bluuebunny/crossref_metadata_2025 huggingface dataset:
Transdermal Administration of Clonidine: A New Approach to Antihypertensive Therapy
Authors: Burris James F. , Mroczek William J.
Published: December 2015

This study assessed the antihypertensive efficacy and side effects of clonidine administered transdermally. Twenty‐five patients with mild to moderate essential hypertension (seated diastolic blood pressure 95–120 mm Hg with diuretic therapy alone) controlled with oral diuretic plus oral clonidine were enrolled. Transdermal clonidine was substituted for oral clonidine and titrated until adequate blood pressure control (seated diastolic blood pressure <90 mm Hg) was attained. At the end of titration, seated morning blood pressure averaged 129/90 ± 15/5 mm Hg (mean ± standard deviation) compared to 136/96 ± 13/7 mm Hg (p < 0.01/0.001) during oral clonidine administration. Standing morning blood pressure was also lower during transdermal than oral therapy (131/94 ± 16/5 vs 136/99 ± 14/7, p < 0.05/0.001). Afternoon blood pressures (at peak effect of oral dose) were virtually identical during oral and transdermal therapy in both seated and standing positions. Typical side effects of oral clonidine, including dry mouth, drowsiness, and sexual dysfunction, were reduced during transdermal therapy. There was less morning‐to‐afternoon variability of blood pressure control and plasma clonidine concentrations during transdermal than during oral therapy. One patient left the study because of drowsiness and two because of skin reactions to the transdermal skin patch. Mild transient local skin irritation occurred frequently. Transdermal clonidine plus a diuretic is an effective treatment for mild to moderate essential hypertension, improves compliance and reduces side effects of therapy.
Cardiac Conduction Abnormalities and Atrial Arrhythmias Associated with Salicylate Toxicity
Authors: Mukerji Vaskar , Alpert Martin A. , Flaker Greg C. , Beach C. L. , Weber Robert D.
Published: December 2015

Cardiac side effects from aspirin are uncommon; however, severe acid‐base imbalance, pulmonary edema, ventricular ectopic activity and cardiopulmonary arrest have been reported in patients with toxic serum salicylate concentrations. We saw a patient with salicylate toxicity who developed a variety of sinus and atrioventricular nodal conduction disturbances and atrial arrhythmias with a relatively low toxic serum salicylate concentration. The cardiac rhythm returned to normal as the serum salicylate concentration decreased, and results of subsequent electrophysiologic testing and Holter monitoring were normal. A low serum albumin level may have resulted in altered salicylate binding in this patient, thereby increasing the availability of unbound (active) drug for toxic effects.
Analgesic Efficacy of Meclofenamate Sodium in Episiotomy Pain
Authors: Hebertson Richard M. , Storey Nelia , Turner Janeth L.
Published: December 2015

Meclofenamate sodium was compared, double‐blind, with codeine and placebo for the treatment of acute episiotomy pain. One hundred sixty‐eight women with moderate or severe episiotomy pain after normal delivery were assigned randomly to one of four treatment groups: one received meclofenamate sodium 200 mg at dose 1 and 100 mg at doses 2 and 3; one received meclofenamate sodium 100 mg at dose 1 and 50 mg at doses 2 and 3; one received codeine 60 mg at all three doses; and one received placebo at all three doses. Efficacy measurements were evaluated periodically for 6 hours after medication. After the first administration, both doses of meclofenamate sodium were significantly superior to placebo and to codeine from 2–6 hours in pain intensity difference and pain relief. For second and third doses, data were available for too few patients to allow valid analysis and interpretation. Adverse effects occurred in 4 patients in each meclofenamate sodium group, and in 8 in the codeine group and in 6 in the placebo group. The study indicates that single 100‐ and 200‐mg doses of meclofenamate sodium are as safe as, and significantly more effective than, codeine 60 mg or placebo for episiotomy pain.
Analgesic Effect of Naproxen Sodium, Codeine, a Naproxen‐codeine Combination and Aspirin on the Postoperative Pain of Oral Surgery
Authors: Forbes James A. , Keller Carolyn K. , Smith John W. , Zeleznock John R. , Sevelius Hilli , Beaver William T.
Published: December 2015

In a double‐blind study, 198 outpatients with pain after oral surgery were randomly assigned to treatment with a single oral dose of naproxen sodium 550 mg, codeine sulfate 60 mg, a combination of naproxen sodium 550 mg with codeine sulfate 60 mg, aspirin 650 mg or placebo. Using a self‐rating record, subjects rated their pain and its relief hourly for 12 hours after medication. Orthogonal contrasts for the four treatments making up the factorial component showed that the naproxen effect was significant for every measurement of total and peak analgesia; the codeine effect was significant for total and peak pain relief and patients' overall evaluation. The naproxen‐codeine interaction was not statistically significant for any measure, which suggests that the analgesic effect of the combination represents the additive effect of its constituents. Based on pairwise comparisons, aspirin was significantly superior to placebo for most measures of effect, naproxen was significantly superior to both aspirin and codeine for all measures and the combination was significantly superior to naproxen for patients' overall evaluation. No more patients experienced adverse effects with aspirin or naproxen than with placebo, but significantly more patients receiving the codeine‐containing treatments experienced adverse effects than those receiving apsirin and naproxen.
Molsidomine: Alternative Approaches To Treat Myocardial Ischemia
Authors: Nitz Rolf‐Eberhard , Fiedler Volker B.
Published: December 2015

The long‐acting antianginal drug molsidomine has been shown experimentally to reduce myocardial infarct size when administered prior to or after cardiac insult. This is due to several drug actions.

1. Dilation of postcapillary capacitance vessels diminishes venous return, preload, heart dimensions, and myocardial oxygen consumption. 2. Relaxation of stenosed conductive coronary arteries increases the perfusion of myocardial areas at risk of infarction due to enhanced collateral circulation. 3. Increased regional blood supply nourishes predominantly subendocardial cardiac muscles as a result of reduction of extravascular coronary pressure, and resistance. 4. The stable heart rate and cardiac contractility favor improved heart performance. 5. The inhibition of platelet aggregation in vivo by molsidomine or its active metabolites, SIN‐1 and SIN‐1A, is linked to the stimulation of prostacyclin synthesis, inhibition of thromboxane release with induction of thrombosis and vasoconstriction, and enhanced concentrations of cyclic guanosine monophosphate. 6. Dilation of coronary arteries after intracoronary administration of SIN‐1, with inhibition of platelet aggregation by restrained release of adenosine diphosphate and stabilization of platelet membranes, facilitates the recanalization of stenosed arteries and reduces coronary muscle tone at the site of thrombosis. 7. Activation of the human fibrinolytic system and drug‐induced release of a plasminogen activator favor dysaggregatory effects. 8. The drug's inhibiting actions on lipoxygenase products of arachidonate (e.g., 12‐hydroperoxy‐eicosatetraenoic acid and leukotrienes) may shift prostaglandin catabolism to cyclooxygenase products (e.g., prostacyclin) that protect against the expansion of ischemia and the induction of coronary spasm.

Experimentally, the hemodynamic effectiveness of molsidomine can be antagonized by catecholamines (afterload effects) and dihydroergotamine (preload and afterload effects) respectively. Further clinical investigations will clarify the application of these mechanisms for the therapeutic success of the drug in human myocardial infarction.
Determinants of Antibiotic‐associated Hypoprothrombinemia
Authors: Schentag Jerome J. , Welage Lynda S. , Grasela Thaddeus H. , Adelman Martin H.
Published: December 2015

Hypoprothrombinemia is a relatively uncommon event in the hospitalized patient. When it does occur, it often is associated with surgery, dietary vitamin K deficiency, renal dysfunction, malignancy, and broad‐spectrum antibiotic therapy. Several mechanisms have been proposed to account for antibiotic‐associated hypoprothrombinemia, including eradication of gastrointestinal bacteria, direct inhibition of vitamin K‐dependent coagulation, and indirect inhibition of coagulation. The anecdotal reports and comparative studies of antibiotic‐associated hypoprothrombinemia were reviewed; these usually implicated broad‐spectrum or the use of several antibiotics. The increased frequency of hypoprothrombinemia associated with moxalactam and cefoperazone also raises questions about the role of their N‐methylthiotetrazole (NMTT) side chains. The hypoprothrombinemia associated with NMTT antibiotics does not occur in healthy volunteers and is rare in patients without complicating conditions. Although NMTT inhibits vitamin K‐dependent carboxylation in vitro, the parent cephalosporins do not. It is not clear whether NMTT‐containing antibiotics liberate sufficient amounts of NMTT in vivo to antagonize clotting in patients. Thus, although moxalactam, and possibly cefoperazone, may in some cases be responsible for increases in prothrombin time, the most important question for further study is whether the newer NMTT‐containing antiobiotics pose a risk of hypoprothrombinemia that is greater than that of antibiotics lacking this side chain.
Lovastatin: A New Cholesterol‐Lowering Agent
Authors: Krukemyer Julie J. , Talbert Robert L.
Published: December 2015

Lovastatin is a potent new drug for lowering serum cholesterol through inhibition of 3‐hydroxy‐3‐methylglutaryl—coenzyme A reductase, the rate‐limiting enzyme for cholesterol biosynthesis. Metabolic studies with lovastatin in healthy volunteers and patients with hypercholesterolemia suggest reduced synthesis of low‐density lipoprotein cholesterol (LDL‐C) as well as enhanced catabolism LDL‐C mediated through LDL receptors as the principal mechanisms for lipid‐lowering effects. Total cholesterol and LDL‐C are reduced by 30% or more on average when added to baseline therapy, with the effects being more pronounced in nonfamilial than in familial hypercholesterolemia. Optimal dosing appears to be 20 mg given twice a day. The most common adverse effects are gastrointestinal, while the most serious are elevated transaminase levels and the potential for lens opacities. Lovastatin is the first of a new class of lipid‐lowering agents, and is effective when added to diet therapy or in combination with other drugs.
Potential Use of Cimetidine for Treatment of Acetaminophen Overdose
Authors: Speeg K. V.
Published: December 2015

Acetaminophen, a drug frequently taken in intentional and accidental overdose, causes liver toxicity when concentration of the cytochrome P‐450‐derived metabolite exceeds the metabolic capacity of available glutathione. Present treatment of acetaminophen overdose involves oral N‐acetylcysteine (NAC), which enhances liver glutathione synthesis. An alternative or additive approach to therapy would be to inhibit the formation of the toxic metabolite by inhibiting the cytochrome P‐450 system. The H2‐receptor antagonist cimetidine inhibits the cytochrome P‐450 system, does not interfere with the administration or function of NAC, and therefore affords additive protection. Also, it has little effect on the nontoxic routes of elimination of acetaminophen and is itself quite nontoxic. That cimetidine protects against acetaminophen toxicity in animal models has been demonstrated on the basis of improved survival, as well as decreases in several critical elements used to monitor acetaminophen toxicity: classic histologic changes, aminotransferase activity, metabolite covalent binding, and liver glutathione depletion. Administration of cimetidine well after the overdose is also protective. In contrast, animal models of acetaminophen toxicity demonstrate that ranitidine does not afford protection from acetaminophen hepatotoxicity. Clinical data in well‐done trials in humans will be needed to support the experimental animal data.
Tissue Plasminogen Activator: An Evaluation of Clinical Efficacy in Acute Myocardial Infarction
Authors: Rogers Susan D. , Riemersma Linda B. , Clements Stephen D.
Published: December 2015

Recombinant tissue plasminogen activator (t‐PA) is a synthetic fibrinolytic protein which activates plasminogen or converts plasminogen to plasmin specifically in the presence of fibrin. With its “clot‐selectivity”, t‐PA is capable of lysing clots without having a significant effect on circulating plasminogen. In contrast, activation by streptokinase and urokinase is non‐specific and affects circulating as well as thrombus plasminogen. These agents, therefore, have a greater potential to induce bleeding than does t‐PA. Plasma levels of t‐PA following intravenous administration are generally proportional to the dose, but there can be significant interpatient variation. The drug is eliminated primarily by hepatic metabolism and is then excreted in the urine. Half‐life of circulating t‐PA ranges from 2–8 minutes. Most clinical trials of t‐PA have evaluated its use in acute myocardial infarction. Indeed, its current indication is for thrombolysis in evolving Ml. Short‐term benefits of t‐PA administration include a prompt reperfusion and restoration of coronary artery patency in patients with total coronary artery occlusion. The degree to which the heart benefits from thrombolysis is unknown, but electrocardiographic changes, changes in cardiac enzymes and alterations in the pattern of chest pain indicate that rapid reperfusion may limit the size of the infarct. Overall, t‐PA appears to be a relatively safe thrombolytic agent. Bleeding is the most significant adverse effect reported with t‐PA administration. In most cases, however, bleeding has been minor. Other reported adverse effects include reperfusion arrhythmias, bradycardia, and chest pain. Allergic reactions were not observed in clinical trials.
Time‐Dependent Disposition of Cyclosporine after Pancreas Transplantation, and Application of Chronopharmacokinetics to Improve Immunosuppression
Authors: Cipolle Robert J. , Canafax Daniel M. , Rabatin Jeff , Bowers Larry D. , Sutherland David E.R. , Hrushesky William J.M.
Published: December 2015

We studied the circadian influences on cyclosporine pharmacokinetics in five recipients of pancreatic allografts. Results from these patients demonstrate a slightly increased area under the concentration‐time curve (p = 0.156) resulting from decreased apparent clearance during the resting (pm) versus activity (am) period (p = 0.199). A significant delay in mean residence time was observed after the pm dose (p = 0.039), and the pm area under the moment curve was larger than the am value (p = 0.063). We propose three chronopharmacokinetic dosing methods that alter either the pm dose administration time or redistribute the daily dose to produce equal exposure to cyclosporine during the active and resting periods. These trends and differences suggest that more sophisticated time‐dependent cyclosporine dosing methods are needed to balance am and pm drug exposure and thereby improve immunosuppression.
Acute Adrenal Insufficiency Mimicking Septic Shock: A Case Report
Authors: Melby Michael J. , Bergman Kerry , Ramos Tammy , Reinhold Randolph , Mackey William
Published: December 2015

Acute adrenal insufficiency is an unusual problem that may mimic overwhelming sepsis. Elevated cardiac output and low systemic vascular resistance in a patient with known risk factors should alert clinicians to the possibility of that condition.
Stereoselectivity: An Issue of Significant Importance in Clinical Pharmacology
Authors: Lam Y. W. Francis
Published: December 2015

Many drugs have one or more asymmetric centers and are administered as a racemate containing an equal mixture of enantiomers with different pharmacologic properties, routes, and rates of disposition in humans. For example, S‐warfarin is more potent than R‐warfarin, and is metabolized by different pathways. The S‐enantiomer is primarily oxidized, and the R‐enantiomer is metabolized by both oxidation and reduction. Nevertheless, because of the difficulty in separating and analyzing individual enantiomers, most pharmacokinetic and pharmacodynamic studies on drugs have been performed without considering the stereochemical factors. This is unfortunate, because a nonstereoselective approach to the study of chiral drugs precludes insight into potential valuable information that may be relevant to drug development and evaluation. On the other hand, when the pharmacologic properties (including activity, disposition, and interaction with the other enantiomer) of enantiomers have been defined, manipulation of the enantiomeric ratio or use of the pure enantiomer can be pursued to optimize therapeutic efficacy.
Evaluation of Creatinine Clearance Estimation in an Elderly Male Population
Authors: Beck Carol L. , Pucino Frank , Carlson James D. , Silbergleit Inger L. , Strommen Gordon L. , Fenelon Jody C. , Lipp Rosalie , Gill Dhanwant S.
Published: December 2015

Thirty‐one medically stable, elderly males (age 75 ± 8.3 yrs) participated in a prospective study evaluating the accuracy of 16 methods of estimating creatinine clearance. Serum creatinine values were determined on the mornings of days 1, 4, and 5 to assure stable renal function. On the morning of day 3, a 24‐hour urine collection was initiated. A statistically significant correlation existed between the measured and estimated clearance values for all 16 formulas. The correlation (r < 0.65) was lower than that in previously published studies, however. Five of the formulas (1A, 5A, 5B, 7A, 7B) demonstrated no statistical difference between mean measured and estimated values. In this population, formula 2B was the least biased and formula 9B the most accurate. For all 16 methods, the bias was minimal and the relative accuracy of the estimated methods was comparable. The results support using methods to estimate creatinine clearance only as a rough bedside prediction of renal function in elderly males.
The Pain Intensity at Analgesic Intake, and the Efficacy of Diflunisal in Single Doses and Effervescent Acetaminophen in Single and Repeated Doses
Authors: Nyström E. , Gustafsson I. , Quiding Hans
Published: December 2015

A double‐blind, randomized analgesic trial was carried out in 150 patients undergoing surgical removal of their 2 impacted lower wisdom teeth. The analgesic efficacy of effervescent acetaminophen 500 or 1000 mg in a 2‐dose regimen was compared with that of diflunisal 500 mg in a single dose. Each dose was taken when subjectively needed and the pain intensity was measured on a visual analog scale during the 10‐hour period after first medication. The best pain reduction was achieved with diflunisal. The difference between diflunisal 500 mg and acetaminophen 1000 mg was significant, as was that between acetaminophen 1000 and 500 mg. The peak effect after the first dose occurred later but was greater with diflunisal than with acetaminophen. Patients needing analgesics at low pain intensities seemed to discriminate better between treatments, and the efficacy of acetaminophen was weakly dependent on the initial pain intensity. This intensity was difficult to predict, and only a poor correlation was found between the initial pain intensity and the patient's prior estimate of this.
Randomized Trial of Imipenem‐Cilastatin versus Gentamicin Plus Clindamycin in the Treatment of Polymicrobial Infections
Authors: Danziger Larry H. , Creger Richard J. , Shwed Jill A. , Stellato Thomas A. , Hau Toni
Published: December 2015

The comparative efficacy of imipenem‐cilastatin versus clindamycin and gentamicin in the treatment of polymicrobial infections was evaluated. Eleven patients completed treatment with the former and nine with the latter. Conditions treated included infected extremity ulcers, peritonitis, perirectal abscess, soft‐tissue abscess, abdominal abscess, and acute diverticulitis. Similar rates of bacteriologic and clinical cure or improvement were achieved with the two treatments. Superinfection occurred in two patients who received imipenem‐cilastatin and one who received clindamycin and gentamicin. No significant difference in adverse effects was noted. Imipenem‐cilastatin appears to be an effective antibiotic in treating polymicrobial infections; however, a much larger patient population would be required to detect a significant difference in the efficacy rates or frequency of adverse effects when comparing the two regimens.
Transdermal Fentanyl: Pharmacokinetics and Preliminary Clinical Evaluation
Authors: Plezia Patricia M. , Kramer Thomas H. , Linford Jennifer , Hameroff Stuart R.
Published: December 2015

A new transdermal drug‐delivery system that administers the synthetic opioid fentanyl through intact skin was evaluated for 24 hours postoperatively in eight patients who had undergone orthopedic surgery. Plasma samples were obtained over a 72‐hour period for pharmacokinetic analysis in five patients. The patients were also evaluated intensively for adequacy of analgesia, frequency of nausea and sedation, and occurrence of ventilatory depression. A median lag time of 2.25 hours after application of the transdermal system was observed before the appearance of fentanyl in the blood. Median peak concentration and time to peak were 1.0 ng/ml and 22 hours, respectively. The apparent elimination of fentanyl after transdermal administration is prolonged relative to previously reported values. Absorption analysis indicates zero‐order fentanyl administration, and in addition, suggests deposition of drug in an epidermal site, with the resultant prolonged absorption process giving the appearance of slow elimination. No significant toxicities were observed. Four patients required no additional analgesia. No consistent correlations among fentanyl concentration and any clinical values were observed. Transdermal administration of fentanyl appears to be a viable alternative to conventional routes of narcotic administration and warrants further study.
The Treatment of Alcohol Withdrawal
Authors: Guthrie Sally K.
Published: December 2015

Abrupt cessation of regular use of alcohol in a dependent person causes a withdrawal syndrome that may range from mild to extremely severe. Most patients require pharmacologic intervention, especially those with severe symptoms. Historically, the pharmacotherapy of alcohol withdrawal has involved a wide variety of agents. Benzodiazepines are currently preferred due to their consistently high degree of efficacy and laudable record of safety. In addition, ß blockers and clonidine are useful, as both effectively combat the hypertension and tachycardia commonly associated with withdrawal. They are ineffective as anticonvulsants; however. Opinions differ concerning the best treatment for withdrawal seizures. Prophylaxis with benzodiazepines may be all that is required, although some authors advocate the use of phenytoin for 5 days, especially in persons with a history of prior seizures during alcohol withdrawal. Once established, delirium tremens are difficult to treat. Benzodiazepines are most commonly used to provide sedation, and extremely large doses may be required. Careful clinical assessment is essential to the proper treatment of patients undergoing alcohol withdrawal since the coexistence of medical problems may complicate the condition.
Prospective Surveillance of Antibiotic‐Associated Coagulopathy in 970 Patients
Authors: Grasela Thaddeus H. , Walawander Cynthia A. , Welage Lynda S. , Wing Patricia E. , Scarafoni Deborah J. , Caldwell John W. , Noguchi Jean K. , Schentag Jerome J.
Published: December 2015

N‐methyl‐thio‐tetrazole (NMTT) has been proposed as a causative factor in antibiotic‐associated coagulopathy. To evaluate this hypothesis, a nationwide surveillance program was initiated to determine the relative frequency of antibiotic‐associated coagulopathy and the importance of specific risk factors. A total of 970 patients were studied, with 491 being treated for infections and 479 receiving antimicrobial surgical prophylaxis. The NMTT‐containing antibiotic cefotetan was compared with non‐NMTT‐containing antibiotics, for example, cefoxitin and cefazolin (prophylaxis only), and an aminoglycoside‐antianaerobic (AG + AA) combination. Prothrombin time (PT) and partial thromboplastin time (PTT) were measured for each patient prior to the start of antibiotics and within 24–96 hours after the conclusion of drug administration. The patient population was relatively young [mean (SD) age 51.0 (20) yrs] with good nutritional status. The overall frequency of hypoprothrombinemia (4.5%) and bleeding (1.7%) was very low, and was highest with the use of AG + AA (p < 0.05). No statistical differences were observed for the remaining antibiotic regimens in either the prophylaxis or treatment group. Logistic regression analysis identified treatment with the AG + AA combination, presence of liver disease, and renal dysfunction as factors associated with an increased risk of hypoprothrombinemia. In conclusion, this study suggests that the frequency of antibiotic‐associated coagulopathy is low, regardless of antibiotic, in patients who are not critically ill and not malnourished.
Angiotensin‐Converting Enzyme Inhibitors: Mechanistic Controversies
Authors: Ujhelyi Michael R. , Ferguson Roger K. , Vlasses Peter H.
Published: December 2015

Many studies have investigated the mechanisms responsible for the therapeutic effects of the angiotensin converting enzyme inhibitors. Initially, the hemodynamic changes that occur with these agents were attributed solely to the inhibition of the renin‐angiotensin‐aldosterone system in plasma. Further research suggested other mechanisms were operable as a relationship was not always evident between hemodynamic changes and inhibition of the plasma renin‐angiotensin‐aldosterone system. A relationship between the pharmacodynamics of these agents and the inhibition of vascular and tissue renin‐angiotensin systems, however, has been observed. Mechanisms less likely to contribute to the actions of the angiotensin converting enzyme inhibitors are increases in bradykinin and prostaglandin concentrations, or inhibition in the renin‐angiotensin system within the central nervous system. Ancillary cardiovascular effects of angiotensin converting enzyme inhibitors offer possible new therapeutic gains. An understanding of these mechanistic controversies and newly‐defined cardiovascular actions of angiotensin converting enzyme inhibitors are important to clinicians using these agents.
A Continuous Flow Method for Organ Culture of Rabbit Epididymis: Morphology, Amino Acid Utilization, Glucose Uptake, RNA, and Protein Synthesis
Authors: ORGEBIN‐CRIST M.‐C. , MÉNÉZO Y.
Published: December 2015

A modified perfusion system was developed to maintain an unconvoluted tubule from the corpus epididymidis of the rabbit in organ culture. The epididymal explant is submerged in a continuous flow of oxygenated medium. The design facilitates pulse incorporation of labeled precursors and subsequent culture of the explant without disturbing the immediate explant environment. The morphology of the explant is well preserved even after six days in culture. Amino acid utilization and glucose uptake by the explants are higher in continuous flow than in static cultures, and continue even after four to seven days in culture, although at a lower rate than in the first three days. Radio‐autographic observations indicate that explants maintain their capacity for protein synthesis. This method of organ culture will prove useful in the study of some aspects of epididymal physiology.
The Aging Leydig Cell: III. Gonadotropin Stimulation in Men
Authors: NANKIN H. R. , LIN T. , MURONO E. P. , OSTERMAN J.
Published: December 2015

To assess the capacity of aging human Leydig cells to respond to intramuscular injection of hCG, six healthy men, 68 to 86 years old, and eight healthy younger subjects, 25 to 42 years old, were studied. After two control specimens, each subject was given hCG (40 IU/kg of body weight intramuscularly) at 0900 hours. Blood specimens were then obtained hourly for 6 hours and at 24, 48, and 72 hours.

The younger men had higher control concentrations of testosterone (P < 0.05). Both groups demonstrated biphasic elevations of circulating testosterone and 170H‐progesterone with a nadir at 5 hours and 6 hours separating the rises. The early (1–6 hours) and late (24, 48, and 72 hours) testosterone and 170H‐progesterone responses to hCG were significantly lower in older men. The older men demonstrated significant estradiol increases at 3, 4, and 6 hours, while the younger group had a significant 2‐hour rise. However, the peak (24‐hour) estradiol rises were significantly greater in the younger men.

We conclude that theb aged Leydig cell demonstrates altered early (1–6 hours) and late(24, 48, and 72 hours) responses to intramuscular injection of hCG, as assessed by circulating concentrations of testosterone, 17OH‐progesterone, and estradiol.
FSH Stimulation of cAMP Accumulation in Hamster Sertoli Cells: Effect of Age and Optic Enucleation
Authors: HEINDEL JERROLD J. , BERKOWITZ ALBERT S. , PHILO RON , PRESLOCK JAMES P.
Published: December 2015

Sertoli cells isolated from immature, adult, and adult optic‐enucleated hamsters respond to FSH, but not to LH, with an increase in cAMP accumulation. There is an age‐related decline in responsiveness of Sertoli cells to FSH. Sertoli cells cultured from optic‐enucleated adult hamsters with regressed testes respond to FSH with an Increased accumulation of cAMP similar in magnitude to that of immature Sertoli cells. These data indicate that optic enucleatlon results in a reversal of the sensitivity of Sertoll cells to FSH, an effect which may be important for the reinitiation of spermatogenesis, which naturally follows the regressed state.
The Sources of Carnitine in Human Semen
Authors: FAHIMI FERESHTEH , BIEBER LORAN , LEWIN LAWRENCE M.
Published: December 2015

A study was initiated to determine the sources of carnitine in the male reproductive system. Free and total carnitine was measured in a group of healthy men before and after vasectomy. Each individual served as his own control. The results show that postvasectomy semen contains about 52% as much total carnitine and 40% as much free carnitine as prevasectomy samples. The data indicate that, in addition to the epididymis, the seminal vesicles and/or vas deferens are major contributors of carnitine in human semen.
Quantitative Correlation Between Testicular Stem Cell Survival, Sperm Production, and Fertility in the Mouse After Treatment With Different Cytotoxic Agents
Authors: MEISTRICH MARVIN L.
Published: December 2015

Treatment of mice with high doses of radiation or certain cytotoxic drugs results in killing of spermatogonial stem cells, a prolonged period of reduced sperm production, and infertility. In this study, quantitative relationships between these parameters are shown to exist after radiation, Adriamycin (Adria Laboratories, Wilmington, Delaware) or thiotepa treatment. The same relationships are valid for the different cytotoxic agents tested.

The survival of spermatogonial stem cells was assessed by counts of repopulating tubule cross sections at five or eight weeks after treatment. Testicular sperm head counts, eight weeks after treatment, were also used as an assay of stem cell survival. These two assays are highly correlated, demonstrating that the sperm head count at eight weeks is directly related to stem cell survival.

Sperm production declines after cytotoxictreatment and partially recovers to a plateau level. The level of this recovery is correlated with stem cell survival. The restoration of fertility is related to the recovery of sperm production. Under the conditions employed, fertility returns when sperm production by the testis reaches about 10% of control levels. The duration of the sterile period is also highly correlated with stem cell survival.

These results strongly suggest that short‐term assays that measure survival of stem cells can be used to predict the duration and extent of sterility, regardless of the cytotoxic agent used.
Effects of the Antiestrogen CI‐628 on Leydig Cell Function
Authors: MELNER MICHAEL H. , ABNEY TOM O.
Published: December 2015

The objective of this study was to use antiestrogens as probes into the relationship between 17β‐estradiol, the estrogen receptor, and Leydig cell steroidogenesis. Leydig cells purified by Metrizamide density gradient centrifugation were shown to contain estrogen receptors. Competitive inhibition studies performed in vitro demonstrated that the antiestrogens, CI‐628, tamoxifen, and enclomiphene, were effective competitors of [3H]‐estradiol binding with half‐maximal inhibition values of 10.8, 35, and 41 nM, respectively. Additionally, CI‐628 was shown to elicit depletion and Inhibit replenishment of the cytoplasmic estrogen receptor In vitro following a 50‐μg intraperitoneal injection. The effect of 10−6 M Cl‐628 on human chorionic gonadotropin (hCG)‐stlmulated testosterone production in purified Leydig cell incubations was assessed. The CI‐628 elicited a significant inhibition of hCG‐stimulated testosterone synthesle at time points from 1 to 3 hours while basal (unstimulated) synthesis was unaffected. These studies demonstrate an interaction between CI‐628 and the Leydig cell estrogen receptor. Furthermore, CI‐628 was shown to have a rapid inhibitory effect on hCG‐stimulated testosterone production in Leydig cells.
Evidence for Direct Transfer of 1, 2‐3H Testosterone From Testicular Veins to the Rete Testis in Rats
Authors: FREE MICHAEL J. , JAFFE RICHARD A.
Published: December 2015

To investigate the origin and route of entry of testosterone into the rat rete testis, samples were drawn from the rete, deep testicular veins, testicular lymph and systemic arteries during testicular or femoral vein infusion of 3H‐testosterone. During infusion into the femoral vein, the level of label in the rete testis fluid (RTF) was only 50% of that in the deep testicular veins. During infusion into the testicular collecting veins at the base of the pampiniform plexus, RTF radioactivity averaged two to three times the level in the deep testicular veins. Premixing the labeled testosterone with albumen prior to infusion may reduce this difference between RTF and deep testicular venous radioactivity. The levels of RTF radioactivity during 14C‐urea infusion were doubled when the labeled molecule was introduced into the testicular collecting veins, in contrast to the femoral vein. However, levels of radioactivity in the RTF never exceeded those in the deep testicular veins. Following stimulation of endogenous testosterone secretion by a single dose of luteinizing hormone, testosterone concentrations in both testicular vein and RTF increased in parallel, and peaked at approximately the same time. The conclusion from this study was that a rapid exchange of testosterone can occur between the rete testis and the veins at the base of the pampiniform plexus.
Testosterone Pretreatment and the Response of Pituitary LH to Gonadotropin‐Releasing Hormone (GnRH) in the Male Dog
Authors: FALVO R. E. , GERRITY M. , PIRMANN J. , WINTER M. , VINCENT D. L. , MILLER J.
Published: December 2015

To characterize the effects of testosterone (T) pretreatment on the resenous gonadotropin‐releasing hormone (GnRH), intact male dogs were injected subcutaneously with either oil or 500 μMg/kg of T in oil at 1, 3, 6, 12, or 24 hours prior to intravenous GnRH administration (50 ng/kg). The pre‐GnRH levels of plasma LH were reduced in all groups of T‐treated dogs except in animals given T 1 hour before GnRH. The concentrations of plasma LH during both the peak‐response period and the recovery period following GnRH administration in animals injected with T did not differ from those in animals injected with oil. These results indicate that T pretreatment has no effect on the ability of the pituitary to respond to exogenous GnRH at all time periods tested, and imply that direct feedback of T on the pituitary may not be acutely involved in steroid negative feedback in the male dog. Unexpectedly, however, there was some indication that the time of injection of either oil or T could affect the response of the pituitary to GnRH, and this may represent a stress phenomenon.
Effects of Prolactin on Prostate Androgen Receptors in Male Rats
Authors: BARAÑAO JOSÉLINO S. , TESONE MARTA , OLIVEIRA‐FILHO RICARDO M. , CHIAUZZI VIOLETA A. , CALVO JUAN CARLOS , CHARREAU EDUARDO H. , CALANDRA RICARDO S.
Published: December 2015

Five groups of immature (30‐day‐old) intact male rats were injected daily for ten days with different doses of ovine prolactin (5, 10, 25, 50, or 500 μg per rat per day). At the end of the treatment period, the animals were killed, serum was collected for LH and androgens measurements and weights of testes, prostates, and epididymides were recorded. Available and exchangeable cytoplasmic and total nuclear KC1‐extractable androgen binding sites in the prostate gland were determined using the synthetic androgen R1881 as radioligand.

A significant increase in the weights of testes and accessory reproductive glands was observed with the highest dose injected (500 μg per rat per day) as follows: testes, 583 ± 21 (SEM) versus 448 ± 38 mg (P <0.05); prostate, 80.0 ± 4.0 versus 64.7 ± 3.1 mg (P <0.05); epididymis, 72.1 ± 5.0 versus 58.2 ± 4.0 mg (P <0.05). Serum levels of LH were significantly higher in prolactin‐treated animals. Maximal values of serum LH were attained with the dose of 50 μg (99.0 ± 11.2 versus 32.0 ± 4.6 ng/ml; P < 0.05).

Increasing doses of prolactin produced a concomitant rise in serum 3α‐androstanediol (2.21 ± 0.45 versus 6.63 ± 0.42 ng/ml in the group treated with 50 μg), whereas testosterone plus dihydrotestosterone levels remained unchanged.

A decrease in the concentration of exchangeable cytosolic androgen binding sites in the prostate (fmoleslmg protein) was observed in prolactin injected animals (88.2 ± 0.8 in the control group versus 80.6 ± 0.3 and 74.9 ± 0.3 for doses of 5 and 50 μg, respectively; P <0.05). No changes in androgen binding sites were detected in the group treated with 500 μg per rat per day. On the other hand, prolactin treatment did not alter the number of available androgen binding sites in the prostate gland. Increasing doses of prolactin induced a dose‐related increase in the total number of nuclear KC1‐extractable receptors, expressed per mg DNA or per organ. In addition, the total content of androgen receptors (cytosolic plus nuclear binding sites) was significantly higher in animals treated with 500 μg of prolactin (385 ± 34 versus 228 ± 37 fmoles per organ; P < 0.05).

These results suggest that, in addition to the previously described effects of prolactin on Leydig cell responsiveness to LH and on androgen metabolism, this hormone could also modify peripheral LH and androgen levels as well as the androgen receptor content in the rat prostate gland.
Comparison of Prostatic Response to Pituitary Grafts in Castrate Rats Treated with Testosterone or Dihydrotestosterone
Authors: PRINS C. S. , LEE C.
Published: December 2015

To understand further the effect of prolactin (PRL) on prostatic growth, the present study was undertaken to determine if the augmentation of testosterone (T)stimulated growth by PRL is mediated before or after the formation of dihydrotestoterone (DHT). Mature male Sprague‐Dawley rats were castrated and treated with subcutaneous Silastic implants containing either T or DHT. Serum PRL was elevated by grafting, under the kidney capsule, pituitaries from two female rats, while controls received grafts of muscle. Three weeks later, all animals were sacrificed. Animals bearing pituitary grafts had an average serum PRL level of 125 to 140 ng/ml while PRL levels for controls were 15 to 20 ng/ml. T treatment provided 1.37 ± 0.11 ng T/ml serum and the DHT capsules produced serum DHT levels of 1.16 ± 0.12 ng/ml. Under these conditions, the lateral prostate showed a specific growth response to PRL: wet weight, protein content, protein concentration, and DNA levels were all significantly greater in engrafted rats treated with either T or DHT than in their respective controls. On histologic examination, elevated PRL levels were associated with proliferative changes of the lateral lobe which included marked papillary infolding and acinar epithelial hyperplasia. This alteration was similar in both steroid‐treated groups. These data show that PRL has the same effect on DHT‐maintained lateral lobes as it does on the testosterone‐maintained prostate and indicate that the PRL effect is not mediated prior to T conversion to DHT but rather at a site beyond DHT formation.
Gonadotropin, Prolactin, and Thyrotropin Secretion in Lepromatous Leprosy
Authors: SHILO SHMUEL , LIVSHIN YOSEF , ZYLBERHARAN EDIT , SHESKIN JACOB , SPITZ IRVING M.
Published: December 2015

Gonadotropin, PRL, and TSH secretion was determined in 14 patients (27 to 56 years of age) with lepromatous leprosy and in 28 controls. Each subject received LHRH (100 μg), TRH (200 μg), and the dopaminergic antagonist, metoclopramide (10 mg), at 30‐minute intervals, with periodic blood sampling. On the basis of the LH response to LHRH, the patients were divided into two groups. Group I consisted of nine patients with an exaggerated LH response to LHRH. The remaining five patients of Group II had a normal response to LHRH. Mean basal and peak FSH responses to LHRH were increased in both groups, but were greater in Group I. Mean 17β‐estradiol (E2) levels were increased in both groups, whereas, testosterone values were normal. Basal PRL levels were similar to those in controls, but there was an increased PRL response to both TRH and metoclopramide in Group I patients. In contrast, Group II patients had PRL responses identical to controls. Both groups had increased TSH responses to TRH in the presence of normal basal thyroxine (T4) and triiodothyronine (T3) levels. The PRL response to TRH correlated with both basal and peak FSH responses to LHRH, but not with LH, E2, nor testosterone. The TSH response did not correlate with either gonadotropins, E2, or thyroid hormone levels. Similar abnormalities in PRL and TSH secretion have been described in patients with primary testicular failure.
Modification of Sertoli Cell Responsiveness to FSH by Cryptorchidism and Hypophysectomy in Immature and Adult Rats
Authors: HEINDEL JERROLD J. , BERKOWITZ ALBERT , STEINBERGER ANNA , STRADA SAMUEL J.
Published: December 2015

Cryptorchid or hypophysectomized rats were used as models to examine the possible relationships between germ cell development and gonadotropins in the age‐related decline in the responsiveness of the cyclic flucleotide system of rat Sertoli cells to FSH. Neither cryptorchidy nor hypophysectomy of adult rats can restore the ability of Sertoli cells to respond to FSH. Thus the age‐related decline in cAMP response to FSH appears to be irreversible by depletion of postmeiotic germ cells in the presence or absence of gonadotropins. In contrast, cryptorchidy or hypophysectomy of immature rats prevents the normal age‐related change in FSH responsiveness, suggesting that the change in responsiveness is not directly related to changes in gonadotropins or to the presence of developing germ cells. It is hypothesized that the decline in responsiveness to FSH may be physiologically important and may be a prerequisite for the completion of meiosis.
The Effect of Acute and Chronic Ethanol Administration on Prolactin Secretion in Male Rats
Authors: SEILICOVICH ADRIANA , RETTORI VALERIA , KOCH OSVALDO R. , DUVILANSKI BEATRIZ , DIAZ MARIA del C. , DEBELJUK AND LUCIANO
Published: December 2015

The effect of acute and chronic administration of ethanol on prolactin secretion in male rats was investigated under basal conditions and after the administration of sulpiride. The effect of ethanol on the activity of glutamic acid decarboxylase (GAD) in the hypothalamus was also examined. Acute administration of ethanol significantly increased serum prolactin levels. This increase persisted after sulpiride administration. In contrast, chronic administration of ethanol did not significantly modify serum prolactin levels. However, the elevation of prolactin levels in response to the injection of sulpiride was significantly lower in rats chronically treated with ethanol than in control animals. Pituitary concentration of prolactin was not significantly modified by acute or chronic administration of ethanol. Sulpiride administration failed to reduce the concentration of prolactin in the pituitary of rats acutely treated with ethanol, in contrast to its effect in control rats. Acute administration of ethanol significantly decreased hypothalamic GAD activity, while chronic ethanol treatment caused an increase in GAD activity in the hypothalamus. These results indicate that ethanol can alter prolactin secretion and the synthesis of GABA in the hypothalamus.
Ultrastructural Observations on the Penetration of Human Sperm into the Zona Pellucida of the Human Egg In Vitro
Authors: SATHANANTHAN A. A. HENRY , TROUNSON A. O. , WOOD CARL , LEETON J. F.
Published: December 2015

Sperm penetration into the zona of 46 human eggs was examined by electron microscopy. Preovulatory oocytes were aspirated at laparoscopy and inseminated by methods which produced normal pregnancies. These were routinely fixed 3–72 hours after insemination and examined for zona penetration.

The mechanism of zona penetration was similar in the non‐activated oocytes, fertilized ova, and embryos obtained, and resembled that which was reported in most mammals. Sperm were tightly bound to the zona by their plasma membranes. Both acrosome‐reacted and unreacted sperm were seen in the cumulus and entering the zona. The acrosome reaction involved multiple fusions and vesiculation of the plasma and outer acrosome membranes. Fine and coarse vesiculation was observed, and the sperm digested a clear pathway through the zona. Sperm were rarely seen in the inner zona and never seen in the perivitelline space of monospermic ova, but freely penetrated these regions in polyspermie ova. A block to polyspermy seemed to operate at the level of the inner zona. Morphologic evidence for the involvement of the inner acrosome membrane in the acrosome reaction and a possible sequence of events in zona penetration is presented. The findings confirm most of late Professor Pierre Soupart's work on zona penetration.
In Vitro Sperm Capacitation and In Vitro Fertilization with Normal Development in the Rabbit
Authors: BRACKETT BENJAMIN C. , BOUSQUET DANIEL , DRESSEL MICHAEL A.
Published: December 2015

The objective was to obtain in vitro sperm capacitation and fertilization to approximate the normal in vivo processes. Rabbit oocytes from follicles, ovarian surfaces, and oviducts were fertilized in vitro with ejaculated spermatozoa which were treated with high ionic strength followed by preincubation in defined conditions for 12 to 22 hours. Five bucks were studied and, in general, high sperm motility scores favored high levels of fertilization. In all, 305 (55%) of 553 oocytes were fertilized and 244 (80% of those fertilized) developed to the four‐cell stage within 24 hours; early blastocysts developed in culture. Transfer of 39 four‐cell embryos into three recipients resulted in seven live young. Marked improvement both in percentages of fertilization and in four‐cell stage development within 24 hours followed the transfer of oocytes from sperm suspensions after 6 hours. In vitro capacitated spermatozoa fertilized 62% of ova in vivo after tubal insemination 13 hours after Human Chorionic Gonadotropin (HCG). Thus, in vitro capacitation and in vitro fertilization approximate the normal in vivo events.