bluuebunny/crossref_metadata_2025 huggingface dataset:
Digoxin Pharmacokinetics in Congestive Heart Failure
Authors: APPLEFELD MARK M. , ADIR JOSEPH , CROUTHAMEL WILLIAM G. , ROFFMAN DAVID S.
Published: March 2013

Abstract: The steady‐state pharmacokinetics of oral digoxin in eight hospitalized patients was compared upon their admission with marked right‐sided congestive heart failure and later when they were compensated. Large intersubject variations in the serum digoxin concentration profiles were observed. However, over a 24‐hour dosing interval, digoxin concentrations in each patient studied during heart failure were either similar or higher than those observed when the patient became compensated. There were no significant differences in digoxin half‐life of elimination between the two states. In contrast, the mean ratio of the fraction of digoxin dose absorbed to its apparent volume of distribution was increased by 37 per cent (P < 0.05) in heart failure. Contrary to the prevailing notion, we found that the oral administration of supplemental doses of digoxin only on the basis of its reduced serum concentration in patients with congestive heart failure is unwarranted.
The Study of Analgesics Following Single and Repeated Doses
Authors: WANG RICHARD I.H. , JOHNSON ROGER P. , ROBINSON NANCY , WAITE ELIZABETH
Published: March 2013

Abstract: The efficacy and safety of 0.3 mg buprenorphine on single and repeated intramuscular administration (every 4 to 8 hours as needed) were compared to those of 10 mg intramuscular morphine. Fifty adult patients experiencing moderate to severe postoperative pain were evaluated up to three days following surgery. Results showed that 0.3 mg buprenorphine was as effective as 10 mg morphine, whether given as a single dose or on a repeat‐dose schedule. The patterns of analgesia were similar and without indication of increasing dosage requirements with time. Minor side effects encountered were brief and minimal, including such conditions as drowsiness, dizziness, diaphoresis, flushing, and nausea.
Development of Pulmonary Edema Related to Heparin Administration
Authors: AHMED S. SULTAN , NUSSBAUM MURRAY
Published: March 2013

Abstract: Bleeding, thrombocytopenia, and osteopenia are recognized as the side effects of heparin administration. We recently noted occurrence of pulmonary edema in a patient with myelofibrosis with myeloid metaplasia being treated with heparin for pulmonary embolism. The hypertensive episodes preceding left ventricular failure were considered related to serotonin released from the immunologically mediated lowering of platelets.
The Case Control or Retrospective Study In Retrospect
Authors: SMITH M. WRYNN
Published: March 2013

Abstract: The epidemiologic case control design is described against background information on its resurgence in popularity despite historical criticisms posed by its detractors. Weaknesses charged to the design by Feinstein and others such as its potential for recall bias in the use of retrospective data, Neyman's case selection bias, and the diagnostic suspicion bias are analyzed and shown to affect both the cohort incidence design and the clinical trial design as well as the case control.
The Effects of Insulin on Vasoconstrictor Responses in Pithed Rats
Authors: CAVALIERE THOMAS A. , TAYLOR DAVID Q.
Published: March 2013

Abstract: Pressor responses to spinal sympathetic outflow and selected vasoactive agents were examined in control and diabetic Wistar‐Kyoto pithed rats. Diabetes was induced by intravenous injection of alloxan (50 mg/kg). One week after the diabetogen, some of the rats were treated with one daily subcutaneous injection of Lente insulin (2 U/100 Gm) for five weeks. All rats were pithed at six weeks after alloxan. Vasoconstrictor responses to spinal sympathetic outflow, serotonin, norephinephrine, tyramine, and angiotensin were reduced in diabetic rats as compared to their age‐matched controls. Administration of insulin caused only partial normalization of these responses. Nondiabetic rats given insulin exhibited vascular responsiveness similar to the treated diabetic group of animals. Blood pressures and heart rates were also found to be similar between the insulin‐treated groups and significantly less than control. The finding that insulin does not produce complete normalization of vasoconstrictor responsiveness in diabetic rats may be relevant to the reduced blood pressure observed following insulin treatment.
Hepatic Microsomal Induction in Rat Liver: Heterogeneity of Response
Authors: KIERNAN THOMAS W. , LUISADA‐OPPER A. , ERTEL NORMAN H.
Published: March 2013

Abstract: The concept that urinary 6‐hydroxycortisol excretion patterns reflect all microsomal enzyme activities remains a subject of controversy. Three different microsomal hydroxylase activities were therefore studied in rat liver after the animals were intoxicated with alcohol, phenobarbital, or a combination thereof. The activities of pentobarbital hydroxylase, aniline hydroxylase, and cortisol 6‐hydroxylase (the enzyme metabolizing cortisol to 6‐hydroxycortisol) were assayed simultaneously after each treatment. A heterogeneity of enzyme activities was noted. Cortisol 6‐hydroxylase activity did not parallel the activity patterns of the two other hydroxylases. The data suggest that before urinary 6‐hydroxycortisol excretion patterns can be utilized as an index of microsomal enzyme induction, the effect of the specific drug on individual cytochrome P‐450 hydroxylases is required.
The Effect of Obesity on Acetaminophen Pharmacokinetics in Man
Authors: LEE WINSTON H. , KRAMER WILLIAM G. , GRANVILLE GEORGE E.
Published: March 2013

Abstract: This study examined the absorption and disposition of orally administered acetaminophen in morbidly obese patients as compared to subjects of normal weight, and possible changes in disposition as the patients underwent weight reduction through dietary modification. The overall disposition of acetaminophen was not affected by a weight loss of 8 to 30 kg; elimination half‐life, time to reach the peak, and peak plasma concentration varied within each subject but not in a systematic way. The half‐life was the same in the obese patients (2.6 ± 0.85 hours) and normal subjects (2.6 ± 0.12 hours). However, maximum plasma concentrations were reached at a significantly later time and were significantly lower in the obese patients as compared to the normals, implying an apparently lower absorption rate. The area under the plasma concentration‐time curve for the obese patients when normalized to ideal body weight was more consistent with that in the normal subjects than when normalized to total body weight. Administration of a normal dose of acetaminophen to an obese patient should yield plasma levels in the same range as persons of normal weight. As total weight may exceed 200 per cent of the ideal weight in this patient group, dosing according to total rather than ideal weight could lead to toxic or lethal effects when using the 10 mg/kg dosing recommendation.
Effect of Obesity on Gentamicin Pharmacokinetics
Authors: SKETRIS INGRID , LESAR TIMOTHY , ZASKE DARWIN E. , CIPOLLE ROBERT J.
Published: March 2013

Abstract: The effect of obesity on gentamicin disposition was studied in 60 obstetric and gynecologic patients receiving treatment for Gram‐negative infections. Thirty patients whose body weights were within 20 per cent of their ideal body weight were the control group. Thirty additional patients had body weights at least 30 per cent greater than ideal body weight and were the obese group. The two groups had similar ages, heights, ideal body weights (IBW), lean body weights (LBW), and elimination rates of gentamicin. The distribution volumes, expressed as liters or standardized to ideal body weight, lean body weight, or total body weight, were significantly different in the controls from those in obese patients. The distribution volume averaged (± S.D.) 0.19 ± 0.06 l./kg in controls. The contribution of excess weight to additional drug volume averaged (± S.D.) 0.05 ± 0.16 l./kg. Excess weight thus contributes less volume per kilogram than ideal body weight or lean body weight. A substantial interpatient variability existed in the measured distribution volume for all groups. Measuring serum concentrations and adjusting a patient's dosage regimen are imperative to ensure therapeutic serum concentrations.
Pilot Study on Bioavailability of Coumarin and 7‐Hydroxycoumarin upon Peroral Administration of Coumarin in a Sustained‐Release Dosage Form
Authors: RITSCHEL W. A. , HOFFMANN K. A.
Published: March 2013

Abstract: Prolonged‐release tablets containing coumarin were compared to intravenous and peroral administration of coumarin solution in man. Unchanged coumarin, the Phase I metabolite 7‐hydroxycoumarin, and the Phase II metabolite 7‐hydroxycoumarin glucuronide were determined in whole blood. Upon peroral administration, only approximately 1 per cent coumarin was found unchanged in the systemic circulation. However, the amount of the glucuronide found indicates complete absorption with extensive first‐pass effect. When the prolonged‐release dosage form was compared to the peroral solution, the extent of bioavailability of coumarin was 35 per cent, whereas the 7‐hydroxycoumarin glucuronide was totally available. This supports the hypothesis that coumarin might be a prodrug and 7‐hydroxycoumarin the active moiety. The drug liberation of coumarin from the sustained‐release tablets follows first‐order kinetics. A linear correlation was found between per cent of drug released in vitro and the area under the concentration‐time curve, AUC (0‐t), of total 7‐hydroxycoumarin (7HC + 7HCG).
The Assessment of the Intrasubject Variability in Digoxin Absorption in Man from Two Oral Dosage Forms
Authors: YACOBI AVRAHAM , STOLL ROGER G. , CHAO GEORGE C. , SCHWARTZ RONALD A. , WEIDLER DONALD J. , AYERS JAMES W. , SAKMAR ERMELINDA , HALLMARK MARGARETTE , WAGNER JOHN G.
Published: March 2013

Abstract: The reproducibility of drug absorption within a given subject as well as the evaluation of bioavailability of two digoxin dosage forms were studied. The data showed (a) a higher initial plasma digoxin concentration after the soft elastic gelatin (SEG) capsule; (b) a more irregular absorption after the tablet; (c) on the average, the coefficients of variation of individual plasma concentrations were lower after the capsule; and (d) for the capsule, the intrasubject variations of the peak plasma concentrations, time of peak, area under plasma concentrations‐versus‐time curve (AUC), and amount digoxin excreted in urine (Ae) were on the average 60 per cent of the variations in the tablet parameters. The ratios of AUC and Ae for capsule/tablet were essentially unity, indicating that the amount digoxin absorbed from the 0.4‐mg digoxin SEG capsule is identical to that from a 0.5‐mg standard reference tablet.
Effect of Probenecid on Response to Bumetanide in Man
Authors: BRATER D. CRAIG , CHENNAVASIN POLAVAT
Published: March 2013

Abstract: We administered 0.5‐ and 1.0‐mg doses of bumetanide intravenously to eight normal subjects with and without pretreatment with probenecid. Probenecid did not affect either the cumulative response or the time course of response of bumetanide. These results are in contrast to results reported in dogs but consistent with similar studies in cats. The data imply that probenecid and potentially other exogenous or endogenous organic acids do not affect the renal handling of bumetanide in normal man.
Hypotensive Effects of Xipamide in Essential Hypertension. Crossover Comparison With Hydrochlorothiazide
Authors: PASQUEL RENATO , TRIBBLE PHOEBE WRIGHT , SIMON ARTHUR
Published: March 2013

Abstract: Twenty‐nine patients with mild to severe essential hypertension were treated with titrated doses of xipamide, before or after treatment with 50 and, if necessary, 100 mg hydrochlorothiazide in a 13‐ to 25‐week open crossover study. Based on supine diastolic pressure readings taken at weekly intervals, xipamide controlled hypertension in all subjects: 17 achieved control with a daily dose of 5 mg; seven, with 10 mg; and five, with 20 mg. In contrast, eight of the 29 patients could not be controlled with 100 mg/day hydrochlorothiazide. The only significant biochemical change observed was an increase in serum uric acid in 12 patients after hydrochlorothiazide but in only six patients after xipamide. Natriuresis was comparable after both drugs: 5 and 10 mg xipamide were as effective as 50 and 100 mg hydrochlorothiazide. The only side effect noted, cramping due to hypokalemia, occurred during treatment with hydrochlorothiazide, but not xipamide, and was reversed by potassium supplements.
Multidose/Observational, Comparative Clinical Analgetic Evaluation of Buprenorphine
Authors: MOK MARTIN S. , LIPPMANN MAURICE , STEEN STEPHEN N.
Published: March 2013

Abstract: Ninety‐eight patients completed a double‐blind, multidose, randomized parallel study in which buprenorphine (Temgesic) was compared to morphine. Drugs were administered at approximately equipotent intramuscular doses for a maximum of three days for the relief of moderate to severe postoperative pain. The two drugs exhibited similar profiles with pain relief evident at ½ hour, peaking at 1 hour, and decreasing to slight relief at 4–5 hours, with no significant differences for time to remedication. The most frequent side effect was somnolence. One patient suffered sudden chest pain shortly after an injection of morphine, and one patient had moderate hypoventilation after buprenorphine; both patients recovered uneventfully. Overall, both drugs provided good or excellent analgesia in 80 per cent of the patients in this unique multidose/observational study. Thus, these data and the reported lack of withdrawal symptoms and the absence of physical dependence liability suggest that buprenorphine may have a role in the management of chronic pain.
The Specificity of the Extraction Fluorescence Assay for Serum or Plasma Quinidine
Authors: GREENBLATT DAVID J. , WOO ELAINE
Published: March 2013

Abstract: A series of 26 randomly selected serum samples from patients receiving long‐term antiarrhythmic therapy with oral quinidine preparation were assayed by both a modification of the extraction fluorescence technique and high‐pressure liquid chromatography, with highly comparable results (r = 0.98). A review of the literature on comparing the extraction fluorescence techniques results with other methods indicates a high degree of agreement. However, because variations from study to study exist, investigators using the extraction fluorescence technique should assess the specificity of the method in their own laboratory.
The Pharmacokinetics and Pharmacology of Oral Diltiazem in Normal Volunteers
Authors: KINNEY EVLIN L. , MOSKOWITZ RALPH M. , ZELIS ROBERT
Published: March 2013

Abstract: Oral diltiazem is being used increasingly in the treatment of Prinzmetal's angina. This study investigated the pharmacokinetics, electrocardiographic effects, and blood pressure response of normal male volunteers to various single oral doses of diltiazem. Doses selected were 30, 60, 90, and 120 mg. Thirteen subjects received 30 mg. 12 subjects received 60 mg, 10 subjects received 90 mg, diltiazem, and four subjects received 120 mg diltiazem AUCs for the 60, 90, and 120 mg doses were 565, 984, and 1258 ng/ml · hr, respectively. The values for t½, β, and tmax were similar after each dosing.
Comparison of the Effects of Dopamine, Hydralazine, and Isosorbide Dinitrate on Myocardial Hemodynamics in Patients with Refractory Heart Failure
Authors: BIDDLE THEODORE L. , MOSES H. WESTON
Published: March 2013

Abstract: Nine patients with refractory congestive heart failure underwent hemodynamic study first with dopamine and then with oral hydralazine and sublingual isosorbide dinitrate. Although hemodynamic improvement was achieved with both forms of therapy, the beneficial effects of hydralazine alone or with isosorbide were superior to those of dopamine, as manifested by a greater reduction of wedge pressure and greater increase in stroke index. Six patients who demonstrated an increased wedge pressure during dopamine infusion were observed to manifesta louder apical systolic murmur and/or V wave in the wedge pressure tracing suggestive of enhanced mitral regurgitation. The rise in wedge pressure on dopamine could also be a consequence of increased myocardial ischemia and a resultant decrease in ventricular compliance. It is possible that a subgroup of patients with heart failure are made worse by dopamine, and in these cases vasodilator therapy may be more beneficial.
Comparison of Molindone and Tranylcypromine in the Treatment of Refractory Depression
Authors: SMALL JOYCE G. , KELLAMS JEFFREY J. , DENNIS JERRY L. , MILSTEIN VICTOR
Published: March 2013

Abstract: A single‐blind parallel study of 20 treatment‐resistant hospitalized depressed patients showed that 10–30 mg/day molindone was more effective and less toxic than 20–30 mg tranylcypromine. Molindone‐treated patients responded during the first week with particular improvement in anxiety symptoms and agitation. Extrapyramidal symptoms developed in half of the patients on molindone, which were effectively managed with amantadine. Early termination from the study because of clinical worsening or side effects occurred in seven patients on tranylcypromine and in none on molindone. These results suggest that molindone in low dosage may be helpful in the management of refractory depression and may have the further advantage of producing a more rapid response to treatment with fewer disabling side effects.
Drug‐Induced Liver Disease
Authors: JICK HERSHEL , WALKER ALEXANDER M. , PORTER JANE
Published: March 2013

Abstract: All cases of diagnosed drug‐induced hepatitis were identified in a series of 66,995 hospitalized medical and surgical patients. There were 11 cases which resulted from drugs taken for the first time in hospital and an additional nine cases resulting from drugs taken by patients prior to admission. Liver damage occurred relatively often after the use of antitumor drugs and anabolic steroids, but it was otherwise rare.
Hydrochlorothiazide‐Induced 131I Excretion Facilitated by Salt and Water
Authors: BEYER KARL H. , FEHR DAVID M. , GELARDEN R. THOMAS , WHITE WILLIAM J. , LANG C. MAX , VESELL ELLIOT S.
Published: March 2013

Abstract: Salt intake is restricted under clinical conditions for which thiazide diuretics are customarily used. Dietary iodide intake offsets any effect of thiazide on iodide loss. However, our correlation coefficients relating Na+ to Cl− to l− excretion indicate that as thiazide administration or sodium chloride intake increases renal Na+ and Cl− excretion, l− reabsorption by the nephron coordinately decreases. Increased sodium chloride and water intake by the dog doubled l−excretion rates. Hydrochlorothiazide increased the sodium chloride and water enhanced l−excretion rate as much as eight‐fold. Without added NaCl, hydrochlorothiazide increased the excretion rate of 131I by three‐ to eightfold, acutely. Within five to seven days after 131I oral administration, hydrochlorothiazide (1 or 2 mg/kg twice daily) doubled the rate of 131I disappearance from plasma, reduced the fecal output of 131I, and increased its rate of renal excretion. When hydrochlorothiazide was administered, as much 131I was excreted in the first 24 hours as occurred in 48 hours when sodium chloride and water were given without hydrochlorothiazide. Thiazide administration in customary clinical dosage twice a day with substantial sodium chloride and water for the first two days after exposure to 131I, should therefore facilitate the safe excretion of 131I. This accelerated removal of 131I might be enhanced even more if thyroid uptake of 131I is blocked by administration of potassium iodide, as judged by the greater 131I recovery from thyroidectomized dogs.
Comparison of the Inotropic and Chronotropic Effects of Metoprolol and Propranolol
Authors: CONRAD KENNETH A.
Published: March 2013

Abstract: The cardiovascular responses to intravenous doses of isoproterenol were measured in eight male volunteers before and during administration of 50 mg metoprolol, orally every 6 hours and 40 mg propranolol, orally every 6 hours for a total of five doses. The dose of isoproterenol required to produce an increase in heart rate of 25 beats/min (the ID25) was 2.0 ± 1.4 μg before beta blockade, 6.2 ± 4.4 μg during metoprolol, and 44.4 ± 12.0 μg during propranolol administration. Similar changes in diastolic blood pressure, QS2I, preejection period, and preejection period/left ventricular ejection time ratio occurred at the ID25 during treatment with both metoprolol and propranolol. In volunteers, propranolol produces a much more intense blockade of the inotropic and chronotropic effects of isoproterenol than does metoprolol.
Comparative Protein Binding of Diazepam and Desmethyldiazepam*
Authors: ALLEN MARCIA DIVOLL , GREENBLATT DAVID J.
Published: March 2013

Abstract: The extent of plasma protein binding of diazepam (DZ) and its major metabolite, desmethyldiazepam (DMDZ), was determined by equilibrium dialysis in plasma samples drawn from 62 nonfasting unheparinized volunteers aged 20 to 85 years. The free fraction for diazepam averaged 1.48 per cent (range 0.85 to 2.30 per cent) and increased with age (r = 0.33). Desmethyldiazepam also was extensively bound. The mean free fraction was 2.97 per cent (range 1.78 to 5.28 per cent) and increased with age (r = 0.27). Free fractions for both diazepam and desmethyldiazepam were negatively correlated with plasma albumin concentration (r = −0.17 and − 0.39). However, age, sex, and albumin explained only a small proportion of variability in free fraction for either compound. Free fraction for desmethyldiazepam always exceeded that for diazepam, and the two were correlated (r = 0.32). Thus, at any given total plasma concentration, the unbound concentration of desmethyldiazepam will exceed that of diazepam.
An Overview of Clinical Pharmacy and Clinical Pharmacology
Authors: MILLER RUSSELL R.
Published: March 2013

Abstract: The relationship between clinical pharmacy and clinical pharmacology can best be assessed by looking at the three major responsibilites of these related professional disciplines—research, education, and patient care. Clinical pharmacologists will continue to dominate clinical research, but clinical pharmacists will continue to expand their contributions in all types of research. Clinical pharmacists are beginning to assume responsibility for providing training in rational therapeutics to medical students and house staff and, because of their greater numbers, probably will ultimately have a greater influence than clinical pharmacologists in this area. Similarly, clinical pharmacists appear to have greater influence on day‐to‐day patient care than clinical pharmacologists. Successful pursuit of all of these activities by clinical pharmacists assumes a continuing supply of well‐trained practitioners. However, many pharmacy schools do not provide adequate classroom and bedside training. This is an unfortunate trend that seems to be accelerating as many schools convert from baccalaureate to doctoral entry degree programs without adequate clinical faculty and teaching hospital facilities.
The Clinical Pharmacist and Research
Authors: EVANS WILLIAM E.
Published: March 2013

Abstract:The question of whether or not clinical pharmacists are capable of performing meaningful research is addressed by reviewing the qualifications necessary for anyone to pursue an independent research career and by examining the current education and training of most clinical pharmacists. The types of research which appear to be best suited for clinical pharmacists include preclinical or clinical evaluations of basic science principles potentially affecting the therapeutic use of drugs in man, or the evaluation of clinical characteristics which alter the response to drugs in routine clinical use. It is concluded that clinical pharmacists with the appropriate postgraduate training and/or experience are capable of conducting meaningful research, and this is documented by current literature citations.
Clinical Pharmacy Functions in Ambulatory Patient Care
Authors: HAWKINS DAVID W.
Published: March 2013

Abstract: A functional interpretation of clinical pharmacy as an implementing mechanism for extending the objectives and responsibilities of clinical pharmacology in ambulatory patient care is presented. Evidence is given to support the effectiveness of the clinical pharmacist in assisting primary care physicians with the design of optimal drug regimens and evaluating and managing patients on chronic drug therapy. Opportunities for the clinical pharmacist to carry out long‐term drug trials and participate in the design and execution of epidemiological drug studies are also discussed. The clinical pharmacist can make important contributions to ambulatory patient care in areas of drug treatment and evaluation by working in concert with primary care physicians and clinical pharmacologists.
The Role of the Clinical Pharmacist in the Institutional Setting
Authors: CUPIT GARY C.
Published: March 2013

Abstract: The role of the clinical pharmacist in the institutional setting has been expanding at an ever increasing rate. His role as a clinical consultant with the rounding team has become firmly established. This is supplemented with rational product selection utilizing a hospital formulary. Both clinical pharmacokinetics and nutrition are services that benefit the patient directly in his inpatient environment. Toxicology and drug information provided directly to the consumer has also become accepted. Services provided to institution‐wide committees allow a comprehensive understanding of the selection, delivery, and follow‐up of medication administration to the patient. Many of these services described have become reimbursable by third‐party carriers and other appropriate agencies. As other services are reimbursed, the role of the clinical pharmacist will expand beyond the limited scopes discussed in this paper.
Role of the Clinical Pharmacologist in Meeting the Educational Needs of the Primary Care Physician
Authors: DiPalma Joseph R.
Published: March 2013

Few doctors suffer under burgeoning state relicensing laws. Most physicians have no trouble complying with recent laws in 15 states, requiring continuing medical education, or CME, to keep their licenses…. CME has therefore become a booming business, with universities and other groups offering 8,081 courses in 1979‐80, up from 4,862 in 1975‐76.
Book Reviews
Authors: PROCITA LEONARD
Published: March 2013

Book reviewed in this article:

Cadmium Toxicity: Monographs on Modern Pharmacology—Toxicology, Vol. 15. J. H. Mennear, editor

Secondary Diabetes: The Spectrum of the Diabetic Syndromes. S. Podolsky and M. Viswanathan, editors.
Clinical Trials with Antiemetic Agents in Cancer Patients Receiving Chemotherapy
Authors: PENTA JOHN S. , POSTER DON S. , BRUNO SALVADOR , MACDONALD JOHN S.
Published: March 2013

Abstract: Vomiting accompanied by nausea is a serious acute toxicity which occurs after chemotherapy with virtually every class of cancer chemotherapeutic agents. The inability to adequately alleviate this toxicity may lead to serious complications such as general malaise, weight loss, and electrolyte imbalance. We have reviewed 34 studies in which more than 2200 cancer patients were administered 25 different antiemetics for treatment of chemotherapy‐induced vomiting. All patients received a variety of cancer chemotherapeutic agents given either as single agents or in combination. The antiemetic agents included phenothiazines, antihistamines, anticholinergics, benzoquinolizines, barbiturates, butyrophenones, procainamides, cannabinoids, steroids, and benzodiazepines. It is apparent from these studies that the use of conventional antiemetic agents for treating cancer chemotherapy‐induced vomiting is of marginal value, and the use of investigational antiemetic agents show conflicting results as to efficacy. More quantitative measures for evaluating emesis need to be defined, and the implications that a particular antiemetic therapy may be efficacious for some but not all classes of cancer chemotherapeutic agents need to be evaluated.
Phylogenic and Neurologic Aspects of the Vomiting Process
Authors: BORISON HERBERT L. , BORISON ROSALINE , MCCARTHY LAWRENCE E.
Published: March 2013

Abstract:Hindbrain morphology is compared in a variety of animals representing species that vomit and those that do not. Special attention is given to the nucleus of the tractus solitarius (NTS) and its synaptic connections with surrounding structures. The role of the area postrema is examined from the standpoints of containing the chemoreceptor trigger zone (CTZ) for vomiting, of its functional relationship to the blood‐brain barrier, and of its significance as part of the circumventricular organ system. A survey is made of the manifold behavioral contributions of NTS to cardiovascular and respiratory regulation, appetite control, arousal, water balance, and digestive and neuroendocrine functions. An overview is presented of neurochemical distribution in the brain stem with respect to aminergic, cholinergic, and peptidergic substances. Finally, causes and prevention of vomiting are discussed in light of the above considerations.
Antiemetic Activity of N‐Methyllevonantradol and Nabilone in Cisplatin‐Treated Cats
Authors: McCARTHY LAWRENCE E. , BORISON HERBERT L.
Published: March 2013

Abstract: The comprehensive emetic response to xenobiotics can be quantified by monitoring the physiological forces which effectuate vomiting. A unique sequence of thoracic pressure pulses, generated by the somatic muscles of ventilation, can be measured by means of a central venous catheter. This unambiguous emetic endpoint is used to record emetic latency, repetitions and duration of action, all on an established time base and dependent of stomach content. Deslanoside (160 μg/kg) produced emesis in 15 cats beginning in 4.4 ± 1.9 min (mean ± S.D.). Subsequent emetic episodes were related in time in a log‐linear but biphasic manner. Cisplatin (7.5 mg/kg) had an emetic latency of 71 ± 18 min in 7 cats. Additional events also had a long‐linear temporal relationship for up to 400 min. This quantified emetic profile of cisplatin served as a measure for assessing antiemetic activity of N‐metyllevonantradol (Pfizer), nabilone (Lilly) and prochlorperazine. The cannabinoids all evinced dose dependent antiemetic activity in terms of either complete protection, or increased latency to the first emetic episode and reduced number of episodes in those animals not completely protected. By comparison prochlorperazine afforded only minimal protection.
Comparative Trial of the Antiemetic Effects of THC and Haloperidol
Authors: NEIDHART JAMES A. , GAGEN MARY M. , WILSON HENRY E. , YOUNG DONN C.
Published: March 2013

Abstract: A prospective, randomized and double‐blinded trial of the compartive effects of delta‐9‐tetrahydrocannabinol (THC) and haloperidol (H) was begun in February 1980. Patients were randomized to initially receive either THC or haloperidol with cross‐over to the other agent after two courses. All patients evaluated efficacy and toxicity of each agent and those patients completing the study expressed a preference for either THC or haloperidol. All patients are receiving chemotherapeutic agents known to induce severe vomiting (cis‐platinum, nitrogen mustard, or doxorubicin) or have a history or retching with chemotherapy. Fifty‐two patients are evaluable as of October, 1980. THC and haloperidol were equally effective in controlling nausea and vomiting as judged by number of vomiting episodes, patient evaluation of efficacy, and patient preference. About 10% of patients had complete control of vomiting and a third had less than five episodes. Patients failing one of the antiemetics had good control with the other about half the time. Toxicities from THC were less well tolerated than those from haloperidol, but most patients had no serious side effects. Non‐overlapping toxicities and efficacy raise the possibility that a combination of the agents might be worthwhile.
Antiemetic Effect of Intramuscular Levonantradol in Patients Receiving Anticancer Chemotherapy
Authors: CRONIN CAROL M. , SALLAN STEPHEN E. , GELBER RICHARD , LUCAS VIRGIL S. , LASZLO JOHN
Published: March 2013

Abstract: Positive results of investigations of the antiemetic activity of delta‐9‐tetrahydrocannabinol (THC) in patients receiving cancer chemotherapy have led to the development of levonantradol, a synthetic derivative of THC. We assessed both the antiemetic activity and toxicity of intramuscular levonantradol in patients receiving cancer chemotherapy who were refractory to conventional antiemetic therapy. An open dose‐finding study was conducted using initial doses of 0.5 mg. Doses were escalated by 0.5 mg when an incomplete response with no toxicity was observed. Of the 28 patients initially treated, 25/28 (89 per cent) achieved a complete or partial antiemetic response at doses ranging from 0.5 to 1.5 mg. There was no difference in response rate with respect to age or patient size. Of the 31 patients evaluable for toxicity, six reported none. Dysphoria, the dose‐limiting toxicity, occurred in five patients (16 per cent) at 1.0 to 1.5‐mg doses. The most commonly reported side effects were somnolence (48 per cent) and dry mouth (32 per cent). We conclude that intramuscular levonantradol is an effective antiemetic at doses as low as 0.5 mg.
Levonantradol for Chemotherapy‐Induced Emesis: Phase I—II Oral Administration
Authors: LASZLO JOHN , LUCAS VIRGIL S. , HANSON DEAN C. , CRONIN CAROL M. , SALLAN STEPHEN E.
Published: March 2013

Abstract: Thirty five patients were enrolled into a Phase I‐II study of oral levonantradol being tested as an antiemetic for chemotherapy patients who were refractory to the aggressive use of standard antiemetic agents. Sixty‐nine total courses were given. Dysphoric reactions (fear, anxiety, hallucinations) were the most serious side effects, and were most prevalent at the highest dose tested (2.0 mg q4h). Somnolence, a “high” feeling, hypotension were also noted. Antiemetic responses were seen at 0.5, 1.0, 1.5 and 2.0 mg dose levels: the two intermediate doses gave responses comparable to those previously reported for oral THC. It is suggested that a combination of oral and parenteral levonantradol may prove to be a very effective program to relieve the otherwise disabling problems of persistent nausea and vomiting.
Cannabinoids in the Management of Severe Nausea and Vomiting from Cancer Chemotherapy. Some Additional Considerations
Authors: GARB SOLOMON
Published: March 2013

Abstract: Although the cannabinoids are effective antidotes to the nausea and vomiting produced by cancer chemotherapy, they also have other properties that may be of therapeutic value. These should be explored. The possibility of interactions, both useful and harmful, between the anticancer drugs and other drugs used at the same time needs intensive study.
Clinical Studies with a THC Analog (BRL‐4664) in the Prevention of Cisplatin‐Induced Vomiting
Authors: STAQUET M. , BRON D. , ROZENCWEIG M. , KENIS Y.
Published: March 2013

Abstract: BRL‐4664, a THC analog, has been administered to 23 patients at a dose of 10 or 15 mg repeated twice. All patients were on cisplatin therapy, and 16 of them had experienced severe vomiting during the previous course of cisplatin. There was a statistically significant difference between the group with prior cisplatin therapy and without prior therapy in terms of number of vomiting episodes, emphasizing the role of conditioned reflexes. The dose of 15 mg administered before and twice after the infusion of cisplatin was well tolerated. Only minor side effects were observed.
Nabilone: An Effective Antiemetic in Patients Receiving Cancer Chemotherapy
Authors: EINHORN LAWRENCE H. , NAGY CATHERINE , FURNAS BECKY , WILLIAMS STEPHEN D.
Published: March 2013

Abstract: Eighty evaluable patients receiving chemotherapy were entered on a random prospective double‐blind study to evaluate the effectiveness of nabilone, a synthetic cannabinoid, compared to prochlorperazine. Most of these patients received cisplatin, a drug that universally produces severe nausea and vomiting, as part of a combination chemotherapy regimen. The patients served as their own controls, receiving either nabilone or prochlorperazine during two consecutive treatment courses with the identical chemotherapy. Side effects consisting of hypotension and lethargy were more pronounced with nabilone. Toxicity, in general, did not preclude antiemetic treatment and in no way interfered with chemotherapy. Sixty patients (75 per cent) reported nabilone to be more effective than prochlorperazine for relief of nausea and vomiting. Of these 60 patients, 46 required further chemotherapy and continued taking nabilone as the antiemetic of choice.
Δ9‐Tetrahydrocannabinol As An Antiemetic For Patients Receiving Cancer Chemotherapy. A Pilot Study
Authors: SWEET DONALD L. , MILLER NANCY J. , WEDDINGTON WILLIAM , SENAY EDWARD , SUSHELSKY LISA
Published: March 2013

Abstract: We conducted a pilot study to ascertain the potential toxicity and possible efficacy of Δ9‐tetrahydrocannabinol (THC) at the oral dose of 5 mg/m2. Over one third of the study population, which consisted of 25 patients, reported significant dysphoric reactions. Four patients (16 per cent) elected not to take THC rather than experience loss of motivation which interfered with their professional life. Paradoxically, on eight occasions nausea seemed to worsen with THC. After the first administration of THC, 18 patients (72 per cent) described less nausea and only two individuals (8 per cent) noted complete resolution of nausea. Two patients reported worsening of their nausea. Eighteen patients noted less vomiting (69 per cent) after the first administration of THC and four patients (15 per cent) reported completed resolution of their vomiting. By the third administration of THC, one of 14 patients (7 per cent) and two of 14 (14 per cent) noted complete alleviation of nausea and vomiting, respectively. Patients who scored high on the Brief Psychiatric Rating Scale, who reported euphoria, or who had psychogenic nausea and vomiting were most likely to have a favorable antiemetic response. The results of this pilot study suggest that orally administered THC is a toxic but transiently effective antiemetic when administered at 5 mg/m2.
Antiemetic Effect of Δ9‐Tetrahydrocannabinol in Chemotherapy‐Associated Nausea and Emesis As Compared to Placebo and Compazine
Authors: ORR LEO E. , McKERNAN JOSEPH F.
Published: March 2013

Abstract: Fifty‐five patients harboring a variety of neoplasms and previously found to have severe nausea or emesis from antitumor drugs were given antiemetic prophylaxis in a double‐blind, randomized crossover fashion. Δ9‐Tetrahydrocannabinol (THC), prochlorperazine, and placebo were compared. Nausea was absent in 40 of 55 patients receiving THC, in 8 of 55 patients receiving prochlorperazine, and in 5 of 55 in the placebo group. THC appeared to be more efficacious in controlling the emesis associated with cyclophosphamide, 5‐fluorouracil, and doxorubicin and less so for nitrogen mustard and the nitrosourea. THC appears to offer significant control of nausea in most patients and exceeds by far that provided by prochlorperazine (P < 0.005).
Oral Levonantradol in the Treatment of Chemotherapy‐Induced Emesis: Preliminary Observations
Authors: DIASIO ROBERT B. , ETTINGER DAVID S. , SATTERWHITE BARBARA E.
Published: March 2013

Abstract: Levonantradol, a new synthetic cannabinoid, was examined for antiemetic effectiveness in 27 patients with refractory chemotherapy‐induced emesis. Thirty‐one courses of levonantradol were administered orally beginning 2 hours before chemotherapy and continuing every 4 hours for a minimum of 12 to 24 hours at one of three different dose levels. At the 0.5‐mg dose, 14 patients were evaluable with seven partial response (50 per cent) and one complete response (7 per cent). At the 1.0‐mg dose, 11 patients were evaluable with five partial responses (45 per cent) and three complete responses (27 per cent). Only one patient has thus far been treated at the 1.5‐mg dose with no response noted. Side effects observed included somnolence (90 per cent), dry mouth (83 per cent), dizziness (67 per cent), decreased concentration (40 per cent), dysphoria (33 per cent), and altered perception (30 per cent). Euphoria (“high”) was infrequent (9 per cent). No relationship between dose (0.5 and 1.0 mg) and side effects was observed. There was a suggestion of improved antiemetic efficacy at the 1.0‐mg dose. Although this study is preliminary, it appears that levonantradol is a relatively well‐tolerated oral antiemetic that deserves further evaluation.
Clinical Experience with Levonantradol Hydrochloride in the Prevention of Cancer Chemotherapy‐Induced Nausea and Vomiting
Authors: HEIM MANFRED E. , ROMER WOLFGANG , QUEISSER WOLFGANG
Published: March 2013

Abstract: Reports suggesting that Δ9‐tetrahydrocannabinol (THC) had a potent antiemetic effect in patients treated with cancer chemotherapeutic agents led to the synthesis of other cannabinol derivatives with possibly less side effects. We report here our initial observations with the antiemetic levonantradol in 12 patients with advanced solid tumors receiving cytotoxic polychemotherapy. All patients had a history of vomiting and nausea without successful treatment with standard antiemetic drugs in previous, identical chemotherapy cycles. No other antiemetic or psychoactive drugs were given. Patients received 1 mg levonantradol i.m. 2 hours before as well as 2 and 6 hours after cytotoxic treatment. When compared to the last course of chemotherapy with alternate antiemetic drugs, we found that 11/12 patients had less nausea and vomiting when treated with levonantradol. 8/12 Patients considered the antiemetic treatment with levonantradol better than the one given before. The following side effects were observed: 4 patients complained of pain and local irritation after injection. 2 patients showed a fall in blood pressure, especially orthostatic hypotension. 8 patients complained of sedation and drowsiness. 7 patients experienced psychic side effects, such as decrease of vigilance and reaction, altered sense of timing, body image distortions and even depersonalization. Levonantradol is a potent antiemetic drug but its applicability, especially in outpatients, may be complicated by a high incidence of side effects.
Initial Observations on the Effects of Δ9‐Tetrahydrocannabinol on the Plasma Pharmacokinetics of Cyclophosphamide and Doxorubicin
Authors: RIGGS CHARLES E. , EGORIN MERRILL J. , FUKS JOACHIM Z. , SCHNAPER NATHAN , DUFFEY PATRICIA , COLVIN O. MICHAEL , AISNER JOSEPH , WIERNIK PETER H. , BACHUR NICHOLAS R.
Published: March 2013

Abstract: We studied the effect of THC upon the pharmacokinetics of cyclophosphamide (CTX) and doxorubicin (ADR). Plasma THC was determined by RIA. Plasma concentrations of CTX and ADR were measured by GLC and fluorescence, respectively. RIA confirmed plasma levels of THC >20 ng/ml for patients who received THC. CTX half‐life was not significantly changed with use of THC (7.7 ± 3.6 hours without versus 5.25 ± 2.6 hours with THC). ADR half‐life with THC was greater than without THC (175 ± 197 hours versus 92 ± 92 hours, respectively). Total drug exposure as determined by areas under the curves were similar (12.4 ± 6 μM · hr without versus 13.8 ± 4 μM · hr with THC). These preliminary data suggest that RIA is reliable for assessing THC plasma concentrations. THC induces no apparent alterations of CTX or ADR pharmacokinetics.
The Effects of Levonantradol Hydrochloride on Tumor Growth and Therapy
Authors: WOLFF J. S. , HEMSWORTH G. R. , DeMAIO M. , SLOAN D.
Published: March 2013

Abstract: The effects of levonantradol on tumor growth, both directly and in combination with the cytotoxic agent cyclophosphamide, were determined. Levonantradol hydrochloride administered alone had no effect on the progression of either murine sarcoma 180J or leukemia L‐1210. Likewise, the increased survival obtained in both tumor systems with cyclophosphamide was not altered by concurrent administration of levonantradol hydrochloride. Levonantradol did not affect the incidence or extent of artificial melanotic lung metastases, nor did it modify lymphoreticular cell stimulation. These data support the use of levonantradol in conjunction with chemotherapy in cancer patients.
Physiologic Observations in a Controlled Clinical Trial of the Antiemetic Effectiveness of 5, 10, and 15 mg of Δ9‐Tetrahydrocannabinol in Cancer Chemotherapy. Ophthalmologic Implications
Authors: LEVITT M. , WILSON A. , BOWMAN D. , KEMEL S. , KREPART G. , MARKS V. , SCHIPPER H. , THOMSON G. , WEINERMAN B. , WEINERMAN R.
Published: March 2013

Abstract: One hundred twenty patients about to receive their first treatment with potentially nauseant cancer chemotherapy were randomized to one of six antiemetic treatments: (1) no treatment; (2) placebo; (3) prochlorperazine (PCPZ), 10 mg; (4) Δ9‐tetrahydrocannabinol (THC), 5 mg; (5) THC, 10 mg; (6) THC, 15 mg. Four doses of each medication were given orally at 4‐hour intervals starting 2 hours before chemotherapy. A study nurse was responsible for both objective (nurse) and subjective (patient) symptom questionnaires. Serum levels were obtained at intervals for cross‐reacting cannabinoids. Physiologic measurements including intraocular pressure (IOP), blood pressure, and pulmonary function were also recorded. In summary, the patients were remarkably free of adverse physiologic effects. All intraocular pressures before and after treatment were within the normal range, although a surprising stastistically significant increase in IOP occurred in the group receiving 5 mg THC.
THC Therapeutic Research by Independent and State‐Sponsored Investigators: A Historical Review
Authors: SCIGLIANO JOHN A.
Published: March 2013

Abstract: A brief history of the control and use of cannabis in the United States is presented. Essential to the discussion are the federal law: the Marihuana Tax Stamp Act of 1937; the Controlled Substances Act of 1970; and the Federal Food, Drug and Cosmetic Act of 1962. On mandate of Congress in 1968, initial studies were directed to determine effects of long‐term use in man. The annual reporting of the status of “Marihuana and Health” was established. In the early 1970s, the scope of research was broadened to include evaluation of THC for use in certain medical conditions. Interest in therapeutic research may have been influenced by anecdotal reports of benefit for nausea and vomiting of cancer chemotherapy and forelevated intraocular pressure of glaucoma, by the lobbying for laws to legalize marihuana by special interest groups, and by the passage of state “Controlled Substances Therapeutic Research” acts (CSTRA). A listing of approved INDs in four therapeutic categories, a chart comparing the components of laws passed by 25 states, and a bibliography of suggested reading for further contact with the subject matter are included.