bluuebunny/crossref_metadata_2025 huggingface dataset:
Epithelial neoplasms
Authors: Weinstein Gerald D.
Published: January 2016

Cutaneous neoplasms play a significant part in the overall cancer picture. In man, approximately 23% of all cancers are found on the skin. Fortunately, the mortality from skin cancer is quite low, and this minimizes our concern. Morbidity, however, can be quite significant in a great number of patients.
Mycosis fungoides lymphoma
Authors: Van Scott Eugene J.
Published: January 2016

This misnamed disease is a lymphoma that always first appears in the skin but eventually involves lymph nodes and internal organs. Although rather uncommon, it has a number of features providing several approaches to treatment that are of special interest. More detailed accounts of the disease, its course, and means of management may be found elsewhere.5 7, 8, 9 Some aspects of the disease and its treatment that are particularly pertinent to this Workshop are briefly discussed here.
Melanocyte function: Influence of cyclic adenosine mono phosphate
Authors: McGuire Joseph
Published: January 2016

The melanocyte is an epidermal cell of specialized function that is derived from the neural crest. Thus, it is close kin with the sympathetic ganglia and cells of the adrenal medulla. The melanocyte resembles a nerve cell in morphology and function. It is characterized by multiple long processes that serve as conduits for its secretory product, melanin, which is passed on to the cells that comprise the fabric of the epidermis, keratinocytes. Keratinocytes as they mature become tightly associated with each other to form a highly impermeable membrane, the stratum corneum, which is the tough outermost layer of the mammalian integument. The epidermis has the paramount function to prevent entry and egress of fluid from the body; this function is served by the stratum corneum alone. The stratum corneum is composed of flattened cells that in their migration outward from the basal layer have lost their nuclei, mitochondria, and endoplasmic reticulum and consist of the fibrillar protein, keratin, combined in some fashion with lipids also synthesized within the epidermal cells. This movement outward from the basal layer to the stratum corneum is an orderly process that takes approximately 2 weeks in the adult human.9 The arrangement of flattened cells of the stratum corneum is ordered like stacks of polygonal pancakes, with a small overlap between individual cells of adjacent stacks.22
Topical insect repellents
Authors: Maibach Howard I. , Akers William A. , Johnson Howard L. , Khan A. A. , Skinner W. A.
Published: January 2016

Female mosquitoes seek man to obtain blood needed for egg maturation. In its search for a blood meal, the female mosquito is guided by several cues, most important being heat, moisture, carbon dioxide, and odor. Sight also plays an important role, especially with regard to a moving target. Repellents interfere with the mosquito's quest in a complex fashion.
Pharmacokinetics of amoxicillin
Authors: Zarowny Donald , Ogilvie Richard , Tamblyn David , Macleod Catherine , Ruedy John
Published: January 2016

Amoxicillin, a new semisynthetic penicillin, was administered in 250‐mg doses intravenously and orally to normal men. After intravenous doses, the mean alpha disposition constant was 3.994 hr‐1 and the mean beta disposition constant was 0.692 hr‐1 with a corresponding beta half‐life of 1.05 hr. The serum clearance rate was 0.264 1.kg‐1 with a volume of distribution at steady state (Vdss) of 0.311 1.kg‐1 • The mean k. of the oral dose was 1.08 hr‐1 with a lag time of 0.34 hr. Calculation of areas under individual oral and intravenous serum concentration‐time curves indicated an absolute availability of the oral dose of 88.7% (range, 70.9 to 105.5). In comparison with ampiCillin, amoxicillin is absorbed at a faster rate and more completely from the gastro‐intestinal tract and has a larger Vdss. The beta phase half‐life and serum clearance rates of the two antibiotics are similar.
Pharmacokinetics of tolbutamide: Prediction by concentration in saliva
Authors: Matin Shaikh B. , Wan Suk Han , Karam John H.
Published: January 2016

The excretion of tolbutamide in saliva of diabetic patients receiving single intravenous doses of 1 gm tolbutamide is described. Gas chromatography with electron capture was used for analysis. Pharmacokinetic parameters could be obtained from either salivary or plasma tolbutamide levels. There was a good linear relationship between tolbutamide concentration in saliva and in plasma; salivary levels were 1.2% of plasma levels. Equations are presented that account for the excretion in saliva based on extent of protein binding and degree of ionization of tolbutamide in plasma and saliva. Correlation of the saliva to plasma concentration ratio was extended to data in the literature on two other drugs.
Piribedil, a dopamine agonist, in Parkinson's disease
Authors: Sweet Richard D. , Wasterlain Claude G. , McDowell Fletcher H.
Published: January 2016

Piribedil, a dopamine agonist that is thought to act directly on the postsynaptic receptor, was adminisered orally to 32 patients with Parkinson's disease. An initial nonblind study of 12 patients showed improvement in 6, in 4 by 33% or more. Subsequently, a double‐blind trial was conducted in 20 patients. Seven improved more than 25% and 3 of these more than 50%. The mean difference between placebo and piribedil scores was 44%, significant at the 1% level. Tremor improved more than the other major criteria of parkinsonism. Adverse effects included dyskinesia, nausea, drowsiness, and confusion. Though some patients were not helped at all and adverse effects made the medicine difficult to use, the benefit of piribedil for some patients demonstrates that dopamine receptor stimulators are potentially very helpful in the treatment of Parkinson's disease.
The biochemical pharmacology of abused drugs; III. Cannabis, opiates, and synthetic narcotics
Authors: Caldwell John , Sever Peter S.
Published: January 2016

In this final part of the review, we cover the widely abused plant drugs, Cannabis obtained from the hemp plant Cannabis sativa, and the opiates, from the opium poppy Papaver somniferum. The psychoactivity of preparations of these plants has been known for a very long time. Cannabis has never found a genuine medical application for its particular psychoactivity and, although it has been in most of the world's pharmacopoeias at one time or another, there is no established medical use for it. The opiates are essential for the alleviation of severe pain and in the treatment of certain gastrointestinal disorders. Their use in the medicine of the nineteenth century was Widespread, but realization of the dangers of prolonged dosage has led to a restriction to circumstances when they are speCifically indicated. Owing to the well‐established dangers of the opiates from the viewpoint of dependence, many attempts have been made to synthesize a “safe” powerful analgesic. There has been no real success, but several such compounds have come to be abused in their own turn. The three most important of these are meperidine, methadone, and pentozocine, and these are reviewed here along with the naturally occurring opiates.
Nicotine regulation and cigarette smoking
Authors: Kozlowski Lynn T. , Jarvik Murray E. , Gritz Ellen R.
Published: January 2016

A study was conducted to determine whether there is nicotine regulation in cigarette smoking. Tar levels, which often covary with nicotine manipulations, were controlled for by the use of nicotine in chewing gums. Nicotine in cigarettes was also used for preloading. High nicotine cigarette preloads were followed by longer latencies to the next cigarette than were the low nicotine cigarette preloads. High nicotine gum preloads were followed by less puffing on the subsequent cigarettes than were the low nicotine gum preloads.
Hypnotic efficacy of diphenhydramine, methapyrilene, and pentobarbital
Authors: Teutsch Grete , Mahler Donald L. , Brown Colin R. , Forrest William H. , James Kenneth E. , Brown Byron W.
Published: January 2016

The antihistamines diphenhydramine and methapyrilene were compared with pentobarbital for hypnotic effect in two Veterans Administration Hospital populations using subjective‐response methods. In the first part of the study, 60 mg and 180 mg of pentobarbital were compared with 50 mg and 150 mg of diphenhydramine. A positive dose‐response relationship was obtained only for pentobarbital; neither dose of diphenhydramine was significantly different from 60 mg of pentobarbital for any response variable. In the second part of the study, 100 mg of pentobarbital, 50 mg of diphenhydramine, and 50 mg of methapyrilene were compared with placebo. One hundred mg of pentobarbital and 50 mg of diphenhydramine were significantly different from placebo, but 50 mg of methapyrilene was not.
Long‐term therapy of vitamin D‐resistant rickets with 25‐hydroxycholecalciferol
Authors: Puschett Jules B. , Genel Myron , Rastegar Asghar , Anast Constantine , DeLuca Hector F. , Friedman Adele
Published: January 2016

The long‐term effects of the vitamin D metabolite, 25‐hydroxycholecalciferol (25‐HCC), were evaluated in 2 children with hypophosphatemic vitamin D‐resistant rickets. Serial total balance studies demonstrated an apparent lack of correlation between the effects of the vitamin on intestinal absorption of calcium and phosphorus and both the onset of healing in 1 of the 2 patients treated with 5,000 to 7,500 u of the metabolite and the absence of demonstrable radiologic improvement in another patient in whom the final dosage was 20,000 u. per day. At first, the metabolite induced a positive calcium balance in both patients resulting largely from a reduction in intestinal calcium excretion. Despite a continued positive calcium balance, 1 of the 2 patients did not demonstrate further healing, while in the other patient healing was noted even when total calcium balance was negative. Serum phosphate levels did not return to normal in either patient, nor was phosphate excretion altered by 25‐HCC. Serum alkaline phosphatase remained elevated in both. Serum immunoassayable parathyroid hormone levels were consistently normal to high‐normal in the 2 patients throughout more than 24 months of observation. No instances of hypercalcemia and only occasional hypercalciuric episodes were noted.
Etorphine in man. II. Detectability in urine by common screening methods
Authors: Gorodetzky Charles W. , Kullberg M. Peter
Published: January 2016

A single highly euphorogenic dose of etorphine, 100 µg, was administered subcutaneously to 7 nontolerant subjects, and all urine samples were collected for 1 day prior to and 3 days following drug administration. Samples were analyzed for the presence of opiates by radioimmunoassay (Abuscreen) and homogeneous enzyme immunoassay (EMIT), with cutoffs for “positives” of 40 and 500 ng/ml, respectively. Samples were analyzed for etorphine by thin‐layer chromatography (TLC) with iodoplatinate preceded by XAD‐2 resin extraction (sensitivity = 0.2 µg etorphine/ml of urine) and by gas‐liquid chromatography (GLC) preceded by organic solvent extraction and trimethylsilyl derivatization (sensitivity = 0.1 µg etorphine/ml of urine). The last pre‐drug and first two post‐drug samples were also analyzed after acid hydrolysis by TLC and after glucuronidase hydrolysis by TLC and GLC. No sample gave a “positive” opiate result in either immunoassay, and no etorphine was detected in the TLC and GLC analyses of any urine sample. Thus, it is unlikely that the abuse of etorphine could be diagnosed by urinalysis using the common screening methods of radioimmunoassay, EMIT, TLC preceded by XAD‐2 resin extraction, or GLC preceded by organic solvent extraction and trimethylsilyl derivatization.
Elimination of procainamide in end stage renal failure
Authors: Gibson Thomas P. , Lowenthal David T. , Nelson Howard A. , Briggs William A.
Published: January 2016

To investigate the effect of end stage renal insufficiency and hemodialysis on the serum half‐life of procainamide, 500 mg of procainamide was given orally to control subjects and dialysis patients on interdialysis days. Procainamide was assayed by spectrophotometry and spectrophotojiuorometry. Mean half‐life in normal subjects was 3.2 hr by spectrophotometry and 3.5 hr by spectrophotojiuorometry. Mean half‐life in patients was 11.3 hr by spectrophotometry and 16.0 hr by spectrophotojiuorometry (p < 0.001 compared to control subjects). Half‐life of procainamide during dialysis in patients given 500 mg of procainamide 1 hr before dialysis was 4.3 hr and 9.6 hr on a nondialysis day (p < 0.001). Both methods of assay gave higher levels of procainamide when the metabolite, N‐acetylprocainamide, was present in serum and the extract allowed to stand in 1 N HCl, but spectrophotometry was less affected. Thus, end stage renal insufficiency greatly prolongs the half‐life of procainamide, procainamide is readily dialyzable, and N‐acetylprocainamide is hydrolyzed in 1 N HCI to procainamide during routine serum determinations.
Acetylation of procainamide in man and its relationship to isonicotinic acid hydrazide acetylation phenotype
Authors: Gibson Thomas P. , Matusik Jean , Matusik Edward , Nelson Howard A. , Wilkinson Joanne , Briggs William A.
Published: January 2016

To assess the extent of the acetylation of procainamide (PA) to N‐acetylprocainamide (NAPA) in man, and its relation to isonicotinic acid hydrazide (INH) acetylation phenotype, the following study was done. Fourteen subjects received 500 mg of PA . HCI orally. INH acetylation phenotype was determined by the serum half‐life of INH after 4 mg/kg of INH orally. Each urine voided for 96 hr after procainamide was saved and levels of procainamide and NAPA measured by gas‐liquid chromatography. The 14 subjects eliminated 52 ± 4% ofthe dose as procainamide and 16 ± 2% ofthe dose as NAPA. Four fast INH acetylators eliminated 23 ± 3% ofthe dose as NAPA compared to 12 ± 1% by the slow acetylators (p < 0.05). The amount of unaltered procainamide excreted by thefast and slow INH acetylators was not significantly different, 50 ± 4% and 53 ± 4%, respectively. Ofthe total amount of drug recovered in the urine ofthefast and slow INH acetylators, NAPA accountedfor 32% and 19%, respectively (p < 0.01). There appears to be a positive correlation between the ability to acetylate INH and the ability to acetylate procainamide.
Effect of glucagon on digital circulation
Authors: Bureh G. E. , Giles T. D.
Published: January 2016

The effect of glucagon on the digital circulation was studied in 7 subjects using the digital rheoplethysmograph (RPG). Rheoplethysmograms were continuously recorded while glucagon (0.1 to 2.0 mg) was injected into the brachial artery of the same extremity being studied with the RPG. The injection of glucagon was associated with a “tingling” or “burning” sensation in 3 subjects. The initial response, which was maximal 8 to 27 sec after the injection of glucagon, was constriction of the arteries, veins, and A‐V shunts. The late response consisted of reopening of the arteries and veins. However, in some patients, there was RPG evidence of persistent constriction of the A‐V shunts. It is suggested that the late response is similar to that observed in reactive hyperemia and following injection of bradykinin and, therefore, may be related to local release of vasoactive substances by glucagon.
Unaltered metabolism of antipyrine and tolbutamide in fasting man
Authors: Reidenberg Marcus M. , Vesell Elliot S.
Published: January 2016

Effects of fasting on the metabolism and distribution of antipyrine and tolbutamide were studied in 13 obese, but otherwise healthy, volunteers. Only 6 of the 13 subjects decreased their metabolic clearance rate (MCR) during fasting; no significant change occurred during fasting in the mean MCR of either drug. These results are in contrast with reported changed rates of drug metabolism in fasting experimental animals. The apparent volume of distribution (aVd) of antipyrine decreased during fasting in each of 7 subjects receiving oral test doses of antipyrine; the mean control value ± standard deviation was 61 ± 16 l, whereas during fasting the mean became 52 ± 17 l. The aVd ± SD of tolbutamide decreased in 4 of the 6 volunteers receiving intravenous test doses of tolbutamide; the mean control value in these 6 volunteers was 8.3 ± 1.7 l; during fasting it was 7.4 ± 1.91.
Carbenicillin therapy in patients with normal and impaired renal function
Authors: Latos Derrick L. , Bryan Charles S. , Stone William J.
Published: January 2016

Optimum therapy with carbenicillin entails the use of high serum concentrations and the risk of significant dose‐related toxicity. We report a study of the serum clearance method of dose adjustment of carbenicillin in patients with normal and impaired renal function. This method was found to provide serum concentrations considered to be satisfactory in every instance, by either constant‐rate or intermittent infusion, and should enable greater precision in the use of the antibiotic. Implications of these findings aimed at providing dosage schedules for patients with renal failure are discussed
Interactions in man of delta‐9‐tetrahydrocannabinol; II. Cannabinol and cannabidiol
Authors: Hollister Leo E. , Gillespie Hampton
Published: January 2016

Oral doses of delta‐9‐tetrahydrocannabinol (THC) 20 mg, combined with placebo or with 40 mg doses of cannabinol (CBN) and cannabidiol (CBD), were given to volunteers. The combination of THC with CBN produced no detectable changes in the quality, intensity, or duration of the effects of THC alone. The THC‐CBD combination tended to delay onset and prolong effects of THC, while making them somewhat more intense. Even this interactive effect was slight, providing no reason to abandon the current practice of basing doses of marihuana for clinical studies solely on THC content.
Effect of dosage regimen on natriuretic response to furosemide
Authors: Wilson T. W. , Falk K. J. , Labelle J. L. , Nguyen K. B.
Published: January 2016

We have examined the differences in urinary excretion of water, sodium, potassium, chloride, urea, and creatinine produced by different dosage regimens of furosemide in normal volunteers. Three oral dosage regimens were compared: 20 mg daily, 20 mg twice daily, and 40 mg daily, Furosemide, 20 mg, did not produce a significant weight loss, diuresis, or natriuresis in 12 normal subjects. With 40 mg there was a significant weight loss, diuresis, natriuresis, and chloruresis over 24 hr. Comparison of the divided regimen with 40 mg daily revealed significantly greater sodium excretion, and chloride excretion with 20 mg twice daiiy, The divided dosage regimen produced a different pattern of diuresis witn most of the sodium and water excretion occurring after the second dose. These differences in response to different regimens are predictable from pharmacokinetic considerations and may have clinical significance.
EPEG, a new antineoplastic epipodophyllotoxin
Authors: Creaven Patrick J. , Allen Larry M.
Published: January 2016

Nine patients were studied with tritium‐labeled EPEG, a new epipodophyllotoxin antineoplastic agent. Four patients received 220 and 5 received 290 mg/sq m body surface area intravenously in 500 ml in 1 hr. Postinfusion plasma decay was biphasic with mean values for the parameters at 220 mg/sq m, A, 25.8 µglml; B, 3.35 µg/ml; α, 0.50 hr−1; β, 0.074 hr−1, and mean values at 290 mg/sq. m, A, 33.7 µg/ml; B, 4.35 µg/ml; α, 0.36 hr−1; ², 0.066 hr−1, Mean volume of distribution was 32.07% of body weight. Urinary recovery was 43.5%, of which 66.8% was unchanged drug. Penetration of drug into the cerebrospinal fluid was poor. The results indicate that both renal excretion and metabolism are important for elimination of the drug.
Elimination of antipyrine from saliva as a measure of metabolism in man
Authors: Welch R. M. , DeAngelis R. L. , Wingfield M. , Farmer T. W.
Published: January 2016

The salivary half‐life of antipyrine was used as a convenient procedure for estimating the relative rates of drug metabolism in man. The concentration ratio of antipyrine in plasma and saliva was one over a 24‐hr period following the oral or parenteral administration of the drug to man and rat. Phenobarbital, a known stimulator of drug metabolism in animals and man, increased markedly the elimination of antipyrine from saliva of rats, while SKF‐525A, a potent inhibitor of drug metabolism, prolonged the elimination of antipyrine from rat saliva. In addition, the known sex difference in the metabolism of drugs in the rat was detected by measuring the elimination rate of antipyrine from saliva of male and female rats. The clinical application of the procedure indicated that a group of epileptic patients treated with anticonvulsants for more than 2 mo had a mean antipyrine salivary half‐life of 4 hr, whereas a mean half‐life of 13 hr was found in a group of normal volunteers. The results show that the elimination rate of antipyrine from saliva is a useful index of drug metabolism in animals and man.
Suppression of cortisol by a progestational steroid, melengestrol
Authors: Nugent Charles A. , Bressler Rubin , Kayan Sabih , Worrall Paul
Published: January 2016

Melengestrol, a steroid with progestational activity but with a structure that does not resemble that of cortisol, suppresses plasma cortisol in humans with a potency 1/40th that of dexamethasone. The 6α‐methyl and 17α‐acetoxy substituents and the 6,7 double bond of melengestrol acetate are known to slow the metabolism of similar steroids. Insertion of a 6a‐methyl group markedly increases the glucocorticoid activity of 17α‐OR‐progesterone. The glucocorticoid activity of melengestrol is presumably attributable to the large dose administered in our study, its slow metabolism and limitations of the specificity of glucocorticoid tissue receptors.
Interaction of sudoxicam and aspirin in animals and man
Authors: Wiseman Edward H. , Chang Vi‐Han , Hobbs Donald C.
Published: January 2016

In rats, both the plasma concentrations and the anti‐inflammatory activity of sudoxicam are depressed by concurrent administration of aspirin, being similar to that reported for other nonsteroidal agents, whereas, in man and monkey, plasma concentrations of sudoxicam are not affected by concurrent administration of aspirin. In this respect sudoxicam differs from such other nonsteroidal anti‐inflammatory agents as indomethacin and naproxen.
Bioavailability and single‐dose pharmacokinetics of intramuscular phenytoin
Authors: Kostenbauder Harry B. , Rapp Robert P. , McGovren J. Patrick , Foster Thomas S. , Perrier Donald G. , Blacker H. Martin , Hulon Walter C. , Kinkel Arlyn W.
Published: January 2016

Comparison of phenytoin plasma concentrations in an intravenous and intramuscular crossover study in 12 healthy ambulant, male subjects indicates that phenytoin administered intramuscularly is absorbed over a period of approximately five days. A model simulating precipitation and redissolution of the drug at the injection site has been shown to satisfactorily fit observed plasma concentration data following intramuscular administration. It is proposed that this model will be useful in the selection of an appropriate dosing regimen in situations in which intramuscular administration of phenytoin is indicated.
Biopharmaceutic influences on the anticholinergic effects of propantheline
Authors: Gibaldi Milo , Grundhofer Barbara
Published: January 2016

With reduction of salivary flow rate as an index of anticholinergic response, 3 subjects manifested demonstrable effects shortly after ingestion of 15‐mg doses of propantheline in conventional tablets. Ingestion of this dose immediately after a standardized breakfast substantially reduced the anticholinergic effects. In 1 subject, a dose‐response relationship was noted after 15 mg and 30 mg doses under both fasting and fed conditions, but at each dose level the influence of food was clear. Administration of a 30‐mg dose of propantheline in a commercially available “prolonged‐acting” tablet induced little if any anticholinergic effects; in 2 subjects, marginal but fleeting indications of salivary suppression were noted about 4 hr after ingestion, while no effects were observed in the third subject (even after 2 “prolonged‐acting” tablets).
Occurrence, transport, and storage of octopamine in human thrombocytes
Authors: Murphy Dennis L. , Cahan David H. , Molinoff Perry B.
Published: January 2016

3H‐octopamine was found to be accumulated in human platelets, achieving a maximum concentration gradient of 30:1. Its accumulation was partially inhibited by reserpine, imipramine, serotonin, ouabain, dinitrophenol, and iodoacetate. When octopamine was added to platelet preparations, it led to a decrease of both endogenous and 14C‐serotonin. To determine whether octopamine accumulates in human platelets in vivo, preparations from 6 patients receiving monoamine oxidase inhibitors and 17 control subjects were assayed enzymatically for octopamine. Octopamine was detectable in all of the drug‐treated patients, averaging 0.45 ± 0.06 ng/mg protein, while only 4 of the 17 control subjects had detectable (>0.05 ng/mg protein) platelet octopamine. Although much lower than platelet serotonin levels, these octopamine levels are in the range of those reported for platelet norepinephrine and epinephrine.
Absolute bioavailability in man of N‐acetylprocainamide determined by a novel stable isotope method
Authors: Strong John M. , Dutcher John S. , Lee Woong‐Ku , Atkinson Arthur J.
Published: January 2016

Absorption of a single oral dose of N‐acetylprocainamide (NAPA) was studied in 3 normal subjects. Approximately 85% of the oral dose was absorbed and peak plasma NAPA concentrations were reached in 45 to 90 min. In 2 subjects, NAPA was absorbed at a fast initial rate, then more slowly, prolonging the apparent elimination phase half‐life. Absolute bioavailability was determined by a new stable isotope method that entailed intravenous injection of NAPA− 13C at the same time that an unlabeled NAPA capsule was given orally. Plasma levels and urine excretion of both compounds were determined by mass fragmentography. Bioavailability was assessed by deconvoluting the plasma level vs time curves resulting from intravenous and oral drug administration, and also by comparing the relative percentage of NAPA and NAPA− 13C excreted unchanged in the 24 hr after simultaneous administration.
Quinine‐induced alterations in drug disposition
Authors: Berlin C. M. , Stackman J. M. , Vesell E. S.
Published: January 2016

In normal volunteers, chronic quinine administration shortened plasma antipyrine half‐life and significantly increased the intra individual correlation between the disposition of quinine and antipyrine. Decreased plasma antipyrine half‐life appears to be due to a quinine‐induced enhancement of antipyrine metabolism. A dose‐dependent prolongation of plasma quinine half‐life was observed and attributed primarily to an increased apparent volume of distribution of quinine, although our data did not permit separation of an effect on quinine metabolism from an effect on quinine distribution between the peripheral and central compartments. Plasma protein binding of quinine was similar at both the low and high doses of quinine. Studies in dogs given quinine intravenously revealed a biphasic plasma decay curve compatible with a 2‐compartment open model for quinine disposition. Dose dependence of plasma quinine half‐life in the dog after intravenous quinine eliminated altered gastrointestinal absorption of quinine as a cause for the dose dependence of plasma quinine half‐life. These studies illustrate the importance of such conditions as dose and time of administration in determining the type and magnitude of interaction observed between drugs.
Fluroxene toxicity induced by phenobarbital
Authors: Munson Edwin S. , Malagodi Marjorie H. , Shields Robert P. , Tham Min K. , Fiserova‐Bergerova Vera , Holaday Duncan A. , Perry Joel C. , Embro William J.
Published: January 2016

Because of reports of fluroxene toxicity in man, the effect of phenobarbital treatment on the toxicity and metabolism of fluroxene was studied in 9 rhesus monkeys. Six monkeys that were exposed to a mean calculated alveolar fluroxene concentration of 5.8% for 4‐hr periods up to a total of 16 hr showed no evidence of toxicity. Two animals were sacrificed after a single 4‐hr exposure to obtain control measures of fluroxene metabolites in tissues. Four monkeys that had previously survived received exposures to fluroxene and 3 monkeys that had no exposure to fluroxene died during fluroxene anesthesia after treatment with phenobarbital (mean time, 3 hr). Toxicity was manifested by arterial hypotension, pulmonary edema, and arterial hypoxemia. Phenobarbital treatment enhanced production of fluroxene metabolites, including the highly toxic trifluoroethanol. Concentrations of trifluoroethanol in mixed‐expired gas, blood, and urine, and of total nonvolatile fluorine in blood, urine, and tissues of animals treated with phenobarbital were 2 to 10 times as high as in control animals. The results suggest that the rhesus monkey is a valuable model for the study of fluroxene pharmacology and that inclusion of an enzyme‐inducing challenge in the evaluation of potential toxicity of other anesthetics seems warranted.
Calcium balance in drug‐induced osteomalacia: Response to vitamin D
Authors: Peterson Patti , Gray Phillip , Tolman Keith G.
Published: January 2016

The effect of oral vitamin D3 therapy on calcium balance was compared in 18 institutionalized subjects with drug‐induced osteomalacia and in 18 similar subjects without osteomalacia. The subjects with osteomalacia were receiving standard doses of phenytoin and phenobarbital. Diagnosis of osteomalacia was based on low serum calcium and phosphorus, elevated alkaline phosphatase, and appropriate roentgenographic bone changes. The study group achieved positive calcium balance at approximately 975 IU of vitamin D3 per day, while the control group achieved positive calcium balance at approximately 380 IU of vitamin D3 per day. The difference is highly significant (p < 0.001). These data support previous observations that the osteomalacia of patients receiving anticonvulsant drugs is related to the drugs and that these patients require supplemental doses of vitamin D.
Influence of magnesium and aluminum hydroxide mixture on chlordiazepoxide absorption
Authors: Greenblatt David J. , Shader Richard I. , Harmatz Jerold S. , Franke Kate , Koch‐Weser Jan
Published: January 2016

Ten healthy male subjects ingested 25 mg of chlordiazepoxide hydrochloride (Librium) with 100 ml of water or with 100 ml of magnesium and aluminum hydroxide (Maalox) in a single‐dose crossover study. Multiple venous blood samples drawn during the first 24 hr after each dose were assayed for concentrations of chlordiazepoxide and its major metabolite, desmethylchlordiazepoxide. The antacid prolonged the mean chlordiazepoxide absorption half‐time from 11 to 24 min, and in 6 of 10 subjects delayed achievement of the peak blood concentration by from 0.5 to 3.0 hrs. The formation of desmethylchlordiazepoxide was also slowed. The areas under the 24 hr blood concentration curve for chlordiazepoxide and for its metabolite were not influenced by the antacid. The apparent elimination half‐life of chlordiazepoxide (8.4 and 8.2 hr) was not significantly affected. Administration of chlordiazepoxide with antacid reduces the rate of its absorption but does not alter the completeness of absorption or the apparent rate of elimination.
Plasma levels and antidepressive effect of imipramine
Authors: Gram Lars F. , Reisby Niels , Ibsen IIse , Nagy Adam , Dencker Sven J. , Bech Per , Petersen Gorm Odden , Christiansen Johannes
Published: January 2016

The relationship between the antidepressive effect of imipramine and the plasma concentrations of imipramine and the active metabolite desipramine was studied in 24 patients suffering from endogenous depression. After a placebo period of 7 days, the patients received imipramine, 75 mg 3 times a day. The dose was reduced in patients with pronounced side effects. Blood samples for drug assay were drawn in the morning, 15 hr after the last drug intake. Imipramine and desipramine in plasma were assayed by quantitative in situ thin‐layer chromatography. Individual variations in plasma concentration were 20‐ to 30‐fold in both imipramine and desipramine. Severity of depression was assessed on the Hamilton Rating Scale (HRS). Eleven of 12 patients who responded satisfactorily to the treatment (H RS post‐treatment score <8) had plasma concentration of imipramine ≧45 µg/L, and desipramine >75 µg/L, whereas the 12 patients not responding satisfactorily (post‐treatment score on HRS ≧8) all had concentrations of imipramine or desipramine or both below these limits.
Acebutolol: Basis for the prediction of effect on exercise tolerance
Authors: Biron Pierre , Tremblay Gerard
Published: January 2016

Twelve unselected males suffering from documented coronary insufficiency and moderately severe angina were submitted to graded multistage treadmill exercise testing on 3 separate days, 3.5 hr after a single dose of 0, 200, or 400 mg of acebutolol, a cardioselective beta blocker. Control measures included random allocation of 2 patients to each of 6 balanced sequences of administration, standardized double‐blind conditions, and variance analysis for Latin‐square design with repeated measures on each subject. Performance was evaluated by measuring time elapsed until anginal pain, peak heart rate, peak product of heart rate and blood pressure, and peak oxygen consumption. Mean values for all criteria were significantly altered by 400 mg of acebutolol. Seven out of twelve patients were classified as responders (i.e., exercise duration increased 100% or more). The response after acebutolol was correlated with the performance on placebo in the case of exercise duration, peak heart rate, and peak product of heart rate and blood pressure. It is concluded that: (1) performance criteria are useful predictors of response to beta blockade and (2) acebutolol is a potent antianginal agent when judged by an objective treadmill exercise test.
Disposition of digitoxin in renal failure
Authors: Vöhringer H. F. , Rietbrock N. , Kuhlmann Spurny, J. , Hampl H. , Baethke R.
Published: January 2016

The disposition of digitoxin was studied for a period of 8 days in 6 uremic patients given a single oral dose of 1 mg 3 H‐digitoxin. in plasma, the time‐course of radioactivity indicated a diminished absorption velocity of tritium compared to that of control subjects already reported20 and, after reaching of a pseudostate‐equilibrium at 24 hr, an exponential decline with a mean half‐life of 8.0 days. in urine, smaller amounts of tritiated compounds were eliminated in uremic patients (8.7% of the dose) than in controls (22.5%). The average fecal excretion of digitoxin and its metabolites was not significantly increased. Chloroform extraction and thin‐layer chromatography in plasma, urine, and feces suggested no qualitative alteration in the metabolism of digitoxin. Calculations of the total body tritium content (body stores) after each 24‐hr interval and its pharmacokinetic behavior showed that the elimination of digitoxin is determined by the transfer constant from tissue to plasma. The differences in elimination kinetics of digitoxin and its metabolites of uremic patients and healthy subjects were not significant
Biliary excretion of digoxin in man
Authors: Caldwell James H. , Cline Charles T.
Published: January 2016

We have measured the biliary excretion of 3 H‐digoxin in normal subjects by intestinal perfusion methods which impose minimal interruption of the enterohepatic circulation. In contrast to data obtained in patients with liver disease and postoperative patients with biliary fistulas. our data show that about 30% of an intravenous dose of 3H‐digoxin reaches the digestive tract in 24 hr. Most of the excreted radioactivity is chloroform‐soluble and presumably reabsorbable and most of this fraction is probably biologically active drug. The results suggest that (1) consideration of hepatobiliary function may be relevant in observations regarding digoxin pharmacokinetics and that this route may be exploited in trials of therapy designed to shorten the duration of digoxin intoxication.
Pharmacokinetics of methotrimeprazine after single and multiple doses
Authors: Dahl Svein G.
Published: January 2016

Concentrations of methotrimeprazine and a metabolite, methotrimeprazine sulfoxide, were measured in plasma after a single intramuscular dose and after single and multiple oral doses of methotrimeprazine. The highest plasma concentrations of methotrimeprazine were found 30 to 90 min after intramuscular injection, and 1 to 3 hr after oral administration. On average 50% of orally administered drug reached the general circulation as unchanged methotrimeprazine. The apparent volume of distribution (V β) was 23 to 42 L/kg body weight, and the biologic half‐life, 15 to 30 hr. The sulfoxide could not be traced in plasma after a 25‐mg intramuscular dose, but was found in higher plasma concentrations than the unmetabolized drug after single and multiple oral doses. This could be due to oxidation of the drug either in the gastrointestinal lumen or in the intestinal wall, or during its first passage through the liver. The apparent half‐life of the sulfoxide was on average 30 % shorter than the half‐life of methotrimeprazine.
Effects of cardioselective beta adrenoceptor blockade on specific airways resistance in normal subjects and in patients with bronchial asthma
Authors: Singh Bramah N. , Whitlock Robert M. L. , Comber Russell H. , Williams Faith H. , Harris Edward A.
Published: January 2016

The effects of single oral doses of the cardioselective beta adrenoceptor blocking drugs, metoprolol and tolamolol, on specific ainvays resistance (SRaw) were compared with those of propranolol and practolol in 6 healthy volunteers and in 12 patients with bronchial asthma. Whole‐body plethysmography was used to measure SRaw and the blocking potency of different antagonists assessed by the degree of inhibition of tachycardia due to exercise on a treadmill. The changes correlated with plasma drug levels. Propranolol and practolol were measured fluorometrically and metoprolol by electron‐capture gas‐liquid chromatography. In normal subjects, about 30% reduction in exercise‐induced tachycardia resulted from single doses of 80 mg propranolol (plasma levels, 50.3, SD, 29.5 to 60.8, SD, 26 ng/ml), 250 mg practolol (plasma levels, 1.05, SD, 0.32 to 1.10, SD, 0.55 μg/ml), 100 mg metoprolol (plasma levels, 137, SD, III to 152, SD, 1OO ng/ml), and 1OO mg tolamolol. In patients, these doses of the drugs produced significant increases in SRaw. These increases were greater than those after placebo but significantly so only during the peak effect 1 hr after propranolol. Compared with changes after placebo, significant effects on SRaw were also found in 3 patients given 200 mg of tolamolol. None of the drugs had a significant effect on SRaw in normal subjects. It is concluded that metoprolol, practolol, and tolamolol may impair ventilatory function in asthmatics less than propranolol and that at high doses this difference may not be demonstrable.
Serum protein binding as a determinant of warfarin body clearance and anticoagulant effect
Authors: Vacobi Avraham , Udall John A. , Levy Gerhard
Published: January 2016

The serum protein binding and elimination kinetics of warfarin were determined in 31 patients with cardiovascular disease who were taking warfarin regularly. The free fraction of warfarin in the serum ranged from 0.00436 to 0.0189, indicating 98.11% to 99.56% protein binding. There was no apparent relationship between the extent of protein binding of warfarin and the concentration of albumin or total protein in the serum. The estimated total body clearance of warfarin in the patients ranged from 1.16 to 4.35 ml/hr/kg of body weight and correlated significantly with the free fraction of warfarin in serum. This correlation has been predicted on theoretical grounds and shows that serum protein binding is a major determinant of the elimination kinetics of warfarin in man and an important cause of interindividual variations in its body clearance. The inter individual variation of free warfarin concentrations in the serum of patients with similar prothrombin times was somewhat smaller than the variations in total serum‐warfarin concentrations and in the daily dose of warfarin. There was no correlation between prothrombin time and the concentration of free warfarin in serum, indicating that variables other than protein binding also affect the anticoagulant response of patients.
Propoxyphene and norpropoxyphene: Influence of diet and fluid on plasma levels
Authors: Welling P. G. , Lyons L. L. , Craig W. A.
Published: January 2016

The influence of various test meals and ingested fluid volumes on the bioavailability and pharmacokinetics of propoxyphene and its major metabolite norporpoxyphene has been studied in healthy human subjects. The absorption of drug was delayed by all test meals, but the overall efficiency of absorption was either not affected or was slightly increased. Increased fluid volume intake decreased propoxyphene bioavailability. Plasma levels of metabolite correlated well with levels of unchanged drug, particularly in the first 2 hr after dosing, but were not markedly influenced by treatments.
Pivampicillin and ampicillin in bile, portal and peripheral blood
Authors: Lund Birger , Kampmann Jens P. , Lindahl Finn , Hansen Jens Mølholm
Published: January 2016

In 7 patients with a catheter in the portal vein and a T tube in the common bile duct, the concentration of unhydrolyzed pivampicillin and of ampicillin was measured simultaneously in portal and peripheral blood and in bile after oral administration of 700 mg pivampicillin. In both portal and peripheral circulation the concentration of unhydrolyzed pivampicillin was always less than 1% of the levels of ampicillin, indicating the effectiveness of the intestinal mucosa in the hydrolysis of pivampicillin. Evidence for the ability of the liver to excrete ampicillin against a concentration gradient into the bile was established by direct measurements. Only about 1% of the dose given could be recovered in the bile. There was an unexplained reduction of about 70% in the absorption of the drug induced by the catheter itself.
Session V. Regulatory differences and similarities; Drug regulation in the United Kingdom
Authors: Dollery Colin T.
Published: January 2016

The British system under the Medicines Act by which new drug applications are evaluated is described in a step‐by‐step manner from submission of application to the issuance of a clinical trial certificate by the licensing authority, At the end of a period of clinical trials the submission is brought backfor a produet license. Once a drug is marketed it falls within the purview of the adverse reaction monitoring group of the Committee on Safety of Medicines (CSM). Arecent innovation is “monitored release,” by which, for a period of time after marketing, case reports are submitted by the pharmaceutical company to the CSM. The advantages of the British system are: (1) the final licensing decisions being made by the academic members of the Committee means that they are insulated from commercial and political pressures, and are addltionaliy reached without undue delay; (2) academic members are not permitted to be retained as consultants to the industry on a long‐term basis; (3) evaluation solelyon British. studies is not obligatory‐foreign studies are also acceptable. Weaknesses in the system are: (1) reeruitment of people experienced in pharmacology and therapeutics is difficult; (2) there is an inordinate work load on the academic members of the Main Committee and Subcommittees. lmportance of an effective monitoring in the postmarketing stage is emphasized, because the long‐term judgment must necessarily be based on wide experience in the filed. The multiplication of the same of similar drugs is deplored, and innovative efforts in the quest for new drugs, especially for rare diseases, are to be encouraged.
Regulatory differences and similarities: Systems in Japan
Authors: Sakuma Akira
Published: January 2016

The historic steps that led up to the present federal drug regulations in the United States are outlined as a background to the development of the current drug regulatory system in Japan, consisting of the procedures for approval of new drugs, of double‐brand naming, by which the same drug under different names can be sold as ethical or over‐the‐counter (OTC). The more recent provisions for re‐evaluation of drugs, the mechanism for monitoring adverse reactions, and the dissemination of the collected information are described. The prescription habits of physicians, the influence of the health insurance systems on these, and the strikingly high level of drug consumption in Japan, as compared with those in other industrial countries, are discussed and illustrated graphically.
A sliding intravenous dose schedule for clonidine in hypertensive patients
Authors: Velasco Manuel , Gallardo Edilio , Plaja Joaquin , Guevara José
Published: January 2016

Cumulative doses of clonidine were administered intravenously to 8 hypertensive patients to a maximal dose of 100 μg or a blood pressure fall to normal. There was a reduction in mean arterial pressure of 35.6 mm Hg (p < 0.001), accompanied by a decrease in heart rate of 11.8 bpm (p < 0.001). There was also a significant linear relationship between the reduction in blood pressure and the intravenous log dose of clonidine with a 6.5‐fold difference in Δ MAP/dose potency. There was no correlation between the baseline blood pressure and the slopes of dose‐blood pressure response curves or the reduction in mean arterial pressure; the rate of the decline of the hypotensive effect of clonidine varied widely between patients and was not related to baseline blood pressure.
Loading and conventional dose therapy with phenytoin in children: Kinetic profile of parent drug and main metabolite in plasma
Authors: Wilson J. T. , Höjer B. , Rane A.
Published: January 2016

Epileptic children were given phenytoin (DPH) in loading (four doses of 4.4 to 6.3 mg/kg/dose given 8‐hourly and then 6 mg/kg/day) or conventional (5 to 9 mg/kg/day) doses. Plasma levels of DPH and its main metabolite (p‐OH‐DPH) were measured by a mass fragmentographic technique. Plasma DPH levels of >10 μg/ml were achieved within 16 to 38 hr in the children given loading doses and within 5 days in the conventionally dosed children. No immediate side effects were noted, but within 8 to 10 days 9 of 13 children developed a generalized skin rash. Plasma p‐OH‐DPH (free or conjugated) paralleled DPH during the accumulation phase but not during DPH elimination. The ratio of metabolite to DPH in plasma showed both an interindividual variation and an inverse relation to the level of DPH. Identical twins in the study had a similar ratio and plasma level‐time course profile. It is concluded that the loading dose regimen achieves an appropriate plasma level of DPH rapidly, that saturation kinetics are operative for p‐OH‐DPH formation, that the ratio of metabolite to DPH in plasma is an individual characteristic in children, and that further studies on the delayed toxicity are needed before the loading dose regimen can be recommended.
Influence of acute viral hepatitis on disposition and pharmacologic effect of warfarin
Authors: Williams Roger L. , Schary William L. , Blaschke Terrence F. , Meffin Peter J. , Melmon Kenneth L. , Rowland Malcolm
Published: January 2016

Five patients received a small oral dose of warfarin during and after recovery from acute viral hepatitis. Mean (± SD) clearance, volume of distribution, and half‐life of the drug were 6.1 ± 0.9 mllhrlkg, 0.09 ± 0.04 L/kg, and 23 ± 5 hr, respectively, during the acute period. After apparent recovery, observed values were 6.1 ± 0.7 ml/hr/kg, 0.21 ± 0.02 L/kg, and 25 ± 3 hr. These differences were not significant. Pattern of renal elimination of warfarin metabolites and drug protein binding did not change between the two phases. During the acute period of illness, prothrombin time increased in 2 of the 5 subjects, but remained within normal limits in all participants during the recovery period. This study shows that warfarin disposition may not change as a consequence of mild or moderate hepatic impairment.