bluuebunny/crossref_metadata_2025 huggingface dataset:
Intravenous Sulfamethoxazole‐Trimethoprim: Pharmacokinetics, Therapeutic Indications, and Adverse Reactions
Authors: Gleckman Richard , Gantz Nelson M. , Joubert Dennis W.
Published: December 2015

Biogenesis of tetrahydrofolate cofactors essential for bacterial growth and survival is blocked by sulfamethoxazole‐trimethoprim. An intravenous form of the antimicrobial combination has recently been approved for the treatment of acute, symptomatic, bacterial pyelonephritis, recurrent urinary tract infections, shigellosis, and Pneumocystis carinii pneumona. Intravenous sulfamethoxazole‐trimethoprim has emerged as an invaluable agent for the management of selected infections, including bacterial meningitis and Salmonella bacteremia, where limited therapeutic alternatives exist. In addition, co‐administration of intravenous sulfamethoxazole‐trimethoprim with a carboxypenicillin provides an empiric treatment for the infected granulocytopenic patient that compares favorably with standard combinations.

Adverse events unique to the intravenous form of the drug consist of phlebitis and fluid imbalances. Fluid overload results from the relatively large volumes of 5% dextrose solution required as diluent.
Glycerol: A Review of Its Pharmacology, Pharmacokinetics, Adverse Reactions, and Clinical Use
Authors: Frank Michael S. B. , Nahata Milap C. , Hilty Milo D.
Published: December 2015

Glycerol is a potent osmotic dehydrating agent with additional effects on brain metabolism. In doses of 0.25‐2.0 g/kg glycerol decreases intracranial pressure in numerous disease states, including Reye's syndrome, stroke, encephalitis, meningitis, pseudotumor cerebri, central nervous system tumor, and space occupying lesions. It is also effective in lowering intraocular pressure in glaucoma and shrinking the brain during neurosurgical procedures.

Hyperosmolality with rebound cerebral overhydration is of concern, especially in patients with altered blood brain barriers. They may be avoided if glycerol is administered on an intermittent rather than a continuous basis. Intravascular hemolysis does not occur with oral use. When administered intravenously, hemolysis can be minimized by using glycerol 10% in dextrose 5% with normal saline at rates of 6 mg/kg/min or less. However, intravenous doses of 1–2 g/kg every 2 hr can be administered safely in severe cases of elevated ICP. In such patients, glycerol serum concentration, serum osmolality and ICP monitoring are required to optimize glycerol therapy.
Pharmacology, Clinical Efficacy, and Adverse Effects of Piroxicam, A New Nonsteroidal Anti‐Inflammatory Agent
Authors: Dahl Stephen L. , Ward John R.
Published: December 2015

Piroxicam, a new non‐steroidal anti‐inflammatory drug, possesses analgesic, antipyretic, and anti‐inflammatory properties and inhibits platelet aggregation in animal models. Its elimination half‐life is 38 hours, and hepatic metabolism to inactive metabolites is the primary route of elimination. Less than 10% of a dose appears unchanged in the urine. Clinical studies demonstrate that piroxicam's analgesic and anti‐inflammatory properties are useful in the management of rheumatoid arthritis and osteoarthritis. Limited clinical studies suggest that piroxicam may be useful in the management of acute gouty arthritis, anklyosing spondylitis, acute musculoskeletal disorders, and as an analgesic.

The gastrointestinal system is the major site of adverse effects. Piroxicam is currently marketed in 20 mg capsules and once daily dosing has proven effective for many patients.
The Use of Intravenous Nitroglycerin in Cardiovascular Disease
Authors: Jaffe Allan S. , Roberts Robert
Published: December 2015

The development of an intravenous form of nitroglycerin has further enhanced the role of nitrates in the therapy of cardiovascular disorders. This new preparation permits prompt initiation of therapy and rapid attainment of high systemic levels; because of its short half‐life, rapid dose titration is both feasible and safe. The antianginal effects of intravenous nitroglycerin are useful in the treatment of coronary vasospasm and unstable angina pectoris. Its hemodynamic effects are of benefit in the therapy of congestive heart failure and in the control of peri‐operative hypertension. Recent data suggest that, with appropriate monitoring, intravenous nitroglycerin can be safely administered to patients with evolving myocardial infarction to reduce the extent of myocardial damage.
Clinical Experience with Diltiazem in Japan
Authors: McGraw Benjamin F. , Walker Steve D. , Hemberger Judith A. , Gitomer Saul L. , Nakama Mototaka
Published: December 2015

In a cooperative postmarketing study, 3,913 Japanese patients received diltiazem, an orally administered calcium channel blocking agent, for 30 to over 360 days. Drug safety was assessed by monthly evaluations of subjective symptoms, electrocardiographic recordings, adverse experiences, vital signs, and biochemical profiles. Original case report forms were processed and analyzed in the United States. None of the observed adverse experiences were serious or life threatening. They occurred in 1.8% of the patients and primarily involved the gastrointestinal system; anorexia and nausea were the most common adverse effects. The majority of the other adverse experiences were extensions of the drug's pharmacologic effects. Diltiazem appears to cause relatively minor clinical toxicity at a low frequency.
Indapamide: Clinical Pharmacology, Therapeutic Efficacy in Hypertension, and Adverse Effects
Authors: Mroczek William J.
Published: December 2015

Indapamide will soon be marketed in the United States as an oral antihypertensive agent and diuretic. Its molecular structure includes both a polar sulfamoyl chlorobenzamide moiety and a lipid‐soluble methylindoline moiety. It differs chemically from the thiazides in that it does not possess the thiazide ring system and it contains only one sulfonamide group. Indapamide is rapidly and well absorbed after oral ingestion, and it has a long terminal half‐life in whole blood which permits once daily administration. Indapamide is extensively metabolized by the liver with excretion of unchanged drug accounting for approximately 5% of the total dose. Although indapamide is thought to exert its antihypertensive effect by its diuretic action, several investigations employing laboratory animal preparations have documented a direct vascular action. It has been categorized as a calcium channel blocking agent and this may account for a portion of its antihypertensive effectiveness. In both the treatment of edema and as an antihypertensive agent, indapamide appears to be comparable to hydrochlorothiazide, chlorthalidone and furosemide and seems to have no clinically important advantage over these agents. Side effects associated with indapamide are minimal and appear to be comparable to those observed with other antihypertensive diuretics. Based on few published studies, indapamide appears to be a useful long acting antihypertensive and diuretic agent that is well tolerated and associated with minimal biochemical abnormalities or side effects.
Analgesic Effects of Oral Propiram Fumarate, Codeine Sulfate and Placebo in Postoperative Pain
Authors: Sunshine Abraham , Laska Eugene M. , Olson Nancy Z. , Colon Ariel , Gonzalez Leoncia , Tirado Sylma
Published: December 2015

Our purpose was to evaluate the analgesic efficacy and safety of single oral doses of propiram fumarate 50 mg, codeine sulfate 60 mg and placebo in the relief of moderate to severe postoperative pain. One hundred and twenty patients completed a randomized, double‐blind, single‐dose, stratified, parallel‐groups trial and were observed for either 4 or 6 hours. Based upon each of the summary efficacy measures — SPID, % SPID and TOTAL — propiram and codeine were approximately equally effective and both were statistically superior to placebo. Propiram was significantly more effective than codeine at hour 5 for Pain Intensity Difference. Two adverse effects were attributed to propiram. Propiram fumarate 50 mg is an effective oral analgesic similar to codeine sulfate 60 mg, with the possibility of a longer duration of action.
The Effects of Fendosal, Aspirin and Placebo on Postoperative Dental Pain A Dose‐Ranging and Efficacy Study
Authors: Desjardins Paul J. , Cooper Stephen A. , Ruderman Carl M. , Gallegos L. Thomas , Reynolds Donald C. , Kruger Gustav O.
Published: December 2015

The purpose of this study was to characterize the analgesic dose‐effect curve of orally administered fendosal, relative to aspirin 650 mg and placebo. A total of 153 patients experiencing moderate to severe pain due to extraction of impacted molar teeth completed this two‐part, single‐dose, double‐blind, randomized trial. In part I, the possible treatments were placebo, aspirin 650 mg, fendosal 100 mg and fendosal 200 mg. In part II, fendosal 400 mg replaced the fendosal 100 mg treatment. A nurse‐observer collected subjective reports of pain intensity and relief at 30 minutes and hourly for eight hours. Fendosal 100 mg was not an analgesic dose but 200 and 400 mg were on the ascending portion of the dose‐effect curve. Fendosal 200 mg was superior to placebo and about equal to aspirin in total effect but not peak effect. Fendosal 400 mg was statistically superior to both fendosal 200 mg and placebo. Fendosal 400 mg appears to provide analgesia similar to that of aspirin 650 mg but with a substantially longer duration, Only a few mild side effects were reported.
Albuterol: An Adrenergic Agent for Use in the Treatment of Asthma Pharmacology, Pharmacokinetics and Clinical Use
Authors: Ahrens Richard C. , Smith Gary D.
Published: December 2015

Albuterol is a long‐acting beta2‐adrenergic receptor‐selective drug that relaxes airway smooth muscle. It is currently available in the United States in oral and metered‐dose inhaler forms. Nebulizer solutions and parenteral preparations are likely to be marketed here in the future. The chemical modifications that make albuterol beta2‐selective also promote oral bioavailability and increased duration of action by decreasing sensitivity to degradative enzymes. Albuterol can also produce undesirable dose‐related effects: (1) metabolic effects including decreased levels of plasma potassium, phosphate, calcium and magnesium; increased levels of plasma glucose, insulin, renin, lactate and ketones; (2) peripheral vasodilation and perhaps some direct cardiac stimulation resulting in decreased systemic and pulmonary vascular resistance, increased pulse pressure and tachycardia; and (3) skeletal muscle tremor. These side effects are most common with parenteral administration and much less prominent with aerosol administration, which yields lower systemic concentrations. Limited pharmacokinetic data suggest a long distribution phase, a terminal half‐life of 3–8 hours, and 10–20% oral bioavailability. Aerosolization of albuterol or a similar agent with a compressed‐air nebulizer appears to be best first‐line management of the patient with acute dyspneic asthma, but appropriate preparations for this kind of therapy are currently missing from the United States market. Intravenous albuterol has also been employed in acutely dyspneic patients, but produces more side effects than carefully administered intraveneous theophylline, is impaired by lack of suffficient pharmacokinetic information to guide dosing, and is of uncertain efficacy in the asthmatic with respiratory failure. However, it appears to lack the potentially life‐threatening side effects that can result when theophylline is used carelessly. In the ambulatory patient, aerosolized albuterol (or a similar agent) administered by metered‐dose inhaler is an excellent agent for treatment as needed and/or for prevention of acute bronchospasm triggered by exercise or other predictable cause. Advantages include a high degree of efficacy, rapid onset and long duration of effect, and minimal side effects. Regularly scheduled administration of albuterol by metered‐dose inhaler is a widely used and effective maintenance medication for patients requiring long‐term prophylactic therapy. However comparisons of the ability of this regimen and the other common maintenance regimens (cromolyn and theophylline) to control chronic symptoms of asthma are needed.
Promising Uses of Calcium‐Channel Blocking Agents
Authors: Bussey Henry I. , Talbert Robert L.
Published: December 2015

It is not surprising that calcium‐channel blocking agents, which have numerous effects on various physiologic systems, have been employed for several “unapproved” uses. This manuscript reviews reports that have appeared within the last two years describing unapproved cardiovascular and noncardiovascular uses of the three available calcium‐channel blocking agents. The cardiovascular uses discussed include hypertensive emergencies, pulmonary hypertension, congestive heart failure, aortic insufficiency, Raynaud's phenomenon, migraine headaches, antiplatelet effects and cardiac surgery. Areas of noncardiovascular use include muscular dystrophy, achalasia, esophageal spasm, dysmenorrhea, preterm labor, asthma, hyperuricemia, mania and depression and endocrinologic and oncologic conditions. While some of the data appear promising, other reports are conflicting and contradictory. Furthermore, because much of the information comes from poorly controlled trials or anecdotal reports, even the more promising uses must be studied further and compared with conventional therapy.
Diflunisal 500–750 mg versus Aspirin 2600–3900 mg in the Treatment of Rheumatoid Arthritis
Authors: Turner Robert A. , Whipple James P. , Shackleford Robert W.
Published: December 2015

Diflunisal was compared to aspirin in a 12‐week, double‐blind, parallel, multicenter rheumatoid arthritis study. One hundred twenty‐six (126) patients received diflunisal and 123 patients received aspirin. Both treatment groups demonstrated significant improvement from baseline in joint pain, morning stiffness, grip strength, walking time and painful and swollen joint scores. For these parameters, the only statistically significant difference between the groups was that diflunisal was more effective than aspirin for overall joint pain at week 2. The overall evaluation by patients and by investigators showed significantly better responses in those treated with diflunisal at weeks 1 and 12. Diflunisal produced significantly less gastrointestinal pain and tinnitus than aspirin. Neither drug showed unusual frequency of adverse effects as determined in the laboratory. Long‐term studies using a higher‐dose regimen are suggested to further define the efficacy and tolerability of diflunisal in the treatment of patients with rheumatoid arthritis.
Ceftazidime versus Tobramycin/Ticarcillin in Treating Hospital Acquired Pneumonia and Bacteremia
Authors: Rapp Robert P. , Young Byron , Foster Thomas S. , Tibbs Phillip A. , O'Neal Welton
Published: December 2015

Thirty‐five patients in a neurosurgical intensive care unit who had nosocomial pneumonia and bacteremia were randomly assigned to receive either ceftazidime (Cef) or the combination of ticarcillin and pharmacokinetically adjusted doses of tobramycin (T/T). Fifteen of 17 patients (88%) who received Cef were cured or improved compared to 15 of 18 (83%) who received T/T. The original pathogen was eradicated from the respiratory secretion in 10 of 15 patients receiving Cef compared to only 6 of 18 patients receiving T/T (p = 0.12). All patients in both treatment groups who had positive blood cultures cleared the organism from the bloodstream. No cases of drug toxicity, including renal toxicity, were seen in either group. Cef used as a single agent in nosocomial pneumonias and bacteremias performed at least as well as T/T.
Toxicity, Immunosuppressive Effects and Carcinogenic Potential of Volatile Nitrites: Possible Relationship to Kaposi's Sarcoma
Authors: Newell Guy R. , Adams Stephen C. , Mansell Peter W. A. , Hersh Evan M.
Published: December 2015

Volatile nitrite in the form of amyl nitrite was used for 100 years for the treatment of angina pectoris. In spite of recognized toxicity, its use in this form was considered safe. During the 1960s prescriptions were not required for purchase of amyl nitrite (called poppers) and its use for recreational purposes became popular. With reinstatement of the prescription requirement in 1969, non‐medicinal, street‐variety volatile nitrites were made commercially available in the form of mixtures of impure butyl and isobutyl nitrite; some of these preparations also included amyl nitrite. These products have been found to be profoundly immunosuppressive for human lymphocytes in vitro, and their by‐products when metabolized into N‐nitroso compounds have been known to be highly carcinogenic in many animal species. Recreational use of inhaled volatile nitrites is prevalent among male homosexuals and the compounds have been suspected as possible cofactors in Kaposi's sarcoma associated with the Acquired Immune Deficiency Syndrome (AIDS). This association could be explained by nitrite‐induced vasodilation of rectal mucosal vessels providing a port of entry for a transmissible agent, by direct immunosuppression of the host allowing expression of a potentially oncogenic virus or by co‐carcinogenic effects of by‐products by themselves or in conjunction with other putative cofactors such as cytomegalovirus. Nitrites should continue to be considered as a possible cofactor in the etiology of Kaposi's Sarcoma among male homosexuals and possibly those with other manifestations of AIDS.
Problems in Designing Hemodialysis Drug Studies
Authors: Gibson Thomas P.
Published: December 2015

A clear understanding of the pharmacokinetics of a drug and of the proper methods for calculating dialyzer clearance is essential in designing hemodialysis studies. Hemodialysis should not begin until drug distribution is complete. Institution of dialysis prior to distribution equilibrium will result in increased removal of drug compared to what would be found in the clinical setting. All methods of calculating dialyzer clearance should be compared to that using total amount of drug recovered in the bath divided by the area under the drug concentration versus time curve during dialysis. To adequately probe the effect of the artificial kidney on drug concentrations sufficient plasma samples must be drawn postdialysis to define the rebound phenomena.
Acebutolol: A Review of its Pharmacology, Pharmacokinetics, Clinical Uses, and Adverse Effects
Authors: Singh Bramah N. , Thoden William R. , Wahl Janice
Published: December 2015

Acebutolol is a new hydrophilic, cardioselective beta‐adrenergic‐blocking agent that posseses partial agonist and membrane‐stabilizing activities. In the treatment of mild to moderate essential hypertension, once‐daily acebutolol as monotherapy provides effective control in a large majority of patients and produces a further reduction in blood pressure when used concomitantly with diuretics. Acebutolol is as effective as other beta‐blocking agents, and in a large, double‐blind, parallel study against propranolol was found to cause less reduction in heart rate, and fewer neurologic side effects and patient withdrawals due to adverse effects. Oral acebutolol is also effective in suppressing premature ventricular contractions, and in small numbers of patients generally beneficial results were obtained in supraventricular and ventricular arrhythmias with intravenous administration. These salutary effects are attributable to beta blockade. Controlled clinical trials documented the antianginal actions of oral acebutolol in chronic stable angina pectoris; its efficacy in this regard is comparable to that of other beta‐blocking agents. The drug produces smaller decreases in heart rate and cardiac output and alterations in peripheral vascular hemodynamics than beta‐blocking drugs without partial agonist activity, and because of its cardioselectivity, it may be used cautiously in patients with bronchospastic disease. Acebutolol has minimal metabolic effects and does not elevate levels of blood lipids during long‐term therapy; high‐density‐lipoprotein cholesterol increased with acebutolol in a small number of patients.
Evaluation of the Pharmacodynamic and Pharmacokinetic Interaction Between Calcium Antagonists and Digoxin
Authors: De Vito Joseph M. , Friedman Basil
Published: December 2015

Therapeutic uses of calcium antagonists have expanded to include not only ischemic heart disease but arrhythmias, systemic hypertension, congestive heart failure, and various pulmonary and gastrointestinal diseases. Many patients receiving a calcium antagonist concomitantly receive digoxin. Although the potential interaction between these agents has frequently been investigated, literature reports are confusing and inconsistent. We summarized the pharmacodynamics, pharmacokinetics, and mechanisms of interaction to help clinicians evaluate the potential calcium antagonist‐digoxin interaction.
The Effect of Cimetidine on Serum Concentrations of Piroxicam
Authors: Mailhot Claude , Dahl Stephen L. , Ward John R.
Published: December 2015

To evaluate the effect of cimetidine on serum concentrations of piroxicam, we administered a single 20‐mg oral dose of piroxicam to 10 healthy male volunteers on 2 occasions. The first was given on day 1 of the study and the second on day 15, 7 days after starting cimetidine 300 mg orally 4 times a day. Nineteen blood samples were drawn for 7 days after each piroxicam dose to characterize its pharmacokinetics. Piroxicam was analyzed by high‐performance liquid chromatography. The mean piroxicam elimination rate constants (Kel), elimination half‐lives, and area under the serum concentration‐time curves (AUC) were as follows (mean ± standard deviation):

Data were analyzed with a Wilcoxon matched‐pairs, signed‐ranks, two‐tailed statistical test. Although the increase in AUC was statistically significant, it was of low amplitude (mean 15%) and is probably not clinically significant. The results of this study suggest that cimetidine does not significantly alter the elimination kinetics of a single dose of piroxicam in young healthy males. Additional investigation is needed to confirm these findings in other patient populations.
Analgesic Efficacy of Amfenac, Aspirin and Placebo After Extraction of Impacted Teeth
Authors: Jain Adesh K. , Hunley Clay C. , Kuebel J. , McMahon F. Gilbert , Ryan Jerome J.
Published: December 2015

Amfenac, an arylacetic acid derivative, is a new investigational, nonsteroidal antiinflammatory agent that has exhibited analgesic properties superior to those of phenylbutazone in animals. This double‐blind, randomized, parallel study was an early clinical trial to evaluate the analagesic efficacy of one oral dose of amfenac 100 mg compared to aspirin 600 mg and placebo in 120 subjects with moderate to severe pain after extraction of impacted molar teeth. Self‐evaluated subjective pain intensity and relief reports for 4 hours were used as indexes of response. Analgesic effects of amfenac were significantly superior to those of placebo (p < 0.001) and aspirin (p < 0.05) by most measurements. Aspirin 600 mg was superior to placebo based on total pain relief and global scores (p < 0.05). Compared with aspirin 600 mg, amfenac 100 mg provided greater and faster analgesia, lasting at least for 4 hours. Ordinal pain intensity scores correlated well with the visual pain analog scale. Seven (17.5%) patients taking amfenac compared to 5 (12.5%) taking placebo reported minor adverse effects).
Ethchlorvynol Pharmacokinetics During Long‐term Administration in a Patient with Hyperlipidemia and Hypothyroidism
Authors: Kolpek Jimmi H. , Parr Michael D. , Marshall Martye L. , Flueck James A.
Published: December 2015

A 33‐year‐old obese, hypothyroid, white male with several medical problems was admitted to University Hospital in September 1984 for treatment of drug intoxication. Admitting medications included ethchlorvynol in addition to other central nervous system depressants. Initial serum concentrations were reported at 70 μg/ml in this somnolent yet totally conscious adult. Established therapeutic concentrations are 2–8 μg/ml, with toxic exceeding 20 μg/ml. A tolerance phenomenon seemed evident. Serum ethchlorvynol concentrations were monitored daily during early hospitalization and continued to be substantially greater than reported toxic concentrations. Kinetic values were as follows: total body clearance 9.92 ml/min, volume of distribution 68.0 liters, and half‐life 78 hours. These values are unique in that they were calculated from a patient who had not suffered an acute overdose, thereby differing markedly from previously published values. The influence of hypothyroidism and hyperlipidemia on these markedly different values appears to be significant. Ethchlorvynol should probably be added to the list of drugs influenced by thyroid disease.
Immunology for the Clinical Pharmacist
Authors: Tami Joseph A.
Published: December 2015

Major advances in the field of immunology within the past decade have led to greater understanding of the immune network. The immune system is finely balanced, with cells communicating both by direct contact and through soluble mediators. Drugs may exert their effects at different sites within the immune network. To understand fully how these drugs act and how side effects may occur, clinicians must comprehend the basic workings of the immune system.
Bone Marrow Transplantation
Authors: Yee Gary C.
Published: December 2015

Since the 1970s major progress in bone marrow transplantation has resulted in long‐term survival and even cure for many patients with serious hematologic disease. Many patients undergoing the procedure, however, experience serious complications, including graft rejection, graft‐versus‐host disease, and infection. Preventing or treating these complications with drugs or other forms of immunotherapy is effective in many, but not all, patients.
Immunotherapy of Idiopathic Thrombocytopenic Purpura and Autoimmune Neutropenia
Authors: Wordell Cindy J.
Published: December 2015

Idiopathic thrombocytopenic purpura (ITP) is a disorder characterized by a low platelet count and purpura. Identification of an antiplatelet antibody suggests that this is an autoimmune disease. Corticosteroids and splenectomy have been the major therapies for many years. High‐dose intravenous immune globulin (IV‐IgG) has been very successful in the management of ITP and has recently received FDA approval for this condition. It was also successful when administered to a few patients with autoimmune neutropenia. The exact mechanism of action of IV‐IgG in autoimmune disorders is poorly understood. Currently, high‐dose IV‐IgG has a definite place in the management of ITP. Its role in therapy includes emergency treatment, preoperative preparation, the postponement of splenectomy in young children, and treatment of ITP during pregnancy.
Evaluation of a New Vancomycin Dosing Method
Authors: Musa David M. , Pauly David J.
Published: December 2015

Thirty‐one patients who were prescribed vancomycin therapy at our institution since January 1, 1986, were dosed using the guidelines as described by Lake and Peterson. Peak and trough vancomycin serum concentrations were measured at steady state: 24 (77%) peak serum concentrations were within the range of 20–30 mg/L, and 24 (77%) trough serum concentrations were within the range of 5–10 mg/L. We have found that the method of Lake and Peterson is satisfactory for initiating vancomycin therapy in most patients. Some, however, may not achieve optimal serum concentrations using these guidelines alone, and their regimens may have to be adjusted based upon actual serum concentration data.
Stress‐Related Mucosal Damage: Critical Evaluation of Potential New Therapeutic Agents
Authors: Knodell Robert G. , Rosenthal Linda E.
Published: December 2015

Cell injury produced by hydrochloric acid is the final common denominator for stress‐related mucosal damage. Actions of therapeutic agents designed to prevent such damage are directed toward either inhibiting acid secretion or stimulating protective mechanisms. Newer agents that fall into the former category include omeprazole, an inhibitor of the H+‐K+–ATPase pump, prostaglandins, and somatostatin. In addition to inhibiting acid, prostaglandins stimulate mucus and bicarbonate secretion and therefore provide a two‐pronged protective action. Tranexamic acid is an antifibrinolytic agent that is postulated to promote clotting at bleeding sites in upper gastrointestinal lesions. Analyses of composite data suggest that (1) prostaglandin E preparations appear to be as effective as currently recognized forms of therapy, such as antacid and H2‐receptor antagonist administration; (2) little enthusiasm can currently be generated for use of somatostatin or tranexamic acid; and (3) omeprazole is a theoretically attractive agent that remains to be tested in the prophylactic treatment of gastrointestinal ulceration due to severe stress.
Histamine H2‐Receptor Antagonists and High‐Density Lipoproteins
Authors: Sabesin Seymour M. , Weidman Stuart W.
Published: December 2015

Epidemiologic evidence has shown that elevated levels of high‐density lipoproteins (HDL) protect against the development of coronary heart disease (CHD). These observations have prompted the evaluation of various factors thought to affect HDL and its subspecies, HDL2 and HDL3. Numerous behavioral and physiologic factors have been shown to elevate HDL levels. These are currently being researched as potential tools in preventing CHD. Several pharmacologic agents are known to alter HDL levels. Studies show that patients with peptic ulcer disease treated with the H2‐receptor antagonist cimetidine show significant elevations in their HDL, HDL2, and HDL3 profiles. In contrast, ranitidine has no effect, or may even decrease HDL levels. These divergent effects may be related to differences in pharmacologic activity unrelated to H2‐receptor blockade. It should be noted that many of the variables affecting HDL levels were not controlled in these studies, and definite conclusions should not be extrapolated to the general population at risk for CHD. Currently, well‐controlled trials to study the effect of cimetidine on HDL levels are in progress.
Evaluation of a Method for Initiating Vancomycin Therapy: Experience in 205 Patients
Authors: Lake Kathleen D. , Peterson Charles D.
Published: December 2015

This study evaluated a dosing method for initiating vancomycin therapy in a large population based on patients' age, weight, and renal function. The aims were to determine the method's efficacy in achieving predetermined peak and trough serum concentrations, and to calculate the cost savings incurred by individualizing therapy. Average doses ±1 SD of 7.93 ± 0.29 mg/kg corrected body weight (lean body weight + 40% excess weight) were administered at intervals predicted by the patients' estimated creatinine clearances (range 22–130 ml/min). The calculated mean dose ± SD was 558 ± 83 mg (range 350–750 mg) and the calculated median interval was 12 hours (range 6–24 hr). Peak and trough concentrations ± SD measured at steady state averaged 26.0 ± 5.4 and 7.3 ± 2.3 μg/ml, respectively. Peak and trough serum concentrations fell within the predetermined therapeutic range in 311 (76%) of 410 samples. Peak concentrations were in the range of 20–30 μg/ml in 145 (71%) of 205 samples. Trough concentrations were in the range of 5–10 μg/ml in 166 (81%) of the 205 samples. This simplified dosing method successfully individualized therapy in most patients, and produced a significant savings to the pharmacy in reduced drug acquisition costs and to patients in reduced drug charges.
Aminoglycosides: Current Role in Antimicrobial Therapy
Authors: Cunha Burke A.
Published: December 2015

Aminoglycosides remain the cornerstone of antibiotic therapy for nosocomial, gram‐negative bacillary infections despite the recent introduction of broad‐spectrum β‐lactam antibiotics and quinolones with antipseudomonal activity. Initially, aminoglycosides were used as antiaerobic gram‐negative antimicrobial therapy. Currently, they have a key role in many types of infections, such as gram‐negative urosepsis and in febrile granulocytopenic patients, because of their established antipseudomonal activity. Empiric treatment of febrile episodes in granulocytopenic cancer patients with an aminoglycoside, in combination with an anti‐pseudomonal β‐lactam, accounts for much of the aminoglycoside use. Amikacin is emerging as one of the most effective aminoglycosides on the basis of resistance rates, pharmacokinetic factors likely to affect clinical efficacy, safety, and overall cost of therapy.
Drug‐Induced Toxicities Associated with High‐Dose Cytosine Arabinoside Infusions
Authors: Graves Terri , Hooks Michael A.
Published: December 2015

The frequency and significance of central nervous system (CNS), ocular, and dermatologic toxicities associated with high‐dose cytosine arabinoside (HDARA‐C) infusions was evaluated. Patients were selected from one of three Southeastern Cancer Study Group protocols using HDARA‐C 2–3 g/m2 body surface area (BSA) and their medical records were reviewed to identify and document the frequency of the toxicities. Those exhibiting CNS toxicity were compared across age, sex, race, previous standard‐dose ARA‐C or HDARA‐C therapy, and infusion rate for toxicity occurrence. Statistical analysis was performed using Fisher's exact test with p < 0.05. Of the 53 patients evaluated, 37.7% exhibited CNS, 37.7% ocular, and 45.3% dermatologic toxicities. Of the risk factors evaluated, only increasing age and previous ARA‐C therapy approached statistical significance. The CNS toxicities associated with HDARA‐C are clinically significant since permanent damage may result. Ocular and dermatologic toxicities usually resolve without medical intervention when HDARA‐C therapy is discontinued. Further study is necessary to determine appropriate prophylaxis for these toxicities.
Proarrhythmia: A Paradoxic Response to Antiarrhythmic Agents
Authors: McCollam Patrick L. , Parker Robert B. , Beckman Karen J. , Hariman Robert J. , Bauman Jerry L.
Published: December 2015

Antiarrhythmic drugs may effectively terminate and prevent symptomatic tachycardias, but they may also provoke life‐threatening rhythm disturbances. The electrophysiologic mechanisms responsible for proarrhythmia can be extrapolated from the existing models of reentry and abnormal automaticity. Although all antiarrhythmic drugs may cause proarrhythmia with seemingly similar frequency, the profile of the disturbance with each class of agents appears somewhat distinct. All agents may cause an increased frequency of premature beats or new or worsened ventricular tachycardia, but the classic form of proarrhythmia due to type Ia agents is torsades de pointes. Recent information has provided clues to the underlying mechanism of drug‐induced torsades de pointes and has provided a clinical picture of patients with this adverse effect. Types Ib and Ic agents only rarely precipitate torsades de pointes. The latter, however, may cause a rapid, sustained, monomorphic ventricular tachycardia in certain high‐risk patients that can be resistant to resuscitation efforts. Amiodarone may cause a broad variety of arrhythmias that are complicated by their extended duration and difficulty in distinguishing proarrhythmia from simple inefficacy. Proarrhythmia is a relatively common, paradoxic side effect that necessitates the clinician to make careful risk‐benefit decisions in choosing antiarrhythmic drug therapy.
Influence of Testicular Steroids on Thyrotropin Releasing Hormone‐induced Prolactin Release in Mature Rams
Authors: SCHANBACHER BRUCE D.
Published: December 2015

Prolactin (PRL) concentrations were measured in serum of intact rams, castrate rams, and steroid‐treated castrate rams to determine whether testicular steroids influence PRL secretion in this species. Testosterone was administered to castrate rams by subdermal Silastic implants providing serum testosterone concentrations similar to those found in intact rams; estradiol was administered similarly to castrate rams, providing a ten‐fold elevation of serum estradiol. Testosterone and estradiol implants decreased serum LH to concentrations found in intact rams, whereas estradiol, but not testosterone, effectively increased basal concentrations of PRL. This effect was most apparent when animals were exposed to short photoperiods (8 hours light:16 hours darkness). When 5 μg of thyrotropin releasing hormone were injected into these animals, peak PRL concentrations were lowest in castrate rams and highest in estradiol‐treated castrate rams. PRL responses in testosterone‐treated castrate rams and intact rams to the releasing hormone were intermediate. Results for peak PRL concentrations and area under the PRL response curves were similar. In conclusion, testicular steroids are suggested to play an important role in the regulation of PRL secretion in mature rams.
Some Aspects of Pituitary Function in the Male Diabetic
Authors: CEDA GIAN PAOLO , VALENTI GIORGIO , SPERONI GUGLIELMINA , BUTTURINI UGO
Published: December 2015

In order to elucidate the hypothalamic—pituitary function in diabetes, the pituitary responsiveness of LH, FSH, prolactin (PRL), and growth hormone (GH) to a thyrotropin releasing hormone (TRH, 200 μg) plus gonadotropin releasing hormone (GnRH, 100 μg) intravenous bolus injection was studied in a group of 13 insulindependent male patients aged 23–47 years. The results obtained for gonadotropin secretion showed LH responses to be significantly higher than those obtained in a group of controls, while basal and stimulated FSH levels were not different from those in the controls. There were no significant differences in PRL secretion between diabetics and control subjects. However, most of the diabetic patients studied (nine out of 12) showed an unexpected but definite GH response to the combined TRH + GnRH test. In conclusion, the observed pattern of gonadotropin release is consistent with gonadal failure previously documented in diabetics. However, the paradoxical GH responses suggest that diabetes also affects the function of the hypothalamic—pituitary unit in a manner similar to that documented in other pathologic conditions.
Observations on Cyclic Nucleotides in Human Semen
Authors: MANN THADDEUS , JONES ROY , SHERINS RICHARD J. , DUFAU MARIA L.
Published: December 2015

In agreement with earlier studies, we have found that the human seminal plasma yields considerably higher values for cyclic nucleotides when compared with spermatozoa. However, we have also shown that these values vary markedly both between different individuals and in specimens from the same individual at different times. Levels recorded for seminal plasma were 25 to 18, 937 nM of cyclic AMP and 0.54 to 3.57 nM of cyclic GMP. These levels were unrelated to those of either fructose (from the seminal vesicles) or zinc and citric acid (from the prostate). We have demonstrated also that in most specimens of seminal plasma the level of cyclic AMP remained stable during a 1‐hour incubation at 37 C or during prolonged storage at −40 C. Washed suspensions contained 13.2 to 27.2 pmol cyclic AMP/100 million spermatozoa. Adenylate cyclase activity of human semen was confined to the spermatozoa; it was several times higher in the presence of Mn2+ than Mg2+ and was unresponsive to sodium fluoride. The latter findings are consistent with enzyme activity derived from a dissociated catalytic component of adenylate cyclase.
Pure Sertoli Cell Cultures: A New Model for the Study of Somatic—Germ Cell Interactions
Authors: GALDIERI MICHELA , ZIPARO ELIO , PALOMBI FIORETTA , RUSSO MARIO A. , STEFANINI MARIO
Published: December 2015

A new technique involving a brief hypotonic treatment was developed for obtaining pure rat Sertoli cell cultures. This method for the selective removal of the germ cells present in Sertoli cell enriched cultures (SCEC) Is based on the differential response of the two cell types to changes in osmolarity. It was found that the optimal conditions for germ cell detachment without Sertoli cell impairment consist of incubation for 2.5 minutes at 20 C in 20 m TRISHCI. When compared with SCEC, the Sertolicell‐only cultures (SCOC) thus obtained retain unaltered morphologic features and responsiveness to FSH stimulation (morphologic modifications and 17 β‐estradiol secretion). The availability of pure Sertoli cell cultures (Ie, free of contaminating germ cells) provides an advantage in the study of their metabolic activity. Moreover, with this technique it is feasible to compare Sertoli cell function in association with germ cells to function in the absence of germ cells.
The Use of BCG (Bacille Calmette Guérin) as an Antispermatogenic Agent: Structural and Hormonal Changes
Authors: TORGERSEN H.M. , STEINER M. , ROVAN E. , ADAM H. , FRICK J.
Published: December 2015

The effectiveness of intratesticularly injected bacille Calmette Guerin (BCG) as an antispermatogenic agent was examined by light microscopy in rats after three, six, ten, twenty, and 56 days and in rabbits 70 days after administration. In rats, the interstitium showed a spot‐like infiltration and development of granuloma. Many tubules degenerated; some of them were invaded by macrophages destroying the remaining elements. After eight weeks, half of the tubules were devoid of germinal cells. The Interstitium was fibrotic or occupied by granuloma. The effects in rabbits were similar to those observed in rats; however, in three cases, a totally granulomatous orchitis had developed. In both species, there were considerable individual differences in response to the agent. In rats injected unilaterally, the contralateral testis was not affected. Plasma testosterone levels seemed to be slightly increased both in rats and rabbits. Plasma FSH levels were decreased in rats. The action of BCG as an antispermatogenic agent is discussed on the basis of these findings.
Retained Undescended Testis in a 51‐Year‐old “Anorchic” Man: The Implications of Endocrine Evaluation in the Adult Male With Impalpable Testes
Authors: KOGAN STANLEY J. , SHAH KUMAR A. , LEVIN JOSEPH , ZUMOFF BARNETT , BARZEL URIEL , KREAM JACOB , SMEY PAUL , LEVITT SELWYN B.
Published: December 2015

A 51‐year‐old man with previously diagnosed bilateral anorchia was shown by endocrine investigation of his hypophyseal‐gonadal axis to have functioning testicular tissue. The implications of endocrine evaluation in adult males who have impalpable testes, or those with bilateral anorchia having undergone previous exploratory surgery, are discussed, as is as an organized diagnostic and surgical approach.
Sperm Penetration into Rat Ova Fertilized In Vitro
Authors: SHALGI RUTH , PHILLIPS DAVID M.
Published: December 2015

The scanning electron microscope was used to study the morphology of sperm entry into the zona‐intact rat ova fertilized in vitro. It is the anteriormost tip of the sperm head, which first associates with and is then incorporated into the ovum. Incorporation progresses caudally, so that the postacrosomal region is the last portion of the spermatozoon to be incorporated into the ooplasm. This tip‐to‐base incorporation is in contrast to the situation which is seen when ova which have been fertilized in vivo are examined with the same techniques. In vivo, the spermatozoon first associates with the ovum at the convex surface of the sperm head. During incorporation the spermatozoon turns on its “side”. The prominent incorporation cone observed in the rat ova, fertilized in vivo, is not observed in ova fertilized in vitro.
Characterization of Boar Sperm Plasma Membranes by Two‐dimensional PAGE and Isolation of Specific Groups of Polypeptides by Anion Exchange Chromatography and Lectin Affinity Chromatography
Authors: PETERSON R. N. , RUSSELL L. D. , HUNT W. , BUNDMAN D. , FREUND M.
Published: December 2015

High resolution, two‐dimensional PAGE was used to characterize purified plasma membranes (PM) from boar spermatozoa. In addition to the abundance of polypeptides resolved, unusual features of PM discerned in gel patterns include a large number of basic polypeptides and the presence of at least three polypeptides with molecular weights in excess of 200 K daltons. In order to reduce these large numbers of polypeptides into smaller fractions, an important step in developing a surface map of these membranes, detergent‐solubilized membranes were fractionated by the techniques of ion exchange chromatography and lectin affinity chromatography. PM polypeptides, solubilized in the nonionic detergents, were fractionated on DEAE Sephadex using phosphate ion gradients containing EDTA. Most of the major acidic polypeptides were eluted as a group at high phosphate ion concentrations. Membrane polypeptides can be separated into smaller populations by affinity chromatography on wheat germ agglutinin‐agarose (WGA) or by Concanavalin A‐agarose. Concanavalin A‐agarose binds most PM glycoproteins, but partial purification of an important group of very basic proteins was obtained by repeated chromatography of polypeptides that failed to bind to this lectin. Since biologic activity (including immunologic potency) is often retained in the detergents used, the ability to fractionate the major polypeptide of the boar sperm PM into different and much smaller populations in large quantity and to characterize these proteins by electrophoresis provides a starting point for determining the functional significance and location of the major surface proteins of the boar sperm PM.
Effect of (+ )‐Gossypol on Fertility in Male Hamsters
Authors: WALLER DONALD P. , BUNYAPRAPHATSARA NUNTAVAN , MARTIN ANNAMARIE , VOURNAZOS CHRIST J. , AHMED MOHAMMED S. , SOEJARTO DOEL D. , CORDELL GEOFFREY A. , FONG HARRY H. S. , RUSSELL LONNIE D. , MALONE JAMES P.
Published: December 2015

( + )‐Gossypol was isolated from the bark of Thespesia populnea and tested for its ability to inhibit the fertility of male hamsters. Male hamsters of proven fertility were treated orally for 54 days with 40 mg/kg of ( + )‐gossypol, 40 mg/kg of racemic gossypol, or 5% gum acacia (vehicle control) and were mated with estrous female hamsters during the fourth and seventh weeks of treatment. Both the control and the (+ )‐gossypol‐treated animals exhibited normal fertility throughout the experiment. The racemic gossypol‐treated animals were infertile when evaluated during both the fourth and seventh weeks of treatment. Morphologic examination of the testicular tissue could not explain the loss of fertility. These data demonstrate the inability of (+)gossypol to decrease male fertility and suggest that the activity of racemic gossypol may be due primarily to the presence of the (‐) optical isomer.
Analysis of Human Sperm Function Following Exposure to the Ionophore A23187
Authors: AITKEN R. JOHN , ROSS ALAN , HARGREAVE TIM , RICHARDSON DAVID , BEST FIONA
Published: December 2015

Time exposure photomicrography and interspecific in vitro fertilization techniques have been used to compare the responses to the divalent cation ionophore A23187 of spermatozoa from normal fertile and oligozoospermic men. The fertilizing capacity of spermatozoa from the fertile controls produced a bell‐shaped dose response curve when assessed in the presence of ionophore. The optimal responses occurred in the presence of 50 and 100 μM A23187. At this concentration, a mean penetration rate of about 75%, in association with multiple polyspermy, was observed without significant changes in motility patterns. At higher doses of A23187, there was a decline in fertilization rates, an independent reduction in sperm motility, and a significant decrease in the amplitude of lateral sperm head displacement. In contrast to the fertile controls, spermatozoa recovered from patients with oligozoospermia failed to exhibit a significant change in their fertilizing potential following exposure to A23187. Calculations based on the Poisson distribution theory indicated that this lack of responsiveness was not related to any differences in the motility of the spermatozoa from the oligozoospermic patients compared to the controls. These results suggest that calcium ionophores may be of value in providing a rapid and sensitive indicator of the functional competence of human spermatozoa, which circumvents problems concerning the rate and efficiency of sperm capacitation encountered with conventional protocols.