability in tissue:serum ratios of digoxin reported in the literature and is consistent with the relatively smaller apparent volume of distribution of digoxin reported in patients with impaired renal function.
The acute effects of intravenous infusion of L‐tryptophan in normal subjects
Authors: Greenwood M. H. , Friedel J. , Bond A. J. , Curzon G. , Lader M. H.
Published: January 2016

The effects of intravenous infusion of L‐tryptophan at doses of 75 and 100 mg/kg were compared with that of normal saline in healthy volunteers by means of a series of psychological and physiological measures. The 100 mg/kg infusion produced a 40 fold increase in free tryptophan and an 8 fold increase in the bound form. Few of the objective tests showed any differences. The electroencephalogram showed a significant increase in slow‐wave activity (4.0 to 7.5 Hz) and a trend toward decreased fast‐wave activity (13.5 to 26.0 Hz). Some impairment of a motor speed task was also noted. Reduction of arousal and increased drowsiness (but no euphoria) were shown by the subjective ratings.
Clinical pharmacology in Australia
Authors: Nixon Peter F.
Published: January 2016

In Australia, clinical pharmacology is a small but developing discipline useful for the generation of data concerning the efficacy and safety of new therapeutic substances. While most clinical pharmacology is carried on as an adiunct to the interests of a specialist in some branch of internal medicine, there are now, in Australia, four units titled “Clinical Pharmacology,” and more are scheduled to be established in the near future. The 1972 report of a Parliamentary Select Committee recommended that clin;cal pharmacology be better established in Australia in the interests of economy in the national drug bill and the welfare of patients. This Government interest in the discipline has resulted in Government‐sponsored training fellowships, but, as yet, there are few senior positions for clinical pharmacologists. Normal subiects and large uniform patient populations are difficult to obtain in Australia, but in specialized units it is relatively easy to arrange good clinical trials involving small patient numbers. Regulatory controls require that there is a logical progression from thorough preclinical to introductory and wider human administration in clinical trials. Regulatory gUidelines state that the protocol for a clinical trial should include written informed consent and that approval of the trial be given by the institutional review committee that functions in most, but not all, Australian teaching hospitals. The Commonwealth Health Department discourages the use of clinical trials as a guise for premarketing promotion, but actively seeks to encourage sponsors of well‐designed clinical trials in Australiq.
Clinical pharmacology in Canada
Authors: Sellers Edward M.
Published: January 2016

Information obtained from a poll of Canadian academic authorities concerning the extent of the need for and role to be served by clinical pharmacology is presented and discussed. Current problems are identified, the implications of the regulatory control of drug testing and marketing are explored, and recommendations for future action are outlined.