bluuebunny/crossref_metadata_2025 huggingface dataset:
Lidocaine disposition kinetics in monkey and man; II. Effects of hemorrhage and sympathomimetic drug administration
Authors: Benowitz Neal , Forsyth Ralph P. , Melmon Kenneth L. , Rowland Malcolm
Published: January 2016

Lidocaine disposition kinetics in normal and hemorrhaged rhesus monkeys was studied. During bleeding there was a reduction in distribution and clearance of lidocaine, along with an increase in half‐life, which was similar to that in human patients with congestive heart failure. In the monkey in shock there was impaired liver extraction of lidocaine. Sympathomimetic drugs, such as isoproterenol and norepinephrine, which influence hepatic blood flow, markedly altered clearance and steady‐state lidocaine concentrations in blood. A perfusion model that simulates blood and tissue levels during hemorrhage in monkey and man by using blood flow measurements during hemorrhagic shock is reported here. This perfusion model allowed a quantitative understanding of the interaction between lidocaine and sympathomimetic drugs and may be clinically useful in man simultaneously receiving a variety of cardioactive drugs ill suggesting appropriate ad;ustments of the dosages of the most critical drugs used.
Application of radioimmunoassay to pharmacology
Authors: Spector Sydney
Published: January 2016

The radioimmunoassay, hased on specific antigen‐antihody hinding, was applied to the measurement of drug concentrations. To elicit antihody formation to drugs (substances usually of low molecular weight), the drug was coniugated to a Zarge molecule, such as a protein or synthetic polymer to form an immunogen. Three morphine derivatives linked to hovine serum alhumin hy an amide hond were used to immunize rah hits with the morphine‐protein coniugate (0.10 mg). After periodic iniections of the antigen into the footpads of the animals, and as soon as high titers of antihodies had heen formed, the animals were hled. Antihodies of high titer and affinity were incuhated in a medium of varying concentrations of unknown drug and laheled drug at 4° C, until equililJrium was achieved. Following incuhation, the laheled drug that exists hoth as free and honnd to a,ntihody was then separated by a variety of procedures, e.g., microfiltration, anti‐gamma globulin, chromatoelectrophoresis, salt precipitation, and coated charcoal. The data ohtained hy precipitating the antihody‐ligand complex yielded the following information: (1) the concentration required to inhihit 50% of the hinding of laheled drug to antibody indicates the senstivity of the method; (2) it also indicates to some extent the specificity of the antibody generated by the immunogens employed to evoke its production, as exemplified hy the fact that 3‐0‐carhoxymethylmorphine coniugate recognizes normorphine equally as weil as rrwrphine. The factors that enhance or reduce the sensitivity of the method are discussed.
Application of blood level data to dinical trials
Authors: Azarnoff Daniel L.
Published: January 2016

In the evaluation of drugs, especially in the early phases, interpatient variation in response to a fixed dose may give misleading results concerning both efficacy and toxicity. Unless blood level determinations are made during the clinical trial, an effective drug could unnecessarily be lost or discarded. A lack of correlation between the administered dose of drug or its metabolites in plasma may be due to a multiplicity of factors: (1) individual difJerences in rate of metabolism (e.g., slow biotransformation); (2) disease states (e.g., gastrointestinal problems leading to malabsorption),'low renal clearance, hepatic disease, congestive heart failure; (3) natural history of the disease (e.g., if characterized by spontaneous remissions, efficacy is difficult to establish); (4) drug interactions (e.g., phenobarbital accelerating cyclophosphamide metabolism); (5) noncompliance (may be interpreted as either poor bioavailability or rapid elimination); (6) nature of formulation used during investigation (e.g" crushed drug in an opaque capsule‐for double‐blind purposes‐may alter bioavailability compared with the formulation finally marke ted); (7) electrolytes, anoxia, aCidosis in certain chronic diseases may modify response of drug at receptor; (8) abnormal protein binding of the drug; (9) environmental factors, such as the difference in response to niridazole in bilharziasis, i.e., well tolerated in Africa, and toxic to central nervous system in South American patients; (10) unknown genetic factors. Accordingly, measurement of plasma concentratiom of drugs during clinical investigations, while not an infallible aid, can be useful when applied under proper circumstances.
Pharmacodynamic and pharmacokinetic measurements in cardiovascular‐renal drugs
Authors: Hayes Arthur H.
Published: January 2016

Methodologic advances in drug assay techniques and their growing availability provide a potentially powerful tool in the optimal use of important GV‐renal drugs. Blood level data have provided the bases for describing the kinetic behavior in the body of a number of agents, and this information in turn has allowed the construction and assessment of dose regimens under varying conditions. For substances with a narrow margin of safety like the cardiac glycosides and for those often used prophylactically like the antiarrhythmics, such pharmacokinetic profiles have been shown to be clinically useful. However, correct interpretation of a drug's blood levels must take into account the factors responsible for the kinetic pattern observed since these may differ as after a single dose and during a steady‐state equilibrium. In addition, the processes of drug absorption, distribution, and bioelimination that influence a compound's pharmacodynamics are themselves subject to normal variability as well as to alteration by pharmaceutical preparation, other drugs, disease states, etc. Appreciation of these modifying effects is crucial in the appropriate application of a drug's general kinetic parameters to specific clinical situations. Besides their role in defining kinetic and dynamic activity, measurements of drug concentrations in the blood may help in the evaluation of inappropriate drug responses as when “standard” dose regimens fail to produce the expected results or lead to unanticipated toxicity. Yet even the usually close correlation between blood level and pharmacologic effect upon which this use is predicated varies normally among individuals and may be changed significantly by various pharmacologic and pathologic factors.
Plasma nortriptyline levels—relationship to clinical effects
Authors: Åsberg Marie
Published: January 2016

One of the baffling problems in the treatment of depression is the dilficulty of differential diagnosis as to type of depression. This may be one complicating factor in selecting the pharmacologic agent that will prove effective for the individual patient. Of the available tricyclic antidepressants, no clear‐cut and consistent differences in effect have been demonstrated olinically, despite the known mode of action: all inhibit reuptake of transmitter substance into monoaminergic neurons. This property is believed to be related to the antidepressant effect. One exception is iprindole, which does not inhibit monoamine uptake, but its antidepressant effects are claimed to be comparable to imipramine. In patients, in all of whom a diagnosis of endogenous depression had been made, the relationship between drug plasma levels and therapeutic effects was studied with nortriptyline (NT) as the therapeutic agent. The basic study design was as follows: after a washout period, with patients on placebo for 4 to 7 days, NT was given for 4 weeks. A single dosage level of 50 mg three fimes daily was found to ensure sulficient variability in plasma level. Ratings for side effects and severity of depression were performed at the end of the washout period and once weekly during active treatment, with NT concentrations in plasma done twice weekly. The incidence of “side etfect symptoms” was high during treatment, and strongly correlated with the severity of depression at base line, as well as on active treatment. However, the estimate of “true” side effects significantly correlated with the plasma level of NT during the first three weeks of treatment. A modified version of the Cronholm‐Ottosson rating scale was used to estimate severity of depression. The ratings on this scale strongly correlated with nurse ratings (r = 0.87), but were lower with the Beck self‐rating scale (r = 0.67). Low agreement between self‐ratings and psychiatrists' ratings supports the observation of others that self‐rating scales should not be relied on exolusively in severely depressed patients. The best classification between “responders” and “nonresponders” to NT was obtained at 175 ng NT per milliliter of plasma. Although the general tendency is for patients to do less well on high plasma levels, some seem to benefit from them, while others do not recover even on moderate levels. Variability in receptor sensitivity and heterogeneity within the depressive disorder may be an explanation. On any standard dosage, a certain number of patients will have plasma levels that are too low to be effective, and some will develop toxic levels even on very low dosages. Monitoring NT plasma levels may be a way to increase the efficacy of treatment in patients who do not respond to standard therapy and in patients with disturbing side etfects.
Blood level measurements and antimicrobial agents
Authors: Kunin Calvin M.
Published: January 2016

This review focuses on some of the unique charaeteristics of antimicrobial agents as distinct from other pharmacologic agents. Antimicrobial agents behave similarly to other drugs, but their unique property rests on their ability to hit their target: an invading mieroorganism rather than a host cell. The blood level of a drug is only indirectly related to distribution in the body. It is useful in assessing potential efficacy of a drug in treatment of bacteremia and in comparative pharmaeokinetic studies, particularly in deriving dosage schedules in normal subiects and in patients with renal or hepatic failure, but serves only as a rough gauge to activity at the site of infection. Design and evaluation of new antimierobial agents therefore depend not only on pharmacokinetic properties but also on an understanding of local factors goveming the distribution and biologic activity of this class of drugs.
Drug dosage in patients with renal disease
Authors: Dettli L. C.
Published: January 2016

Patients with renal impairment excrete drugs more slowly than normal individuals. Ta avoid the increased risk of toxicity as the consequence of drug accumulation tollowing repeated administration of the “usual” dose, the dosage regimen has to be modified in aceordanee with the lower speed of drug elimination. A simple graphie method is deseribed to estimate the individual overall elimination rate constant of a drug trom the ereatinine clearanee of the patient with renal disease. Based on the estimated elimination rate eonstant, the individual dosage regimen is ealculated according to pharmaeokinetie principles. As a result, two simple dosage rules tor intermittent and for eontinuous administration of drugs to patients with renal impairment are reeommended. For special circumstanees, two more sophistieated dosage rules are given.
Colestipol and clofibrate in hypercholesterolemia
Authors: Dujovne Carlos A. , Hurwitz Aryeh , Kauffman Ralph E. , Azarnoff Daniel L.
Published: January 2016

The effects of colestipol, clofibrate, and placebo were compared in 30 patients with serum cholesterollevels higher than 250 and triglyceride levels under 150 mg per 100 ml in a crossover fashion during a one‐year period. Colestipol reduced mean serum cholesterol concentration 13%. C lofibrate had a similar effect but aLm significantly decreased triglyceride levels. Four patients expressed nonspecific displeasure with colestipol, and 2 abandoned the study for this reason.
Delta‐9‐tetrahydrocannabinol and glucose tolerance
Authors: Hollister Leo E. , Reaven Gerald M.
Published: January 2016

Intravenous doses of 6 mg of delta‐9‐tetrahydrocannabinol (THC) produced moderately severe marihuana intoxications. Glucose tolerance was impaired, and this deterioration of glucose tolerance was associated with increased plasma levels of growth hormone. Although large doses of marihuana might aggravate diabetes, the rarity of this phenomenon in clinical practice may be due to the lower doses of THC used socially or development of tolerance to this specific pharmacologic effect.
Acute heroin withdrawal in Viet Nam An immunochemical evaluation of excretio
Authors: Robinson Maleolm G. , Howe Richard C. , , Norman W. Rea , Siegel Howard W. , Hegge Frederick W.
Published: January 2016

Heroin use by American military personnel in Viet Nam differed from the classically reported civilian setting in the following ways: short duration, absence of medical complications, purity of drug, infrequency of concomitant drugs, and use of nasopulmonary routes rather than intravenous iniection. Urine morphine equivalent levels were assessed immunochemically (FRAT) in 10 patients and 5 controls for 15 days following withdrawal from heroin. The initial urine morphine equivalent concentration was over 20,000 ng per milliliter. Concentration declined exponentially over the first five days to fluctuating low levels thereafter. A linear relations hip between urine morphine concentration and total urinary morphine output suggests the existence of an active renal mechanism for morphine excretion. Historical assessment of heroin consumption and individual morphine excretion patterns indicated levels of opiate tolerance far higher than norrnally found in heroin‐dependent civilians.
Disopyramide phosphate: Clinical efficacy of a new oral antiarrhythmie drug
Authors: Vismara Louis A. , Mason Dean T. , Amsterdam Ezra A.
Published: January 2016

The efficacy of disopyramide phosphate (DP), a new oral antiarrhythmic agent, was evaluated by serial ten hour, portable electrocardiographic monitoring during placebo (P) and DP administration. In this 16 week outpatient study, DP therapy reduced the frequency of all cardiac ectopic depolarizations (ED) in 10 of 17 patients (average occurrence: P 145 per hour and DP 4 per hour, p < 0.05). Further, ventricular arrhythmias (VA): ventricular tachycardia (VT), and complicated VED, were recorded during P in 8 of 17 and in 16 of 17 patients, respectively, but this prevalence diminished with DP administration (VT 1 of 17, P < 0.05; VED 10 of 17 patients, p < 0.05). Atrial tachycardia (AT), noted in 6 patients during P, was abolished in 4 during active drug treatment. Despite minor anticholinergic adverse effects in 6 patients, DP was well tolerated in 17 of 18 patients and appeared safe even in 5 patients with cardiac decompensation prior to its administration.
The genetic contribution to unwanted drug effects
Authors: Lader Maleolm , Kendell Robert , Kasriel Judith
Published: January 2016

A questionnaire was devised to inquire into unwanted effects experienced after commonly used drugs. The questionnaire was sent to 475 pairs of normal, healthy monozygotic twins and to 407 pairs of dizygotic twins. Two‐thirds replied. Concordance rates were generally higher in the monozygotic than in the dizygotic twin pairs, suggesting that genetic factors playa role in drug reactions.
Hepatic toxicity of nitrosourea analogues
Authors: Lokich Jacob J. , Drum David E. , Kaplan William
Published: January 2016

Two patients with neoplastic diseases were treated with nitrosourea derivatives and developed chemical “hepatitis.” Serialliver scintigraphy demonstrated a shift of radioactive colloid distribution that was reversible. Pathologie changes within the hepatic architecture were typical for subacute hepatitis and persisted in spite of apparent clinical recovery.
Factors influencing the metabolie availability of ascorbic acid
Authors: Loh H. S. , Odumosu A. , Wilson C. W. M.
Published: January 2016

Ascorbic acid (AA) is an essential vitamin (C) and is found in all plant and animal tissues. All plants and most animals, except for guinea pigs, fishes, insects, a few birds native to India, and primates, are able to synthesize their own AA. Lack of the vitamin in those species unable to synthesize it leads to the clinical state of scurvy with all its pathological and bioehemieal abnormalities.
Pharmacokinetics of thiothixene in man
Authors: Hobbs Donald C. , Welch Willard M. , Short Marvin J. , Moody William A. , van der Velde C. D.
Published: January 2016

A new specific and sensitive assay for thiothixene, using mass fragmentography, has been developed and used to measure plasma concentrations in psychotic patients on long‐term therapy. Drug plasma concentrations reach an early peak following an oral dose and decline slowly thereafter. Despite considerable differences in doses, peak plasma concentrations fall within a relatively narrow range, indicating that, during earlier ad;ustments of dose to achieve therapeutic control, optimum plasma concentrations were also being achieved.
Bronchodilator effects of terbutaline and epinephrine in obstructive lung disease
Authors: Sackner Marvin A. , Greeneltch Ned , Silva Grace , Wanner Adam
Published: January 2016

A double‐blind crossover comparison was made of the effects of terbutaline, a new adrenergic drug with maior action on beta 2 receptors, epinephrine, and saline, on pulmonary function in 16 patients with chronic bronchitis or emphysema and 9 patients with bronchial asthma. Serial determinations of lung volumes, dynamic mechanics of breathing, and distribution of ventilation were made after subcutaneous administration. Terbutaline, 0.5 mg, was a more effective bronchodilator and had a longer duration of action than epinephrine 0.25 mg, but was associated with a higher incidence of side effects. These were generally minor and transient and included tremor, nervousness, and palpitations. Terbutaline may be useful in the management of bronchospasm of asthma, chronic bronchitis, and emphysema.
Heparin half‐life in normal and impaired renal function
Authors: Perry Paul J. , Herron George R. , King James C.
Published: January 2016

The half‐life of heparin was calculated in persons with normal renal function and in patients in chronic renal failure. Intravenous heparin, 0.3 and 0.6 U/ml of blood volume, was administered. The anticoagulant half‐life of heparin was found to be dose‐related. The normal renal function group gave a mean anticoagulant half‐life of 36.S minutes for the 0.6 U/ml dose and 22.7 minutes for the 0.3 U/ml dose. The chronic renal failure population had a mean half‐life of 47.5 minutes for the 0.6 U/ml dose and a mean half‐life of 32.6 minutes for the 0.3 U/ml dose. By use of the equations of first‐order pharmacokinetics, a heparin dosage schedule was derived through which anticoagulation of patients can proceed by means of constant infusion of the drug. The schedule not only is applicable to patients in renal failure but also may be used in heparinization of patients with normal renal function.
Problems in the organization of clinical pharmacology in Denmark
Authors: Hvidberg Eigill F.
Published: January 2016

Until now, clinical pharmacology has not existed as a distinct discipline in medical schools, hospitals, and the pharmaceutical industry in Denmark. Various sources and their expected relative contributions to the establishment of clinical pharmacology in Denmark are discussed and evaluated. Danish regulatory statutes regarding drug registrations are described, and anticipated charges occasioned by Denmark's entry into the European Economic Community are discussed.
Present status of clinical pharmacology in Italy
Authors: Sirtori Cesare
Published: January 2016

An outline of the regulations and present activities in the field of clinical pharmacology in Italy is presented. Regulations concerning preclinical work are those of the European Economic Community, but no specific gUidelines for conducting clinical trials are available at the moment. The United States FDA requirements, however, are currently followed by most companies. A regulatory scheme on clinical pharmacology is being prepared and should become available shortly. Research work is being carried out in several industries as well as in University institutions. There is one official chair (University of Florence: Director, Prof. F. Sicuteri), and two courses are given at other universities. Leading work in Italy has been in the cardiovascular field, pain receptors, intermediary metabolism, antibiotics, and psychopharmaceuticals.
Clinical pharmacology in the United Kingdom
Authors: Smith Robert N.
Published: January 2016

The impetus for the establishment of academic clinical pharmacology units in the United Kingdom has often originated from concern regarding the teaching of pharmacology, and because of the unavailability of sufficient, trained personnel, and individual academic unit often centered around the interests of one pharmacologically oriented investigator. While industry had initiated clinical pharmacology independently, the thalidomide disaster with its resultant governmental legislation markedly accelerated the development of the field u;ithin the pharmaceutical industry. Although the workload upon the Committee for the Safety of Medicines (CSM) has increased currently with a resultant increase in the “process time,” the CSM, by utilizing a flexible and realistic attitude, has managed to avoid many of the problems the Food and Drug Administration (FDA) in the United States has encountered.
An overview from the United States
Authors: Besselaar G. Hein , Tempero Kenneth F.
Published: January 2016

This essay attempts, from personal conversations as well as from the foregoing papers, to collate and contrast the multifaceted situations and challenges being faced by clinical pharmacologists in various portions of the world and therefrom to delineate and contrast the logiC and approaches utilized, not only among the areas represented but also with regard to the United States. An effort is made to provide a brief overview of academia, government, and industry.
The biochemical pharmacology of abused drugs
Authors: Caldwell John , Sever Peter S.
Published: January 2016

All of the so‐called drugs of dependence have a powerful central nervous system (CNS) action as their main attraction for the prospective drug abuser. In the first part of our review, we cover the maior CNS stimulants, amphetamine and cocaine, and the hallucinogen, lysergic acid diethylamide (LSD). Cocaine is not of great significance in the current drug abuse scene due to its high cost (it is a plant product) and the difficulty in obtaining it. It now finds little application in medicine, so that it can rarely be obtained either by prescription or burglary of pharmacies. Its place has been taken by the amphetamines, most notably by methamphetamine (Speed); the amphetamines are readily available synthetic drugs. Cocaine and the amphetamines are popular with drug abusers seeking mood elevation. The appeal of LSD is to the introverted who perhaps seek self‐knowledge, and it has been used experimentally as an adiunct to psychotherapy of a range of mental disorders. While the therapeutic uses of LSD are outside normal practice, its illicit use to achieve self‐awareness has led to the appearance of the psychedelic subculture and to the development of alternative views of society.
Rating the presence and severity of opiate dependence
Authors: Wang Richard I. H. , Wiesen Richard L. , Lamid Sofian , Roh Byung L.
Published: January 2016

The means for rating dependence to narcotic drugs and determining the severity of physical dependence is examined, using the administration at 0.8 mg naloxone intramuscularly and assessing the severity of dependence mainly by the presence and time of appearance of withdrawal signs. Responses were studied in 75 patients with drug abuse problems. Naloxone or saline was administered double blind and at random. In methadone‐ and opiate‐dependent sub;ects, net withdrawal scores after naloxone differed significantly from those after saline. In nonopiate‐dependent patients, there was no significant difference between net scores after naloxone and after saline. The results at the investigation were confirmed by a crossover study in which naloxone and saline were administered to 4 patients with suspected opiate dependence.
Free and conjugated dopamine in plasma during levodopa therapy
Authors: Tyee Gertrude M. , Sharpless Nansie S. , Muenter Manfred D.
Published: January 2016

A method is described for the isolation aOO measurement of dopamine in plasma. Only nanogram quantities of dopamine were detected in plasma of patients during levodopa treatment for Parkinson's disease or of dogs given single oral doses of levodopa. Concentrations of conjugated dopamine in these plasma samples, determined by isolation and measurement of the dopamine produced after enzymatic hydrolysis of the conjugate, always greatly exceeded those of free dopamine. In contrast to most of the metabolites of levodopa, conjugated dopamine appeared to accumulate in plasma during levodopa treatment of patients. There was evidence of occasional occurrence of small amounts of conjugated 3‐0‐methyldopa in plasma of patients during levodopa treatment.
Metabolism and excretion of digitoxin in man
Authors: Vöhringer H. F. , Rietbrock N.
Published: January 2016

The levels of digitoxin and its metabolites in the plasma, urine, and feces of 6 subjects given a single oral dose of 1 mg 3H‐dgt have been determined using CHCl3‐extraction and thin‐layer chromatography (TLC). The peak plasma level of 4.1% of the given dose per 1 plasma occurred at 40 min after drug administration and was followed by an exponential decline with a mean half‐life (T/2) of 6.8 days. The T/2 of the eliminated radioactivity in urine and feces was 7.2 and 4.8 days, respectively. Within 192 hr, 22% of the given dose has been excreted in urine and 13% in feces. The TLC separation of the CHCl2‐soluble fraction in plasma yielded the unchanged digitoxin (dgt) and traces of digitoxigenin‐bisdigitoxoside (dgt‐bis). In urine, dgt accounted for 60% of the eliminated amount within the experimental time. Dgt‐bis and the hydroxylated products digoxin (dg) and dgt‐bis were also found in lesser anwunts. The monodigitoxoside of digitoxigenin (dgt‐mono) could be denwnstrated as a conjugative partner of glucuronic acid. In feces, the unchanged dgt and its monoderivative were the main excretion products. However, since dgt‐mono and the more polar compounds have shown an inverse relationship during the study, a bacterial cleavage following a conjugation of dgt‐mono and an enterohepatic circulation of its lipophilic nwiety are suggested. These results demonstrate the limited degradation of dgt in man and suggest that the pharmacologic effects are mediated by dgt itself.
The absorption of digoxin tablets
Authors: Binnion Peter F.
Published: January 2016

The digoxin in tablets from 4 different manufacturers was measured and found to be the same. The disintegration times for these tablets were different, and this measurement did not correlate with the plasma levels in subiects who took them. The tablet with the slowest disintegration rate produced satisfactory plasma digoxin concentrations. Another tablet, with slow dissolution rate, failed consistently to produce a therapeutic plasma level. All packages containing digoxin tablets should be labeled with data on their dissolution characteristics, but none should be sold unless these data are consistent with biologic availability.
Comparison of one‐ and six‐day urinary digoxin excretion in single‐dose bioavailability studies
Authors: Greenblatt David J. , Duhme David W. , Weser Jan Koch , Smith Thomas W.
Published: January 2016

Eight healthy males received oral and parenteral digoxin by 10 modes of administration in a total of 91 single‐dose, multicrossover bioavailability trials. One‐ and six‐day urinary excretions of digoxin were compared as measures of bioavailability. One‐ and six‐day eXCfetions were highly correlated (r = 0.94). Overall variability in the two measures was nearly identical. Thus 24 hours of urine collection is sufficient for single‐dose studies of digoxin bioavailability.
Aspects of skin biology pertinent to pharmacology
Authors: Van Scott Eugene J. , Yu Ruey J.
Published: January 2016

Diseases are clinically manifest as disturbances or distortions of normal cell form and/or function due to some etiologic influence. The etiology of only comparatively few diseases has been identified, and this has permitted development of pharmacologic materials that specifically attack the cause of disease (e.g., antibiotics) or that interfere with the etiologic agent exerting its adverse effects (e.g., sunscreens). Specific etiologies, however, are not known for most diseases. Hence, therapeutic materials available today are mostly drugs that either block the abnormal expressions of cell form or function manifest in the disease (e.g., corticosteroids) or exert inHuences re‐enforcing or enhancing expression of normal cell form or function (e.g., cancer immunotherapy). Despite the fact that most pharmacologic agents today do not attack cause of disease, their modification of disease expression constitutes effective therapy.
Pharmacokinetics of methotrexate
Authors: Azarnoff Daniel L. , Han Wan Suk , Huffman David H.
Published: January 2016

Methotrexate (Mtx) is a competitive inhibitor of the enzymatic activity of dihydrofolate reductase, decreasing the reduction of folic acid to tetrahydrofolate and thereby the activity of thymi dilate kinase. The net effect is a decrease in biosynthesis of deoxyribonucleic acid (DNA) primarily, but also of ribonucleic acid (RNA) and protein. Whereas the plasma elimination halflife of Mtx has previously been reported as 2 to 10 hours, we have recently demonstrated that intravenous administration of 30 mg 3H‐Mtx/M2 to patients with a variety of malignancies is followed by a triphasic disappearance of the drug from plasma with a half‐life of 0.75 ± 0.11, 3.49 ± 0.55, and 26.99 ± 0.44 hr, respectively.1 Similar values were obtained when the rate of excretion of MTx in urine was determined. The clearance in urine was 78 ml/min, and Mtx appeared to be reabsorbed at very low plasma concentrations. It was also noted that ingestion of meals, but not changes in pH, were associated with an increased rate of excretion, suggesting an enterohepatic circulation.
Urticaria
Authors: Greaves Malcolm W. , Yamamoto Shoso
Published: January 2016

The urticarial wheal can be looked upon as a local histamine secretory process consisting of three components: (1) a stimulus to secretion, (2) a cellular stimulus‐secretion coupling mechanism, and (3) a secretion.
Fungal infections
Authors: Utz John P. , Shadomy Smith
Published: January 2016

The number of effective chemotherapeutic agents presently available for serious mycotic infections is limited.5, 6 This is due in part to many problems encountered by both the basic scientist and the clinician, in the laboratory and clinical evaluation of such drugs. This report summarizes some of these problems particularly as they have affected our studies with such compounds as amphotericin B, flucytosine, hamycin, and clotrimazole.
Molecular and clinical pharmacology of psoriasis
Authors: Voorhees John J. , Duell Elizabeth A. , Stawiski Marek , Harrell E. Richard
Published: January 2016

Psoriasis appears in most cases to be a genetic disease8 in which stratified squamous epithelium (epidermis) of skin in involved versus normal‐appearing uninvolved areas has the following prototypic features: (1) excessive cell proliferation and an accelerated cell cycle of the proliferating cells21; (2) incomplete epidermal specialization (keratinization) for tissue function; and (3) marked increase in glycogen content.7 It has been widely held that the relative lack of epidermal specialization is due to the rapid transit of cells through the epidermis (i.e., the cells are shed from the patient without sufficient time for normal keratinization to occur). However, an alternate explanation is that the excessive cell proliferation is the result of an inability of differentiated basal cells to make the commitment of specialization. For this reason we have listed incomplete specialization as one of the three characteristic findings in psoriasis lesions.
Cutaneous uses of the antiproliferative drugs
Authors: McDonald Charles J.
Published: January 2016

The fortuitous observations of Richard Gubner, an internist, that psoriasis responded to systemic treatment with the antimetabolic agent aminopterin stimulated an interest in the use of anti proliferative drugs for skin diseases.10 The subsequent reports of Rees, Bennett, and Bostick,22 VanScott, Auerbach, and Weinstein,27 Callaway, McAfee, and Finlayson,5 and others corroborated these findings using aminopterin and the analogue methotrexate (MTX). Other investigators extended these observations on antimetabolic agents in psoriasis to include such antiproliferative drugs as triacetyl‐6‐azauridine26 and hydroxyurea.12
Actinic manifestations; Cutaneous diseases induced by the sun
Authors: Epstein John H.
Published: January 2016

Cutaneous disease induced by actinic rays from the sun have become commonplace within the last few decades due to a variety of factors. Among the most important of these are the increasing desire for the beneficial effects of a “good suntan” and the ever‐increasing numbers of photosensitizers entering our environment from pharmaceutical, industrial, and cosmetic sources.
The specificity of potassium canrenoate, a steroidal antidysrhythmic drug
Authors: Yeh Billy K. , Sung Pei-Kun , Lazzara Ralph
Published: January 2016

The antidysrhythmic property of potassium canrenoate [potassium 3‐(3‐oxo‐17β‐hydroxy‐4, 6‐androstadien‐17α‐yl) propanoatel was studied in ventricular dysrhythmias induced by ouabain, norepinephrine, barium, and strontium, as well as ligation of the anterior descending coronary artery in dogs anesthetized with sodium pentobarbital. Potassium canrenoate (KC) (12 mg/kg) was effective in abolishing the ouabain‐induced ventricular bigeminy and ventricular tachycardia without significantly altering the inotropic response of the heart to ouabain. Our previous data indicate that equimolar amounts of potassium chloride were ineffective under the same circumstances. KC (12 mg/kg) had no effect on ventricular dysrhythmias caused by norepinephrine and myocardial infarction. Up to 30 mg/kg KC did not suppress ventricular tachycardia induced by barium or strontium. The canrenoate molecule appears to be a specific antagonist to the electrophysiologic toxicity of cardiac glycosides.
Effect of propranolol on morphine metabolism
Authors: Brunk S. Fred , Delle Margrieta , Wilson William R.
Published: January 2016

Morphine metabolism was studied in 12 normal subjects. Six were studied before and while receiving propranolol, 20 mg every 6 hr, and 6 were studied before and while receiving propranolol, 40 mg every 6 hr. The study was performed to determine whether propranolol affects morphine metabolism or morphine‐induced respiratory depression. Plasma and urinary levels of free morphine and conjugated morphine when propranolol and morphine were given together were similar to the levels after morphine alone. Respiratory minute volumes, while breathing a 4% CO2 in air mixture, were also unchanged from control. The findings indicate that propranolol does not affect morphine metabolism or morphine‐induced respiratory depression in man.
Comparison of plasma levels of antipyrine, tolbutamide, and warfarin after oral and intravenous administration
Authors: Andreasen Per Buch , Vesell Elliot S.
Published: January 2016

Separated by an interval of at least one week, single oral and intravenous doses of either antipyrine (18 mg/kg), tolbutamide (15 mg/kg), or warfarin (0.75 mg/kg) were given to normal volunteers. Each drug was administered as an aqueous solution. The oral and intravenous routes of administration of each of these drugs produced very similm extrapolated Y intercepts, plasma half‐lives, apparent volumes of distribution, and metabolic clearance rates. Three patients with cirrhosis of the liver also received antipyrine by oral and intravenous routes; there were no significant pharmacokinetic differences.
Radioimmunoassay of plasma nicotine in habituated and naive smokers
Authors: Haines Carroll F. , Mahajan Damodar K. , Miljkovic̄ Dusan , Miljkovic̄ Momc̄ilo , Vesell Elliot S.
Published: January 2016

A new radioimmulWassay sufficiently sensitive and specific to permit estimation of nicotine in human plasma in the presence of its principal metabolite, cotinine, is described. Plasma nicotine concentrations determined after inhalation of ten puffs of cigarette smoke were higher for each of seven time points in habituated than in naive smokers. Mean nicotine concentrations of 6 habituated and 6 naive smokers one minute after cessation of smoking were 20.6 ± 3.4 and 7.6 ± 2.9 ng/ml, respectively. Studies on buccal absorption of nicotine in volunteers who smoked 10 puffs, holding each puff in the mouth for 10 seconds without inhalation of smoke, revealed similar plasma nicotine concentrations one minute after smoking of 1.4 ± 0.4 and 1.2 ± 0.2 ng/ml for habituated and naive smokers, respectively. Blank values for nicotine in each subject were obtained prior to smoking and subtracted from subsequent plasma nicotine concentrations. Means of blank values for nicotine in fasted naive and habituated smokers who refrained from smoking at least 8 hours prior to the experiments were 4.5 ± 1.3 and 3.8 ± 0.7 ng/ml, respectively.
Intravenous digoxin as a bioavailability standard
Authors: Stoll Roger G. , Wagner John G. , Greenblatt David J. , Duhme David W. , Koch-Weser Jan , Smith Thomas W. , Tilstone W. J. , Reavey P. C.
Published: January 2016

In a recent publication in this JOURNAL, Greenblatt and associates3 recommended that the “administration of digoxin by slow infusion is preferable as an intravenous standard in bioavailability testing” as opposed to a rapid intravenous injection. While we do not necessarily disagree with this conclusion, we do disagree with the reasons cited in their publication to support this contention. Because of the likely influence an article such as this may have on federal regulatory procedures, we would like to express our alternative viewpoints as related to their study.
Hemolysis induced by 6‐N‐hydroxylaminopurine riboside, an adenosine analogue
Authors: Dollinger Malin R. , Krakoff Irwin H.
Published: January 2016

6‐N‐Hydroxylaminopurine riboside (HAPR) was studied in man because of its therapeutic activity in several transplanted animal neoplasms. It was not cross‐resistant to other antimetabolites useful in the treatment of human neoplasia. HAPR produced marked hemolytic anemia at doses far below those that might have produced any cytotoxic or therapeutic effect. There was evidence of hemolysis at total doses as low as 0.5 mg/kg given intravenously. For man, HAPR is one of the most active hemolytic drugs.
Clinical pharmacology of O2,2'‐cyclocytidine
Authors: Ho D. H. W. , Rodriguez V. , Loo Ti Li , Bodey G. P. , Freireich E. J
Published: January 2016

Two metabolites of 2‐14C‐cyclocytidine (cyclo‐C) were found in the plasma and urine and a hydrolytic product, arabinosylcytosine (ara‐C), and its deaminated product, arabinosyluracil (ara‐U), were found in patients with cancer; 80% of the dose was found in urine in 24 hr, 70% as cyclo‐C and 10% as ara‐C and ara‐U. The plasma disappearance curve of ara‐C is curvilinear; the half‐life of ara‐C estimated from the terminal phase is 8 hr. By 6 hr, the ara‐C level is 0.35 µg/ml and falls exponentially to 0.06 µ/ml by 24 hr. Plasma concentration ratios of ara‐U to ara‐C are 0.1 to 0.3, 0.3 to 0.4, and 1.1 to 1.3 at 10 min, 1 hr, and 4 hr following intravenous injection of cyclo‐C at 200 mg/m2. Five min after an equal dose of ara‐C, this ratio is approximately 2, and by 4 hr, plasma ara‐C levels are immeasurable. After intramuscular and subcutaneous administration, cyclo‐C is rapidly absorbed. The plasma disappearance curves of the cyclo‐C hydrolytic product, ara‐C, are similar to those of the intravenous route. Intramuscularly, subcutaneously, and intravenously cyclo‐C should be equally effective. Intrathecal injections of cyclo‐C (50 mg/m2) result in an effective ara‐C level (0.1 µ/ml) in cerebrospinal fluid (CSF) at 24 hr. When cyclo‐C is given orally to fasting patients, less than 15% of the dose is excreted in urine in 24 hr and none can be detected in the plasma.
Anticoagulant potency of mucosal and lung heparin
Authors: McMahon F. Gilbert , Jain Adesh K. , Ryan Jerome R. , Lefton Theodore E.
Published: January 2016

Hog mucosal heparin was compared with beef lung heparin in 24 healthy male and female subjects by double‐blind crossover study, by both intravenous and subcutaneous routes, to determine their relative anticoagulation effects as estimated by the activated partial thromboplastin test. Both drugs by both routes induced therapeutically comparable anticoagulation effects, without adverse experience. Thus both products are equivalent, unit for unit.
Long‐term treatment of hypercholesterolemia with colestipol hydrochloride
Authors: Ryan Jerome R. , Jain Adesh K. , McMahon F. Gilbert
Published: January 2016

Colestipol hydrochloride (15 gm/day) (an anion exchange resin that binds bile acids) or placebo was administered to 92 patients with hypercholesterolemia who were followed for periods up to 36 months. There was a prompt (1 month), significant (p < 0.05‐0.001), and sustained (36 months) lowering of serum cholesterol in the colestipol HCl‐treated group, but no significant change in the placebo group. Serum triglycerides increased in both treatment groups in parallel; the reason was not apparent. Side effects were equally distributed between colestipol HCI and placebo and were primarily gastrointestinal (upper abdominal distress, constipation). Colestipol HCI appears to be a safe and effective treatment for hypercholesterolemia; tolerance does not seem to develop.
Antiarrhythmic activity of four pteridine compounds in ouabain intoxication
Authors: Yeh Billy K. , Francis James S. , Gosselin Arthur J. , Elias Richard A.
Published: January 2016

The antiarrhythmic effects of 4 pteridine analogues, 2 of which are potassium‐sparing diuretics, triamterene (2, 4, 7‐triamino‐6‐phenylpteridine) and [2‐phenyl‐4, 7 diaminopteridine‐6‐(N‐diethylaminoethyl) carboxamide] and 2 of which have no diuretic effects [2‐phenyl‐4, 7‐diaminopteridine‐6‐(N‐2‐hydroxyethyl) carboxamide] and [2‐phenyl‐4, 7 diaminopteridine‐6‐(N‐dimethylaminopropyl) carboxamide], on ouabain‐induced ventricular tachycardia in intact pentobarbital‐anesthetized dogs were investigated. Ouabain was given as a continuous infusion 2 µg/kg/min intravenously until 5 min after the onset of a sustained ventricular tachycardia. It was found that both 6‐(N‐dimethylaminopropyl) and 6‐(N‐diethylaminoethyl) carboxamide derivates of the pteridine had a significant protective effect against ouabain‐induced ventricular tachycardia in dogs that had been pretreated with a dose of 5 mg/kg intravenously. At this dose the 2 pteridine compounds with diuretic activity exhibited a transient antiarrhythmic effect in abolishing the ouabain‐induced ventricular tachycardia while those without diuretic properties failed to suppress the ventricular tachycardia.
Pharmacology and Therapeutics
Authors: Carr Edward A.
Published: January 2016

To become competent and to stay competent in any area of clinical pharmacology and therapeutics gets more difficult each year. The problem of keeping up with the rapid and accelerating growth of new knowledge is compounded by the difficulty in choosing among a large number of meetings, courses, and workshops that compete for our time, our attention, and our shrunken travel budgets.
Heparin half‐life in normal and impaired renal function
Authors: Ignoffo Robert J. , Perry Paul J. , Blachly Paul H.
Published: January 2016

I read with great interest the article by Dr. Paul Perry and associates entitled “Heparin half‐life in normal and impaired renal function,” which appeared in the September, 1974, issue of the JOURNAL. It appears that the heparin infusion rate equation as derived by Dr. Perry is not substantiated by the half‐life values obtained from the study patients. A half‐life of 37 min is reported for normal patients given a dose of heparin sufficient to produce a plasma concentration of 0.6 U/ml. A half‐life of 37 min can be converted to a plasma elimination constant of 1.13 hr−1.
Double‐blind study of the analgesic effect of indoprofen (K 4277)
Authors: Fuccella Luciano M. , Conti Franco , Corvi Giulio , Mandelli Virginio , Randelli Mario , Stefanelli Giuseppe
Published: January 2016

In a double‐blind study, indoprofen was superior to placebo in decreasing pain in patients with primary and metastatic cancer and with neuralgia. A single oral dose of 200 mg was more active than a 100‐mg dose. The preferences of patients proved to be a more sensitive parameter in this study than scores of pain intensity, pain relief, and other related measurements (SPID, TOTPAR, and Peak PID).
Indoprofen, a new analgesic and anti‐inflammatory drug in cancer pain
Authors: Ventafridda V. , Martino G. , Mandelli V. , Emanueli A.
Published: January 2016

Evaluation of the analgesic activity of indoprofen was carried out in patients with cancer pain under double‐blind conditions and compared with aspirin and placebo. A randomized experimental design was followed. Single oral doses were given of the test drug (100 and 200 mg), aspirin (600 and 1,000 mg), and placebo. For measuring analgesia, 5‐point pain intensity and pain relief semiquantitative scales were used. Potency ratio between drugs was calculated on SPID (sum of pain intensity differences) and TOTPAR (total pain relief) and resulted in 10.3 by combination of estimates. In a group of only 24 patients, the data supported the following conclusions: indoprofen at 100 and 200 mg single doses is effective in relieving cancer pain; it displays a dose‐related analgesic effect comparable to that of aspirin with only one‐tenth the dose.
Pharmacokinetics and metabolism of digoxin‐ and β‐methyl‐digoxin‐12α‐3H in patients with acute hepatitis
Authors: Zilly W. , Richter E. , Rietbrock N.
Published: January 2016

Pharmacokinetics and metabolism of digoxin and β‐methyldigoxin have been studied in patients with acute hepatitis after intravenous administration of both 3H‐labeled glycosides. In contrast to digoxin, the rate of decline of radioactivity after administration of β‐methyldigoxin was significantly retarded in patients with acute hepatitis. The increase in plasma concentration after β‐methyldigoxin to patients with acute hepatitis is probably related to decreased demethylation.
Studies on digitalis. III. Biliary excretion and enterohepatic circulation of digitoxin and its cardioactive metabolites
Authors: Storstein Liv
Published: January 2016

Simultaneous serum, urine, and bile measurements of digitoxin and its cardioactive metabolites were performed in 5 cholecystectomized patients with T tube drainage. A 86Rb method was used for serum and urine analysis. The recovery of digitoxin and cardioactive metabolites in two extractions with dichloromethane was 93%; 7% was left in bile. Peak bile concentrations had a mean value of 41.6 ng/ml and were seen after 15 to 60 min. Bile concentration was higher than serum and urine concentration after 24 hr. Mean T/2 of serum elimination was 4.3 days and 8.1 days in 5 control subjects (p < 0.01). Mean urine concentration T/2 was 10.4 days and 7.2 days in the control subjects (not significant). Mean bile concentration T/2 was 3.5 days. Urinary excretion of digitoxin and cardioactive metabolites was the same in the two groups. The biliary fistula group excreted 22.5% in urine and bile of a dose after 8 days, whereas it was 15.8% in the control subjects. The ratio between the cumulative excretion in urine and bile varied between 1.6 and 2.2. These findings demonstrate that direct interruption of the enterohepatic circulation leads to a marked reduction in serum half‐time of digitoxin and cardioactive metabolites, but T/2 is still longer than for other glycosides, indicating that factors other than the enterohepatic circulation are of importance in the slow elimination of digitoxin.