bluuebunny/crossref_metadata_2025 huggingface dataset:
The Interaction of Maintenance Interferon with Cytolytic Cells in Patients with Multiple Myeloma Who Responded to Cytotoxic Chemotherapy
Authors: Hall Philip D. , Self Sally E. , Hall Rayna Kneuper
Published: October 2023

Study Objective. To determine the long‐term effects of maintenance interferon on CD56+ and CD3+ cell activity.

Design. Prospective phase II trial.

Setting. Tertiary medical center and level 2 Veterans Administration hospital.

Patients. Seven patients (age 45–74 yrs) with multiple myeloma who had reached the plateau phase from cytotoxic chemotherapy, and seven age‐ and sex‐matched controls.

Interventions. All patients were given interferon‐α2b 3 × 106 U/m2 3 times/week.

Measurements and Main Results. The CD56+, CD3+, and CD16+ counts were determined by flow cytometry in both peripheral blood and bone marrow. Natural killer (NK) cell functional activity was determined by a 51chromium release assay. Monocyte cell numbers were determined from the white blood cell count with differential. Interleukin‐6 (IL‐6) concentrations were determined by a commercially available enzyme‐linked immunosorbent assay. During the 24‐week study, the peripheral blood CD3+ and monocyte counts in patients with myeloma remained constant (p>0.39) but their absolute CD56+ counts decreased significantly (p=0.05). In peripheral blood, CD56+, CD16‐, CD3‐ was the predominant phenotype in patients. The predominant phenotype in bone marrow was CD56+, CD16‐, CD3+ at baseline but changed to CD56+, CD16‐, CD3‐ by week 24. The cytolytic activity of NK cells significantly increased in bone marrow (p=0.05) whereas it remained stable in the peripheral blood (p=0.55), but only half that of the controls. Concentrations of IL‐6 did not increase significantly during the study.

Conclusion. In peripheral blood, NK cell activity remained stable in patients but was significantly lower than that in controls, probably secondary to the predominance of the CD56+, CD16‐, CD3‐ phenotype in the patients. In contrast, NK cell activity increased significantly in bone marrow despite the predominance of the CD56+, CD16‐, CD3‐ phenotype by week 24.
Effects of Dialysis Membrane on Intradialytic Vancomycin Administration
Authors: Scott Meri K. , Macias William L. , Kraus Michael A. , Clark William R. , Carfagna Mark A. , Mueller Bruce A.
Published: October 2023

Study Objective. To quantify the influence of hemodialyzers on vancomycin removal when the drug was infused during hemodialysis.

Design. Prospective, controlled, crossover study with three arms.

Setting. A university‐affiliated medical center.

Patients. Eight subjects receiving outpatient hemodialysis.

Interventions. The three treatment arms were vancomycin 1000 mg infused after dialysis was completed (control), and the same dosages infused during the last hour of hemodialysis with a cellulose triacetate (CT) and a cellulose acetate (CA) hemodialyzer.

Measurements and Main Results. The areas under the curve from time zero to 44 hours (AUC0‐44 hrs) for the three study arms were significantly different (p<0.05), with the mean vancomycin AUC0–44 hrs being significantly lower when administered during CT and CA dialysis (73.7% and 87.2% of control; p<0.05 vs control). The mean vancomycin peak concentration achieved during CT dialysis was significantly lower than for the CA and control arms (20.5, 23.9, 27.0 mg/L, respectively). Forty‐four‐hour postinfusion concentrations were similarly lower.

Conclusion. Clinicians should recognize that the composition of the hemodialyzer significantly influences vancomycin serum concentrations when the drug is administered during hemodialysis.
Lansoprazole: A Comprehensive Review
Authors: Zimmermann Anthony E. , Katona Brian G.
Published: October 2023

Lansoprazole is the second member of the substituted benzimidazole class of antisecretory agents approved for use in the United States. These drugs decrease parietal cell acid secretion by inhibiting H+,K+‐adenosine triphosphatase, the final step in the secretion of acid. Lansoprazole has been studied extensively for the short‐term treatment of duodenal and gastric ulcers, reflux esophagitis, and Helicobacter pylori‐positive peptic ulcer disease; long‐term treatment of Zollinger‐Ellison syndrome; and maintenance treatment of erosive esophagitis. A dosage of 30 mg/day produced higher healing rates and equivalent or faster relief of ulcer symptoms than ranitidine or famotidine in patients with duodenal or gastric ulcers and reflux esophagitis. Compared with omeprazole 20 mg/day, that dosage provided faster epigastric pain relief in these patients after 1 week, although healing rates for the two agents were equivalent at 4 and 8 weeks. In patients with peptic ulcer refractory to 8‐week therapy with histamine2‐receptor antagonists, healing rates were not significantly different between lansoprazole and omeprazole. In patients with Zollinger‐Ellison syndrome, lansoprazole was superior to histamine2‐receptor antagonists and was similar in efficacy, safety, and duration of action to omeprazole. Combinations of lansoprazole or omeprazole with one or two antibiotics produced equivalent eradication of H. pylori. In clinical trials, lansoprazole was well tolerated, with frequency of adverse effects similar to that reported with ranitidine, famotidine, and omeprazole.
Retrospective Pharmacoeconomic Evaluation of Dosing Vecuronium by Peripheral Nerve Stimulation versus Standard Clinical Assessment in Critically Ill Patients
Authors: Zarowitz Barbara J. , Rudis Maria I. , Lai Katie , Petitta Antonio , Lulek Martin
Published: October 2023

Adjusting the dosage of vecuronium by peripheral nerve stimulation versus standard clinical dosing in critically ill patients reduces drug requirements to maintain a desired depth of paralysis and, on average, produces faster recovery of neuromuscular function. We retrospectively analyzed the health and economic outcomes of using train‐of‐four (TOF) end points by peripheral nerve stimulation in dosing neuromuscular blocking agents during continuous infusion in a medical intensive care unit (ICU). A decision‐analytic model was used to calculate outcomes and costs of treatment using and not using TOF end points of dosing vecuronium. Data from our TOF trial provided the difference in neuromuscular and functional recovery time. Charges billed by the Patient Financial Services Department were used to determine hourly costs of ICU stay for recovery from neuromuscular blockade using costsxharges ratios estimated from a sample of 20 patients. The cost of vecuronium was determined using the hospital acquisition cost and the actual number of milligrams of drug given to each patient in the TOF trial. The cost of performing one TOF event was determined by timing six events performed by six pharmacists, and randomly selecting 60% of these to calculate a mean time/TOF event. The economic impact of dosing by TOF was determined by calculating the cost savings/patient dosed by TOF compared with those who had doses individualized by standard clinical assessment. One‐way and multiway sensitivity analyses were performed to assess model uncertainty. The mean drug cost was $286 in the TOF group versus $580 in the standard dosing group. With a mean time/TOF assessment of 5.8 ± 1.6 minutes, each episode cost $2.92 for a total TOF cost/patient of $23. At $54/hour of recovery time in the ICU, the estimated cost of ICU care for the TOF group was $34,214 versus $118,681 for the standard group. The estimated costs/patient were $459 and $1197, respectively, for a total cost savings/patient of $738. Sensitivity analyses showed the model to be robust. Estimated annual savings of $146,103 are projected by using TOF to individualize vecuronium doses in patients in the ICU. Individualizing vecuronium doses to TOF end points has both therapeutic and economic advantages. When considering costs of drug, TOF monitoring, and ICU, the total cost/patient was 40% of that in the control group.
Hyponatremia in Relation to Treatment with Antidepressants: A Survey of Reports in the World Health Organization Data Base for Spontaneous Reporting of Adverse Drug Reactions
Authors: Spigset Olav , Hedenmalm Karin
Published: October 2023

To determine the risk factors associated with the development of hyponatremia during treatment with antidepressant drugs, we conducted a retrospective register study of the World Health Organization (WHO) data base for spontaneous reporting of adverse drug reactions. From the start of the WHO Collaborating Centre for International Drug Monitoring in 1968 until the end of 1993, 668 reports of antidepressant‐associated hyponatremia disorders were submitted. Seventy‐eight percent of them concerned women, compared with 69% for all other adverse drug reactions with antidepressants (p<0.0005). The mean age of all patients was 66.6 years, compared with 48.6 years for the other adverse drug reactions (p<0.0001). In 51.3% of the patients the reaction occurred within the first 2 weeks of treatment. Significantly more cases occurred during the summer than during the other seasons (p<0.02). The risk for hyponatremia during treatment with antidepressants seems to be highest in women, in the elderly, during the summer, and during the first weeks of treatment.
Short‐Term Intravenous Milrinone for Severe Congestive Heart Failure: The Good, Bad, and Not so Good
Authors: Varriale Philip , Ramaprasad Sunil
Published: October 2023

We evaluated the overall hemodynamic and clinical effects, beneficial and deleterious, of short‐term intravenous milrinone in the management of severe congestive heart failure (CHF). Numerous hemodynamic measurements were obtained in 24 patients (mean age 65 yrs) with advanced, severe CHF (New York Heart Association class IV, ejection fraction 24 ± 5%), including 3 with concomitant clinical sepsis. Hemodynamic data were recorded at baseline and after a bolus of intravenous milrinone 50 μg/kg and maintenance infusion based on creatinine clearance at 0.5, 3, 24 and 48 hours. Cardiac index increased and pulmonary capillary wedge pressure decreased significantly (p<0.001; 2.07 ± 0.36 to 3.6 ± 0.36 L/min/m2 and 20.6 ± 4.0 to 13.5 ± 2.8 mm Hg, respectively) in 24 patients 0.5 hour after initiation of therapy. These favorable hemodynamic responses, including significant decreases in systemic vascular resistance index and right atrial pressure, were sustained throughout the 48‐hour study in 19 patients (79%). Severe hypotension occurred in three patients with superimposed sepsis as the result of exaggerated vasodilatation. One patient had recurrent ventricular tachycardia and another tolerance to milrinone. In two patients, excessive decline in preload and fall in cardiac index were reversed with volume expansion. Intravenous milrinone offered significant short‐term hemodynamic benefits in most patients with severe CHF.
Phenytoin‐Oxacillin Interactions in Normal and Uremic Sera
Authors: Dasgupta Amitava , Sperelakis Antoinette , Mason Albert , Dean Roger
Published: October 2023

Displacement of phenytoin (90% bound to albumin) by other strongly albumin‐bound drugs such as salicylate and valproic acid may result in an increase in pharmacologically active free concentrations. The antibiotic oxacillin is also strongly bound to albumin and is often administered to patients receiving phenytoin. Oxacillin at a concentration of 15 μg/ml caused no significant displacement of phenytoin in a serum pool prepared from patients receiving phenytoin. However, a significant increase in the free phenytoin concentration was seen at an oxacillin concentration of 50 μg/ml. We also prepared a serum pool from uremic patients and another from patients with hypoalbuminemia and supplemented both of them with phenytoin. Significant increases in the free phenytoin concentration occurred with both 15‐ and 50‐μg/ml concentrations of oxacillin. In one hypoalbuminemic patient receiving both phenytoin and intravenous high‐dose oxacillin, the free phenytoin fraction was 22.5% before oxacillin therapy, 24.1% 12 hours after first dose of oxacillin, and 27.2% after 60 hours, indicating the possibility of in vivo displacement of phenytoin by oxacillin. We conclude that the phenytoin‐oxacillin interaction is not significant at lower dosages of oxacillin usually prescribed for oral therapy. However, the interaction may be significant at high concentrations of oxacillin, especially in patients with hypoalbuminemia or uremia.
Kaposi's Sarcoma: Advances in Tumor Biology and Pharmacotherapy
Authors: Sung Jennifer C.Y. , Louie Stan G. , Park Sunny Y.
Published: October 2023

Kaposi's sarcoma (KS) is a highly vascularized neoplasm that primarily results in raised, highly vascularized lesions. Before the 1980s, KS was a rare disorder that occurred predominantly in elderly men of Mediterranean or Eastern European Jewish descent. With the advent of the acquired immunodeficiency syndrome (AIDS) epidemic, its occurrence has increased dramatically. It can be classified into four types: classic, African endemic, iatrogenic or drug associated, and AIDS related. Classic KS usually follows an indolent and benign clinical course that rarely requires treatment. In contrast, AIDS‐KS is a fulminant disease that requires aggressive pharmacotherapy, especially when it involves visceral organs. The epidemiology, clinical presentation, pathogenesis, and management strategies of AIDS‐KS are reviewed, including recent pharmacologic advances.
Ceftibuten: An Overview
Authors: Owens Robert C. , Nightingale Charles H. , Nicolau David P.
Published: October 2023

Ceftibuten is an orally active third‐generation cephalosporin that exhibits good microbiologic activity against many gram‐negative and select gram‐positive organisms. It is stable against plasmid‐mediated β‐lactamases, including extended‐spectrum β‐lactamases. Ceftibuten has been shown to be effective in the treatment of upper and lower respiratory tract infections and, although not approved indications, complicated and uncomplicated urinary tract infections in both adults and children. It is readily absorbed (75–90%) after oral administration, with peak serum levels of 17 μg/ml in healthy volunteers. Its half‐life is 2.5 hours in healthy volunteers and is increased in elderly patients to approximately 3.2 hours. Elimination occurs primarily through the kidneys, requiring dosage adjustments to be made when creatinine clearance falls below 50 ml/minute. The drug's safety profile is favorable and similar to that of most other cephalosporins. Based on pharmacokinetic information and clinical trial data, ceftibuten can be dosed once/day for most infections. It is an alternative to other currently available antimicrobial agents in the treatment of indicated upper and lower respiratory tract infections.
Antianginal Response to Once‐Daily Diltiazem CD in Patients Receiving Concomitant β‐Blockers, Long‐Acting Nitrates, or Both
Authors: Heller Gary V , Sridharan Marandapalli , Morse John , Glasser Stephen , Beach C. L. ,   Diltiazem CD Study Group
Published: October 2023

Study Objective. To determine the safety and efficacy of diltiazem CD 180 mg administered once/day in patients with chronic stable angina inadequately controlled with β‐blockers, long‐acting nitrates, or both.

Design. Multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group trial.

Setting. Medical clinics in the private and academic sectors.

Patients. Of 172 patients, 170 completed the 2‐week double‐blind treatment period.

Interventions. Patients received either diltiazem CD 180 mg or placebo once/day in combination with existing antianginal therapy.

Measurements and Main Results. The time to termination of exercise tolerance testing, 24 hours after the dose increased significantly in the diltiazem CD group (37.2 sec) compared with the placebo group (21.3 sec, p=0.0438). Time to onset of angina during exercise testing also increased (57.6 vs 35.0 sec, respectively, p=0.0324), as did time to moderate angina (37.5 vs 20.6 sec, respectively, p=0.0354). The rates of total angina attacks and of angina attacks on exertion were significantly reduced in the diltiazem CD group versus placebo (p<0.05). Significant reductions in systolic and diastolic blood pressures and heart rate‐blood pressure product measured at rest, submaximum exercise, and exercise termination were observed in diltiazem CD‐treated patients compared with placebo (p<0.05). The frequency of treatment‐related adverse events was identical in the two groups, 15.1%.

Conclusion. Diltiazem CD 180 mg once/day is an effective, safe, and beneficial initial dosage when added to existing antianginal therapy.
Evaluation of Effects of Terbinafine on Single Oral Dose Pharmacokinetics and Anticoagulant Actions of Warfarin in Healthy Volunteers
Authors: Guerret Madeleine , Francheteau Patrice , Hubert Martine
Published: October 2023

Study Objective. To evaluate the potential effects of oral terbinafine, a new synthetic antifungal agent of the allylamine class, on the pharmacokinetics and pharmacodynamics of racemic warfarin.

Design. Randomized, double‐blind, placebo‐controlled, crossover study.

Subjects. Sixteen healthy men.

Interventions. Placebo or terbinafine 250 mg was administered once/day for 14 consecutive days, separated by a washout period lasting at least 2 weeks. A single oral dose of racemic warfarin 30 mg was coadministered with placebo or terbinafine on day 8 of each treatment period. Blood samples were collected for 168 hours after administration of warfarin to determine the drug's pharmacokinetics and anticoagulant effects.

Measurements and Main Results. No major differences were seen in the plasma concentration‐time profiles of a single dose of warfarin administered with terbinafine or with placebo.

Conclusions. Because of the lack of clinically significant interactions between terbinafine and warfarin during multiple‐dose administration of terbinafine, no adjustment of warfarin dosage during concomitant therapy appears to be necessary.
The Influence of Bromfenac on the Pharmacokinetics and Pharmacodynamic Responses to Glyburide in Diabetic Subjects
Authors: Boni Joseph P , Cevallos William H. , DeCleene Sheryl , Korth‐Bradley Joan M.
Published: October 2023

Study Objective. To assess the effect of bromfenac sodium, a nonnarcotic analgesic drug under development, on the pharmacokinetics and pharmacodynamics of glyburide in patients with type II diabetes.

Design. Randomized, double‐blind, placebo‐controlled, multiple‐dose study with a two‐period crossover design.

Patients. Eleven men and one woman (age 36–64 yrs) whose diabetes was responsive to oral sulfonylurea therapy.

Interventions. Placebo or bromfenac 50 mg was given as a single oral dose 3 times/day for the first 3 days of the study. On days 4–6, patients received the alternative treatment. For at least 3 months before and during the study, patients took their usual single daily dose of glyburide 10 mg.

Measurements and Main Results. Bromfenac concentrations were measured by high‐performance liquid chromatography with ultraviolet detection. Glyburide concentrations were measured by gas chromatography with nitrogen‐phosphorus detection. Glycemia was measured repeatedly on day 3 of each treatment. Pharmacokinetic analysis was performed with noncompartmental techniques. No significant differences in the pharmacokinetics of glyburide or in the pharmacodynamic response of serum glucose levels were observed between placebo and bromfenac. Intersubject variability of concentrations was modest for glyburide and glucose, with a CV of 43% or less.

Conclusion. Glyburide levels are not changed during concomitant administration of bromfenac.
Azathioprine‐Induced Multisystem Organ Failure and Cardiogenic Shock
Authors: Brown Glen , Boldt Camilla , Webb John G. , Halperin Lawrence
Published: October 2023

Azathioprine is administered to treat increasing numbers of disorders over a wide range of organ systems. The potential for the drug to cause widespread organ dysfunction is not fully appreciated. In fact, azathioprine can cause multisystem organ dysfunction involving the kidneys, liver, and cardiovascular system. The discovery of global cardiac dysfunction as one component of this complication may indicate a mechanism of hypotension. Clinicians must be aware of the potential for azathioprine to cause such toxicities to facilitate appropriate patient management.
A Prospective, Open‐Label Study of Single‐Dose Ciprofloxacin Absorption after Chemotherapy in Patients with Malignancy
Authors: Gattis Wendy A. , Petros William P. , Pickard William W. , Drew Richard H. , May Byron , Hathorn James W.
Published: October 2023

The absorption of a single oral dose of ciprofloxacin 750 mg in patients with cancer who had chemotherapy‐induced Cancer and Leukemia Group B grade I or II mucositis was evaluated. Ciprofloxacin was administered after an overnight fast. Plasma samples were collected before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after the dose. Drug concentrations were determined by reverse‐phase high‐performance liquid chromatography with fluorescence detection. Pharmacokinetic values were characterized by noncompartmental methods. The mean ± SD for area under the curve, mean peak concentration (Cmax), and time to Cmax (Tmax) were 18.7 ± 5.03 mg/L • hour, 4.41 ± 1.74 mg/L, and 1.81 ± 0.843 hours, respectively. The absorption of oral ciprofloxacin in patients with chemotherapy‐induced grade I or II mucositis compares with that in healthy volunteers. These findings may call for further pharmacokinetic evaluation of the drug in a similar patient population.
A Review of Enzyme Induction of Warfarin Metabolism with Recommendations for Patient Management
Authors: Cropp Jacquelyn S. , Bussey Henry I.
Published: October 2023

We conducted a review of literature from the MEDLINE data base (1966‐January 1997), and bibliographies of published articles, reviews, and letters to classify enzyme induction of warfarin metabolism interactions by onset, extent, and offset. Ten hepatic microsomal enzyme agents were assessed. Likelihood of interaction was based on the strength of supporting literature. Enzyme induction of warfarin metabolism by rifampin and barbiturates is considered likely, although the characteristics of the interactions are different. An interaction is probable with carbamazepine, griseofulvin, aminoglutethimide, nafcillin, and dicloxacillin. A suspected interaction may occur with smoking and long‐term alcohol consumption. Ingestion of a small amount of alcohol is unlikely to interact with warfarin. The effect of phenytoin on warfarin metabolism is unpredictable. Anticipation of the expected time course and extent of interaction may allow for better therapeutic decisions and decrease the chance of inappropriate anticoagulation with its potential for complications. (Pharmacotherapy 1997;17(5):917–928)
New and Investigational Treatment Options for Ischemic Stroke
Authors: Ryan Melody , Rhoney Denise H. , Luer Mark S. , Hatton Jimmi
Published: October 2023

We conducted a MEDLINE search of new treatment strategies and experimental agents for treating acute ischemic stroke published from 1989–1996. Clinical trials involving thrombolytics, glutamine release inhibition, N‐methyl‐d‐aspartate receptor antagonism, opioid antagonism, calcium channel blockade, free radical scavenging, membrane stabilization, intercellular adhesion molecule‐1 antagonism, ganglioside administration, and growth factor administration were included. Basic research articles were selected based on progress of the therapeutic class toward clinical trials. Approval of tissue plasminogen activator indicates progress in new treatments for acute ischemic stroke. Experimental therapies with potential may become available soon. Recognizing signs and symptoms of stroke is crucial to ensure prompt administration of these agents. The time to diagnosis determines the therapeutic approach for acute ischemic stroke. (Pharmacotherapy 1997;17(5):959–969)
Levodopa Dependence and Abuse in Parkinson's Disease
Authors: Spigset Olav , von Scheele Christian
Published: October 2023

Two patients with Parkinson's disease repeatedly increased their levodopa dosage on their own to 1500–2000 mg/day to reach and sustain a state of euphoria, regardless of the fact that dosages of 400–800 mg/day were sufficient to suppress their parkinsonian symptoms. Both were markedly unwilling to consent to recommendations of dosage reductions, and they readily accepted adverse effects such as hyperkinesias, anorexia, and hallucinations to achieve the positive mental effects. Thus, both patients fulfilled the diagnostic criteria for substance dependence.
Suspected Betamethasone‐Induced Leukemoid Reaction in a Premature Infant
Authors: Hoff David S. , Mammel Mark C.
Published: October 2023

he use of antenatal corticosteroids in threatened pregnancies of less than 34 weeks' duration is a valuable tool for assisting fetal lung maturation. Although this practice has existed for over 20 years, little is known about a rare extreme elevation of the newborn's white blood cell count, called a leukemoid reaction. A case of leukemoid reaction is discussed to assist the clinician with the current thought processes and diagnostic differential behind this benign condition.
Penetration of Levofloxacin into Lung Tissue after Oral Administration to Subjects Undergoing Lung Biopsy or Lobectomy
Authors: Lee Ling‐Jar , Sha Xue , Gotfried Mark H. , Howard Joan R. , Dix Robert K. , Fish Douglas N.
Published: October 2023

Study Objective. To evaluate the pulmonary tissue distribution of levofloxacin, the new once‐daily fluoroquinolone, after a single 500‐mg oral dose.

Design. Open‐label study.

Setting. One pulmonary clinic and two university‐affiliated teaching hospitals.

Patients. Eighteen adults undergoing lung biopsy or lobectomy.

Interventions. Levofloxacin plasma and lung tissue concentrations were determined by high‐performance liquid chromatography with fluorescence detection. Lung tissue levofloxacin concentrations were corrected for blood contamination by measuring hemoglobin.

Measurements and Main Results. After a single 500‐mg oral dose, concentrations of levofloxacin in lung tissue consistently exceeded those in plasma at every time point over the 24‐hour sampling period, with tissue:plasma penetration ratios of 2.02 (2–3 hrs), 5.02 (4–6 hrs), 5.13 (11–17 hrs), and 4.13 (22–25 hrs). The mean penetration ratio over the 24‐hour sampling period was 3.95 (range 1.06–9.98). Lung tissue concentrations of levofloxacin also exceeded minimum inhibitory concentration values for most community‐acquired respiratory tract pathogens over the 24 hours.

Conclusion. This study supports clinical evaluation of levofloxacin as once‐daily oral therapy for community‐acquired lower respiratory tract infections.
Sertindole, a New Atypical Antipsychotic for the Treatment of Schizophrenia
Authors: Brown Leigh Anne , Levin Gary M.
Published: October 2023

The introduction of antipsychotics for the management of schizophrenia greatly improved the quality of life of many patients suffering from this debilitating disease. Although typical antipsychotic drugs represent a significant advancement in psychopharmacology, they carry a heavy side effect burden, have little efficacy in the management of negative symptoms, and are ineffective in about one‐third of patients with schizophrenia. Atypical antipsychotic agents characterized the next major advancement in pharmacotherapy They differ from typical antipsychotics in their mechanism of action, side effect profiles, and clinical efficacy. Sertindole is a new atypical antipsychotic.
Clinical Guidelines for the Treatment of Cancer‐Related Anemia
Authors: Koeller Jim M.
Published: October 2023

Defining clinical guidelines for the treatment of cancer‐related anemia requires investigation into causes and characteristics of this malady, uses, benefits, and adverse effects of current treatments; and recognition of currently accepted guidelines set forth by the American College of Physicians and the American Association of Blood Banks. Anemia, the most common hematologic abnormality in patients with cancer, originates from a variety of causes, including occult blood loss, hypoproliferation, and hemolysis, and often involves more than one mechanism. Clinical manifestations include fatigue, dyspnea, tachycardia, dizziness, anorexia, and hypersensitivity to cold. Although the majority of cancer‐related anemias are hypoproliferative, establishing their pathophysiology in individual patients is critical to effective treatment. Anemia usually, but not always, resolves with successful treatment of underlying disease. Symptomatic relief can be managed in accordance with established treatment guidelines.
Cloning and Partial Sequence of the Rabbit Androgen Receptor: Expression in Fetal Urogenital Tissues
Authors: KRONGRAD ARNON , WILSON JEAN D. , MCPHAUL MICHAEL J.
Published: October 2023

ABSTRACT: Genetic studies indicate that the actions of testoster‐one and dihydrotestosterone are mediated by a single androgen receptor (AR). The basis for the differential effects of these hormones during development is not known. To address this problem, we have turned to the rabbit, a species in which the endocrine and metabolic events in male sexual differentiation have been studied in detail. As a first step, we have cloned a partial cDNA encoding the rabbit prostate AR and have analyzed the expression of the cDNA in tissues of rabbit embryos at the time during which male phenotypic differentiation takes place. The coding sequence of the rabbit AR cDNA reveals a high degree of conservation with the sequences of the human, mouse, and rat ARs. By Northern analysis the principal transcript expressed in the mesonephros and the anlage of the external genitalia on gestation day 18 appeared to be identical to the mRNA expressed in adult prostate and epididymis.
Development of Male Urogenital Epithelia Elicited by Soluble Mesenchymal Factors
Authors: Shima Hiroki , Tsuji Motomu , Elfman Fred , Cunha Gerald R.
Published: October 2023

ABSTRACT: Androgen‐dependent development of male secondary sexual glands is mediated by paracrine mesenchymal‐epithelial interactions that regulate a complex array of biological events such as epithelial morphogenesis, growth, and cytodifferentiation. It is not known whether the action of mesenchyme on epithelial development in the male genital tract requires cell‐cell contact or whether soluble, diffusible mediators are involved. To examine paracrine effects of urogenital sinus mesenchyme (UGM) on epithelial development, conditioned media (CM) from embryonic mouse UGM of normal (wildtype) and androgen‐insensitive Tfm (testicular feminization) mice were tested for growth and morphogenetic effects on heterotypic tissue recombinants composed of rat or mouse bladder mesenchyme plus neonatal mouse seminal vesicle epithelium (BLM + SVE) or rat or mouse bladder mesenchyme plus neonatal mouse bulbourethral gland epithelium (BLM + BUG‐E). Addition of a concentrate of CM from wild‐type UGM grown in the presence of dihydrotestosterone (DHT) induced epithelial growth and complex epithelial morphogenesis in BLM + SVE recombinants, whereas CM from DHT‐treated Tfm UGM or a saline control were without effect. CM from wild‐type UGM elicited similar trophic effects in BLM + BUG‐E recombinants, but in addition induced precocious mucous epithelial differentiation in BLM + BUG‐E recombinants. These results suggest that the normally androgen‐dependent epithelial growth and branching morphogenesis in developing male urogenital organs is elicited by soluble mesenchymal factors. Two‐dimensional gel electrophoresis of proteins synthesized and secreted by wild‐type UGM revealed several androgen‐dependent proteins with molecular weights of approximately 30 kDa that are absent in CM of Tfm UGM either in the presence or absence of DHT. These androgen‐dependent proteins may be involved as paracrine mediators of the growth and morphogenetic effects of UGM on epithelial development.
Monoaminergic and Peptidergic Contributions of the Superior and the Inferior Spermatic Nerves to the Innervation of the Testis in the Rat
Authors: ZHU BAO CHANG , CHIOCCHIO SARA R. , SUBURO ANGELA M. , TRAMEZZANI JUAN H.
Published: October 2023

ABSTRACT: Sections of the rat testis and whole‐mounts of the testicular capsule were studied microscopically using the glyoxylic acid‐induced fluorescence method, to detect monoamines, and immunohistochemical procedures for the detection of immunoreactivities to protein gene‐product 9.5 (PGP 9.5), the C‐terminal accompanying peptide of neuropeptide Y (CPON), and vasoactive intestinal polypeptide (VIP). Monoaminergic nerves were only observed around the intracapsular blood vessels: the initial segment of the testicular artery and the superior venous plexus, and in the anterior aspect of the upper and lower testicular poles. These capsular nerve networks were associated with the superior and inferior ligaments of the testis. Nerves displaying PGP 9.5 and CPON immunoreactivity appeared in the same sites and followed the same distribution as monoaminergic nerves. By contrast, VIP‐immunoreactive fibers were only found in the nerve network of the lower pole. Observations done after different surgical denervation procedures demonstrated that the superior spermatic nerve was the source of fibers for testicular vessels and for the nerve network of the upper pole. On the other hand, fibers from the inferior spermatic nerve were restricted to the nerve network of the lower pole.
Acrosin Activity of Human Spermatozoa by Means of a Simple Gelatinolytic Technique: A Method Useful for IVF
Authors: HENKEL RALF , MÜLLER CHRISTINA , MISKA WERNER , SCHILL WOLF‐BERNHARD , KLEINSTEIN JÜRGEN , GIPS HOLGER
Published: October 2023

ABSTRACT: Acrosin activity was determined using a gelatinolysis technique in 100‐μl semen aliquots of 114 patients (normozoospermia, n = 90; asthenozoospermia, n = 12; oligozoospermia, n = 10; polyzoospermia, n = 2) attending an in vitro fertilization (IVF) program. Halo diameter, halo formation rate, and a calculated acrosin activity index correlated significantly with the IVF rates (P = 0.0054, r = 0.396; P = 0.0009, r = 0.401; and P = 0.0003, r = 0.428, respectively). In cases where the halo diameter was <10 μm and halo formation rate was <60%, all patients were subfertile or infertile, that is, they showed poor or no fertilization in vitro, respectively. The assay demonstrated a relatively low sensitivity: 25.7% for halo diameter, 37.1% for halo formation rate, and 25.7% for acrosin activity index, respectively. This might be attributed to other sperm functional aspects, such as disturbed acrosome reaction or impaired zona binding.
Search for Androgen Response Elements in the Proximal Promoter of the Canine Prostate Arginine Esterase Gene
Authors: Dubé Jean Y. , Chapdelaine Pierre , Guerin Sylvain , Leclerc Steve , Rennie Paul S. , Matusik Robert J. , Tremblay Roland R.
Published: October 2023

ABSTRACT: We have demonstrated the binding of the recombinant DNA binding domain of the rat androgen receptor to a DN A sequence of the canine prostate arginine esterase gene and have determined the functional significance of this sequence in transient transfection experiments. One of the binding sites was localized to a region (−172 to −148 bp) containing the sequence AGGACAACAGGTGTT that has 73% homology with the prostate‐specific antigen (PSA) androgen response element (ARE) found at a similar position in the PSA promoter. Competition experiments showed that the androgen receptor had an approximately 100‐fold more affinity for the PSA ARE than for the arginine sequence at −172 to −148. Transient co‐transfection of 5′‐deletion mutants of the arginine esterase promoter and 5′‐flanking sequences driving the activity of the reporter gene negligible inductions of chloramphenicol acetyl transferase (CAT) activity when dihydrotestosterone (DHT) was added to the culture medium. The introduction of one to four repeats of the −172 to −148 sequence of the arginine esterase gene upstream of the basal promoter of the mouse p12 gene in p12.108 also resulted in a minimal induction of CAT activity compared with a 10‐fold induction of PSA AREs under similar conditions. These results suggest that the regulation of the canine arginine esterase gene by androgens is most probably achieved by mechanisms that differ from the ones prevailing with the human PSA and kallikrein‐2 (hKLK2) genes.
The Potent Relaxant Effect of Adenosine in Rabbit Corpora Cavernosa Is Nitric Oxide Independent and Mediated by A2 Receptors
Authors: Mantelli Laura , Amerini Sandra , Ledda Fabrizio , Forti Gianni , Maggi Mario
Published: October 2023

ABSTRACT: In the present study the effect of adenosine and adenosine analogues on rabbit isolated cavernosal smooth muscle has been evaluated in comparison with the effect of acetylcholine and electrical field stimulation. In the presence of guanethidine and indomethacin, acetylcholine and electrical field stimulation relaxed the rabbit corpus cavernosum, which was precontracted with phenylephrine. The nitric oxide synthesis inhibitor, Nω‐nitro‐L‐arginine‐methylester (L‐NAME), greatly reduced the relaxation induced by electrical stimulation and completely abolished the relaxant effect of acetylcholine. A concentration‐dependent relaxation of the rabbit corpus cavernosum was produced by adenosine; this effect was not modified by L‐NAME, but was reduced by adenosine deaminase. On the other hand, the adenosine‐induced relaxation was potentiated by the inhibitor of adenosine deaminase, erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine and by the adenosine uptake inhibitor dipyridamole. Moreover, the effect of adenosine was antagonized by the unspecific adenosine receptor antagonist 8‐phenyttheophyllnie. The receptor subtypes involved in cavernosal relaxation were characterized by using selective receptor antagonists: 1,3‐dipropyi‐8‐cydopentylxanthine, a blocker of A, receptors, did not modify adenosine‐induced relaxation. This effect was, however, antagonized by the A2‐receptor antagonist CGS15943. A relaxant effect was also obtained with nanomolar concentrations of two synthetic adenosine analogues, the preferential A2 receptor agonist 5′‐N‐ethylcarboxamidoadenosine and the A2a selective agonist CGS21680. These results demonstrated that adenosine has potent relaxant activity on the corpus cavernosum, acting through a mechanism different from the nitric oxide pathway, and that receptors involved in the effect of adenosine belong to the A2. subtype.
Functional Characterization of the Primate Sperm Acrosomal Antigen (PSA‐63)
Authors: ARCHIBONG ANTHONY E. , LEE C. Y. GREG , WOLF DON P.
Published: October 2023

ABSTRACT: Monoclonal antibody (HS‐63) raised in mice against human ejaculated sperm, polyclonal antibodies raised in rabbits against the cognate mouse testicular antigen (MSA‐63; or Fab) and polyclonal antibodies raised in the rabbit against recombinant fusion proteins (GST‐63) showed acrosomal localization in permeabilized rhesus monkey and human ejaculated sperm. Tail localization of the cognate prima+te sperm antigen (PSA‐63) was also seen with intact MSA‐63 antibodies and Fab fragments. The ability of these antibodies to inhibit sperm binding to the zona pellucida was measured with hemizona binding assays (HZAs). HS‐63 (1.2 mg/ml) inhibited rhesus monkey sperm binding (mean ± SEM) to homologous hemizonae (treatment, 15.5 ± 3.3; control, 58.9 ± 9.4; P < 0.025), whereas comparable concentrations of protein from nonimmunized mouse preparations were inactive (ascites fluid, 67.6 ± 43.5; no ascites fluid, 72.0 ± 44.6). Intact MSA‐63 antibodies inhibited (up to 99%) monkey sperm‐zona binding in a concentration‐dependent manner. Moreover, inhibition in this case by intact MSA‐63 antibody was limited to capacitated sperm. Similarly, intact MSA‐63 antibodies inhibited (up to 85%) human sperm binding to homologous zonae in an antibody concentration‐dependent manner. Fab fragments derived from MSA‐63, when present in insemination mixtures (0.5 mg/ml), inhibited (P < 0.01) primate sperm binding to homologous hemizonae (monkey, 9.6 ± 3; human sperm 9.4 ± 2) compared with matched hemizona controls (monkey, 117 ± 29; human, 20.4 ± 3). Furthermore, rhesus monkey sperm‐zona binding was reduced by 84% in the presence of rabbit anti‐GST‐63 antibodies. Purified rabbit immunoglobulins, used as controls, did not influence sperm‐hemizonae binding and sperm agglutination did not contribute to the antibody effect. These results suggest that an accessible pool of PSA‐63 is important for an initial step in mammalian fertilization and this antigen is a legitimate candidate for an antifertility vaccine.
Endocrine and Exocrine Effects of Testicular Torsion in the Prepubertal and Adult Rat
Authors: BECKER ELMORE J. , TURNER TERRY T.
Published: October 2023

ABSTRACT: Previous studies of experimental torsion have suggested that there may be important differences between the adult testis and the prepubertal testis in their responses to torsion, especially with regard to the potential for contralateral damage following unilateral testicular torsion. In the present study, adult Sprague‐Dawley rats and prepubertal Sprague‐Dawley rats (35 days of age) were subjected to unilateral 1‐, 2‐, and 4‐hour periods of 720° or 360° testicular torsion. Ipsilateral and contralateral testes were examined 30 and 60 days after torsion repair for effects on testis weight, histology, and daily sperm production (DSP). Other animals were subjected to 1‐/or 4‐hour 720° torsion, and testicular vein testosterone concentrations were determined 30 days later. In adult animals, 1‐, 2‐, and 4‐hour 720° torsion resulted in a significant decline in ipsilateral testis weight within 30 days. Endocrine and exocrine function were also dearly disrupted. In prepubertal animals, 1‐hour 720° torsion significantly reduced testis weight 60 days after surgery. Also, prepubertal DSP values and testicular vein testosterone concentrations were not significantly reduced from control values by 1‐hour 720° torsion when examined 30 days after surgery. Longer periods of 720° torsion resulted in damage similar to that seen in the adult animals. Neither adult nor prepubertal animals regained any lost function when examined 60 days after insult. Torsion of 360° induced no testicular injury in adult or prepubertal animals. Contralateral testes were not affected by degree or duration of torsion in either adult or prepubertal animals. These results suggest that the prepubertal testis may be more refractory to the effects of short periods of torsion than the adult. More importantly, these results demonstrate that ipsilateral torsion does not result in contralateral testicular damage in either adult or prepubertal animals.
Intratesticular Testosterone Concentration Following Intratunical Administration in the Hypogonadal Animal
Authors: SHAFIK AHMED
Published: October 2023

ABSTRACT: The serum and intratesticular testosterone concentration (ITC) after testosterone administration in the tunica vaginalis (TV) sac compared to parenteral administration was studied in 20 dogs that were rendered hypogonadal by gonadotropin‐releasing hormone antagonist (‘Nal‐Glu’ GnRH antagonist) in a daily dose of 80 μg for 15 days. The 20 dogs were divided into two equal groups. Twenty milligrams of testosterone propionate were administered In the TV cavity in the TV group and intramuscularly (IM) In the IM group. In add‐on four dogs acted as controls and another four as sham controls.

Serum and ITC were determined In all the dogs 1,2, and 15 days after testosterone administration. Biopsies from TV were taken 3 weeks after testosterone injection for histologic examination. Serum and ITC were significantly reduced (P < 0.01) 15 days after GnRH antagonist. They increased after intratunical testosterone administration to reach the pre‐GnRH antagonist level (P > 0.05). After IM testosterone injection, the serum testosterone increased to the pre‐ GnRH antagonist level (P > 0.05), while the ITC did not. The TV did not show histopathologic abnormalities apart from submesothelial infiltration with Inflammatory cells in one dog.

In conclusion, TV testosterone administration delivers a major dose of testosterone to the testicle without exposing other tissues to high testosterone levels. The method is safe and may be used as an office treatment. It may be tried in the treatment of patients who are Infertile due to a low ITC.
Notulae Seminologicae. 5. Mathematical Evaluation of Interdependent Submicroscopic Sperm Alterations
Authors: Baccetti B. , Bernieri G. , Burrini A. G. , Collodel G. , Crisa N. , Mirolli M. , Moretti E. , Piomboni P.
Published: October 2023

ABSTRACT: This paper concerns the mathematical evaluation of sperm quality as examined by electron microscopy. Proceeding with a Bayesian technique, we have developed a formula considering all statistical possibilities for defects of the examined sperm to be present in a sperm cell, the total number of affected spermatozoa, and, as consequence, that of sperm devoid of defects, also considering the probability of association characteristic of some of them. The formula has been studied in three applications. The first concerns the number of healthy spermatozoa present in ejaculates of fertile men. We have found an enormous variability, but we have observed that the minimal number of spermatozoa free of defects assuring a normal fertility seems to be a little higher than 2 × 106. The second and third examples concern varicocele and assisted fertilization. In both cases the formula allows a precise simultaneous evaluation of the totality of studied characters and a determination of the number of spermatozoa free from defects. This comparative analysis shows that the formula is sufficiently sensitive to distinguish the different degrees of the varicocele condition and the various possibilities of fertility power in cases of natural or artificial insemination. In this way we will easily control the level of improvement of sperm quality in cases of varicocele treated pharmacologically or surgically, or we will better predict the success of artificial insemination.
Effects of Long‐term Psychological Stress on Sexual Behavior and Brain Catecholamine Levels
Authors: Sato Yoshikazu , Suzuki Nobukazu , Horita Hiroki , Wada Hideki , Shibuya Akihiko , Adachi Hideki , Tsukamoto Taui , Kumamoto Yoshiaki , Yamamoto Minoru
Published: October 2023

ABSTRACT: The effects of long‐term psychological stress on sexual behavior and brain catecholamines were investigated in rats. Stress was applied using the communication box developed by Ogawa and Kuwabara (1996), and a psychological stress group (n = 12), a physical stress group (n = 5), and a control group (n = 5) were established. Stress was applied for 1 hour every day for 10 consecutive weeks. Sexual behavior was observed before the start of exposure to stress and 2,4,6,8, and 10 weeks thereafter. The results showed that long‐term psychological stress impaired the sexual behavior of male rats. Long‐term psychological stress decreased the concentrations of catecholamine and its metabolites in the brain, especially in the medial preoptic area (MPOA). Thus, we hypothesized that low catecholamine neurotransmission in the brain results in impairment of male rat sexual behavior. We then tried to restore the impaired sexual behavior by administration of a cerebral‐activating drug, indeloxazine hydrochloride. The administration of indeloxazine hydrochloride for a 3‐week period restored the sexual behavior that had been impaired by long‐term psychological stress. These present results suggest that impairment of neurotransmission in the central nervous system could be a cause of sexual dysfunction, and activation of neurotransmission may result in restoration of impaired male sexual behavior.