bluuebunny/crossref_metadata_2025 huggingface dataset:
Methyldopa as an adjunct to levodopa treatment of Parkinson's disease
Authors: Sweet Richard D. , Lee John E. , McDowell Fletcher H.
Published: January 2016

Chronic levodopa treatment of 22 patients with Parkinson's disease was supplemented with methyldopa, an inhibitor of dopa decarboxylase, in doses from 125 to 750 mg. daily. Improvement in maior parameters of Parkinson's disease was seen in 14 patients, 10 of whom had had troublesome fluctuations in response to levodopa. Seven patients were still improved after 20 weeks. Methyldopa worsened dyskinesia in 14 patients, did not affect nausea, and was associated with agitation in 6 patients. Blood pressure did not change significantly. Although inhibition of dopa decarboxylase is methyldopa's most likely mechanism of action, methylated metabolites may also play a role. Methyldopa is a tolerable adiunct to levodopa therapy for Parkimon's disease for patients with rapid fluctuations in motor status.
Amantadine and levodopa in the treatment of Parkinson's disease
Authors: Walker Jonathan E. , Potvin Alfred , Tourtellotte Wallace , Albers James , Repa Brian , Henderson William , Snyder Dorothy
Published: January 2016

Twenty‐eight ambulatory patients with Parkinson's disease participated in successive double‐blind crossover trials of amantadine and levodopa. A comprehensive battery of tests was used to evaluate patient preference, neurologic symptoms and signs, quantitative neurologic performance, practical skills used in daily living, and neuropsychological performance. These permitted differential assessment of specific areas of function affected. Levodopa ameliorated functional disabilities, tremor, and loss of associated movements. It also improved grip strength, foot speed, foot coordination, gait, and several skilled activities more than did amantadine. The combination of levodopa and amantadine was more effective than levodopa alone in the management of total functional disability, tremor, and gait and in tests of grip strength, finger coordination, tracking, and tandem gait, as well as in the practiced skills of zipping, cutting, and opening a door. One neuropsychologic test‐picture completion‐was also better on the combination. The safety of the combination was affirmed and the relative efficacy quantitated.
Evaluation of nalbuphine for abuse potential
Authors: Jasinski Donald R. , Mansky Peter A.
Published: January 2016

Nalbuphine is a narcotic antagonist and analgesic. A dose of 8 mg. per 70 Kg. of nalbuphine in man produces subjective effects which resemble those of 10 mg. per 70 Kg. of morphine. Nalbuphine, in doses of 24 and 72 mg. per 70 Kg., produces mild effects which more closely resemble those of nalorphine. Nalbuphine is ¼ as potent as nalorphine in precipitating abstinence in subjects dependent on 60 mg. of morphine per day. Chronic administration of nalbuphine produces physical dependence which resembles that produced by pentazocine, since it has elements of both morphine and nalorphine dependence. It is concluded that nalbuphine has an abuse potential which approximates that of pentazocine, but equianalgesic doses of nalbuphine produce less nalorphine‐like effects than does pentazocine.
Evaluation of muscle relaxants in tetanus
Authors: Tikare Satyanarayana K. , Krishnamurthi Sankaran , Dasgupta Debajyoti , Tikare Snehalata
Published: January 2016

A new but simple and objective method of assessment of the muscle relaxant effect of drugs in tetanus, with the use of ventilatory lung function tests, has been described. The vital capacity and the tidal volume values were significantly lower in patients with tetanus compared to normal control values. The vital capacity, tidal volume, inspiratory reserve volume, and expiratory reserve volume were measured in 15 patients with tetanus before and after parenteral administration of chlorpromazine, phenobarbital, and meprobamate. There were significant increases in ventilatory function after each drug. This effect can be attributed to the muscle relaxant properties of these drugs in tetanus.
XIV. The purposes of prognostic stratification
Authors: Feinstein Alvan R.
Published: January 2016

The Eastern Research Support Center and the Department of Medicine of the West Haven Veterans Administration Hospital, and the Departments of Medicine and Epidemiology of the Yale University School of Medicine
Effect of activated charcoal on aspirin absorption in man Part I
Authors: Levy Gerhard , Tsuchiya Tamehiro
Published: January 2016

The effect of activated charcoal (AC) on the gastrointestinal absorption of aspirin teas determined quantitatively in adult volunteers from the amount of total salicylates excreted in the urine. If administered promptly and in sufficient quantity, AC has a significant inhibitory effect on the absorption of aspirin from solution, conventional tablets, enteric coated tablets, and sustained‐release tablets. This effect is increased with an increaiing dose of AC, decreased as the time interval between aspirin and AC administration increases, and decreased by the presence of food in the gastrointestinal tract. There is appreciable desorption of aspirin from AC in the gastrointestinal tract, and therefore, it is necessary to use relatively large doses of the adsorbent in the initial treatment of accidental aspirin poisoning. The efficacy of AC increases with increasing dose at a constant aspirin‐AC dose ratio of 1:10. AC will reduce aspirin absorption even if administered three hours after mpirin ingestion, provided that the drug is still in the gastrointestinal tract at that time.
The acute effects of metolazone on electrolyte and acid excretion in man
Authors: Smiley Joseph W. , Onesti Gaddo , Swartz Charles
Published: January 2016

The acute effects of oral metolazone were studied in 10 normal volunteers. During hydropenia, natriuresis was maximal in 1 ½ to 3 hours. Na excretion increased by a mean of 196 µEq per minute, Cl by 385 µEq per minute, K by 9.6 µEq per minute, free water reabsorption (TcH2O) by 1.2 ml. per minute, Ca by 0.4 µEq per minute, Mg by 0.4 µEq per minute, and P by 4.2 µEq per minute. During water diuresis, natriuresis was maximal in 11½ to 3 hours. Na excretion increased by 234 µEq per minute, Cl by 395 µEq per minute, K by 4.4 µEq per minute, Ca by 0.2 p.Eq per minute, Mg by 1.1 µEq per minute, P by 8 µEq per minute, and urine flow by 0.9 ml. per minute. Free water clearance (CH2o) decreased by 1.4 ml. per minute. Urine pH decreased as titratable acidity increased. NH4 and HCO3 did not change significantly. A distal site of action is suggested by the decreased CH2o associated with an insignificant rise in urine volume. Associated proximal effect is suggested by the increased TcH2O and the significant increase in P excretion during hydration. The decrease in urine pH and the absence of significant bicarbonaturia are evidence against carbonic anhydrase inhibition. Metolazone produced no change in glomerular filtration rate or renal plasma flow, which suggests that metolazone may somehow alter renovascular resistance at the time of maximal diuresis.
Pharmacokinetics of theophylline; Application to adjustment of the clinical dose of aminophylline
Authors: Jenne J. W. , Wyze E. , Rood F. S. , MacDonald F. M
Published: January 2016

On a multiple‐dose schedule of oral aminophylline (200 to 300 mg. every 6 hours) “trough” levels of serum theophylline in 83 patients ranged from 2.9 to 32.6 µg per milliliter. Levels usually remained in the same range for each individual. Kinetic studies demonstrate dependence of the mean serum level during multiple dosing on the intravenous theophylline half‐life. Theophylline renal clearances are small and constant. Thus, wide variations in metabolism appear to be chiefly responsible. Specific studies are needed to document this and to assess the contribution of absorption variables. Persistent nausea, vomiting, or anorexia were common with trough levels over 20 flg per milliliter but were not seen when trough levels were under 13 µg per milliliter. This suggests that these gastrointestinal side effects usually arise by some mechanism mediated through serum theophylline levels rather than from direct irritation of the gastric mucosa. Serial airway resistances in 7 asthmatic patients following a large single oral dose of aminophylline indicated that the minimum theophylline level required for maximum bronchodilator effect ranged between eight and 20 µg per milliliter. To achieve trough concentrations of 10 to 20 µg per milliliter, final dosage adjustments ranged from 400 to 3,200 mg. of aminophylline per 24 hours, averaging 1,200 mg. General guidelines are offered for aminophylline dose adjustment.
Levodopa and pressor amine sensitivity in parkinsonism
Authors: Reid John L. , Caine Donald B. , George Charles F. , Vakil Sarosh D.
Published: January 2016

Departments of Medicine and Clinical Pharmacology and Medical Research Council Clinical Pharmacology Research Group, Royal Postgraduate Medical School, Hammersmith Hospital, London, England
Delta‐9‐tetrahydrocannabinol and synhexl: Effects on human sleep patterns
Authors: Pivik R. T. , Zarcone V. , Dement W. C. , Hollister L. E.
Published: January 2016

A series of experiments was conducted to determine the effects of orally administered 1‐trans‐Δ‐9‐ tetrahydrocannabinol (THC) on both undisturbed and experimentally altered (by rapid eye movement [REM] deprivation) sleep patterns of young adult male volunteers. In the deprivation experiments, the effects of a semisynthetic Δ‐6a‐10‐THC homologue, synhexl, were also studied. In the normative studies, 4 subjects received THC in doses ranging from 61 to 258 µg per kilogram shortly before sleep onset, while in the deprivation experiments 2 subjects received either THC (244 µg per kilogram and 259 µg per kilogram) or synhexl (733 µg per kilogram and 777 µg per kilogram) the morning after the second of 2 consecutive nights of REM deprivation. In both normative and deprivation experiments, all‐night sleep recordings were taken during base‐line, drug, and postdrug conditions. The results of both types of experiments were consistent in demonstrating increments in Stage 4 sleep and decrements in REM sleep. In the normative experiments, reduction in Stage 1 and time awake after sleep onset were observed at the highest dose level. Interpretation of these results and their relation to the effects of other psychoactive compounds upon sleep patterns are discussed.
Fibrinolytic activity and thromboembolism
Authors: Boyles Paul W.
Published: January 2016

Fibrinolysis is reduced in acute thromboembolism. Titers of fibrinolysin inhibitor vary diurnally in the same directions and to the same degree as in the sex‐ and age‐matched normal control subject, but always within a higher range. The acute thromboembolic episode apparently involves an initial fall in inhibitor, followed by a gradual rise to an abnormally elevated plateau. If this occurs consistently, it may prove useful as a further means of recognizing and monitoring the thromboembolic episode. No correlation was demonstrated between the titer of fibrin degradation products and the degree of reduction in fibrinolytic activity after acute thromboembolism.
Allergic reaction to procarbazine
Authors: Lokich Jacob J. , Moloney William C.
Published: January 2016

Procarbazine is a methylhydrazine derivative used in the treatment of Hodgkin's disease. Two patients who developed allergic hypersensitivity reactions, one with near‐fatal allergic pneumonitis and one with allergic dermititis are described. A mechanism of sensitization is suggested, and the importance of awareness of this reaction and the need for early lung biopsy are stressed.
Treatment of parkinsonism by amantadine and levodopa
Authors: Mawdsley C. , Williams I. R. , Pullar I. A. , Davidson D. L. , Kinloch N. E.
Published: January 2016

The results of treatment in 83 parkinsonian patients are reviewed. Forty‐two patients were included in a double‐blind, crossover trial of amantadine. Forty of these patients, together with 41 others, had been treated with levodopa for at least 3 months. Seven had been treated for 2 years and 22 for more than 1 year. Results of treatment with the 2 drugs are compared. Subnormal levels of cerebrospinal fluid (CSF) homovanillic acid were found in 22 of these patients. Amantadine produced no significant change in CSF homovanillic acid concentrations. The administration of levodopa resulted in increased CSF levels of homovanillic acid. It is concluded that amantadine produces rapidly discernible but mediocre and ill‐sustained improvement in parkinsonism. Its administration infrequently produces side effects which are rarely bothersome. Amantadine's benefits are much less striking than those produced by levodopa whose efficacy is maintained over long periods. The modes of action of these drugs remain undefined.
The levels of methadone in the plasma in methadone maintenance
Authors: Inturrisi Charles E. , Verebely Karl
Published: January 2016

The time course of methadone in the plasma of 5 methadone maintenance subjects receiving a single daily oral dose of 100 or 120 mg. has been determined. The predose mean plasma level of methadone was 0.48 fig per milliliter. The peak plasma level occurred at 4 hours with an average value of 0.86 fig per milliliter. This level slowly declined so that 24 hours after administration the mean plasma level had reached a value (0.46 fig per milliliter) approximately equal to the predose level. The mean apparent half‐life of methadone in these sub;ects was 25 hours. Data on the renal clearance of methadone indicate that the drug is partially reabsorbed by the kidney and that this reabsorption is pH dependent.
Effects of a single, large, intravenous iniection of dexamethasone
Authors: Czerwinski Anthony W. , Czerwinski Anthony B. , Whitsett Thomas L. , Clark Mervin L.
Published: January 2016

In a double‐blind study, 60 normal adult volunteers were infused with 2.0 mg. per kilogram of dexamethasone disodium phosphate or an equal amount of the diluent. The men and women receiving dexamethasone complained within 2 minutes of itching, burning, or tingling, all of which were most intense in the anogenital area, and which subsided within minutes. Prolonging the infusion time minimized or prevented this complaint.
The liver microsomal monooxygenase system in the human fetus: Distribution in different centrifugal fractions
Authors: Ackermann Else , Rane Anders , Ericsson Jan L. E.
Published: January 2016

The distribution of microsomal, mitochondrial, and lysosomal enzyme activities in different centrifugal fractions of the human fetal liver was studied. Sixty to 70 per cent of the total activities of glucose‐6‐phosphatase and reduced nicotinamide adenine dinucleotide phosphate (NADPH)‐cytochrome C reductase and the amount of cytochrome P‐450 was found in the 200 × g pellet; 10 to 15 per cent was recovered in the 105,000 × g pellet while the rest appeared in the 9,000 × g pellet. Succinic dehydrogenase activity was found only in the 200 × g and 9,000 × g pellets while acid phosphatase was found in all pellets. The 105,000 × g pellet contained only 11 per cent, however. These results were in agreement with the electron microscopic findings. The 200 × g pellet contained hepatocytes with endoplasmic reticulum, erythrocytes, hematopoietic cells, and naked nuclei in equal proportions. The 9,000 × g pellet predominantly contained mitochondria and cisternae of (unbroken) endoplasmic reticulum, while the 105,000 × g pellet was composed of microsomal vesicles of different appearance and free ribosomes. The levels of NADPH‐cytochrome C reductase and cytochrome P‐450 per gram of liver in human fetuses were comparable to those reported previously for adult human liver. In contrast, the activities (per gram of liver) of glucose‐6‐phosphatase and succinic dehydrogenase were lower and that of acid phosphatase higher in human fetuses compared to adults. The low recovery of microsomes from human fetal liver and the pattern of distribution of the enzymes in the different fractions of the liver are discussed in relation to the electron microscopic findings.
Correlation of beta blockade with serum practolol levels after oral administration
Authors: Schneck D. W. , Aoki V. S. , Kroetz F. W. , Wilson W. R.
Published: January 2016

This study relates practolol levels with the ability to block changes in heart rfite, blood pressure, and systolic time intervals (STI) during two levels of upright exercise and two levels of intravenous isoproterenol infusion. Normal men received placebo or oral practolol (1.5, 3.0, and 12 mg. per kilogram) on separate days in random fashion. Responses to exercise and isoproterenol were determined 2 and 4 hours later and those to exercise only at 7.5 hours. Serum pmctolol was measured in a serial manner after dosage. Practolol did not change oxygen uptake at rest or during exercise. Practolol produced a serum concentration‐dependent reduction in average heart rate and systolic blood pressure responses to exercise. Exercise shortened STI. Following practolol, electromechanical systole and left ventricular ejection time during exercise were markedly prolonged, whereas the duration of the prejection period did not change. Pmctolol produced a serum concentration‐dependent reduction in heart rate, systolic and diastolic blood pressure, and STI changes during isoproterenol infusion. Near maximal beta blockade occurred at serum practolollevels of 2 εg per milliliter. The half‐life of practolol was 6.9 hours. Practolol is a potent beta blocking drug with a relatively long duration of action when given orally. The serum concentration‐dependent reduction of the diastolic response to isoproterenol by practolol suggests blockade of peripheral beta receptors.
Plasma levels and absorption of methaqualone after oral administration to man
Authors: Morris Robert N. , Gunderson Gwendolyn A. , Babcock Steven W. , Zaroslinski John F.
Published: January 2016

Following oral administration of 300 mg. of methaqualone to 7 subiects there was an average peak plasma level of 3.0 p.g per milliliter in 2 hours. Average plasma half‐life was 2.6 hours. Per cent absorption at each time point after administration indicated that 67 per cent absorption occurred in one hour and 99 per cent was absorbed in 2 hours.
Effect of protein binding on levels of ampicillin and cloxacillin in synovial fluid
Authors: Howell Anthea , Sutherland Robert , Rolinson George N.
Published: January 2016

The penetration of ampicillin and cloxacillin into synOVial fluid has been measured after oral administration of these penicillins to patients with osteoarthritis or rheumatoid arthritis. The results show that both penicillins diffuse readily into synovial i0int fluid and that concentrations inhibitory for bacteria commonly associated with septic arthritis can be readily attained in infected synOVial ioints following systemic administration of ampicillin or cloxacillin. The penicillins differed with respect to the levels appearing in the synovial fluid relative to the levels in serum; in the case of ampicillin (which is not highly bound to serum) the total levels in synovial fluid were similar to the total serum levels, whereas with cloxacillin (which is highly bound to serum) the total levels in synOVial fluid were notably lower than in serum. However, the unbound levels of cloxacillin in synOVial fluid and serum were similar, as with ampicillin, indicating that the degree of binding is imp01tant in distribution between serum and tissue.
Combination chemotherapy for advanced Hodgkin's disease in relapse following extensive radiotherapy
Authors: Canellos George P. , Young Robert C. , DeVita Vincent T.
Published: January 2016

Twenty one patients with Hodgkin's disease who were in relapse following extensive radiation therapy were treated with a combination chemotherapy program (MOPP), which included nitrogen mustard, vincristine, prednisone, and procarbazine for 6 monthly cycles. Sixteen patients (76 per cent) achieved complete remission. In a comparable group of patients with extensive disease but no previous radiotherapy the over‐all remission rate and the degree of myelosuppression were similar. The interval between the end of radiotherapy and the onset of chemotherapy did not correlate with the extent of subsequent drug tOXicity. Relapse of Hodgkin's disease in the patients following intensive radiotherapy with curative intent does not preclude a subsequent excellent response to combination chemotherapy and a prolonged disease‐free interval.
Guidelines for accepting volunteers: Consent, ethical implications, and the fundion of a peer review
Authors: Morris R. Curtis
Published: January 2016

Concern for both human and legal rights of volunteers used in scientific research is a recent phenomenon. Abuses of the past were justified by the traditional “greater good for the greater number.” Peer review boards were established to approve the manner in which volunteers are sought and selected, the information given them, and the rewards offered. They pass on the protocol of the study, with particular attention to the safeguards assured the volunteers, probable value of the study, and the ability of the investigator. And finally they must protect the volunteer from an all‐inclusive coment form which, in effect, denies him his human rights. The effectiveness of the board obviously rests upon the character of its members. Certain categories of patients may be impossible to protect from exploitation. Patients with chronic diseases who enioy a close personal relationship with their doctors are most vulnerable, as are prison volunteers. The “internal duress” factors in the prison setting seem to make true evaluation of motive impossible. The need for a prisoner to choose between neglected boredom and significant research is particularly deplored. Unless other attractive alternatives are offered to the dull life, negative motivation may well tip the scales in favor of inappropriate research participation.
Discussion
Authors: Carr Edward A.
Published: January 2016

My discussion is about three committees on which I serve at the University of Michigan. Perhaps this will help to establish some principles with a few specific examples. The committee meetings must keep a certain confidentiality, which is easily solved here by omitting individuals' and investigators' names. Also, I'll confine myself to classes of compound rather than specific ones.
Clinical pharmacology in pediatrics
Authors: Shirkey Harry C.
Published: January 2016

Clinical pharmacology as related to childhood lags far behind that for adults. This unfortunate circumstance plus the difference in the therapeutic milieu and the basic peculiarities in childhood, some of which have been delineated below, make most difficult the comparison between adults (volunteers and patients) and pediatric patients. In fact, adult studies may be misleading.
The Deer Lodge Research Unit
Authors: Moore James D.
Published: January 2016

The Deer Lodge Research Unit was opened in the spring of 1968 by the University of Montana Foundation with support from a private research grant. The building itself was newly designed and built after studying other similar prison units and after consultation with all concerned. The unit is located in the open country of the Deer Lodge Valley on Montana State Prison grounds, some 85 miles southeast of the University of Montana campus at Missoula. Wehave over 5,000 square feet of floor space for offices, workrooms, the ward, laboratory, and equipment storage (Fig. 1).
Absorption of ampicillin and nalidixic acid by infants and children with acute shigellosis
Authors: Nelson John D. , Shelton Sharon , Kusmiesz Helen T. , Haltalin Kenneth C.
Published: January 2016

Thirty‐seven infants and children with acute shigellosis were treated with orally administered ampicillin or nalidixic acid. Peak plasma levels and dose‐response curves suggested two patient populations. Five of 16 patients receiving nalidixic acid had a pronounced delay in absorption, while the others had the anticipated peak levels and plasma half‐lifes. All patients had a lower percentage of conjugated drug and of drug present as the hydroxynalidixic acid metabolite on the first day of treatment than during convalescence. Thus, some patients with diarrhea had altered absorption and all had altered metabolism of nalidixic acid during the acute phase of shigellosis. In 10 of 21 ampicillin‐treated patients there were depressed plasma levels and prolonged half‐lifes. These were statistically likely to be younger, to have more severe diarrhea, and to have lower body weight than those with normal peak plasma levels and plasma clearance rates.
Effect of renal failure and hemodialysis on cephacetrile pharmacoki netics
Authors: Nissenson Allen R. , Levin Nathan W. , Parker Richard H.
Published: January 2016

Cephacetrile, a new injectable cephalosporin antibiotic that is allegedly not nephrotoxic, was evaluated in 15 subjects with varying degrees of renal functional impairment Cephacetrile has a serum half‐life of 1.3 hours in normal subjects which depends on the glomerular filtration rate. The total plasma clearance rate and the renal clearance rate of cephacetrile are high compared with the clearance rates of other cephalosporins, so also is the fraction of the injected dose excreted in the urine. Renal excretion of cephacetrile is accomplished by glomerular filtration and tubular secretion in normal subjects, but in patients with renal failure there is little evidence of tubular secretion. Cephacetrile is partially dialyzable, but higher serum levels during hemodialysis are noted after a standard dose than are expected after a similar dose of cephalothin or cephaloridine.
Effect of aspirin, caffeine, and codeine on the metabolism of phenacetin and acetaminophen
Authors: Thomas Barry H. , Coldwell Blake B. , Zeitz W. , Solomonraj G.
Published: January 2016

The metabolism of phenacetin (P) and acetaminophen (A') alone and with aspirin (A), caffeine (C), and codeine (C') (APCC' and AA'CC') was studied in 24 human volunteers. The principle route of phenacetin metabolism and the total obsorption of phenacetin were not affected by the drug combination. The proportion of the dose of phenacetin metabolized to 2‐hydl'Oxyphenetidine (2‐0HP) was increased from 1.9 to 3.4 per cent when APCC' was ingested. Large individual variations in the amounts of 2‐0HP excreted were observed. The changes produced in the metabolism of acetaminophen when it was taken as AA'CC' were minor. No 2‐0HP was detected after administration of acetaminophen. No changes in blood and urine were observed with any of the drug treatments.
Disposition of methadone in man after a single oral dose
Authors: Inturrisi Charles E. , Verebely Karl
Published: January 2016

The levels of methadone in the plasma and urine of 5 subjects giaven a single oral dose of 15 mg. have been determined using solvent extraction and gas‐liquid chromatography. Methadone was detected in plasma 30 minutes after drug administration. The peak plasma level occurred at 4 hours and was followed by an exponential decline during the next 20 hours. The mean apparent half‐life of methadone was 15 hours. The time action of methadone‐induced pupillary constriction closely coincided with the time course of methadone in plasma. An average of 52 per cent of the dose was excreted in the urine as methadone and metabolites in the 96 hours after drug administration. Nearly one half of the methadone and metabolites recovered in the urine was excreted during the first 24 hours. The renal clearance of methadone indicates that the drug is partially reabsorbed by a pH‐dependent process. These results demonstrate the importance of biotransformation and renal excretion as determinants of the disposition of methadone in man.
Comparative study of tobramycin and gentamicin with special reference to anti‐Pseudomonas activity
Authors: Klastersky J. , Daneau D. , de Maertelaer V.
Published: January 2016

Tobramycin was compared to gentamicin in vitro and was found more active on Pseudomonas aeruginosa. When tobramycin and gentamicin were administered to volunteers as a single intramuscular iniection (2 .. 5 mg. per kilogram), similar blood levels were observed (mean peak levels of 7.3 p.g per milliliter and 7.1 p.g per milliliter, respectively). Sera from these subiects was more active (p < 0.05) against strains of Ps. aeruginosa, which had similar susceptibility to tobramycin and gentamicin.
Gastrointestinal blood loss from aspirin and sodium salicylate tablets in man
Authors: Leonards Jack R. , Levy Gerhard
Published: January 2016

In view of conflicting reports on gastrointestinal blood loss produced by aspirin, sodium salicylate, and salicylic acid, a rigorously controlled comparative study has been carried out. Thirteen healthy adult volunteers took twelve 325 mg. aspirin or sodium salicylate tablets (plain and with antaCid) daily for 7 day periods in a crossover study. The 3 preparations produced similar steady state plasma‐salicylate concentrations. Sodium salicylate tablets caused gastrointestinal blood loss (1.2 ml. per day above control values), but the blood loss produced by aspirin tablets was appreciably greater (5.6 ml. per day above control values). However, other studies have shown that aspirin‐induced gastrointestinal bleeding can be minimized by use of specially formulated dosage forms.
Pharmacodynamics and pharmacokinetics of isosorbide in man
Authors: Nodine J. H. , Modi K. N. , Rhodes M. , Paz-Martinez V. , Ibarra L. , Santos R. J.
Published: January 2016

The pharmacodynamics and pharmacokinetics of isosorbide, a recently developed, well‐tolerated, orally effective osmotic diuretic, were evaluated. Normal male volunteers received 0.25 to 1.5 Gm. per kilogram of isosorbide and 50 mg. of hydrochlorothiazide, alone and in combination with isosorbide. Dose response effects of isosorbide on water and osmolar excretion were statistically significant. The diuretic effect of isosorbide and hydrochlorothiazide was synergistic. The absorption, distribution, and fate of 14C isosorbide were studied before and after loading with unlabeled drug. Orally administered isosorbide appeared rapidly in the plasma and was excreted unchanged in the urine with a mean disappearance half‐time of 8 hours. There were no significant side effects.
Oral contraceptives and the red blood cell
Authors: Fisch Irwin R. , Freedman Shanna H.
Published: January 2016

Red blood cell parameters were analyzed in a group of 3,736 women, which included 1,083 current, 1,079 past, and 1,574 never users of contraceptive drugs. After adiustment for age and menstrual blood loss, oral contraceptive users exhibited a slight but statistically significant elevation in RBC indices coupled with decreased hemoglobin, hematocrit, and red blood cell count (RBC). These findings are consistent with a folate and/or vitamin B12 deficiency that becomes more significant considering the high socioeconomic level of our subjects, but the hazard of a clinically significant macrocytic anemia in a healthy, well‐nourished woman using an oral contraceptive is probably minimal.
Indoleamine metabolites in the cerebrospinal fluid of depressed patients before and during treatment with nortriptyline
Authors: Åsberg Marie , Bertilsson Leif , Tuck Dick , Cronholm Börje , Sjoqvist Fölke
Published: January 2016

Cerebrospinal fluid (CSF) levels of the indoleamine metabolites, 5‐hydroxyindole‐3‐acetic acid (5‐HIAA) and indole‐3‐acetic acid (IAA) were measured by a specific mass fragmentographic method in 43 depressed psychiatric in‐patients. The mean level of 5‐HIAA was 19.7 ± 7.9 ng per milliliter. The 5‐HIAA concentration was positively correlated to age, and there was a tendency for women to have higher values than men. The distribution of 5‐HIAA concentrations appeared to be bimodal in the 27 patients with a depression of endogenous type. The bimodality could not be explained by differences in age or sex. The mean level of IAA was 6.4 ± 4.1 ng per milliliter. The distribution of IAA was unimodal. The correlation to age was not significant, and there was no sex difference. There was a positive correlation between the concentrations of the two metabolites. Twenty patients were treated with nortriptyline, 50 mg three times daily by mouth. After three weeks treatment, the concentrations of 5‐HIAA and IAA had decreased significantly. The mean decrease was 4.8 and 2.0 ng per milliliter, respectively. The magnitude of the decrease was not cormlated to the plasma level of nortriptyline. The data suggest that endogenous depression is a hiochemically heterogenous disease. There may be a subgroup of patients within the endogenous syndrome where indoleamine metabolism is disturbed. In these patients, treatment with drugs that influence indoleamines more directly than a typical noradrenaline uptake inhibitor like nortriptyline, may lead to better therapeutic results.
Methadone binding to human plasma proteins
Authors: Olsen George D.
Published: January 2016

The interaction of L‐(1‐3H) methadone with solutions of purified human gamma globulin and with human plasma was studied by equilibrium dialysis. The per cent of methadone bound to gamma globulin was dependent on drug and protein concentration. In the normal range of serum gamma globulin concentration and the therapeutic range of plasma methadone concentration, gamma globulin bound 13.4% to 17.4% ot the total drug concentration. The binding of methadone to plasma from 2 healthy male volunteers, nontolerant to narcotic analgesics, was dependent on drug concentration. Methadone bound to plasma proteins decreased from 87.3% to 83.7% as drug concentration increased in the therapeutic range. This small decrease is most likely due to decreased binding by the gamma globulin fraction since albumin binding is constant in this range. The data in this study, as weil as a previous study with albumin, suggest that methadone may also bind to other plasma proteins such as beta, alpha‐I, and alpha‐2 globulins.
Delta‐8‐ and delta‐9‐tetrahydrocannabinol; Comparison in man by oral and intravenous administration
Authors: Hollister Leo E. , Gillespie H. K.
Published: January 2016

Delta‐8‐tetrahydrocannabinol (THC) has activity in man similar to that of its double‐bond isomer, delta‐9‐THC. Its relative potency to the other isomer, as judged following both oral and intravenous administration, is 2:3. Intravenous administration of ethanolic solutions of cannabinoids in clinically active doses is feasible and desirable for experimental purposes. A range of doses of 1 to 6 mg of delta‐9‐THC intravenously produced a wide spectrum of cannabis‐like effects. Relatively simple clinical techniques clearly detect cannabis‐like activity in man, making both qualitative and quantitative camparisions of unknown materials with delta‐9‐THC feasible.
Effect of halofenate on serum lipids
Authors: Aronow Wilbert S. , Harding Phillip R. , Khursheed Mohammed , Vangrow Jack S. , Papageorge's Nicholas P. , Mays James
Published: January 2016

Forty‐eight people with hypertriglyceridemia associated with types III, IV, V, and nondefinitive lipoprotein patterns participated in a double‐blind 14 month study to determine the effects of halofenate on serum lipids. One month after starting dietary control, a 2 month control period began. After this, 25 patients were given placebo and 23 patients were given halofenate for 48 weeks. Five of the 35 patients with coronary heart disease developed a myocardial infarction and died within 14 months. Halofenate lowered mean serum triglyceride levels 49%j from the control period in comparison with placebo but did not significantly tower mean serum cholesterollevels. Halofenate also did not significantly affect myocardial infarction or mortality rate.
Effect of halofenate on exercise performance in coronary heart disease
Authors: Aronow Wilbert S. , Harding Phillip R. , Khurshee Mohammed , Vangrow Jack S. , Papageorge's Nicholas P.
Published: January 2016

The effect of halofenate, which lowers serum triglyceride but not blood cholesterol, on exercise performance and exercise electrocardiograms was evaluated in 48 patients (31 with angina, 4 with healed myocardial infarction but no angina, and 13 without coranary disease). Four of 17 cardiac patients an placebo and 1 of 18 cardiac patients an halofenate died within 14 months. No significant difference in exercise performance or in the exercise electrocardiograms in patients on halofenate versus patients on placebo was observed at 12 weeks, 24 weeks, 36 weeks, or 48 weeks after medicatian. There was no difference between the effects of halofenate and placebo on exercise electrocardiograms in the patients without angina. Changes in exercise performance or in exercise electrocardiograms were not significantly correlated with changes in serum cholesterol or triglyceride
Theophylline compounds and myasthenia gravis; II. Clinical report of nine cases
Authors: Brumlik Joel , Jacobs Robert , Karczmar Alexander G.
Published: January 2016

The clinical effects of oxtriphylline (Choledyl), a choline salt of theophylline, was investigated in 9 patients with myasthenia gravis. Five of the patients with severe generalized myasthenia were clinically refractory to anticholinesterase medication. In these patients, oxtriphylline (1) increased the level of strength when used alone, (2) potentiated the effects of the anticholinesterases in sorne patients for a variable period of time, (3) tended to prevent corticotropin‐induced weakness when used with the latter, and, when both were used tagether (4) accelerated and intensified the beneficial effect of corticotropin. When used alone, oxtriphylline only partially alleviated the symptoms of myasthenia gravis. It had little effect in patients with mild symptoms and in those who responded reasonably well to anticholinesterase medication.
Elimination kinetics of amobarbital in mothers and their newborn infants
Authors: Krauer Beatriee , Draffan G. H. , Williams Faith M. , Clare R. A. , Dollery C. T. , Hawkins D. F.
Published: January 2016

Plasma concentrations of amobarbital were measured in mothers with mild hypertension at term and their newbom infants after administration of a single dose of sodium amobarbital before delivery. Similar drug concentrations were found in cord and matemal plasma immediately after delivery. From the declining amobarbital concentration values, first order elimination kinetics were demonstrated in all cases. The plasma half‐life of amobarbital was 2.5 fimes as long in the newborn as in the mothers. The plasma concentration of the drug's major metabolite, hydroxyamobarbital, increased during 12 to 24 hours after delivery in 2 of the mothers and children and decreased thereafter.
Acute respiratory effects of ethanol in man
Authors: Johnstone Robert E. , Reier Charles E.
Published: January 2016

Six healthy subjects received ethanol 0.35, 0.70, and 1.05 ml per kilogram intravenously in 1 hour, causing average blood ethanol concentrations of 40, 99, and 121 mg per milliliter, respectively. Resting ventilatory minute volume (VE) and end tidal carbon dioxide tension (PACO2) were inconsistently affected. The ventilatory response to CO1 was depressed in a dose‐dependent manner. The PACO2 at a VE of 20 I per minute was 3.9 torr greater than control after the 1.05 ml per kilogram dosage. Respiratory exchange ratio decreased from 0.779 to 0.709 1 hour after the 1.05 ml per kilogram infusion. Vital capacity decreased from 5.42 to 5.09 1, and expiratory reserve volume decreased from 1.14 to 0.9311 hour following this dosage. Irregular ventilatory patterns with transient inspiratory and expiratory apnea were observed frequently following the 0.70 and 1.05 ml per kilogram dosages.
Pharmacokinetics of intravenous theophylline
Authors: Mitenko Paul A. , Ogilvie Richard I.
Published: January 2016

Plasma theophylline concentrations were measured after single intravenous infusions of aminophylline to asthmatic patients and normal volunteers. Using two‐compartment kinetic analysis, no basic differences in drug disposition were found. For the 16 subiects studied the overall mean plasma clearance rate was 0.0719 I per kilogram per hour, and overall mean beta or slow disposition constant was 0.159 hr−1, corresponding to a plasma half‐time of 4.36 hr. This information should be useful in determining precise dosage requirements for theophylline in clinical situations.
Dose‐dependent enzyme induction
Authors: Breckenridge A. , Orme M. L'E. , Davies L. , Thorgeirsson S. S. , Davies D. S.
Published: January 2016

Administration of qUinalbarbitone, 100 mg nightly, caused a fall in steady‐state plasma warfarin concentration ranging from 5% to 64.5% in 6 patients. There was no correlation between the extent of this fall and either the plasma concentration of quinalbarbitone or the initial rate of warfarin metabolism. Increasing the dose of qUinalbarbitone to 200 mg nightly (2 patients) and 300 mg nightly (1 patient) permitted a study of the relationship between dose and degree of induction. By administration of varying doses of 4 inducing agents to rats and constructing a dose‐response curve, it was shown that phenobarbitone was a more potent inducing agent than quinalbarbitone, amylobarbitone, or antipyrine. Possible reasons for this include the longer plasma half‐life of phenobarbitone and the higher liver/plasma drug ratio. These data suggest that more information about the indUCing ability of drugs in man and animals can be derived by performing enzyme induction studies at several rather than at a single dose level.
Diphenylhydantoin side effects and serum albumin levels
Authors:   The Boston Collaborative Drug Surveillance Program
Published: January 2016

In a comprehensive drug monitoring program adverse reactions to diphenylhydantoin (DPH) were recorded in 11.4% of 88 patients with an admission serum albumin lower than 3.0 gm per 100 ml1'eceiving DPH and in 3.8% of 234 patients with a normal serum albumin receiving DPH. This difference was sustained after taking into account factors such as dosage, age, sex, primary diagnosis, and admission blood urea nitrogen. It is suggested that hypoalbuminemic patients have increased circulating levels of unbound DPH that increases the risk of toxicity to this drug.
Pharmacokinetics and metabolism of adriamycin in man
Authors: Benjamin Robert S. , Riggs Charles E. , Bachur Nicholas R.
Published: January 2016

A pharmacokinetic evaluation of adriamycin and its metabolites was undertaken in cancer patients treated according to an intermittent single high‐dosage schedule. The long plasma half‐life of adriamycin and metabolites, 26.7 hours, was similar to that of daunorubicin and its metabolites. Long plasma half‐life of adriamycin, 16.7 hours, was shorter than that of its metabolites, 31.7 hours. In addition to differences in the metabolism of the two drugs, the cumulative 5 day urinary excretion of adriamycin and its metabolites was only 5.7% of the administered dose in contrast to 23% for daunorubicin and its metabolites. This study establishes that after a single intravenous dose plasma levels of adriamycin are maintained for long periods; it lays a rational foundation for the empirically effective intermittent single high‐dosage schedule. That adriamycin undergoes extensive metabolic degradation in patients is described for the first time.
Epidemiology of drugs taken by pregnant women: Drugs that may affect the fetus adversely
Authors: Forfar John O. , Nelson Matilda M.
Published: January 2016

The epidemiology of drug consumption during pregnancy has been studied retrospectively in 911 randomly selected mothers. The drugs used, the proportions of pregnant women taking them, the duration and timing of drug administration were ascertained. Excluding iron, drugs were prescribed for 82 % of women during pregnancy and the average number of drugs prescribed for these women was 4. Self‐medicated drugs were taken by 65% of mothers and the average number of drugs taken by these was 1.5. The proportion of mothers taking different categories of drugs ranged from 82% to 1.2%. The mean duration of drug therapy for the various categories of drugs ranged from 125 to 10 days. The duration of treatment with individual drugs was also ascertained. Some drugs tended to be administered early, some late, and some throughout pregnancy. A drug “consumption in pregnancy” factor has been calculated by which the over‐all consumption of a drug can be measured and comparisons made of the consumption of one drug relative to another. Drugs that may carry a risk of teratogenicity if administered early in pregnancy are listed, as are those drugs that, if administered later in pregnancy, may adversely affect fetal functioning or the functioning of the newborn infant at or after birth.
Drugs ingested by pregnant women
Authors: Hill Reba M.
Published: January 2016

Gravid women in this country today are consuming analgesics, diuretics, antihistamines, artificial sweeteners, and anticonvulsants in large amounts. Some effects of these on their unborn infants are known; much more study is needed.
The lesson of thalidomide
Authors: Stern Leo
Published: January 2016

The association between thalidomide and phocomelia was discovered because of the rarity of phocomelia. When we give a drug to a pregnant woman we are also giving it to the fetus whether we want to or not. We must therefore insist that every precaution be taken to identify possible harm to the fetus before any new drug is released.
Drug metabolism by placenta
Authors: Juchau Mont R. , Pedersen Mark G. , Fantel Alan G. , Shepard Thomas H.
Published: January 2016

Measurable catalysis of mixed‐function oxidations of foreign organic compounds in human placental tissues appears to occur only with a limited number of substrates including 3,4‐benzpyrene, 3'‐methyl‐4‐monomethylaminoazobenzene, and N‐monomethylaniline. Evidence now indicates that mixed‐function oxidations of the classical “type 1” drug substrates (the hepatic biotramformations of which are markedly accelerated following pretreatment with phenobarbital and decreased or unchanged following pretreatment with polycyclic aromatic hydrocarbons) occur at extremely low or negligible rates in human placentas. Xenobiotic monooxygenation reactions that are induced strongly by exposure to polycyclic aromatic hydrocarbons appear more likely to be catalyzed by placental enzyme systems, although exceptions exist and sufficient studies to warrant broad generalizations have not yet been carried out. Enzymes that catalyze the ω‐oxidation of 14C‐laurate could not be detected in human placentas. No relationships between the highly active human placental aromatase system and placental drug hydroxylation reactions were found, whereas an inverse correlation between specific activities of the placental aryl hydrocarbon hydroxylase and cholesterol side‐chain oxidase may exist.
Diagnostic implications of drug‐fetus interactions
Authors: Hirschhorn Kurt
Published: January 2016

Deleterious effects on the fetus can be classified as teratogenic, mutagenic at single gene loci, and mutagenic as expressed by chromosome damage. Possible damage caused by amniocentesis is now under study. Effects of drugs on the fetus may extend over several generations.