bluuebunny/crossref_metadata_2025 huggingface dataset:
Indacrinone: Natriuretic and Uricosuric Effects of Various Ratios of Its Enantiomers in Healthy Men
Authors: Vlasses Peter H. , Rotmensch Heschi H. , Swanson Brian N. , Irvin John D. , Johnson Cynthia L. , Ferguson Roger K.
Published: December 2015

Indacrinone is an investigational loop‐acting diuretic. To evaluate the natriuretic and uricosuric effects of varying ratios of its enantiomers, 10 healthy men, on a controlled Na (100 mEq) and K (80 mEq) diet, participated in a double‐blind, randomized, balanced incomplete block, multiple‐dose (one week) study of a fixed daily dose (10 mg) of (–) enantiomer combined with increasing doses (40, 90 and 140 mg) of (+) enantiomer versus 50 mg hydrochlorothiazide and placebo. On day 1, mean 24‐h urinary Na increased (p < 0.01) comparably (–285 mEq) after each enantiomer combination and hydrochlorothiazide; however, the enantiomer combinations had marked uricosuric and hypouricemic effects that were enhanced with increased (+) enantiomer doses. By day 7, while enantiomer combinations and hydrochlorothiazide demonstrated comparable natriuretic activity, mean serum uric acid levels (mg/dl), in comparison to placebo, were increased (p < 0.05) with hydrochlorothiazide but progressively decreased with increases in (+) enantiomer. Thus varying the ratio [(+, uricosuric):(–, natriuretic)] of the enantiomers of indacrinone caused natriuresis similar to hydrochlorothiazide, but had an opposite effect on serum uric acid.
Buspirone Hydrochloride: A Unique New Anxiolytic Agent; Pharmacokinetics, Clinical Pharmacology, Abuse Potential and Clinical Efficacy
Authors: Goldberg Harold L.
Published: December 2015

Buspirone is the first of a new class of anxioselective agents, the azaspirodecanediones. It achieves peak serum concentrations within one hour and has a serum half‐life of 2 to 5 hours. Animal studies have suggested antianxiety activity and the absence of abuse potential. Buspirone is both a dopamine agonist and antagonist, and appears to interact with numerous neurochemical systems in the brain, but not with gamma‐aminobutyric acid or at benzodiazepine receptors. Buspirone increases prolactin and growth hormone levels under experimental conditions. In healthy subjects, it has much less effect on psychomotor performance and electroencephalographic results than diazepam. Buspirone offsets some of the impairment due to alcohol when the agents are combined. The drug has anxiolytic properties comparable to those of diazepam, with less sedating effects. It had no abuse potential in tests with casual drug users.
Bitolterol Mesylate: A Beta‐adrenergic Agent; Chemistry, Pharmacokinetics, Pharmacodynamics, Adverse Effects and Clinical Efficacy in Asthma
Authors: Walker Susannah B. , Kradjan Wayne A. , Bierman C. Warren
Published: December 2015

Bitolterol, (3–4 diester colterol) is a new β2‐adrenergic agonist. Since it in itself is biologically inactive, bitolterol is considered a pro‐drug. When administered it is activated within the lung by esterase hdyrolysis to the active compound colterol catecholamine N‐t‐butyl‐arterenol). In preclinical and clinical studies to date, bitolterol has proved to be an effective bronchodilator for adult and pediatric patients with chronic stable asthma and for some with chronic obstructive pulmonary disease.

Bitolterol has been compared with other β2 agents, including isoproterenol, metaproterenol and albuterol. There is no evidence for cardiotoxicity when bitolterol is used in combination with theophylline in human studies. It is effective for control of exercise‐induced asthma.
Antihypertensive Therapy with Once‐daily Administration of Terazosin, a New Alpha1‐adrenergic‐receptor Blocker
Authors: Abraham Paul A. , Halstenson Charles E. , Matzke Gary R. , Napier Jerold L. , Keane William F.
Published: December 2015

The antihypertensive activity of terazosin, an investigational alpha1‐adrenergic‐receptor blocker, and its effect on blood lipids were compared with placebo in a double‐blind study. After a 3‐week placebo baseline period, patients were randomized to receive terazosin (n = 22) or placebo (n = 16). The dose of terazosin was titrated over 2 weeks to a maintenance dosage of 10 mg once daily for 4 weeks. Antihypertensive efficacy was assessed: (1) at the end of the 24‐hour dosing interval by comparing the average blood pressure (BP) after 3 and 4 weeks of maintenance therapy to the average BP after 2 and 3 weeks of placebo therapy, and (2) for 3 hours after drug ingestion at the final visit in comparison to the predose BP at that visit. At the end of the 24‐hour dosing interval, 10 mg of terazosin reduced the mean supine systolic BP from 155.6 to 152.2 mm Hg and mean supine diastolic BP from 101.9 to 99.0 mm Hg (p < 0.05). During the 3 hours after drug ingestion, mean supine systolic and diastolic pressures decreased maximally from 151.8 to 142.7 mm Hg (p < 0.05) and from 99.5 to 91.0 mm Hg (p < 0.05) respectively. No supine BP reduction differed significantly from the placebo response. During terazosin therapy there was a nonsignificant increase in mean body weight of 1.4 ± 2.9 kg and no change in blood lipids. Thus the drug demonstrated greater antihypertensive activity 1–3 hours after ingestion than at the end of the 24‐hour dosing interval. The role of terazosin 10 mg once daily in the treatment of mild to moderate hypertension remains to be established.
Pharmacogeriatrics
Authors: Pucino Frank , Beck Carol L. , Seifert Randall L. , Strommen Gordon L. , Sheldon Peggy A. , Silbergleit Inger L.
Published: December 2015

The elderly comprise one of the fastest growing populations in the United States. By the year 2020, an estimated 45 million will be classified as elderly. Aging is a highly variable process as declines occur in physiologic functions. Alterations in cardiovascular, renal and hepatic function have the greatest effect on drug therapy. All pharmacokinetic and pharmacodynamic variables may be altered by age. Adverse drug reactions, drug interactions and poor compliance are frequent and may further complicate drug therapy. A review of those processes that commonly influence pharmacologic response and patient compliance to drug therapy is appropriate.
The Hemodynamic Effects of Ibopamine, a Dopamine Congener, in Patients with Congestive Heart Failure
Authors: Leier Carl V. , Ren Jiang Hua , Huss Patricia , Unverferth Donald V.
Published: December 2015

Ten patients with congestive heart failure underwent noninvasive and invasive hemodynamic testing before and sequentially after the administration of ibopamine to determine the cardiovascular effects of this oral dopamine congener. Single doses of 200, 400 and 600 mg were administered to all patients and 5 repeated doses of 200 or 400 mg were studied in 8. Hemodynamic effects occurred as early as 30 minutes and lasted up to 4 hours after dosing. In general, ibopamine elicited statistically significant dose‐related increases in cardiac output and reductions in the derived resistance of the systemic and pulmonary circulations. A biphasic response in central and peripheral pressures was observed; up to 1 hour after administration, ibopamine elevated mean right and left atrial pressures and pulmonary and systemic arterial pressures with a significant reduction of these measurements beyond 1 hour. It did not alter heart rate. Repeated doses qualitatively affected hemodynamics similar to the initial dose and did not appear to be accompanied by short‐term tolerance. While oral ibopamine elicits some favorable hemodynamic effects in humans with cardiac failure, the biphasic hemodynamic response is generally undesirable in the majority of these patients.
Initial Therapy for Mild Hypertension
Authors: Wikstrand John
Published: December 2015

The treatment of mild hypertension has been a subject of controversy because its benefits versus risks are not as well established as they are for moderate to severe hypertension. Results of several studies, however, now show that treatment reduces the frequency of stroke in those with milder blood pressure elevations. New guidelines published by the Joint National Committee recommend that treatment of mild hypertension begin with either a diuretic or a beta blocker. The effect on the most common complication of mild hypertension, that is, coronary heart disease (myocardial infarction and sudden cardiac death), has, however, not been encouraging in studies in which diuretics have been used as first‐line treatment. Two large‐scale primary preventive studies compared the efficacy of diuretics and beta blockers in reducing coronary heart disease in hypertensive patients; results were in favor of beta blocker regimens in men. So far there is some evidence, but no hard scientific proof, that certain beta blockers offer advantages over diuretics in preventing myocardial infarction and sudden cardiac death in hypertensive patients. A major concern with the use of diuretics is the risk of hypokalemia; this can be reduced when they are combined with beta blockers.
Once‐ and Twice‐daily Nitrendipine in Patients with Hypertension and Noninsulin‐dependent Diabetes
Authors: Fagan Timothy C. , Nelson Edward B. , Lasseter Kenneth C. , Crook James , Morledge John , Conrad Kenneth A.
Published: December 2015

One hundred and six patients with uncomplicated mild to moderate essential hypertension received nitrendipine 10 mg twice a day or 20 mg once a day in a double‐blind, randomized design. At the end of the dosing interval, supine and standing blood pressures were lowered 6/4 and 6/3 mm Hg respectively with the former regimen, and 2/3 mm Hg with the latter. In 10 patients, blood pressure variability through the dosing interval was not increased by nitrendipine 10 mg twice daily, but in another 10, 20 mg daily increased the variability by 28% compared to placebo. Significantly more patients had adverse effects with 20 mg daily than 10 mg twice daily; and both regimens caused more side effects than placebo. In 20 patients, serum glucose levels did not change significantly during treatment with nitrendipine, but in 10 of those with noninsulin‐dependent diabetes, the range of maximum plasma insulin in response to a high‐carbohydrate meal was 7 times as great during treatment with nitrendipine as it was during treatment with placebo. Nitrendipine lowers blood pressure when given once or twice daily, but twice‐daily administration appears to be better tolerated.
Vancomycin: An Update
Authors: Cheung Richard P. F. , DiPiro Joseph T.
Published: December 2015

Vancomycin is a narrow‐spectrum glycopeptide antibiotic with potent antistaphylococcal activity. It is primarily active against gram‐positive organisms. Bacterial resistance rarely develops due to its numerous modes of action. The toxic potential of vancomycin is less significant than previously thought. “Red neck syndrome” seems to be the most common side effect and appears to be caused by rapid intravenous infusion. It is characterized by erythema at the base of the neck and the upper back; hypotensive episodes may also occur. Nephrotoxicity and ototoxicity are rare. Relationships between toxicities and serum concentrations have not been established. The disposition of vancomycin after intravenous administration proceeds biphasically — rapid distribution followed by elimination. The drug is excreted primarily unchanged in the urine by glomerular filtration. Vancomycin clearance is reduced and elimination half‐life is prolonged in patients with renal insufficiency. Various methods have been published to aid in dosing the drug in these patients. Vancomycin is the drug of choice in the treatment of methicillin‐resistant staphylococcal infections. It is also useful in the treatment of gram‐positive endocarditis and has been used as alternative therapy in the treatment of prophylaxis of gram‐positive infections in penicillin‐allergic patients. Oral vancomycin is the preferred therapy in antibiotic‐associated colitis.
The Effect of Low‐Dose Hydrochlorothiazide on Blood Pressure, Serum Potassium, and Lipoproteins
Authors: McKenney James M. , Goodman Robert P. , Wright Jackson T. , Rifai Nader , Aycock Deborah G. , King Mary Ellen
Published: December 2015

Recent clinical trials in hypertension suggest that thiazide diuretics may increase coronary heart deaths in selected patients, possibly through adverse effects on serum potassium, lipids, lipoproteins, and/or apolipoproteins. Administration of smaller doses of diuretics has been recommended to decrease this risk. We evaluated 12.5‐mg and 112.5‐mg daily doses of hydrochlorothiazide (HCTZ) administered for 1 month to nine postmenopausal black female hypertensives using a double‐blind, randomized, crossover design. Both regimens produced significant reductions in sitting diastolic blood pressure, a mean of 11 mm Hg with the high dose and 8 mm Hg with the low dose. The high dose produced a mean 0.7 mEq/L reduction in serum potassium while the low dose caused no change. Both doses produced similar changes in serum lipoproteins. Statistically significant elevations were seen in total cholesterol (approximately 12%), LDL cholesterol (approximately 20%), cholesterol: HDL ratio (approximately 15%), and apolipoprotein B (approximately 20%). Apolipoprotein A1 was significantly reduced (approximately 6%). These results support the use of low doses of HCTZ in mild hypertension to avoid hypokalemia, but suggest that adverse changes in serum lipids will occur.
Crossover Trials in Clinical Analgesic Assays: Studies of Buprenorphine and Morphine
Authors: Wallenstein Stanley L. , Kaiko Robert F. , Rogers Ada G. , Houde Raymond W.
Published: December 2015

Analgesic studies of buprenorphine, a thebaine derivative and potent partial narcotic agonist, were carried out in patients with cancer who had postoperative or chronic pain. Intramuscular buprenorphine was compared with intramuscular morphine in a series of sequentially related, twin crossover assays and was found to be about 25 times as potent as morphine. Side effects were essentially morphinelike. In a second assay, the acceptability and analgesic activity of sublingual buprenorphine was studied in a 6‐dose, balanced, incomplete block assay, a modification of the twin crossover design employed in the all‐intramuscular trial. Sublingual buprenorphine was found to be about 15 times as potent as intramuscular morphine and was well accepted by our patients. The 4‐dose twin crossover trial in which doses are adjusted sequentially is more flexible in that a wide range of doses may be studied, but it lacks the ability of the 6‐dose design to provide estimates of the curvature of the dose‐response slopes of the study drugs. When first‐dose‐only data were analyzed as parallel group assays, the main difference in results compared with the crossover studies was a decrease in efficiency and sensitivity.
Ketorolac versus Aspirin for Postpartum Uterine Pain
Authors: Bloomfield Saul S. , Mitchell Jeanette , Cissell Gail B. , Barden Tom P. , Yee James P.
Published: December 2015

Ketorolac tromethamine, a new nonsteroidal antiinflammatory analgesic, was evaluated for relative efficacy, safety and time course of analgesia in a stratified, randomized, parallel, double‐blind trial. The study involved 120 hospitalized women (4 groups of 30) with moderate or severe postpartum uterine pain treated with single oral doses of ketorolac 5 mg and 10 mg, aspirin 650 mg or placebo. At regular interviews for 6 hours patients rated pain intensity, pain relief and side effects. Significant differences (p ≤ 0.05, two‐tailed) occurred among the 4 treatments for various measurements of summed and peak analgesia. Ketorolac 10 mg was significantly superior to placebo in 5 of 5 major efficacy measurements, and aspirin was significantly superior in 3 of 5. Ketorolac 10 mg gave the highest mean rating for summed pain intensity differences (13.6, p = 0.0002 versus placebo), followed by aspirin (11.9, p = 0.012), ketorolac 5 mg (10.9, p = 0.072) and placebo (8.6). With ketorolac 10 mg and 5 mg and aspirin, analgesia lasted 6 hours, with peak efficacy at 3 hours. Side effects were not significant. Our results suggested a positive dose‐response relationship for ketorolac. Compared to aspirin, ketorolac 10 mg induced equal or more analgesia, whereas ketorolac 5 mg was near the minimum effective dose and seemed less effective than aspirin.
Antidepressants in Chronic Pain: A Review of Efficacy
Authors: Stimmel Glen L. , Escobar Javier I.
Published: December 2015

Antidepressant drugs have gained widespread clinical usage alone or as adjuncts in the treatment of chronic pain disorders. Of 17 controlled studies of antidepressants in chronic pain, 13 demonstrated significant pain relief with antidepressants compared to placebo. These studies were too different from one another to allow any general conclusions concerning efficacy, however. Five studies of either migraine or chronic tension headache all demonstrated superior efficacy of antidepressants versus placebo, while those of back and arthritic pain yielded mixed results. Of 3 studies of pain of several etiologies, 2 failed to demonstrate efficacy of antidepressants over placebo. These studies do not provide answers to many clinical questions on the use of antidepressants for chronic pain, such as drug of choice or appropriate dosage. Rather, they suggest that these agents may be beneficial in some patients with chronic pain.
Topical Minoxidil in the Treatment of Male Pattern Alopecia
Authors: Kvedar Joseph C. , Baden Howard P.
Published: December 2015

Male pattern hair loss (androgenetic alopecia) is a common problem. In fact, it affects nearly all males to some degree. Expression of the disorder is variable, and while it is never life‐threatening, it often becomes a major source of consternation. The biology of the process is poorly understood, and no current therapy can halt or reverse the process. Only cosmetic surgery, which is painful, time consuming, and expensive, has been effective. In the past 7 years, since it was noted that a patient taking minoxidil for hypertension had reversal of male pattern hair loss, awareness of a possible therapeutic role for topical minoxidil in the management of this disorder has grown among physicians, scientists, and the general public. It can be concluded from available data that topical application of minoxidil is effective in providing cosmetically satisfying thickening of hair in a select group of individuals with male pattern hair loss. The drug's mechanism of action remains obscure. No serious side effects have been demonstrated with its use, however, and it is therefore advised in selected patients.
Excretion of Flurbiprofen into Breast Milk
Authors: Cox Steven R. , Forbes Kristi K.
Published: December 2015

The extent of flurbiprofen's excretion into mature (postcolostrum) breast milk was evaluated in 10 healthy, nursing mothers after administration of a single 100‐mg tablet. Samples of milk and blood were subsequently obtained over a 48‐hour period and assayed for flurbiprofen by high‐performance liquid chromatography. The average peak plasma flurbiprofen concentration, 15 μg/ml, occurred at 1.5 hours, and the harmonic mean half‐life of the drug was 5.8 hours. The average peak milk concentration of flurbiprofen was 0.09 μg/ml, and the maximum recovery of the dose in breast milk was only 0.07%.
Clinically Important Adverse Effects and Drug Interactions with H2‐Receptor Antagonists: An Update
Authors: Sax Michael J.
Published: December 2015

The H2‐receptor antagonists cimetidine, ranitidine, and famotidine are well tolerated, with a low frequency and similar spectrum of adverse effects. The occasional problematic effects that have been associated with these agents include central nervous system symptoms (mental confusion, headache, and depression), rare cases of thrombocytopenia, and cardiovascular events related to the rate of intravenous infusion. Severe renal and hepatic impairment appear to be associated with a higher occurrence of central nervous system effects. Because the H2‐receptor antagonists elevate gastric pH, bind to and inhibit the hepatic cytochrome P‐450 enzyme system, and undergo renal tubular secretion, competition with other drugs sharing these pathways has resulted in a number of drug interactions, most of which are not clinically significant. The interaction that occurs with theophylline and warfarin when the cytochrome P‐450 enzyme system is inhibited by cimetidine and ranitidine requires monitoring. Recent data suggest that administering cimetidine 800 mg at bedtime has less effect on the serum concentrations of warfarin and theophylline than other dosing regimens. Evidence to date indicates that famotidine does not bind to cytochrome P‐450 to a significant extent, and interactions with drugs metabolized by this system have not been reported; however, clinical experience with this agent is very limited.
The Use of Carbamazepine and Lithium in Controlling a Case of Chronic Rapid Cycling
Authors: Laird Lyle Knight , Knox Ellen P.
Published: December 2015

A 34‐year‐old white female with a long‐standing and deteriorating course of rapid cycling affective disorder was successfully treated by discontinuing a tricyclic antidepressant drug and then using a combination of carbamazepine and lithium. This suggests that rapid cycling affective disorder could be an underdiagnosed disorder, especially in patients with affective disorders who are receiving conventional antidepressant drugs who otherwise exhibit a stormy clinical course with numerous medication changes and hospitalizations. It is further suggested that a change in treatment strategy is warranted in such patients, as it could benefit both patients and society by decreasing hospitalizations and increasing the patients' quality of life.
Ofloxacin: Its Pharmacology, Pharmacokinetics, and Potential for Clinical Application
Authors: Drew Richard H. , Gallis Harry A.
Published: December 2015

Ofloxacin is a 4‐quinolone antibiotic with rapid bactericidal activity against a wide variety of organisms. Its proposed mechanism of activity is interference with DNA gyrase, an enzyme essential for the replication of bacterial DNA. In vitro activity of ofloxacin includes a variety of aerobic and anaerobic bacteria. Enteric gram‐negative bacilli and cocci are generally sensitive to ofloxacin; nonaeruginosa strains of Pseudomonas are less so. Numerous bacterial pathogens of the gastrointestinal tract are also sensitive to the drug. Although its MIC values for gram‐positive aerobic organisms are generally higher, ofloxacin's bactericidal activity against these organisms is considered by some to be adequate, and superior to that of most other fluoroquinolones. Ofloxacin is well absorbed after oral administration. Wide tissue and body fluid distribution is demonstrated. Urinary excretion is thought to be the primary route of elimination, with 80% of the dose recovered in the urine within 24 hours. The serum half‐life ranges between 2.9 and 9 hours in a dose‐dependent manner. Only modest accumulation is reported after multiple‐dose administration. Clinical trials using daily dosages of 100–800 mg/day in single or divided doses have been reported in the treatment of a variety of conditions such as skin and soft tissue infections, tonsillitis, sexually transmitted disease, respiratory tract infections, cystitis, and complicated and uncomplicated urinary tract infections. English reports of these trials, however, are generally limited to abstract form, making evaluation of trial design difficult. Side effects most frequently encountered include gastrointestinal and central nervous system reactions.
Controlled Beta‐Receptor Blockade with Esmolol and Flestolol
Authors: Murthy V. Shrinivas , Frishman William H.
Published: December 2015

Beta‐receptor‐blocking agents are commonly used in the management of various cardiovascular diseases. Recently, esmolol, a pharmacokinetically novel cardioselective beta‐receptor‐blocking agent, has been introduced for use in the treatment of critically ill patients. It is devoid of intrinsic sympathomimetic activity and in doses used clinically, it has no direct depressant effect on the heart. Esmolol is an ester and is metabolized by choline‐esterase to ASL 8123, an inactive molecule. Esmolol has an elimination half‐life of nine minutes which accounts for its ultra‐short duration of action. This unique pharmacokinetic property provides two advantages over other longer‐acting beta‐receptor‐blocking agents. First, the magnitude of beta‐receptor blockade can be titrated to a desired level. Second, if adverse effects are experienced, reducing the dosage or terminating the infusion results in rapid reversal of its pharmacological effects. Another ultra‐short‐acting, non‐cardioselective beta‐receptor blocking agent, flestolol is undergoing clinical evaluation. Esmolol has been approved for the management of supraventricular tachycardia. The clinical safety of these novel drugs will expand the use of beta‐receptor‐blocking agents in the management of cardiovascular diseases in critically ill patients.
Nicotinic Acid: A Review of Its Clinical Use in the Treatment of Lipid Disorders
Authors: Figge Helen Luciw , Figge James , Souney Paul F. , Mutnick Alan H. , Sacks Frank
Published: December 2015

Nicotinic acid (niacin) is a water‐soluble vitamin widely used for the treatment of lipid disorders. In pharmacologic doses (1 g or more/day), alone or in combination with other lipid‐lowering drugs, nicotinic acid lowers very low‐density (VLDL) and low‐density lipoprotein (LDL) levels, while concurrently increasing high‐density lipoprotein (HDL) levels. It may reduce long‐term mortality in patients with known coronary artery disease and may slow or reverse the progression of atherosclerosis. A major consideration against using nicotinic acid is the occurrence of frequent, bothersome, adverse reactions such as cutaneous flushing, skin rash, and gastric upset. Careful dosing titration may, however, minimize these effects. The beneficial effects, taken together with the low cost of nicotinic acid therapy and the relative freedom from serious side effects, have made nicotinic acid the agent of choice for the treatment of many patients with hyperlipidemia.
Prolonged Paralysis Associated with Long‐Term Pancuronium Use
Authors: Haas Janet L. , Shaefer Mark S. , Miwa Linda J. , Wood R. Patrick , Shaw Byers W.
Published: December 2015

We cared for a 4‐year‐old patient who had undergone orthotopic liver transplantation and was placed on a ventilator for respiratory distress associated with Pneumocystis carinii pneumonia. The neuromuscular blocking agent pancuronium bromide 1.0–1.2 mg every hour as needed was used to facilitate artificial ventilation for 40 days. On discontinuation of pancuronium, the patient experienced severe, generalized neuromuscular dysfunction. Because no improvement was seen for 2 weeks, the acetylcholinesterase inhibitors edrophonium and pyridostigmine were instituted. Shortly thereafter the patient's condition began to improve. Gradual improvement occurred over 3–4 months and the patient has since returned to baseline neurologic function. We suggest that long‐term pancuronium use was the cause of the patient's prolonged paralysis. The improvement experienced after the initiation of antidotal therapy strongly supports our proposal.
The Safety and Effectiveness of Long‐Term Warfarin Therapy in an Anticoagulation Clinic
Authors: Bussey Henry I. , Rospond Raylene M. , Quandt Christine M. , Clark Gary M.
Published: December 2015

Whenever long‐term anticoagulation is prescribed, the risks of such therapy must be evaluated accurately. Whether these risks are influenced by the duration of therapy, the indication for therapy, patient demographics and social habits, or the use of an anticoagulation clinic is controversial. This study examined the occurrence rates of major hemorrhage, minor hemorrhage, and thromboembolic events among an inception cohort of 82 patients receiving long term‐warfarin therapy in an anticoagulation clinic. During 199.34 patient‐years of observation, there were 4 major hemorrhages (0.0201/patient‐year), 31 minor hemorrhages (0.1555/patient‐year), and 7 thromboembolic events (0.0351/patient‐year). Although each type of event tended to occur during the first 6 months of therapy, this trend was not statistically significant. Failure to demonstrate statistically significant influence of any of the evaluated variables may have been due to the unusually low rate of complications, a finding that may reflect the safety of anticoagulant therapy when managed by a specialized clinic.
Treatment of Hypertension in the Elderly with Labetalol
Authors: Sirgo Mark A. , Boyd Brenda K. , Applegate William B.
Published: December 2015

Elderly and young hypertensive patients differ with regard to clinical and pathophysiologic profiles. In the elderly, hypertension is generally characterized by elevated peripheral vascular resistance and decreased cardiac output. To establish an individualized or patient‐specific approach to their treatment, antihypertensive agents must be evaluated specifically in this subpopulation. Labetalol, an α‐and β‐blocking agent, has been shown to lower blood pressure in young and elderly hypertensive patients primarily by reducing peripheral vascular resistance without compromising cardiac output. Examination of recent reports on the pharmacokinetics and pharmacodynamic effects, and on the efficacy and safety of labetalol in elderly persons with hypertension, leads us to conclude that the drug appears to be well suited for use in these patients.
The Effects of Encainide versus Diltiazem on the Oxidative Metabolic Pathways of Antipyrine
Authors: Bottorff Michael B. , Lalonde Richard L. , Kazierad David J. , Hoon Timothy J. , Tsiu Sandra J. , Mirvis David M.
Published: December 2015

The effects of diltiazem and encainide on the pharmacokinetics and metabolism of antipyrine were compared in nine healthy male volunteers. Diltiazem 90 mg every 8 hours for 5 days decreased the oral clearance of antipyrine from 2.34 to 1.86 L/hour (p < 0.05) and increased half‐life from 12.7 to 15.9 hours (p < 0.05). Diltiazem reduced the formation rate constants for 3‐hydroxymethylantipyrine by 27% (p < 0.05) and 4‐hydroxyantipyrine by 37% (p < 0.05). There was also a 21% reduction in the formation rate constant for norantipyrine (0.05 < p < 0.10). Encainide 25 mg every 8 hours for 5 days had no apparent effect on the oral clearance or half‐life of antipyrine, or on the formation rate constants for metabolites of antipyrine. In contrast to a previously published report in rats, encainide, unlike diltiazem, does not inhibit the oxidative metabolism of antipyrine in humans.
Evaluation of Flurbiprofen, Acetaminophen, an Acetaminophen‐Codeine Combination, and Placebo in Postoperative Oral Surgery Pain
Authors: Forbes James A. , Butterworth Geraldine A. , Burchfield William H. , Yorio Christine C. , Selinger Lawrence R. , Rosenmertz Stanley K. , Beaver William T.
Published: December 2015

Eighty‐eight outpatients with postoperative pain after the surgical removal of impacted third molars were randomly assigned, on a double‐blind basis, to receive a single, oral dose of flurbiprofen 100 mg, acetaminophen 600 mg, a combination of acetaminophen 600 mg with codeine 60 mg, or placebo. Using a self‐rating record, subjects rated their pain and its relief hourly for 12 hours after medicating. Estimates of sum of pain intensity differences, peak pain intensity differences, total relief, peak relief, and hours of 50% relief were derived from these subjective reports. Flurbiprofen and the acetaminophen‐codeine combination were significantly superior to placebo for every measure of total and peak analgesia and significantly superior to acetaminophen alone for most measures of efficacy. Based on the 12‐hour data, acetaminophen alone did not differ significantly from placebo; however, it was superior to placebo for measures of total effect based on the 4‐hour data. Flurbiprofen was significantly superior to the acetaminophen‐codeine combination with respect to the number of hours until remedication. All medications had manifested an effect by hour 1; analgesia persisted for 12 hours for flurbiprofen, 6 hours for acetaminophen‐codeine, and 3 hours for acetaminophen alone. The frequency of adverse effects was similar for the active medications.
Pharmacokinetics of Felbamate, a Novel Antiepileptic Drug: Application of Mixed‐Effect Modeling to Clinical Trials
Authors: Graves Nina M. , Ludden Thomas M. , Holmes Gregory B. , Fuerst Robin H. , Leppik Ilo E.
Published: December 2015

Felbamate is a novel antiepileptic drug currently undergoing clinical trials in the United States. Serum felbamate concentration data from a phase II safety and efficacy trial were analyzed using nonmem. A one‐compartment, open model with first‐order absorption and elimination was used. Body weight, sex, concurrent folic acid therapy, and Phenytoin dose and dose concentration ratio did not affect the estimates for felbamate clearance (CI). Carbamazepine dose and dose Concentration ratio (CDCR) led to significant improvements in the objective function. The final models for felbamate clearance and volume of distribution (Vd) were as follows: CI(L/hr) = 2.43 + 0.429*CDCR/240, Vd (L) = 51. The coefficient of variation of clearance was only about 12%, which may be indicative of the highly selective patient population. The clearance estimates are similar to those obtained in healthy volunteers and in patients receiving lower dosages of felbamate. The volume of distribution estimate, however, is slightly smaller than that reported previously. Valuable pharmacokinetic information can be obtained from the routine monitoring of serum concentrations during safety and efficacy trials.
Observations of the Results of 300 Vasovasostomies
Authors: LEE HEE YONG ,   MEMBERS OF THE VASECTOMY STUDY PROJECT
Published: December 2015

The results of 300 conventional vasovasostomies were evaluated clinically. The operations were carried out bilaterally under spinal or general anesthesia. Depending on the size of the nodule and the level of vasectomy, an end‐to‐end or side‐to‐side anastomosis technique was used. A higher rate of success was associated with 1) a shorter period of obstruction, 2) bilateral straight vas‐to‐straight vas anastomosis, 3) bilateral leakage of fluid with spermatozoa, and/or 4) seven or more days of hospitalization. Patency was established in 84% of the patients, and fertility was restored in 35%. The anatomical success rate in patients in which a two‐fold magnifying loupe, four sutures of 6‐0 nylon, and a stent were used in anastomosis (this procedure was used before 1970) was below 80%. Thereafter, four‐ to six‐fold magnification and eight sutures of 9‐0 nylon without stents were employed and were associated with a success rate of over 85%. The functional success rate increased from 20% before 1970 to 40% thereafter. Although several factors contribute to anatomical or functional failures, the most important is scar formation with sperm and suture granulomas at the anastomosis site. Perhaps these problems will be overcome by the new microsurgical technique for anastomosis.
A Comparison of Blood Chemistry, Reproductive Hormones, and the Development of Antisperm Antibodies After Vasectomy in Men
Authors: ALEXANDER N. J. , FREE M. J. , PAULSEN C. ALVIN , BUSCHBOM R. , FULGHAM D. L.
Published: December 2015

Serum chemistry parameters as well as levels of follicle‐stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and spermimmobilizing and sperm‐agglutinating antibodies were measured prior to vasectomy and at 1.5, 3, 6, 9, and 12 months afterwards in 99 men. We did not, however, acquire a sample from every man for every point in time. Since the development of antibodies to sperm is a well‐documented change that occurs in about half of vasectomized individuals, we investigated whether men who develop circulating antibodies exhibit any changes in serum chemistry and/or hormone levels when compared to those who do not. Although no men had antisperm antibodies at the time of vasectomy, 40.5% of the study population subsequently developed them. The number of men with circulating antisperm antibodies increased significantly for the first 3 to 6 months and then remained stable for the remainder of the study period. Some individuals had only agglutinating or immobilizing antibodies, but more commonly both types were found. The group of men who exhibited early antibody formation may have had slightly higher mean counts of spermatooa before vasectomy, but there was no difference in counts between those men who never exhibited antisperm antibodies and those that did. Furthermore, there was no difference in ages between those that did and did not exhibit antibodies to sperm. All blood values were within the normal range. Values for FSH were consistently, albeit slightly, lower for those individuals who developed circulating antisperm antibodies. No differences were found in LH and testosterone levels.
Testicular and Adrenal Steroid Profiles During PRL Suppression by Lisuride in Men
Authors: MAGRINI GINO , ROUSSELLE JEAN , HOROWSKI REINHARD , GASPERI MAURIZIO , FELBER JEAN‐PIERRE
Published: December 2015

Lisuride hydrogen maleate is known to reduce serum prolactin (PRL) in rodents and humans. The authors have examined the effects of short‐term lisuride administration on testicular and adrenal functions in normal male volunteers as reflected by plasma hormone levels in basal and stimulated conditions. After five days of treatment, a decrease in PRL levels was observed, whereas no substantial changes occurred in the levels of testosterone, 17 αOH progesterone (17 αOHP), androstenedione, dehydroepiandrosterone sulfate (DHEA‐S), and 17 β‐estradiol (estradiol). The response to hCG (2000 IU on two consecutive days) in terms of testosterone, 17 αOHP, estradiol, and androstenedione levels was within the normal range, even though the testicular response of estradiol was enhanced and that of testosterone reduced, compared to controls. Finally, short‐term treatment with lisuride had no detectable effects on the peripheral levels of adrenal secretions. The present findings indicate that lisuride does not interfere with adrenal or testicular function in men and, therefore, may be suitable for therapeutic use as a PRL‐suppressing agent in hyperprolactinemic men.
A Natural “Venous Bypass” Causing Postoperative Recurrence of a Varicocele
Authors: SAYFAN J. , ADAM Y. G. , SOFFER Y.
Published: December 2015

Operative treatment of varicocele by anatomically high ligation of the internal spermatic vein carries a 5% surgical failure rate, resulting In recurrence. Detection of the cause of the recurrence can be done efficiently by intraoperative internal spermatic phlebography. In this case report, an unusual collateral vein causing operative failure is described with its management. The subject, a 28‐year‐old man, was seen for recurrence of varicocele following operative treatment by anatomically high ligation of the Internal spermatic vein. An unusual collateral venous “bypass” of the ligated vein was detected by phlebography. Reoperation using the lower transinguinal approach was curative. The operative correction of recurrence of varicocele by transinguinal approach combined with phlebography Is recommended.
A Rapid and Simple Method for Isolating Principal Cells from the Rat Caput Epididymidis
Authors: KILLIAN GARY J.
Published: December 2015

A technique is described for the rapid isolation of principal cells from enzymatically dispersed rat caput epididymidis by differential sedimentation into calf serum. Sedimentations were prepared in common glass separatory funnels. Sperm‐free, principal cell populations that were 66.6% pure and averaged 106 cells were isolated after 10 minutes of sedimentation. This represents a twofold enrichment in principal cells over that achieved in the dispersed tissue suspension. Based on dye exclusion tests, viability of principal cells after separation was 90% suggesting that the cells are well suited for physiologic study.
Focal Changes in the Seminiferous Tubules of Vasectomized Hamsters
Authors: FLICKINGER CHARLES J.
Published: December 2015

The hamster testis was studied by light and electron microscopy at intervals of two weeks, five months, and one year after vasectomy. No changes were detected at two weeks, but most testes showed microscopic alterations at subsequent intervals. The most striking characteristic of the lesions was their patchy distribution, in which severly altered profiles lay next to apparently normal seminiferous tubules. A spectrum of changes was present, characterized by varying degrees of depletion of germ cells. There were numerous vacuoles in the cytoplasm of Sertoli cells and dilatations of the extracellular space between adjacent Sertoli cells. Both spaces frequently were surrounded by a layer of cytoplasm that resembled that of Sertoli junctional specializations. One testis prepared a year after vasectomy contained multiple infiltrates of phagocytic cells. Possible mechanisms of focal testicular damage after vasectomy are considered.
Cryopreservation of Spermatozoa and Artificial Insemination: Past, Present, and Future
Authors: FOOTE ROBERT H.
Published: December 2015

This review article is intended to provide an in‐depth analysis of the principles and programs established, as well as problems overcome, that have led to a successful artificial insemination (Al) program using cryopreserved semen in cattle. The components of such a program considered are: semen production, evaluation, processing, storage, and insemination. Advances with cattle and other species of domestic animals may provide clues to mechanisms involved which could lead to methods of improving the cryopreservation of human spermatozoa. Several current developments give hope for substantial improvements in the future.
Characterization of Cholinomimetic Agents that Inhibit In Vitro Fertilization in the Mouse Evidence for a Sperm‐Specific Binding Site
Authors: FLORMAN HARVEY M. , STOREY BAYARD T.
Published: December 2015

Spermatozoa from the cauda epididymidis of the mouse bind 3‐quinuclidinyl benzilate (QNB), a highly specific antagonist of the muscarinic type of acetylcholine receptor; inhibition of in vitro fertilization of mouse eggs parallels this binding. Characterization of 3H‐QNB binding to mouse spermatozoa by means of Scatchard and Hill plots showed a single class of non‐interacting sites with KD = 5 nM. The stereospecificity of this site was determined by testing the ability of specific probes to displace competitively 3H‐QNB bound to spermatozoa. Unlabeled QNB, atropine, and scopolamine, which are antagonists of muscarinic receptors, and carbamylcholine and muscarine, which are agonists, competed with 3H‐QNB for the spermatozoon binding site. Propylbenzilylcholine mustard (PrBCM), a specific, irreversible antagonist of muscarinic sites, did not compete for the 3H‐QNB binding site. Those compounds that occupied the QNB binding site on mouse spermatozoa also inhibited the fertilization of the zonapellucida‐intact mouse eggs in vitro, whereas PrBCM, which did not occupy the binding site, had no effect on fertilization. There was a close correspondence between the affinity of these compounds for the QNB binding site and their ability to inhibit fertilization. This correspondence held for both agonists and antagonists of muscarinic sites. From these results, we conclude that the 3H‐QNB binding site of mouse spermatozoa differs from the conventional class of muscarinic sites: while the steric requirements are similar, they are far from identical. This fact suggests that compounds could be synthesized that would be potent inhibitors of fertilization by binding on the sperm surface, but would have no effect on neural tissues. Such compounds would offer a new approach to the design of male fertility control agents.
Comparative C19‐Radiosteroid Metabolism in Primary Monolayer Cultures of Epithelial Cells and Fibroblasts from Rat Ventral Prostate, Canine Prostate, and Rat Lung
Authors: OFNER PETER , VENA RICHARD L. , TERRACIO LOUIS , DOUGLAS WILLIAM H. J.
Published: December 2015

Stromal‐epithelial cell interactions may be important for the regulation of normal and abnormal prostatic growth. While androgen transformation by rat ventral prostate and canine prostate has been investigated in vivo and in organ culture, little is known about metabolic pathways in cultures of epithelial cells and fibroblasts. Metabolism of radioisotope‐labeled 17β‐hydroxy C19‐steroids was studied in primary cultures of highly‐enriched rat ventral prostate and canine prostate epithelial cells and fibroblasts isolated by selective attachment procedures. The fibroblasts contained little testosterone 5α‐reductase in contrast to high activity in epithelial cells. We found high levels of 5α‐androstane‐3α,17β‐diol (3α‐diol) dehydrogenase and the terminal 5α‐androstane‐3β,17β‐diol (3β‐diol) hydroxylases in both cell types; 3α‐diol was a more effective precursor of 5α‐dihydrotestosterone than was testosterone. For prostatic fibroblasts these pathways seem to be differentiated functions, since rat‐lung fibroblasts converted 3β‐diol to 5α‐dihydrotestosterone and 3α‐diol. We conclude that epithelial cells and fibroblasts make interactive contributions to prostatic androgen metabolism.
Effects of Experimental Cryptorchidism on Testicular Function in Adult Rats
Authors: JEGOU BERNARD , RISBRIDGER GAIL P. , DE KRETSER DAVID M.
Published: December 2015

The effects of surgically‐induced cryptorchidism on testicular function in adult rats was studied, with particular emphasis on the temporal relationship between the onset of cryptorchidism and a number of parameters of Sertoli cell, Leydig cell, and pituitary function. Sertoli cell function assessed by measurement of testicular ABP content, ABP production rate, testicular fluid production, and FSH receptor levels was found to be disrupted very rapidly (one to two days) after inducing cryptorchidism. By four days, ABP production rate and fluid production were found to represent only 12% and 65% of control levels, respectively. However, these parameters were maintained at these levels even 70 days following cryptorchidism. The binding of 125I‐FSH to testes homogenates was found to decrease steadily to less than 10% of control levels after 70 days of cryptorchidism. Serum FSH levels were elevated 14 days postcryptorchidism and there was a highly negative correlation between the rise and both ABP and fluid production. Serum levels of LH rose after 14 days of cryptorchidism, although testosterone levels were not significantly altered throughout the experiment. The binding of iodinated hCG to testes homogenates also decreased significantly within six days of inducing cryptorchidism and remained low (16%) after 70 days of cryptorchidism. The results demonstrate rapid changes in aspects of both Sertoli and Leydig cell function after surgically‐induced cryptorchidism.
The Ability of the Rat Epididymis to Concentrate Spermatozoa Responsiveness to Aldosterone
Authors: TURNER T. T. , CESARINI D. M.
Published: December 2015

Experiments have been performed to determine if aldosterone is involved in the control of water reabsorption from the epididymal lumen in vivo. Micropuncture samples of lumen content were collected from the epididymides of control rats and those receiving adrenalectomy, adrenalectomy + 25 μg aldosterone/day, 10 mg spironolactone/kg body weight/day, 10 mg spironolactone + 1 mg testosterone/kg body weight/day, 5 mg desoxycorticosterone acetate (DOCAV day, 50 μg aldosterone/day, or 0.1 ml vehicle alone. The treatment period was three days. Seminal vesicles weights and testis weights were obtained. Sperm concentrations (SEM) in the caput, corpus, and cauda epididymidis of normal rats were 0.75 ± 0.05, 1.24 ± 0.13, and 1.99 ± 0.15 ± 109 sperm/ml, respectively. Both inhibition and removal of aldosterone caused significant reduction (P < .01) of intraluminal sperm concentrations. Sham treatment had no effect. Sperm concentrations were normal in animals receiving aldrenalectomy plus aldosterone replacement. It is concluded that water resorption in the rat epididymis is responsive to aldosterone.