bluuebunny/crossref_metadata_2025 huggingface dataset:
Albuterol Extended‐Release Products: A Comparison of Steady‐State Pharmacokinetics
Authors: Hussey Elizabeth K. , Donn Karl H. , Powell J. Robert
Published: October 2023

A new extended‐release formulation of albuterol, Volmax, was developed based on the oral osmotic drug delivery system. Proventil Repetabs, another extended‐release formulation of albuterol, is a repeat‐action tablet. The steady‐state pharmacokinetic profile of Volmax 8 mg orally every 12 hours for 3 days was compared with that of Proventil Repetabs 8 mg orally every 12 hours for 3 days in a randomized, two‐way, crossover study in 23 healthy men. Results were determined for both daytime and nighttime dosing intervals. Volmax demonstrated significantly less peak‐trough fluctuation during both dosing intervals than Proventil Repetabs (p < 0.05). Peak plasma concentrations were higher and occurred earlier with Proventil Repetabs. There were no significant differences between the two formulations with respect to reported adverse experiences. Volmax exhibited a more controlled release of albuterol during both daytime and nighttime dosing intervals than Proventil Repetabs.
Recent Advances in Cyclosporine Pharmacokinetics
Authors: Yee Gary C.
Published: October 2023

Although cyclosporine has been in clinical use for more than a decade, many questions persist concerning its pharmacokinetics. Gastric emptying, bile acids, and gastrointestinal motility can influence drug absorption after oral administration, but the relative importance of each of these factors and their interactions as determinants of absorption are not clear. The fraction unbound in plasma has been determined in several studies and may be associated with clinical effects. Biochemical and molecular studies have identified the specific cytochrome P‐450 enzymes that metabolize cyclosporine to its primary metabolites. The drug's basic pharmacokinetic profile has been defined and many factors have been identified that can influence clearance, such as age, hepatic function, hematocrit, and lipoprotein concentrations. With the development of sensitive and specific analytical methods, many new cyclosporine metabolites have been identified in humans. The major metabolites are present in relatively high concentrations in human blood and have some immunosuppressive activity in vitro, but their contribution to in vivo immunosuppression is not clear.
Analysis of Cefepime Tissue Penetration Into Human Appendix
Authors: Okamoto Mark P. , Chin Alfred , Gill Mark A. , Yellin Albert E. , Berne Thomas V. , Heseltine Peter N.R. , Appleman Maria D. , Knupp Catherine A. , Sclar David A.
Published: October 2023

Cefepime is a new extended‐spectrum cephalosporin with gram‐positive and gram‐negative coverage including Staphylococcus aureus and Pseudomonas aeruginosa. We evaluated the drug's plasma, peritoneal fluid, and appendix tissue concentrations in patients with a postoperative diagnosis of perforated or gangrenous appendicitis. Patients 18 years of age or older were randomly assigned to receive either cefepime 2 g every 12 hours plus metronidazole 500 mg every 6 hours intravenously, or gentamicin 1.5 mg/kg plus clindamycin 900 mg every 8 hours intravenously. During surgery, appendix tissue, plasma, and peritoneal fluid samples were obtained, and frozen at −70°C for high‐pressure liquid chromatographic analysis. Thirty‐five patients with perforated (26) or gangrenous (9) appendicitis had concentrations acceptable for analysis. The mean time between the administration of cefepime and the time of sampling (referred to as A time) was 5.99 ± 3.75 hours (mean ± SD). The values for plasma (n=34), tissue (n=33), and peritoneal fluid (n=25) concentrations were 16.27 ± 21.87 μg/ml, 4.84 ± 6.15 μg/g, and 14.4 ± 22.84 μg/ml, respectively. The appendix tissue:plasma ratio was 0.66 ± 0.52 and the peritoneal fluid:plasma ratio was 0.66 ± 0.51. Spearman rank correlations indicated statistically significant correlations between plasma concentration (r=‐0.889; p<0.0001), peritoneal fluid concentration (r=‐0.783; p=0.0002), and appendix tissue concentration (r=‐0.704; p=0.0016) versus Δ time. There was a significant correlation between peritoneal fluid and plasma concentration (r=0.853; p<0.0001), and appendix tissue and plasma concentration (r=0.815; p=0.0001). These results indicate that tissue and peritoneal fluid concentrations are approximately 51% and 74%, respectively, of a simultaneous plasma sampling after approximately 5.8 hours.
Pharmacokinetic Evaluation of Ethionamide Suppositories
Authors: Peloquin Charles A. , James Gordon T. , McCarthy Eileen , Goble Marian
Published: October 2023

The absorption and elimination of ethionamide (ETA) after oral tablets and rectal suppositories were determined in 12 healthy, adult male volunteers. A randomized, double‐blind, double‐dummy, crossover design was used. Treatments compared 250‐mg ETA tablets and a placebo suppository to a 500‐mg ETA suppository and two placebo tablets, given 7 days apart. Blood samples were collected at predetermined intervals for 12 hours after the dose. Serum concentrations of ETA were determined using high‐performance liquid chromatography. The area under the serum concentration‐time curve was used to compare the relative bioavailability of ETA from the two preparations. Relative bioavailability after rectal administration was 57.3% of that after oral administration. The maximum serum concentration after rectal administration was 33% of that after oral administration. Higher doses of ETA and serum concentration monitoring are recommended whenever the suppositories are used.
The Use of Immunosuppressive Drugs in Kidney Transplantation
Authors: Salomon Daniel R.
Published: October 2023

The proper management of immunosuppression in transplantation requires a working knowledge of immunology and pharmacology. In practice we employ two to four agents in one of several complicated protocols. If we consider the variability of individual patients, the potential for drug interactions, and significant compliance problems inherent in any long‐term multidrug regimen, the dimensions of the challenge of immunosuppression to the practicing clinician become apparent.
Comparison of Pharmacokinetic and Safety Profiles of Amantadine 50‐ and 100‐mg Daily Doses in Elderly Nursing Home Residents
Authors: Somani Salma K. , Degelau John , Cooper Susan L. , Guay David R.P. , Ehresman David , Zaske Darwin
Published: October 2023

Pharmacokinetic and adverse event profiles of 50‐ and 100‐mg amantadine doses administered daily for up to 21 days for influenza prophylaxis were compared in 82 elderly nursing home residents (mean age 85 yrs, 68% female). We sought to determine if a standard daily dose of 50 mg would achieve mean steady‐state trough serum concentrations (CPSSt) of 300 ng/ml and be associated with a lower frequency of adverse events than 100‐mg doses. Statistically significant relationships were found between CPSSt and dosage (in mg/kg/day) and serum creatinine. Adverse events were more common with the 100‐mg dose (24% vs 14%); 94% occurred in women. Amantadine CPSSt and apparent clearance were not significantly different between sexes. Thirty‐nine residents (89%) receiving 50 mg daily achieved CPSSt below 300 ng/ml compared to 42% receiving 100 mg. Standard daily amantadine doses of 50 mg may not achieve adequate CPSSt in elderly nursing home residents, but 100 mg may lead to excessive CPSSt and adverse events, especially in the presence of renal impairment.
Antimicrobials and Therapeutic Decision Making: An Historical Perspective
Authors: Quintiliani Richard , Nightingale Charles H.
Published: October 2023

In an effort to remedy inappropriate and excessive use of antimicrobials and to control costs, most hospitals have developed some type of antimicrobial management program. At Hartford Hospital, our most effective approaches have been those that reduce the chances for physician error, decrease the burden on ancillary services, and encourage short hospital stays. These include automatic correction of dose and dosing intervals of antimicrobials and, if possible, their conversion by pharmacy to cost‐effective alternative agents; daily review of patients who are taking the drugs by an antimicrobial team; and replacement of parenteral with oral agents as soon as possible. Physician acceptance of these approaches will require significant changes in traditional prescribing styles and willingness to allow pharmacists to implement the recommendations of therapeutic and medical staff committees. (Pharmacotherapy 1991;11(1 Pt 2):6S‐13S)
Antimicrobial Formulary Management: A Case Study in a Teaching Hospital
Authors: Wright David B.
Published: October 2023

The role of the formulary system for effective cost containment is becoming increasingly important. With antimicrobial agents taking up a large proportion of most pharmaceutical budgets, this group of agents is an obvious target for cost reduction. The responsible interchange of selected antimicrobial agents offers a promising method to achieve this goal. The Pharmacy and Therapeutics Committee at Henry Ford Hospital implemented the formulary replacement of cefoxitin with cefotetan on a cost basis after the agents were evaluated and considered to be therapeutically equivalent. Drug usage guidelines were developed to implement this change. Educational materials were distributed to the medical staff, and lectures on the appropriate use of cefotetan were given to the house staff. On implementation, all orders written for cefoxitin were automatically changed to cefotetan in the appropriate dosage. After the first 12 months of cefotetan usage no unanticipated problems with treatment failures or adverse effects were noted. Based on analysis of cefotetan use for the first year, a savings of $229,811 was achieved with this interchange. (Pharmacotherapy 1991;11(1 Pt 2):27S‐31S)
Postinduction Carbamazepine Clearance in an Adult Psychiatric Population
Authors: Martin Emory S. , Crismon M. Lynn , Godley Paul J.
Published: October 2023

The objective of this study was to describe the postinduction clearance of carbamazepine (CBZ) in adult psychiatric patients by population pharmacokinetic analysis using the NONMEM program. Specifically, an estimate of CBZ clearance and insight into the effect of common patient characteristics on clearance were sought. Steady‐state trough CBZ serum concentrations, CBZ dosing history, concomitant drug administration, and other data from 45 patients were collected retrospectively. A one‐compartment model with first‐order absorption and first‐order elimination was used, with absorption rate, bioavailability, and volume of distribution fixed to literature values. No evidence was found that race, sex, age, ethanol use, smoking, and concomitant lithium significantly affected CBZ clearance. In the final model, clearance was based on lean body weight. The coefficient of variation for clearance estimates was 16.5%. Residual variability was modest. Estimates for volume of distribution, rates of absorption and elimination, and bioavailability could not be pursued rigorously. Although these results may assist in understanding CBZ disposition in this population, their general clinical application should be approached with caution.
The Disposition of Alfentanil in Neonates with Respiratory Distress
Authors: Wiest Donald B. , Ohning Bryan L. , Garner Sandra S.
Published: October 2023

The disposition of continuous infusion alfentanil was evaluated in 13 mechanically ventilated neonates (gestational age 37.6 ± 2.4 wks) with hyaline membrane disease (n=7) or persistent pulmonary hypertension of the newborn (n=6). Alfentanil was administered as a loading dose 8 μg/kg, followed by a variable‐rate continuous infusion (maximum 10 μg/kg/hr; minimum 2.5 μg/kg/hr) for 27 hours. Serial plasma samples were obtained for pharmacokinetic analysis. Noncompartmental pharmacokinetic analysis of the data revealed the following estimates (mean ± SD): total‐body clearance 3.24 ± 2.23 ml/kg/minute, volume of distribution 0.54 ± 0.21 L/kg, and elimination half‐life 4.14 ± 2.58 hours. A significant effect of alfentanil plasma concentration on total‐body clearance was found (r=‐0.75; p=0.02), suggesting nonlinear pharmacokinetics. No correlation was seen between total‐body clearance and alfentanil dose (r=‐0.37; p=0.32). The results suggest that a larger dose‐proportionality study is required to determine the linearity or nonlinearity of alfentanil pharmacokinetics in neonates.
The Influence of Heparin on the Prothrombin Time
Authors: Schultz Nathan J. , Slaker Ralph A. , Rosborough Terrill K.
Published: October 2023

We studied the effect of known concentrations of heparin on the prothrombin time (PT) in patients receiving warfarin and in controls who were not anticoagulated. Plasma from the subjects and controls was serially diluted with known concentrations of heparin, and PT was measured. Linear regression of heparin concentration versus percentage change in PT resulted in r=0.86 in the warfarin group and r=0.72 in the control group. The warfarin group was more sensitive to the effects of heparin than the control group, as manifested by a steeper slope of the regression line (p<0.001). Over the therapeutic range of heparin concentration (0.2‐0.4 units/ml), the 95% prediction interval of the percentage change in PT was −6–12% at 0.2 units/ml, and 2–20% at 0.4 units/ml in the warfarin group. These results demonstrate a strong relationship between the heparin concentration in plasma and the percentage change in the PT. This effect should be considered when adding warfarin to the regime of patients receiving heparin therapy.
Effect of Low‐Dose Troleandomycin on Theophylline Clearance: Implications for Therapeutic Drug Monitoring
Authors: Kamada Alan K. , Hill Malcolm R. , Brenner A. Manon , Szefler Stanley J.
Published: October 2023

Troleandomycin (TAO) is an alternative agent used in the treatment of severe, steroid‐requiring asthma. Its mechanism of action, once thought to be inhibition of theophylline clearance, remains unclear. Twenty‐four‐hour theophylline profiles were obtained in 11 children with severe asthma prior to and after 2 and 12 weeks of low‐dose TAO therapy. Theophylline dosages were adjusted by blinded investigators to maintain serum theophylline concentrations (STCs) between 10 and 20 μg/ml. Dosages were decreased from 877 ± 60 mg/day (mean ± SEM) before TAO to 811 ± 56 mg/day (NS) after 2 weeks and 764 ± 56 mg/day (p<0.05) after 12 weeks. Because of the dosage adjustments, STCs did not increase significantly. Theophylline clearance was reduced from 65.7 ± 9.8 ml/kg/hour at baseline to 50.2 ± 4.1 ml/kg/hour (p<0.05) after 2 weeks and 50.1 ± 6.2 ml/kg/hour (p<0.05) after 12 weeks of TAO therapy. We conclude that TAO can significantly reduce theophylline clearance, resulting in increased STCs if dosages are not titrated. We recommend an empiric 25% reduction of daily theophylline dose with the initiation of TAO. We also recommend monitoring STCs 4 hours after the morning dose (with twice‐daily dosing of sustained‐release products) after 3, 7, 14, and 30 days of TAO therapy, then periodically as indicated.
A Pharmacokinetic Evaluation of the Combined Administration of Triazolam and Fluoxetine
Authors: Wright C. Eugene , Lasher‐Sisson Theresa A. , Steenwyk Rick C. , Swanson Carl N.
Published: October 2023

The influence of fluoxetine on triazolam pharmacokinetics was studied because of changes in diazepam pharmacokinetics reportedly produced by fluoxetine. Twenty‐four healthy volunteers received a single 0.25‐mg triazolam tablet alone, and another 0.25‐mg tablet after 8 days of fluoxetine therapy 60 mg/day. All subjects received these treatments in the same sequence. Several blood samples were drawn from the subjects after the triazolam doses and were assayed by high‐performance liquid chromatography (HPLC). Blood samples were drawn immediately before the last three fluoxetine doses to determine the concentration of fluoxetine and its metabolite norfluoxetine, also by HPLC. The pharmacokinetics of triazolam did not change significantly when the tablets were administered after multiple doses of fluoxetine. These results indicate that no pharmacokinetic interaction exists between triazolam and fluoxetine or norfluoxetine. However, each patient's clinical response to therapy should be monitored when triazolam tablets and fluoxetine capsules are administered concomitantly.
Decision Analysis: Treatment of Pneumocystis carinii Pneumonia in Patients With AIDS
Authors: Jankiewicz Ann M.
Published: October 2023

Controversy exists as to the most appropriate drug for the initial treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Decision analysis can be used to evaluate the choice between parenteral pentamidine and trimethoprim‐sulfamethoxazole. Sensitivity and threshold analyses illustrate how the choice is affected by the probabilities of success and adverse reactions, as well as by the values placed by the patient and practitioner on treatment outcomes. A test that predicts trimethoprimsulfamethoxazole toxicity may have potential benefit.
Treatment and Prophylaxis of Cytomegalovirus Disease
Authors: Levinson Miriam L. , Jacobson Pamala A.
Published: October 2023

The diseases caused by cytomegalovirus (CMV) may threaten the life or sight of immunocompromised individuals such as patients undergoing transplantation and those with the acquired immunodeficiency syndrome. The management of CMV disease can be difficult. The antiviral agents ganciclovir and foscarnet are effective against CMV retinitis and gastrointestinal diseases, although dose‐limiting adverse effects and the need for long‐term maintenance therapy may hinder their use in many patients. When used to treat CMV pneumonitis in bone marrow transplant recipients, ganciclovir alone is not as effective as when it is combined with immune globulin. Since CMV disease can be fatal, several protocols have been developed for the transplant patient population, including administration of acyclovir, ganciclovir, screened blood products, and immune globulins.
Theophylline‐Mexiletine Interaction: A Case Report
Authors: Kendall James D. , Chrymko Margaret M. , Cooper Brad E.
Published: October 2023

Theophylline and mexiletine can be prescribed in patients with chronic obstructive pulmonary disease with coexistent arrhythmias. The drugs have common metabolic pathways that may result in an interaction. A patient who was taking theophylline became toxic after the initiation of mexiletine. Discontinuation of mexiletine led to an improvement in theophylline clearance.
Therapeutic Frontiers in Alzheimer's Disease
Authors: Miller Susan W. , Mahoney Janelle M. , Jann Michael W.
Published: October 2023

Alzheimer's disease (AD), the most common type of primary degenerative dementia, is the leading cause of cognitive impairment in the geriatric population. It is a devastating illness, both to the patients and the families involved. Although much research continues to be conducted, the etiology and effective treatment for the disease remain to be found. One of the primary hypotheses of the disease is that the cognitive decline of AD involves the loss of related cholinergic neurons. Although the cholinergic theory is still valid, efforts aimed at increasing levels of acetylcholine have yielded disappointing results. Currently, in the United States, several drugs are in various stages of development for the treatment of AD. The mechanisms of these agents include cerebral protectants, enhancers of neuronal signal amplification, tonic stimulation, and nerve growth factors. Other avenues being investigated include the development of novel drug delivery systems to enhance CNS concentrations of therapeutic agents.
1992 National Clinical Pharmacy Services Study
Authors: Bond C.A. , Raehl Cynthia L. , Pitterle Michael E.
Published: October 2023

Study Objective. To determine the extent of hospital‐based clinical pharmacy services in 1992.

Design. National survey with trend comparison to 1989.

Setting. All 1597 United States acute care, general medical‐surgical and pediatric hospitals with 50 or more licensed beds and one or more full‐time pharmacists (43% of all U.S. hospitals).

Measurements and Main Results. Fourteen clinical pharmacy services, carefully defined to indicate pharmacist proactive or concurrent patient care provision, were assessed to determine pharmacists' specific patient care responsibilities. The percentage of hospitals offering each of the services increased from 1989 to 1992, with greatest growth in management of adverse drug reactions (22% increase), pharmacokinetic consultations (14%), and drug therapy protocols (12%). The mean percentage of patients actually receiving clinical pharmacy services ranged from 0.2% for pharmacist participation on the cardiac arrest team to 36.1% for daily monitoring of drug therapy. Pharmacists conducted clinical research in 13% of all hospitals, averaging 3.9 ± 4.3 protocols per year with a total budget of $79,765 ± $128,641.

Conclusions. Clinical pharmacy services continue to expand; however, even the most common direct patient care service is provided to a small number of inpatients.
Evaluating New and Traditional Methods for Aminoglycoside Dosing in Patients With Various Degrees of Renal Function
Authors: Tsubaki Tsuneo , Chandler Mary H.H.
Published: October 2023

Aminoglycosides are widely used, and clinicians continue to seek newer and better methods for initial dosing of these agents. Recently, three new methods were introduced: Thomson, Reesor Nimmo, and dosing in Tenopathy by easy‐to‐use multipliers (DREM). In comparing them with older, traditional dosing methods in patients with various degrees of renal function, the pharmacokinetic variables of gentamicin were determined from steady‐state peak (Cmax) and trough (Cmin) serum concentrations using individualized regimens in 88 patients. Dosages were determined in each patient using the method of Hull‐Sarubbi, rule of eights, and the three new methods, and the resultant Cmax and Cmin values were calculated from dosages generated by each method. The daily doses and Cmax values derived with the Hull‐Sarubbi, Thomson, and Reesor Nimmo methods were not significantly different (p>0.05). The Hull‐Sarubbi was the most precise (root mean squared prediction error 1.3) and least biased (mean prediction error −0.05) of the five methods in predicting target gentamicin serum peak concentrations (Cmax 6.5 mg/L). The Hull‐Sarubbi (69%), Thomson (86%), and Reesor Nimmo (70%) methods yielded therapeutic Cmax (5–8 mg/L) in a significantly higher percentage of patients than did the rule of eights (32%) and DREM (35%), (p<0.05). Therefore, if gentamicin serum concentrations are not available, the first three appear to be reasonable methods for initiating gentamicin dosage regimens, but the last two may not be desirable to use in a clinical setting. These conclusions are based on the assumption that patients are adults with stable renal function and relatively stable clinical conditions.
Octreotide‐Induced Hyperkalemia
Authors: Sargent Andrea I. , Overton Carroll C. , Kuwik Richard J. , Varcelotti Jorge R. , Deppe Scott A.
Published: October 2023

A 68‐year‐old woman was admitted with numerous injuries after being hit by an automobile. On day 16 of hospitalization octreotide was started for treatment of a pancreatic fistula, and within 2 days the patient's serum potassium increased. By the third and fourth days of octreotide therapy the level had increased to the point at which it required treatment. The patient was asymptomatic, however, and had normal renal function. Octreotide was discontinued on the fifth day of the course, with a subsequent decrease in serum potassium. Two days later, one dose of the drug was given; serial serum potassium levels were measured before and after the dose, and increased after the rechallenge. Octreotide was not administered for the remainder of the patients hospitalization, and hyperkalemia did not recur.
Effect of Continuous Arteriovenous Hemodiafiltration on the Pharmacokinetics of Fluconazole
Authors: Nicolau David P. , Crowe Helen , Nightingale Charles H. , Quintiliani Richard
Published: October 2023

In critically ill patients with acute renal failure, continuous arteriovenous hemodiafiltration (CAVHD) has become an increasing popular supportive technique. An adult with acute renal failure during CAVHD therapy received fluconazole. Drug clearance by the hemodiafilter system and its total body clearance during the CAVHD period were 23–28 ml/minute and 22 ml/minute, respectively, indicating that the rate of systemic clearance was solely dependent on CAVHD in this patient. Total body clearance, area under the curve, and half‐life values for this patient closely resembled those in healthy subjects. These observations suggest that patients treated with fluconazole during CAVHD should receive standard maintenance dosages, and neither supplementation nor dosage adjustment is required.
Extracellular Calcium and Luteinizing Hormone Effects on 22‐Hydroxycholesterol Used for Testosterone Production in Mouse Leydig Cells
Authors: MEIKLE A. WAYNE , LIU XAN‐HUA , STRINGHAM JOHN D.
Published: October 2023

ABSTRACT: The effect of extracellular calcium on testosterone synthesis in response to luteinizing hormone (LH) or 22‐hydroxycholesterol (22‐OH‐C) by isolated adult mouse Leydig cells was studied. Leydig cells were isolated by linear density gradient centrifugation. The cells were incubated in minimum essential medium with or without calcium (1.36 mmol/L) in an atmosphere of 95% air and 5% carbon dioxide at 37°C for 3 hours with or without LH (10 ng/sample), or with or without 22‐OH‐C (10 μmol/L). Testosterone production in response to LH was significantly lower (P < 0.02) in the absence of extracellular calcium and in the presence of verapamil (10 μmol/L), a calcium channel blocking agent. Extracellular calcium did not significantly (P > 0.05) affect testosterone production in cells incubated with 22‐OH‐C in either the presence or absence of LH. The results suggest that steps in steroidogenesis from 22‐OH‐C to testosterone are unaffected by extracellular calcium content and that extracellular calcium affects the use of intracellular cholesterol by the cholesterol side‐chain cleavage enzyme.
LHRH Agonists A Nonsurgical Treatment for Benign Prostatic Hyperplasia
Authors: OESTERLING JOSEPH E.
Published: October 2023

Luteinizing hormone‐releasing hormone (LHRH) agonist, when administered in a continuous, nonpulsatile manner, causes desensitization of the LHRH receptor complex on the gonadotroph cells in the anterior pituitary gland. Biosynthesis and secretion of luteinizing hormone cease, and testicular androgenic production is inhibited. When used in this capacity, LHRH agonists can be an effective treatment for benign prostatic hyperplasia. After 4 to 6 months of therapy, prostatic volume decreases by 25% to 30%, voiding symptoms improve significantly in approximately 25% to 33% of patients, and the peak urinary flow rate increases substantially (more than 15 ml/second) in approximately 25% to 33% of patients. During the first month of treatment, serum luteinizing hormone, follicle‐stimulating hormone, testosterone, dihydrotestosterone, 17β‐estradiol, and prostate‐specific antigen decline to low values and remain low throughout treatment. Prostatic 5α‐reductase activity and androgen receptor content also decrease with treatment. Side effects are significant: impotence, decreased libido, and hot flushes are the most common. Because the effect of LHRH agonist therapy on the serum testosterone concentration is reversible, treatment of benign prostatic hyperplasia with an LHRH agonist must be considered life‐long therapy. Thus, this therapy should be reserved for patients who are impotent or who are poor surgical risks.
Atamestane, a New Aromatase Inhibitor for the Management of Benign Prostatic Hyperplasia
Authors: ETREBY M. FATHY EL , NISHINO YUKISHIGE , HABENICHT URSULA‐F. , HENDERSON DAVID
Published: October 2023

Atamestane is a new, competitive, and irreversible inhibitor of estrogen biosynthesis. Its pharmacologic action has been evaluated in mice, rats, rabbits, dogs, monkeys, and humans. In rats, atamestane leads to a decrease of pregnant mare serum gonadotropin‐stimulated ovarian estrogen production, and inhibits androstenedione‐induced estrogenic effects such as uterine growth and abortion. In all species tested, atamestane lacks other intrinsic hormonal or antihormonal activities, and shows no inhibition of other cytochrome P450‐dependent enzymes of adrenal steroidogenesis. However, it inhibits estrogen‐related negative feedback. The extent and consequences of the induced counterregulation of the pituitary‐hypothalamic axis show major sex‐ and species‐specific differences. Atamestane is highly effective in inhibiting estrogen‐induced hyperplastic changes in the fibromuscular stroma of the prostate in androstenedione‐treated dogs and monkeys. In male volunteers and patients with benign prostatic hyperplasia (BPH), atamestane induces an expected reduction of serum (and BPH tissue) estrogen concentrations without significant changes in androgen levels. In conclusion, all available results indicate that atamestane is a selective (no inhibition of adrenal function), pure (no endocrine side effects), and highly effective steroidal aromatase inhibitor, with an excellent safety profile. Based on the discussion of its clinical potential, atamestane seems to be a promising compound for the management of BPH.
Use of Neonatal Tolerization and Chemical Immunosuppression for the Production of Monoclonal Antibodies to Maturation‐Specific Sperm Surface Molecules
Authors: ENSRUD KATHY M. , HAMILTON DAVID W.
Published: October 2023

ABSTRACT: Mammalian sperm acquire functional maturity as they move from the caput to the cauda epididymidis. Changes occur in the protein/glycoprotein composition of the sperm plasma membrane during this time, and may be essential to the maturation process. The production of monoclonal antibody (Mab) probes to the maturation‐specific molecules has been difficult since new proteins comprise a minor portion of total membrane proteins. This report describes a protocol for enhancing the production of Mabs to maturation specific molecules. By injecting neonatal mice with caput epididymal sperm plasma membranes, in combination with chemical immunosuppression at adulthood, the mice were made tolerant to the antigens expressed on the caput sperm membranes. Subsequent immunization with cauda epididymal sperm plasma membranes allowed the production of Mabs to the maturation‐specific moieties without the necessity for extensive antigen purification procedures. The majority of the resulting Mabs recognize cauda, not caput, epididymal sperm plasma membranes as determined by enzyme‐linked immunosorbent assay (ELISA), immunocytochemistry on unfixed cells, and Western blot analyses, even though the protein profile from caput epididymal sperm plasma membranes is very similar to that from cauda membranes. The five Mabs described also recognize cauda fluid antigens, suggesting that the maturational changes on the sperm plasma membranes arise from interactions with the epididymal fluid. Use of the tolerization/immunosuppression protocol has provided Mab tools to assist in the study of sperm maturation during epididymal transit.
Intracellular Calcium Accumulation and Responsiveness to Progesterone in Capacitating Human Spermatozoa
Authors: BALDI ELISABETTA , CASANO ROSARIA , FALSETTI COSTANZA , KRAUSZ CSILLA , MAGGI MARIO , FORTI GIANNI
Published: October 2023

ABSTRACT: Progesterone induced a rapid, long‐lasting, dose‐dependent increase of intracellular free calcium concentration ([Ca2 +]i) in human sperm capacitated overnight. This effect was not counteracted by the cytosolic progesterone receptor antagonist RU486 (1 μmol/L) nor by the GABA‐A receptor antagonists bicuculline (10 μmol/L) and picrotoxin (50 μmol/L). Also, the rank order of potency of several progestative steroids on [Ca2 +]i differed from that previously reported for uterine intracellular progesterone receptor or for P‐GABA interaction in the central nervous system, indicating a different pathway for progesterone stimulation of human sperm. Modifications of basal and progesterone‐stimulated [Ca2 +]i during sperm capacitation were also studied. A progressive, parallel increase of basal and progesterone‐stimulated [Ca2 +]i in capacitating spermatozoa was found. In particular, progesterone‐stimulated [Ca2 +]i increased from a basal concentration of 147% ± 17% at 10 minutes to 327% ± 65% after 120 minutes of incubation in capacitating medium. This increase was well correlated with basal [Ca2 +]i (r = 0.93). In contrast, basal and progesterone‐stimulated [Ca2 +]i concentrations were constantly low in spermatozoa incubated in noncapacitating medium. In capacitated spermatozoa, initial responsiveness to progesterone and basal [Ca2 +]i was higher than in capacitating and noncapacitated samples, and remained constant throughout the duration of the experiment. The progressive, parallel increase of [Ca2 +]i and response to progesterone observed during in vitro capacitation of human spermatozoa might be physiologically relevant in vivo during capacitation of sperm in the female genital tract.
Impact of Clinically Silent Inflammation on Male Genital Tract Organs as Reflected by Biochemical Markers in Semen
Authors: WOLFF HANS , BEZOLD GUNTRAM , ZEBHAUSER MARTIN , MEURER MICHAEL
Published: October 2023

ABSTRACT: Three hundred eighty‐nine healthy, infertile patients were studied to determine the effects of inflammation on genital tract organs. Clinically silent inflammation was diagnosed by measuring polymorphonuclear granulocyte (PMN) elastase in semen. Seminal vesicle, prostate, and epididymis functions were assessed by measuring fructose, citric acid, and neutral alpha‐glucosidase in semen. There was a significant relationship between high PMN elastase levels and low citric acid levels in semen; fructose and neutral alpha‐glucosidase were not related to PMN elastase. Semen samples with increased PMN elastase levels (>250 and >1,000 ng/ml) showed a high incidence of pathologic citric acid levels (67% and 73%, respectively). These biochemical data indicate that the prostate is the main target in clinically silent male genital tract inflammation.
Thiol‐Disulfide Status and Acridine Orange Fluorescence of Mammalian Sperm Nuclei
Authors: KOSOWER NECHAMA S. , KATAYOSE HARUO , YANAGIMACHI RYUZO
Published: October 2023

ABSTRACT: The relationship between thiol‐disulfide status and acridine orange fluorescence of testicular, epididymal, and ejaculated spermatozoa in several mammalian species was investigated. Spermatozoa were fixed with acetic alcohol, stained with acridine orange, and examined with a fluorescence microscope. The majority of the nuclei of testicular spermatozoa of the hamster, mouse, and rabbit exhibited red acridine orange fluorescence. The proportion of sperm nuclei with red acridine orange fluorescence decreased as the spermatozoa descended the epididymis. Red acridine orange fluorescence was replaced by green acridine orange fluorescence. The site in the epididymis where 100% of the nuclei exhibited green fluorescence was the distal caput in the mouse, the corpus in the rabbit, and the proximal cauda in the hamster. In semen samples from men with proven fertility, normal semen parameters, or both, about 60% to 90% of the nuclei exhibited green acridine orange fluorescence. The proportion of sperm nuclei exhibiting green acridine orange fluorescence was higher in the spermatozoa pellet (containing highly motile spermatozoa) obtained by centrifugation through a Percoll gradient. From experiments using disulfide‐reducing, thiol‐oxidizing and thiol‐detecting agents, we concluded that sperm nuclei fluoresce red when they are treated with acid while their DNA‐associated protamines are poor in disulfides. Under such conditions, DNA is vulnerable to denaturation. Acridine orange binds to denatured (single‐stranded) DNA as aggregates and emits red fluorescence. In contrast, when sperm nuclei are treated with acid while their DNA‐associated protamines are rich in disulfides, DNA is resistant to denaturation. Acridine orange binds to native (double‐stranded) DNA as a monomer and emits green fluorescence. Transformation of sperm nuclei from red‐fluorescing to green‐fluorescing in the epididymis reflects extensive cross‐linking of nuclear protamines by disulfide bonds. In human semen, spermatozoa with red‐fluorescing nuclei are commonly observed. This could be associated with the exceptionally rapid transit of human spermatozoa through the epididymis. Extensive cross‐linking of nuclear protamines is a normal process of sperm maturation. As the resulting stability of the nucleus is apparently important for normal fertilization, assessment of the nuclear integrity by acridine orange fluorescence might be helpful in diagnosing and understanding the causes of infertility in some individuals.
Detection and Quantitation of Sperm‐Bound Antibodies by Flow Cytometry of Human Semen
Authors: RÄSÄNEN MARITA L. , HOVATTA OUTI L. , PENTTILÄ ILKKA M. , AGRAWAL YASH P.
Published: October 2023

ABSTRACT: Detection of sperm surface antibodies is important for the diagnosis and treatment of infertility. The authors have investigated the methodologic aspects of flow cytometry (FCM) to detect sperm‐bound antibodies and to quantitate the sperm antibody load (antibody molecules/spermatozoa). To obtain reliable results, dead spermatozoa must be excluded from analysis because they can bind antibody nonspecifically, and comprise 10% to 58% (n = 28) of the ejaculate in subfertile men. Flow cytometry estimation of dead cells correlates (r = 0.83) significantly with the manual Eosin Y method. After staining washed sperm samples (n = 26) with fluorescein‐isothiocyanate‐conjugated F(ab')2 fragments of anti‐IgG and IgA antibodies, the sperm load was 11,500 ± 8,600 IgG molecules and 13,200 ± 9,500 IgA molecules per spermatozoa. The sperm antibody load measured on different occasions could be compared between patients or in the same patient by the use of calibration standards. Since the inter‐ and intra‐assay variation of the FCM assays was <10%, FCM has the potential reliably and objectively to monitor the sperm antibody load during cortico‐steroid treatment.
Effects of Subchronic Treatment with Cis‐Platinum on Testicular Function, Fertility, Pregnancy Outcome, and Progeny
Authors: SEETHALAKSHMI L. , FLORES C. , KINKEAD T. , CARBONI A. A. , MALHOTRA R. K. , MENON M.
Published: October 2023

ABSTRACT: Cis‐platinum‐based chemotherapy is known to impair spermatogenesis, but the effects of paternal cis‐platinum treatment on the progeny are unknown. To study this effect, sexually mature male Sprague‐Dawley rats were administered intraperitoneal injections of saline or cis‐platinum (0.5 mg/kg per day) for 9 weeks. Every week, one set of control and treated animals was mated with females in proestrus. Nineteen days later, the females were subjected to laparotomy, and the numbers of corpora lutea, resorptions, and normal and abnormal fetuses were noted. In conjunction, the effects of treatment on the hypothalamo‐pituitary‐gonadal axis of the treated males were evaluated. Cis‐platinum‐treated animals failed to grow; the weights of the reproductive organs and the sperm counts declined from week 2 onward, and sperm motility was reduced throughout the testing period. Circulating and intratesticular levels of testosterone declined from week 3 of treatment and follicle‐stimulating hormone levels were not affected. Serum levels of luteinizing hormone declined from week 3 and were not detectable from week 6 onward. However, the pituitary response to gonadotropin‐releasing hormone was intact in all treated groups. There was no significant decrease in fertility, but a prominent increase in pre‐ and postimplantation losses of fetuses after cis‐platinum treatment was observed. There was also a decrease in the male‐to‐female ratio of the offspring. A small but significant number of malformed and growth‐retarded fetuses was also found among the offspring of cis‐platinum‐treated males. These results suggest that subchronic treatment with low doses of cis‐platinum may affect progeny; such effects are seen in addition to the apparent alteration in a number of measures of reproductive function of treated males.
Movement Characteristics of Boar Sperm Obtained from the Oviduct or Hyperactivated In Vitro
Authors: SUAREZ SUSAN S. , DAI XIAO‐BING , DEMOTT ROBERT P. , REDFERN KEMBER , MIRANDO MARK A.
Published: October 2023

ABSTRACT: The objectives of this study were to describe hyperactivated motility in boar sperm and to determine the incidence of hyperactivation among boar sperm flushed from the oviduct. Oviducts were surgically removed from 13 gilts 32 hours after mating them to fertile boars. The majority of the sperm flushed from the oviducts was immotile, weakly motile, or stuck to mucus or cellular debris. The mucus could not be penetrated by the sperm. The remaining 3% to 19% of the flushed sperm was free‐swimming. Only five hyperactivated sperm were recovered, all from the ampulla of the oviduct. The remainder of the free‐swimming sperm travelled in linear trajectories and possessed significantly higher flagellar curvature ratios (the flagella were less bent) than boar sperm measured in diluted semen. Hyperactivated motility was induced in washed ejaculated boar sperm, using a 1‐minute pulse of 4 μmol/L calcium ionophore A23187. The ionophore‐treated sperm had significantly lower straight‐line velocities, linearities, and flagellar curvature ratios than controls, as would be expected for hyperactivated sperm. They were vigorous and swam in circles. It was concluded that, although few hyperactivated boar sperm could be recovered from the oviduct, boar sperm are capable of undergoing hyperactivation.
Regulation of Testosterone Production in the Adjuvant‐Induced Arthritic Rat
Authors: BRUOT BRENT C. , CLEMENS JEFFREY W.
Published: October 2023

ABSTRACT: Serum testosterone concentrations are reduced in men with rheumatoid arthritis and in rats with adjuvant‐induced arthritis, a common model for rheumatoid arthritis. To understand the mechanism responsible for this reduction, testosterone production by testicular cells and Percoll‐purified Leydig cells from nonarthritic and arthritic rats was studied. Leydig cells in crude interstitial cell preparations from arthritic rats secreted significantly less testosterone in response to human chorionic gonadotropin (hCG) stimulation than cells from nonarthritic animals. In contrast, no differences in hCG and dibutyryl cyclic adenosine monophosphate‐stimulated testosterone production by Percoll‐enriched Leydig cells from arthritic and nonarthritic animals were observed. To determine whether a secretory product from testicular macrophages was important to this reduction, macrophages from arthritic and nonarthritic animals were cultured. The conditioned media from these cultures were added to cultures of interstitial cells from nonarthritic animals. Nonarthritic rat testicular macrophage‐conditioned medium had no significant effect on testosterone production. In contrast, conditioned medium from arthritic rat testicular macrophages significantly reduced testosterone production. These results suggest that testicular macrophages secrete a factor that may be important in the regulation of testosterone production in the adjuvant‐induced arthritic rat.
Effects of Insulin‐like Growth Factor‐I on Androgen Production by Highly Purified Pubertal and Adult Rat Leydig Cells
Authors: GELBER SIGRID J. , HARDY MATTHEW P. , MENDIS‐HANDAGAMA S. M. L. CHAMINDRANI , CASELLA SAMUEL J.
Published: October 2023

ABSTRACT: Leydig cells were isolated and purified from adult and midpubertal rats to study the effects of insulin‐like growth factor‐I (IGF‐I) on steroidogenesis. Androgen production, as measured in Leydig cell conditioned culture media, from four different treatment groups (1 = no hormone; 2 = 70 ng/ml IGF‐I; 3 = 0.1 ng/ml LH; 4 = 70 ng/ml IGF‐I + 0.1 ng/ml LH) were compared daily. After 3 days in culture, the cells were treated with a maximally stimulating dose of luteinizing hormone (LH) (100 ng/ml) for 3 hours. Androgen production was highest in the cells treated with both IGF‐I and low concentrations of LH. In the presence of IGF‐I, regardless of LH, cells derived from pubertal animals had a greater increase in steroidogenesis during the culture period than did cells from adult animals. Pretreatment with IGF‐I prior to maximal LH stimulation induced a greater increase in androgen production in cells from pubertal rats than in cells from adult animals. It is concluded that IGF‐I has a direct effect on Leydig cells and may act synergistically with LH to promote androgen synthesis. The greater response in pubertal cells raises the possibility that IGF‐I is important in the maturing process of the testis.
Clinical cut scores for the Persian version of the personality inventory for DSM‐5
Authors: Komasi Saeid , Rezaei Farzin , Hemmati Azad , Nazari Amin , Nasiri Yeganeh , Faridmarandi Behrooz , Zakiei Ali , Saeidi Mozhgan , Hopwood Christopher J.
Published: October 2023

Background

The cut points of psychological tools to diagnose clinical conditions are not universal and depend on the region and prevalence of the disorder. Thus, we aimed to identify the cutoff points of the Persian original version of the personality inventory for DSM‐5 (PID‐5; 220 items) that would optimally distinguish nonclinical from clinical groups.

Methods

Both nonclinical (N = 634, 73% female, 34.0 ± 10.8 years) and clinical (N = 454, 29% female, 29.5 ± 7.4 years) samples from the West of Iran participated in the study. Data were analyzed using receiver operating characteristic (ROC) and Youden's index was used to determine the cutoff scores across the PID‐5 domains and facets. The means and standard deviations of both the clinical male and female were compared with the nonclinical group using Cohen's d and independent t‐tests.

Results

All the PID‐5 algorithms and facets significantly distinguished clinical from nonclinical samples with some unique findings for male and female samples. The mean score of all the PID‐5 algorithms and facets in the clinical male and female samples were respectively 1.0−2.0 SD and 0.5−1.0 SD above the mean for the nonclinical counterparts. A score higher than 1.5 on ranging from 0 to 3 in each domain or facet indicated clinical status.

Conclusion

Raw cutting scores throughout the PID‐5 algorithms can be well used to diagnose any pathology of personality and the severity of the disorder in clinical patients. The cut scores provide a useful tool for the clinical use of the original version of PID‐5 in Iran.
Pain and quality of life in persons with spinal cord injury: Mediating effects of mindfulness, self‐efficacy, social support, and functional independence
Authors: Bhattarai Muna , McDaniels Bradley , Jin Yuanyuan , Smedema Susan M.
Published: October 2023

Objective

To identify mediating roles of mindfulness, self‐efficacy, social support, and functional independence in the relationship between pain and quality of life (QOL) in persons with spinal cord injury (SCI).

Methods

A cross‐sectional descriptive study was conducted using a sample of 272 persons with SCI living in the United States. The participants completed self‐report standardized questionnaires on a Qualtrics survey. A parallel mediation analysis adjusting for covariates was performed to test the hypotheses.

Results

Findings showed significant direct effects of pain on functional independence, self‐efficacy, mindfulness, and social support. Self‐efficacy, mindfulness, and social support had significant direct effects on QOL. In the mediation analysis, mindfulness, self‐efficacy, and social support significantly mediated the relationship between pain and QOL, controlling for other variables in the model.

Conclusions

This study adds to the extant literature by providing evidence that mindfulness, self‐efficacy, and social support not only directly contribute to QOL but are likely to mitigate the negative effect of pain on QOL in persons with SCI. Identifying these potential factors that can assuage the adverse effects of pain on QOL is a first step toward active intervention to facilitate the adjustment of persons with SCI.