bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of the West German drug law upon development of clinical pharmacology
Authors: Kampifmeyer Hermann
Published: January 2016

Depending on definition, there are as many as five or six clinical pharmacology units in the Federal Republic of Germany. None of these units have been fully integrated into both a clinical division and a department of clinical pharmacology. The German drug law regulates mainly the final registration of the drug development process. Various facets and applications, including the interaction of this law with health insurance, are discussed.
The effect of cirrhosis on the disposition and elimination of meperidine in man
Authors: Klotz U. , McHorse T. S. , Wilkinson G. R. , Schenker S.
Published: January 2016

The disposition and elimination of meperidine were compared in drug and alcohol‐free, age‐matched groups of 8 normal volunteers and 10 patients with cirrhosis of the liver, while controlling the urinary pH at 7.0 or more. After a single rapid intravenous injection, 0.8 mg/kg, plasma meperidine concentration declined biexponentially with the fast (α) and slow (ß) phases having half‐lives in the normal group of 0.19 hr and 3.2 hr (mean values), respectively. In the cirrhotics T½α was not changed but T½ß increased to 7.0 hr (p < 0.001), and this was associated with a reduction in the total plasma meperidine clearance from 1,316 ml/min to 664 ml/min (p < 0.002). Analysis of the data by a two‐compartment open model indicated that meperidine was extensively distributed; initial distribution volume (V1)2 1.54 lIkg and volume of distribution at steady‐state (Vdss), 4.17 lIkg in control subjects. Similar volumes of distribution were noted in cirrhotic patients. The overall first‐order elimination rate constant, k13, decreased from 0.672 hr‐1 in the normal subjects to 0.242 hrs in the cirrhotics (p < 0.001). The plasma binding (64.3%) and the blood/plasma concentration ratio (0.683) of meperidine in control subjects were not altered in cirrhosis. There were no Significant correlations found between T½ß or plasma clearance in the cirrhotics and the usual biochemical hepatic function tests. The metabolite, normeperidine, was not detected in the plasma of either group. It is concluded that the elimination of meperidine is prolonged in cirrhosis, probably due to impairment of drug‐metaboliZing activity in the liver. Accordingly, caution should be exercised when this drug is administered, particularly for long periods, to patients with cirrhosis.
Comparison of the O‐dealkylation of 7‐ethoxycoumarin and the hydroxylation of benzo [a] pyrene in human placenta
Authors: Jacobson M. , Levin W. , Poppers P. J. , Wood A. W. , Conney A. H.
Published: January 2016

A highly sensitive method is described for measuring the in vitro metabolism of 7‐ethoxycoumarin or coumarin to 7‐hydroxycoumarin. This method was used to measure the O‐dealkylation of 7‐ethoxycoumarin and the hydroxylation of coumarin by placentas from 12 nonsmokers or from 12 women who smoked cigarettes. Although an induced level of benzo[a]pyrene (BP) hydroxylase activity was found in each placenta obtained from women who smoked cigarettes during pregnancy, 7‐ethoxycoumarin O‐dealkylase activity was induced (about 2 fold) only in placentas whose BP hydroxylase activity was markedly induced (50 to 100 fold). These results indicate that ethoxycoumarin dealkylase activity parallels BP hydroxylase activity in human placenta only in individuals with markedly induced BP hydroxylase activity. No detectable hydroxylation of coumarin in the 7‐position was observed in placental homogenates from nonsmokers 0., from women who smoked cigarettes.
Modification by diluents of effects of intramuscular atropine on heart rate in man
Authors: Sidell Frederick R.
Published: January 2016

The effects of intramuscularly administered atropine on the human heart rate were significantly delayed when the atropine was mixed with pralidoxime chloride (300 mg/ml) or sodium chloride (8.5%). The time‐course of the atropine effects was unchanged when atropine was mixed with 180 mg/ml of pralidoxime chloride. These findings suggest that the delay is because absorption of atropine is slowed by solutions of higher osmolarity.
Pyrvinium pamoate
Authors: Buchanan Robert A. , Barrow William B. , Heffelfinger John C. , Kinkel Arlyn W. , Smith Thomas C. , Turner Janeth L.
Published: January 2016

In a clinical study of pyrvinium pamoate in the treatment of 93 patients infested with Enterobius vermicularis (pinworms), the cure rate for the suspension form of the drug was significantly higher than that for the existing tablet form. In further studies with 209 infested patients, a new tablet form in which the pyrvinium particles were less than 10 p. in diameter (in contrast to the 50 to 90 p. size in the previous tablet), the cure rates with both tablet and suspension were not significantly different. The only side effect was vomiting, which occurred in some patients who received the suspension. The results indicate that the micronized tablets are therapeutically equivalent to the suspension. Spectrophotofluorometric assay for drug in blood and urine demonstrated no pyrvinium pamoate.
Specific beta adrenergic blockade by practolol
Authors: Thompson Mark E. , McDonald Robert H. , Leon Donald F. , Shaver James A.
Published: January 2016

Cardiospecific beta blockade by practolol was studied in 9 normal volunteers on three separate occasions. Three adrenergic stimuli (epinephrine, 0.1 mcg/kg/min, isoproterenol, 0.025 mcg/kg/min, and exercise, 50 watts) and three intravenous doses of practolol were randomly paired in three Latin squares. Observations of heart rate, arterial blood pressure, cardiac output, and systolic time intervals were obtained under baseline control conditions; during beta adrenergic stimulation; after a recovery period of 30 minutes; under resting conditions; after administration of practolol; and during repeated beta adrenergic stimulation to assess the effect of practolol as a cardioselective beta adrenergic blocking agent. Under basal conditions, blood levels of practolol (0.37, 0.89, and 1.86 mcg/ml) resulted in physiologically unimportant changes in the parameters measured. Dose levels of 0.3 to 0.6 mg/kg of practolol administered intravenously significantly reduced the response of heart rate, cardiac index, pre‐ejection period, and tension time index to at least two of the three adrenergic stimuli used. There was no evidence for dimct myocardial depression by practolol although the direct inotropic effect of catecholamine infusion was significantly attenuated by the highest doses of practolol.
Antimicrobial drugs
Authors: Finland Maxwell
Published: January 2016

When the Executive Secretary of the Drug Research Board called to ask if I would participate in a Workshop on Dermatopharmacology, I pleaded that I knew little of the subject beyond the fact that the skin is a frequent site of toxic reactions to antimicrobial drugs, some of which are used with varying success to treat acne, pyodermas, and fungal diseases of the skin. The idea of learning more while renewing old acquaintances and meeting with the leaders in the field, plus a visit to San Francisco, were enough to overcome my reticence, so I accepted and became an instant dermatologist. In 1953, Louis Weinstein coauthored with me a brief review of the complications of antimicrobial therapy.6 About a third of that review was devoted to the cutaneous reactions and other manifestations of hypersensitivity. It may be appropriate, therefore, for me to devote this presentation primarily to these aspects of antimicrobial therapy, particularly since more experienced dermatologists will be discussing the use of these drugs in therapy of dermatologic diseases.
Acne
Authors: Strauss John S.
Published: January 2016

In a workshop on dermatopharmacology, acne must be one of the major topics to be discussed. While it is not the leading cause of incapacitating dermatologic morbidity, it is definitely the most common skin disease seen by the dermatologist in practice. Almost every teenager has some degree of acne at some time, and the often stated comment that acne clears at the age of 20 to 21 is not true in many cases. Particularly in women, acne may persist into the twenties and thirties. Because of the prevalence of acne, it is rather obvious that only a small percentage of those with acne are seen by a dermatologist, and millions of dollars are spent yearly on OTC acne preparations.
Hormonal drugs
Authors: Haynes Robert C.
Published: January 2016

The pharmacologic effects of the adrenal cortical hormone, cortisol, and its synthetic congeners on normal tissues can be viewed as a reallocation of the resources of the organism. Under the influence of these compounds, peripheral organs, including the skin, are systematically robbed of their constituents in an exaggerated reenactment of primitive defense reactions. Teleologically, it appears that the glucocorticoids remove materials from some tissues in an effort to preserve normal functioning in other organs. One finds wastage of lymphatic, osseous, muscular, and dermal tissues; at the same time, the liver, receiving the breakdown products of these organ systems, has an enhanced synthesis of ribonucleic acid (RNA), produces increased amounts of glucose and glycogen, and synthesizes selected enzymes of amino acid and carbohydrate metabolism at increased rates.
Local toxicity
Authors: Stoughton R. B.
Published: January 2016

Local toxicity covers a wide range of possible injuries to the skin as well as to the underlying organism to which it happens to offer a protective enclosure. There are chemical and physical factors such as acids, alkalis, strong solvents, heat, cold, electromagnetic energy, and ultrasound that can damage the skin. Some chemicals can induce sensitization of the subject so that what were previously innocuous contacts with the agent become highly damaging on future contact and lead to disabling, painful, and pruritic eruptions. A wide spectrum of microorganisms are capable of invading and disrupting the normal functions of skin (fungi, bacteria, spirochetes, viruses). Severe systemic toxicity can be initiated solely by skin contact with some toxic chemicals, and these toxic agents may be much more damaging locally and systemically if they are in intimate contact with hydrated, warm, and macerated areas.
Pemphigus
Authors: Tuffanelli Denny L.
Published: January 2016

Pemphigus is a disease affecting principally the epidermis and mucous membranes of man. The disease is quite distinctive clinically, histologically, and immunologically. It is of importance to discuss in this Workshop because of two interesting facets: the role played in pathogenesis by circulating autoantibodies and the huge doses of corticosteroids required in management.
Hypersensitivity reactions
Authors: Tan Eng M.
Published: January 2016

There are many well‐known hypersensitivity reactions to drugs such as penicillin and sulfa drugs, but this paper will emphasize other aspects of hypersensitivity reactions to drugs that are not as widely known. Certain drugs such as hydralazine and procainamide are widely used in the treatment of hypertension and cardiac arrhythmia. It has become increasingly clear that these drugs are implicated in a hypersensitivity reaction that is different in its manifestations from most drug hypersensitivity reactions. Hydralazine and procainamide produce an untoward clinical syndrome that resembles spontaneous systemic lupus erythematosus. These drugs, therefore, arc able to induce an autoimmune reaction that results not only in clinical manifestations of a spontaneous autoimmune disease but also in the production of autoantibodies in the sera of patients with drug‐induced disease. The pathogenetic mechanisms by which drugs such as hydralazine and procainamide can produce autoimmune reactions are the subject of increasing interest to immunologists, since there is a possibility that understanding this reaction may lead to the elucidation of the factors that produce spontaneous autoimmune disease in man.
Immunosuppressives
Authors: Kirkpatrick Charles H.
Published: January 2016

In this paper, I propose to review some of the current concepts of development of immunocompetence, to describe the cellular events that follow exposure to antigen, and to show how these data may be applied to therapy with immunosuppressive drugs. The greatest emphasis will be placed on the glucocorticoids, because these agents are widely employed in treatment of inflammatory and immunologic diseases, and there are several important, recent observations on their mechanisms of action.
Metabolic disposition of diphenhydramine
Authors: Glazko A. J. , Dill W. A. , Young R. M. , Smith T. C. , Ogilvie R. I.
Published: January 2016

Maximum plasma levels of diphenhydramine in normal subjects ranged from 81 to 159 ng/ml in 2 to 4 hr after single 100 mg oral doses, with an estimated half‐life of 7 hr. Multiple oral doses of 50 mg four times daily for 3 days produced mean peak levels of approximately 110 ng/ml by the second day, with an estimated half‐life of 6 hr. Total amine levels were 50% to 100% higher, due to the presence of N‐dealkylated metabolites. Single 100 mg oral doses of diphenhydramine also produced a progressive increase in the plasma levels of acidic metabolites over a 24 hr period, reaching values 10 times those of the maximum diphenhydramine levels. Urinary excretion of total diphenhydramine metabolites represented about 64% of the dose in single dose studies, and 49% after multiple doses. These observations are consistent with earlier studies on the metabolic disposition of labeled diphenhydramine in laboratory animals.
Determination of propoxyphene and norpropoxyphene by chemical ionization mass fragmentography
Authors: Walen Robert L. , Ziege Edgar A. , Gruber Charles M.
Published: January 2016

The development of a gas‐liquid chromatographic method9 for the measurement of propoxyphene (Darvon) in plasma and extension of this technique to norpropoxyphene6, 8 has led to the examination of the kinetics of the drug and its primary metabolite.2, 5, 6, 8, 10 Calculations indicated that a considerable “first pass effect”3 influences drug plasma levels. Low assay sensitivity has prevented plasma level measurement for the extended periods of time necessary to establish terminal plasma concentrations.7
Thioridazine: Central dopamine turnover and clinical effects of antipsychotic drugs
Authors: Bowers Malcolm B.
Published: January 2016

Thioridazine was administered to 14 patients diagnosed as within the “schizophrenic spectrum” with the result that substantial improvement in psychotic symptoms was achieved while significant extrapyramidal side effects occurred in only 1 patient. Under these conditions lumbar cerebrospinal fluid homo vanillic acid following probenecid was significantly elevated (48%). Cerebrospinal fluid probenecid and 5‐hydroxyindoleacetic acid declined significantly during treatment with thioridazine. Taken in conjunction with the results of other studies, it appears that cerebrospinal fluid homo vanillic acid can be moderately elevated in man during successful treatment with antipsychotic drugs when extrapyramidal side effects are virtually absent. Possible interpretations of these results are discussed with regard to the clinical effects of antipsychotic drugs as they relate to central dopaminergic activity.
Hemodialysis in an infant with propoxyphene intoxication
Authors: Mauer S. Michael , Paxson Charles L. , von Hartizsch Barry , Buselmeier Theodore J. , Kjellstrand Carl M.
Published: January 2016

A 10‐month‐old infant was treated with intensive supportive care and hemodialysis for severe propoxyphene intoxication. Dialysis clearance studies demonstrated that propoxyphene was removedfrom the serum at approximately 50% of the rate of blood urea nitrogen removal. Possibly because of tissue binding of the drug, the absolute quantity of propoxyphene removed by dialysis was small. The child survived the acute episode of intoxication but died of pulmonary complications several days later. The role of dialysis in propoxyphene intoxication remains to be established.
Interaction of physostigmine and delta‐9‐tetrahydrocannabinol in man
Authors: Freemon Frank R. , Rosenblatt Jack E. , El-Yousef M. Khaled
Published: January 2016

To investigate the hypothesis that delta‐9‐tetrahydrocannabinol (THC), the major psychoactive ingredient of marihuana, acts by interfering with cholinergic brain mechanisms, 0.75 to 1.25 mg of physostigmine, a centrally active cholinergic drug, was given intravenously to 5 normal volunteers who had ingested 20 to 40 mg of THC 2 hours earlier. Physostigmine decreased the degree of tachycardia and conjunctival injection produced by THC. The major psychologic effects of physostigmine were amplification of the lethargy and somnolence which occur late in the course of THC intoxication. We interpret the lack of physostigmine counteraction of the peak psychologic effects of THC as evidence against the hypothesis that THC acts predominantly by an anticholinergic mechanism.
Antiarrhythmic potency of N‐acetylprocainamide
Authors: Elson James , Strong John M. , Lee Woong-Ku , Atkinson Arthur J.
Published: January 2016

Compared to procainamide in an animal arrhythmia model, the antiarrhythmic potency of the N‐acetylated metabolite of procainamide (NAPA) was 92% with respect to dose and 70% with respect to plasma level. The antiarrhythmic effects of combinations of the drugs were additive. Measurements of procainamide and NAPA plasma levels needed to suppress ventricular extrasystoles suggested that both compounds are nearly equipotent in patients as well. The average plasma level required for arrhythmia control in these patients was equivalent to 5.1 mcg/ml procainamide. Since patients on long‐term procainamide therapy have plasma concentrations of NAPA that are usually comparable to, and occasionally greater than, their procainamide levels, dose regimens based on procainamide levels alone need revision to include consideration of the levels of this metabolite.
Effect of nortestosterone decanoate on red cell 2,3 diphosphoglycerate and hematocrit in hemodialysis patients
Authors: Goodman Jay , Bessman Alice N.
Published: January 2016

The effects of intramuscular 200‐mg nortestosterone decanoate (ND) on red cell 2,3 diphosphoglycerate (DPG) concentration and packed cell volumes (PCV) were compared in 9 patients undergoing chronic hemodialysis for renal failure and in 18 control patients undergoing hemodialysis but not receiving ND. Subjects had received the drug 4.3 ± 0.3 (SEM.) months at the time of DPG determinations. DPG was similar in treated patients and in the control subjects: 6.27 ± 0.22 mM/L RBC and 6.16 ± 0.23 mM/L RBC, respectively. The initial PCV was also similar: 21.72% ± 1.36 and 20.13% ± 0.91. Although the mean PCV during treatment was higher for 5 of 9 ND‐treated patients (p < 0.01), the final PCV prior to termination of therapy was greater than the initial pretreatment PCV in only 2 of these 5 patients (p > 0.05). We conclude that 200 mg ND weekly has no effect on the red cell DPG and a transient unsustained effect in raising the PCV in male chronic hemodialysis patients over a 5‐month period of treatment.
Effects of clofibrate and a fat‐modified diet on serum lipids
Authors: Brown Helen B. , Lewis Lena A. , Page Irvine H.
Published: January 2016

The combined effect of clofibrate and a fat‐modified diet was determined in 17 hyperlipidemic patients: 7 type IIA, 7 type IV, 2 type VI(IIB), and I type III. Control serum lipid levels and lipoprotein patterns and their alteration with a fat‐modified diet had been determined previously 1/2 to 2 years for 3 patients, and 6 to 10 years for 14 patients. Two grams of clofibrate a day (0.5 gm four times daily) was taken along with the fat‐modified diet for 2 to 6 months by 5 patients and for 2 years by 13 patients. The effect of clofibrate and a fat‐controlled diet was also determined in 10 normolipidemic men who were subjects of an 18‐day test in which the polyunsaturated fat diet was quantitatively prepared and eaten along with 2 gm clofibrate a day (0.5 gm four times daily). The effect of clofibrate on serum cholesterol levels was a further mean reduction in type IIA patients by 19%, in type III by 23%, in type IV by 12%, in type VI by 7%, and in normolipidemic subjects by 8%. The extent of the additional serum cholesterol reduction with clofibrate in individual hyperlipidemic patients varied from + 10% to −44 % and was not related directly to the type of hyperlipidemia. The extent of reduction appeared related directly to the level of −S 40‐70 (similar to Sf 12‐20) lipoproteinjraction in the control serum sample. Serum triglyceride levels were unaffected in type IIA and normolipidemic subjects. Serum triglyceride levels did not change consistently in the 2 type VI patients, rising by 11 % in 1 and dropping by 31% in the other. Serum triglyceride levels were significantly (p = 0.001) and consistently reduced by 39% only in type IV patients.
Drug metabolism in normal children, lead‐poisoned children, and normal adults
Authors: Alvares Alvito P. , Kapelner Stephen , Sassa Shigeru , Kappas Attaliah
Published: January 2016

Drug‐metabolizing capacities were determined in 10 normal adults and 10 children in the age range from 1 to 8 years. Among the latter, 2 were normal and 8 had biochemical evidence of lead poisoning but no clinical expression of plumbism. There were no differences between the 2 normal children and the 8 lead‐poisoned children in their capacities to metabolize two test drugs, antipyrine and phenylbutazone. The mean antipyrine half‐life in the whole group of 10 children, 6.63 hr, was significantly lower than the mean half‐life of 13.58 obtained in adults. The mean phenylbutazone half‐lives in the children and adults, 1.68 and 3.16 days, respectively, also differed significantly. Thus children in the age range studied appear to metabolize drugs at almost twice the rate of adults, which differs from findings in animals in which drug‐metabolizing capacities increase with maturation. In two other children who showed clinical as well as biochemical manifestations of acute plumbism, antipyrine half‐lives were significantly longer than normal and therapy with EDT A led to restitution toward normal.
The normal volunteer in clinical investigation: How rigid should selection criteria be?
Authors: Joubert Pieter , Rivera-Calimlim Leonor , Lasagna Louis
Published: January 2016

Twenty‐nine healthy young male volunteers were screened by history, physical examination, urinalysis, 24 different blood tests, and electrocardiography for admission to a Phase I drug study. The protocol submitted to, and approved by, the FDA listed the normal ranges for the local laboratories and stipulated that the test results for any volunteers accepted should all he within these ranges. During screening 46 abnormal values were found in the labaratory tests. Only 4 subjects had all their test data within the “normal” range, aresult that could have been anticipated simply from the number of tests performed. These jindings indicate the need for deciding on realistic protocol criteria for studies invalving healthy volunteers.
Etorphine in man. I. Subjective effects and suppression of morphine abstinence
Authors: Jasinski Donald R. , Griffith John D. , Carr Carter B.
Published: January 2016

The effects of etorphine, a potent morphine‐like drug, were qualitatively and quantitatively compared to those of morphine. In nondependent subjects, etorphine in doses of 0.025, a .050, and 0.100 mg produced pupillary constriction and morphine‐like subjective effects and euphoria. Etorphine was 500 times as potent as morphine, with a very rapid onset and short duration of action. In morphine‐dependent subjects, etorphine suppressed abstinence but for a shorter period than morphine. These studies indicate that in man etorphine is a morphine‐like drug with a high abuse potential.
Cardiac rate and rhythm changes with atropine and methscopolamine
Authors: Neeld John B. , Allen A. T. , Coleman Elliott , Frederickson Evan L. , Goldberg Leon I.
Published: January 2016

The effects of methscopolamine bromide (MSB) and atropine were compared in patients prior to elective surgery. After administration of the second dose of MSB (total dose 1.5 µg/kg) all patients exhibited at least 20% increase in heart rate. In contrast, three doses of atropine (total dose 5.3 µg/kg) were required for most patients to attain a 20% increase in heart rate while 2 patients did not attain this heart rate with a dose of 10.6 µg/kg of atropine. Comparison of single injections of MSB and atropine in normal subjects also demonstrated a more reliable dose‐response relationship with MSB. Electrocardiographic changes recorded were typical of those reported with anticholinergic agents. Sinus and atrial arrhythmias were more common with atropine and nodal arrhythmias and conduction disturbances were more common with MSB. This study demonstrated that MSB can be reliably substituted for atropine when an anticholinergic drug is needed to increase heart rate. Since MSB has a limited ability to cross the blood‐brain barrier, it may be the more desirable drug in patients in whom the central nervous system effects of atropine may be deleterious.
Relationship between digoxin concentrations in serum and saliva
Authors: Huffman David H.
Published: January 2016

The concentration of digoxin in serum and saliva was determined in 18 patients receiving digoxin. Unlike serum, it was necessary to extract saliva with chloroform in order to quantitate digoxin levels accurately. An excellent linear correlation (r = +0.988, p < 0.001) was observed between the saliva and serum digoxin concentrations. This indicates that saliva digoxin concentrations can be used to monitor digoxin therapy, particularly in patients in whom blood sampling is inconvenient or difficult. The saliva/serum ratio for digoxin concentration was 0.78 ± 0.07 (SD). Since the digoxin binding to plasma proteins is 23%, it is the free drug that is in equilibrium between serum and saliva.
Morphology of gastrointestinal effects of aspirin
Authors: Hahn Klaus-Jürgen , Krischkofski Dietmar , Weber Ellen , Morgenstern Eberhard
Published: January 2016

The effect of acetylsalicylic acid (aspirin) on the ultrastructure of the gastric and jejunal mucosa was investigated in patients undergoing gastric surgery and in guinea pigs. The drug caused various degrees of damage to the surface mucous cells in both species perceptible as general signs of cytolysis in situ or as desquamation. In patients pretreated with aspirin, an increase of secondary lysosomes was noted in the gastric parietal cells but not in the animals. In the intestinal epithelial cells of both species there was a marked increase of secondary lysosomes, probably representing autophagolysosomes. The simultaneous increase of multi vesicular bodies and the occurrence of transitional stages between the two organoids suggest a functional interrelationship. Since no specific alteration of any cellular organoid was detected, the drug‐induced injury is assumed to occur on a molecular level in the cytoplasm. It is concluded that the intracellular concentrations of aspirin in gastrointestinal mucosal cells during absorption cause cellular injury that can usually be restored by cellular repair mechanisms but that high drug concentrations may lead to irreversible cell damage.
Comparison of amikacin and gentamicin
Authors: Klastersky Jean , Odio Wobin , Hensgens Colette
Published: January 2016

The sensitivity to gentamicin (G) and to amikacin (A) of 25 strains of Escherichia coli (EC), 25 Klebsiella sp, (K), 25 Proteus and Providence sp. (PP), and 25 Ps. aeruginosa (PA) were tested in vitro by the disc method, by the inocula‐replicating method, and by a tube dilution technique using 105 microorganisms/ml. Bactericidal concentrations active on 50% and 90% of the strains were 1.5 and 4.5 µg/ml for EC, 3 and 3 µg/ml for K, 1.5 and 3 µg/ml for pp, and 3 and 3 µg/ml for PA. Resistance to killing by 12 µg/ml of G was foundfor 16 strains (1 EC, 9 K, 4 PP, and 2 PAY but only 5 strains were also resistant to 12 µg/ml of A. Conversely, 4 strains (1 EC, 1 pp, and 2 PAY were resistant to 12 µg/ml of A but were killed by 6 µg/ml of G or even less. G (1.5 mg/kg) and A (5 mg/kg) were administered to 5 volunteers in a crossover fashion. The mean bactericidal activity of the sera obtained at 1 hr after the injection of G and A was, respectively, % and % for ED, % and 1/8 for K, V2 and V2 for PP, and V2 and V2 for P A. Sera obtained in A ‐treated patients killed at a dilution of Va, 8 strains of ED, 17 K, 1 PP, and 0 PA; at that dilution sera from G‐treated patients killed 5 ED, 9 K, 0 P, and 0 PA. The main advantage of A over G might be the absence of cross‐resistance between A and G for particular pathogens.
Effect of tolamolol and propranolol on exercise heart rate and angina
Authors: Aronow Wilbert S. , Spivack Nordy , Laverty Wayne , Warren Max
Published: January 2016

Fifteen patients with angina pectoris participated in a double‐blind study evaluating the effect of intravenous saline, 10 mg of intravenous tolamolol, 20 mg of intravenous tolamolol, and 10 mg of intravenous propranolol on resting and exercise heart rate and on exercise time until angina. Twenty mg of tolamolol and 10 mg of propranolol caused a similar decrease in mean resting heart rate, heart rate after a similar amount of exercise, heart rate at angina, resting product of systolic blood pressure times heart rate, and product of systolic blood pressure tim es heart rate at angina and were, therefore, judged equipotent. Tolamolol, 10 and 20 mg, and propranolol, 10 mg, were not followed by a significant change in mean exercise duration until angina, but there was a 25% increase in exercise time until angina in 4 of 15 patients (27%) after 10 mg of propranolol and in 3 of 15 patients (20%) after 20 mg of tolamolol.
Binding‐site interaction of chlorthalidone and acetazolamide, two drugs transported by red blood cells
Authors: Beermann Björn , Hellström Kjell , Lindström Björn , Rosen Anders
Published: January 2016

When 14C‐chlorthalidone was administered orally to 2 healthy volunteers, the total recovery of radioactivity in urine (about 75%) and feces was close to 100%. Most of the label recovered in the blood was bound to the blood cells. When the procedure was repeated while the 2 subjects were receiving acetazolamide, the excretion of labeled material in urine and feces was essentially unchanged, but the blood cells contained less and the plasma more of the blood radioactivity. The half‐life of the radioactivity in plasma and blood cells had decreased by about 65%. Intravenous administration of acetazolamide (single dose) to 2 other subjects who had received 14C‐chlorthalidone orally resulted in a marked drop in the blood cell radioactivity, whereas that in plasma increased. The affinity of chlorthalidone for red blood cells was further evidenced on incubation of 14C‐chlorthalidone with human blood. Of the incubated radioactivity, 94% to 99% was recovered in the erythrocytes. Preincubation of the blood sampies with acetazolamide prior to the addition of 14C‐chlorthalidone, as weil as incubation of acetazolamide in blood sampies previously incubated with 14C‐chlorthalidone, demonstrated that acetazolamide is able to inhibit and to displace chlorthalidone from blood cells. There are several lines of evidence indicating that chlorthalidone is transported attached to the erythrocyte carbonic anhydrase.
Plasma protein binding of carbamazepine
Authors: Hooper Wayne D. , Dubetz Dennis K. , Bochner Felix , Cotter Lesley M. , Smith Gabrielle A. , Eadie Mervyn J. , Tyrer John H.
Published: January 2016

The binding of carbamazepine to the pro teins of human plasma has been studied using ultrafiltration techniques. In vitro studies at 37° C showed the relation between concentration of unbound drug and total drug to be linear thraugh the range of total concentration of 5 to 50 µg/ml. The per cent unbound drug increased slightly as concentration increased. There was tittle difference between the extent 0/ binding at 4° C and 20° C, but more carbamazepine was unbound at 37° C. Under in vitro conditions, 6 other anticonvulsants, and aspirin, were tested individually, each at high therapeutic or toxic concentration, and shown not to displace carbamazepine from plasma proteins to a significant degree. The extent of binding of carbamazepine in vivo was determined in a total of 54 plasma sampies collected from treated patients; 26.9 ± SD 9.4% of the drug was unbound. In blood sampies from 23 of these patients, the red cell concentration of carbamazepine averaged 38.3 ± SD 17.9% of the plasma concentration. The effects of hepatic and renal diseases on the carbamazepine binding capacity of plasma proteins were assessed by comparing the binding capacity of plasma from diseased persons with that from normal subjects. There was no significant difference in binding capacity between plasma from patients with renal disease and that from normal subjects. However, the plasma from patients with hepatic disease bound a stightly lower percentage of carbamazepine than did normal plasma (p < 0.05). This alteration did not correlate with changes in any of 15 biochemical parameters measured in these patients. The clinical significance of these results is discussed.
Effeets of etiocholanolone‐indueed fever on plasma antipyrine half‐lives and metabolie elearanee
Authors: Elin Ronald J. , Vesell Elliot S. , Wolff Sheldon M.
Published: January 2016

The plasma half‐life and metabolie clearanee rate of antipyrine, a drug metabolized by hepatie microsomal enzymes, were determined in 33 normal volunteers du ring a basal state and during fever indueed with a single intramuseular injeetion of etioeholanolone. Of the 14 normal volunteers who aehieved signifieant fever (fever index> 50), in 11 plasma antipyrine half‐life was prolonged after a single oral dose of 10 mg/kg and antipyrine metabolie clearanee rate was deereased. There was no signifieant ehange of these mean values in 19 normal volunteers who failed to develop signifieant fever (fever index <50). Therefore, under the eonditions of this study plasma antipyrine half‐life was prolonged, probably due to impaired hepatie metabolism, during etiocholanolone‐indueed fever, although no eorrelation was observed between the magnitude of fever and the extent to whieh plasma antipyrine half‐life was prolonged. Failure to obtain sueh a eorrelation may be attributable to the very small range of temperature elevation, extending from 37.9° C to 39.2° C, in the group of 14 subjeets achieving signifieant etioeholanolone‐indueed fever (fever index > 50). A higher dose of antipyrine (18 mg/kg) suppressed induetion of fever by etiocholanolone; antipyrine is the only orally administered drug thus far shown to be effeetive in repressing etiocholanolone‐indueed fever.
Effect of foodstuffs on the absorption of zinc sulfate
Authors: Pécoud A. , Donzel P. , Schelling J. L.
Published: January 2016

Single doses of zinc sulfate were given to healthy young volunteers, either in the fasting state or with various types of meals. Dairy products (milk and cheese) and brown bread decreased zinc absorption, as indicated by a significant drop in peak serum zinc levels. Zinc absorption was decreased when zinc was given in the fasting state with the same amounts of purified phosphate or phytate as those found in foods above. Experiments in vitro have shown that zinc is precipitated by phosphate and phytate at pR values dose to that of the intestinal lumen. Coffee also seems to inhibit zinc absorption. A.
Pharmacokinetics of ifosfamide
Authors: Allen Larry M. , Creaven Patrick J.
Published: January 2016

A multicompartment pharmacokinetic model Jor ifosJamide has been employed using a system of first‐order differential equations, which includes a term for metabolism according to Michaelis‐Menten kinetics in order to describe the distribution and elimination parameters of ifosfamide in man. The model satisJactorily accounts for all the administered drug. The pseudometabolic rate constant Jor ifosfamide in man is found to be less than 20% of that reported for cyclophosphamide in man, in agreement with the more extensive metabolism of cyclophosphamide than ifosfamide. A number of the pharmacokinetic parameters for ifosfamide differ substantially from those reported for cyclophosphamide. The volume of distribution for ifosfamide metabolites was found to be approximately equal to the plasma space volume. The central compartment volume for intact ifosfamide is slightly larger than for cyclophosphamide and includes the easily diffusible extravascular space of the body and suggests lack of protein binding. The renal clearance of ifosJamide is low and about twice that of cyclophosphamide. The model indicates that only a small fraction of the total metabolites distribute into the peripheral compartment and suggests that multiple doses of the drug may be useful.
The disposition of morphine in surgical patients
Authors: Berkowitz B. A. , Ngai S. H. , Yang J. C. , Hempstead J. , Spector S.
Published: January 2016

The disposition of serum morphine following administration of 10 mg/70 kg was determined by a sensitive and specific radioimmunoassay in 31 anesthetized surgical patients ranging in age from 23 to 75 yr. Following iv injection. 93% of the morphine disappeared from the serum within 5 min. The early serum levels of the drug (2 min) correlated directly with the patients' ages (r = 0.63. p < 0:01). Patients 23 to 50 yr of age averaged 0.29 μg/ml. whereas patients 51 to 75 yr of age averaged 70% higher. 0.49 μg/ml. The serum half‐life between 10 and 240 min was independent of age and averaged about 2 hr after either iv or im administration. Following im administration. morphine was rapidly absorbed. with peak levels occurring within 10 to 20 min. The decline in morphine serum levels paralleled the decline in morphine analgesia and was coincident with the appearance of morphine glucuronide in the serum. These studies demonstrate the applicability and specificity of the radioimmunoassay for morphine and suggest that serum levels of morphine may be a useful and objective indicator of its pharmacologic activity
Pharmacokinetics of actinomycin 0 in patients with malignant melanoma
Authors: Tattersall M.H.N. , Sodergren J. E. , Sengupta S. K. , Trites D. H. , Modest E. J. , Frei Emil ,
Published: January 2016

The distribution and excretion of tritiated actinomycin D have been determined in 3 adult patients with disseminated malignant melanoma. In the blood, the drug was preferentially taken up into nucleated cells. The urinary and fecal excretion was prolonged and only about 30% of the dose of actinomycin was recovered in 9 days. There was evidence that the drug was concentrated in bone marrow and tumor cells, but did not readily cross the blood‐brain barrier. The long tissue half‐life of actinomycin D suggests that an intermittent schedule of administration would be the most effective.
Polymorphic acetylation of procainamide in man
Authors: Reidenberg Marcus M. , Drayer Dennis E. , Levy Micha , Warner Howard
Published: January 2016

N‐Acetylprocainamide (NAPA) and procainamide plasma and urine concentrations were determined by thin‐layer chromatography (TLC) densitometry in people of known acetylator phenotype (dapsone phenotyping) taking procainamide for more than 3 days. The plasma NAPA / procainamide ratio 3 hr after the last dose for fast acetylators (mean ± SD) is 1.8 ± 0.59 (N = 8) and for slow acetylators, 0.61 ± 0.09 (N = 6)(p < 0.001). The renal clearance of NAPA averaged 1.2 times the simultaneously measured endogenous creatinine clearance, whereas procainamide clearance was approximately double the creatinine clearance. There was no difference between slow and rapid acetylators in the renal clearance of either drug or the urine pH, indicating that the difference in plasma NAPA /procainamide ratios between these two groups is due to differences in their rates of acetylation. Therefore, procainamide is probably acetylated by the polymorphic N‐acetyltransferase in man. Reflecting the blood level differences, the NAPA/procainamide ratio in urine (collected 90 to 180 min after last dose) was found to be higher in rapid than in slow acetylators. The plasma protein binding of NAPA and of procainamide are similar. Since NAPA seems to have an antiarrhythmic potency similar to procainamide, NAP A probably contributes to the antiarrhythmic activity of procainamide therapy, especially in genetic rapid acetylators.
Sulfamethizole‐induced inhibition of diphenylhydantoin, tolbutamide, and warfarin metabolism
Authors: Lumholtz Bo , Kaj Siersbaek‐Nielsen , Skovsted Lis , Kampmann Jens , Hansen Jens Mølholm
Published: January 2016

The influence of sulfamethizole on the metabolism of diphenylhydantoin (DPH), tolbutamide, and warfarin is examined. In 8 patients DPH mean half‐life (T/2) increased from 11.8 ± 3.3 hr to 19.6 ± 5.2 hr and mean metabolic clearance rate (MCR) decreasedfram 43.7 ± 16.8 to 28.1 ± 9.1 ml/min during sulfamethizole treatment. In 6 patients mean tolbutamide T/2 increased from 5.7 ± 1.2 to 9.2 ± 1.2 hr MCR decreased from 17.0 ± 5.4 to 10.5 ± 1.2 ml/min. In 2 patients warfarin T/2 increased from an average of 64.7 to 92.7 hr and MCR decreased from 1.65 ml/min to 1.05 ml/min. In 4 patients on long‐term DPH treatment after 1 wk on sulfamethizole, there was an increase in serum DPH concentration in 3. It is suggested that sulfamethizole inhibits hepatic metabolism of DPH, tolbutamide, and warfarin.
Electrophysiologic effects of glucagon on human cardiac muscle
Authors: Prasad Kailash
Published: January 2016

The effects of glucagon (5, 10, and 40 µg/ml) on the amplitude and duration of action potential, effective refractory period, dv Idt of phase 0 of action potential, membrane responsiveness, and contraction in human papillary muscles obtained from patients undergoing corrective open heart surgery were investigated. Glucagon, in none of the concentrations, produced any significant change in the amplitude and duration of action potential, or in force of contraction. Shortening of the effective refractory period was not significant. Glucagon enhanced the conduction and the membrane responsiveness by increasing the dvldt of phase 0 of action potential and a shift of curve to the left. It is suggested that the latter properties of glucagon would abolish the “re‐entrant” type of cardiac arrhythmias produced by cardiac glycosides or other drugs that initiate and perpetuate arrhythmias due to altered conduction.
Prediction of drug dosage in patients with renal failure using data derived from normal subjects
Authors: Welling P. G. , Craig W. A. , Kunin C. M.
Published: January 2016

A one‐compartment model designed to predict alterations in persistence of drugs in uremic patients was constructed using information obtained from normal subjects. Data obtained from the literature in which the fraction of absorbed drug eliminated unchanged in the urine and the apparent elimination rate constants were compared in both normal control subjects and in severely uremic patients. Twenty‐two drugs were examined. Despite changes in apparent volume of distribution and metabolism reported in uremia, the model was able to predict overall elimination rate constants in severe uremia with an error under 10% for 12 and under 20% for 7 additional drugs. The method appears to be most informative for drugs that tend to be retained in the presence of renal failure. Great error was observed with doxycycline and erythromycin. Studies with erythromycin lactobionate and a cupplate assay reduced the error for this drug from 56% for the glucoheptonate to 18%. Doxcycline is known to have a complex enterohepatic circulation. The model is offered as a useful approach to predict dosage adjustment in uremic patients with drugs for which data are not available.
Pharmacokinetics and metabolism of lidocaine in patients with renal failure
Authors: Collinsworth Ken A. , Strong John M. , Atkinson Arthur J. , Winkle Roger A. , Perlroth Frank , Harrison Donald C.
Published: January 2016

The kinetics of distribution and elimination of lidocaine and two of its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), were studied in 4 uremic patients on chronic hemodialysis. Each patient received a loading dose of 75 mg of lidocaine, followed by a 30 µg/kg Imin lidocaine infusion. No toxic side effects from lidocaine were seen during the study. Average values for lidocaine steady‐state plasma levels (2.3 µg/ml) clearance (12.3 ml/min/kg), terminal half‐life (148 min), and total volume of distribution (1.9 L/kg) were found, and are similar to those values reported for normal subjects. MEGX plasma levels during and after lidocaine infusion averaged ⅕−⅔ of the corresponding lidocaine level, as in nonuremic subjects, and plateaued by 6–8 hr. GX levels did not reach plateau level by 12 hr and remained relatively unchanged after infusion. 1t is concluded that lidocaine infusion in uremic patients is safe, with no abnormal cumulation of lidocaine or MEGX. GX levels, however, may increase progressively, even after 12 hr.
The analgesic properties of delta‐9‐tetrahydrocannabinol and codeine
Authors: Noyes Russell , Brunk S. Fred , Avery David H. , Canter Arthur
Published: January 2016

The administration of single oral doses of delta‐9‐tetrahydrocannabinol (THC) to patients with cancer pain demonstrated a mild analgesic effect. At a dose of 20 mg, however, THC induced side effects that would prohibit its therapeutic use including somnolence, dizziness, ataxia, and blurred vision. Alarming adverse reactions were also observed at this dose. THC, 10 mg, was well tolerated and, despite its sedative effect, may have analgesic potential.
Digoxin pharmacokinetics: Role of renal failure in dosage regimen design
Authors: Koup Jeffrey R. , Jusko William J. , Elwood Charles M. , Kohli Romesh K.
Published: January 2016

Radioimmunoassayed serum concentration and urinary excretion data for digoxin from azotemic patients were characterized using a 2‐compartment open model. Urinary excretion rates of digoxin as well as serum concentration data are needed to accurately characterize the disposition of the drug. Seven patients with renal failure showed highly variable steady‐state volumes of distribution (VSSD = 195 to 489 liters/1.73 m2) and tÛβ values (1.5 to 5.2 days). This variability is a major limiting factor in the use of dosage regimen nomograms that assume a constant VSSD and a rigorous relationship between tÛβ and creatinine clearance (ClCR). Body clearance (ClB) is a parameter that is affected by both elimination and distribution of drugs. A linear relationship between ClB and renal clearance of digoxin or ClCR was found and was used to develop a model‐independent approach to calculation of maintenance doses of digoxin. Several methods for calculating steady‐state serum concentrations of digoxin (CSSD) were compared with actual measurements obtained in 16 chronically medicated patients. Optimum computation of CSSD is obtained by use of digoxin renal and body clearances. Variability in the digoxin: creatinine renal clearance ratio is the major limiting factor in prediction of digoxin dosage regimens.