bluuebunny/crossref_metadata_2025 huggingface dataset:
Bar Code Documentation of Pharmacotherapy Services in Intensive Care Units
Authors: Zarowitz Barbara J. , Petitta Antonio , Rudis Maria I. , Horst H. Mathilda , Hyzy Robert
Published: October 2023

Bar code technology has been used for 5 years to improve the efficiency of identifying and documenting clinical pharmacy services at our institution. Data for an entire year (1993) were analyzed to quantify the nature and magnitude of pharmacy services provided for critically ill patients in intensive care units (ICU). Patients in the medical (MICU), respiratory (RICU), intermediate (IMU), and surgical (SICU) units (3234/3743 patients, 86%) were reviewed. Clinical interventions and expected outcomes were documented by pharmacists using an automated bar code system. There were 11,628 pharmacotherapy interventions, 3.6/patient; 12/pharmacist work day. Of patients whose drug therapy was reviewed at least once, 50% (1610/3234) received at least one intervention. The mean number of interventions/patient was 7.2 in the MICU, 6.1 in RICU, 3.4 in IMU, and 2.4 in the SICU, corresponding to APACHE III scores of 71.2, 66.2, 42.8, and 43.3, respectively. The majority of interventions were to modify dosages of antimicrobial agents, and were performed to achieve optimum efficacy (42%) and to minimize toxicity (46.2%). These data support the necessity for pharmacists to provide individualized care to critically ill patients.
Recruitment and Funding for Clinical Pharmacy Residency and Fellowship Programs
Authors: Flaherty John F , Boucher Bradley A. , Bahal‐O'Mara Neeta , Hutchinson Richard A.
Published: October 2023

A survey was conducted to determine if a shortage exists of graduates interested in residency and fellowship training, and whether program preceptors experience difficulty maintaining funding. Questionnaires were mailed to 195 preceptors listed in the American College of Clinical Pharmacy Directory of Residencies and Fellowships, and responses from 143 (73%) were compiled. Average numbers of applicants interviewed per available position were 3.1, 3.3, and 2.6 for general clinical residency, specialized residency, and fellowship positions, respectively. Approximately 20% of specialty residency and fellowship positions were reported to be unfilled, and 70% of preceptors of these programs expressed the opinion that a shortage of interested graduates exists. Difficulty maintaining funding was most frequently reported by fellowship preceptors (54%), and several sources of funding were required to maintain such programs.
The Role of Clarithromycin in the Prophylaxis of Disseminated Mycobacterium Avium‐Intracellulare Infection in Patients with AIDS
Authors: Mertl Sue Lyon
Published: October 2023

Clarithromycin is a first‐line agent in the treatment of disseminated disease due to Mycobacterium avium‐intracellulare (dMAC) in patients with the acquired immunodeficiency syndrome, and its role in dMAC prophylaxis is nearing definition. Fifteen abstracts described clinical outcomes when clarithromycin was given in various dosages as monoprophylaxis or in combination with other agents. Patients totaled 1063, the majority of whom had CD4+ counts of 100 cells/mm3 or below. In one study, MAC disease occurred in 4.5% of 343 clarithromycin‐treated patients compared with 12.6% of 341 receiving placebo (p<0.001). The remaining studies combined to report only two positive blood cultures, one positive sputum culture, and one positive culture of unidentified origin during their respective study periods. Gastrointestinal intolerance caused discontinuation of therapy in 21 (2.9%) of 722 patients receiving clarithromycin. Clinical evaluations show that the drug decreases the risk of dMAC, prolongs survival, and is well tolerated. Controlled clinical trials continue.
Resistance to Nondepolarizing Neuromuscular Blocking Agents
Authors: Tschida Suzanne J. , Graupe Kimberly J. , Hoey Lori L. , Vance‐Bryan Kyle
Published: October 2023

Several case reports of resistance to short‐term administration of nondepolarizing neuromuscular blocking agents (NNMBAs) have been reported in research and surgical settings. Recently, several reports documented resistance to NNMBAs during therapy for prolonged paralysis in critically ill patients. Adverse outcomes associated with NNMBA resistance may include inadequate ventilatory management or suppression of patient movement, and an increased risk of dose‐dependent cardiovascular adverse effects. Pharmacoeconomic issues must be considered in that the cost of NNMBA therapy in a resistant patient may be significant. Although the specific etiologies of resistance are not clear, several pharmacodynamic and pharmacokinetic alterations may occur as a consequence of disease state or concomitant drug therapy. Pharmacodynamic changes include altered acetylcholine receptor physiology or sensitivity, inhibition of serum cholinesterase activity, and interaction with plasma constituents. Alterations in distribution volume, protein binding, and clearance may also contribute to resistance in several disease states.
The Effects of Sevoflurane and Isoflurane on Recovery from Outpatient Surgery
Authors: O'Hara Dorene A. , DeAngelis Vincent , Lee Herbert , Zedie Nishat , Seuffert Patricia A. , Amory David W.
Published: October 2023

This randomized, open‐label study compared the investigational inhalational anesthetic sevoflurane with isoflurane in 47 healthy women undergoing elective ambulatory surgery. The women were randomized to receive either sevoflurane or isoflurane in 60% nitrous oxide‐oxygen. Induction with thiopental 3–6 mg/kg was followed by vecuronium 0.1 mg/kg and fentanyl 0–200 μg. Duration of anesthesia, time to emergence, orientation, length of stay in the surgical unit, and hospital discharge were recorded. The emergence, length of stay, and discharge times after discontinuation of sevoflurane were 9.7 ± 0.7, 120.6 ± 8.0, and 244 ± 15 minutes, respectively, and for isoflurane were 11.9 ± 1.4, 106.8 ± 7.1, and 282 ± 24 minutes, respectively (NS). The isoflurane group had a higher frequency of postoperative cough. At the end of surgery, the sevoflurane group received a deeper level of anesthesia (minimum alveolar concentration 1.5 vs 1.3), however, these patients were oriented earlier (13.6 ± 1.1 min vs 17.0 ± 1.5 min isoflurane; p = 0.02) after discontinuation of anesthesia, although this difference is of little clinical significance.
Fosphenytoin: A Novel Phenytoin Prodrug
Authors: Boucher Bradley A.
Published: October 2023

Fosphenytoin is a phenytoin prodrug that received an approvable letter from the Food and Drug Administration in February 1996. It was designed to overcome many of the shortcomings associated with parenteral phenytoin sodium. Specifically, fosphenytoin is a highly water‐soluble, phosphate ester of phenytoin that has no known pharmacologic activity before its conversion to phenytoin. Dosing of fosphenytoin uses phenytoin equivalents (PE) to minimize dosage errors when converting from the conventional formulation. Pharmacokinetic studies documented that the agent is rapidly and completely converted to phenytoin after intravenous and intramuscular dosing. Reported conversion half‐lives after intravenous administration range from 8–15 minutes. The absorption rate appears to be the rate‐limiting step in the conversion of fosphenytoin to phenytoin after intramuscular administration (half‐life range 22–41 min). Bioavailability of phenytoin derived from both intravenous and intramuscular fosphenytoin is essentially 100%. As a consequence of concentration‐dependent protein binding, fosphenytoin is bioequivalent to phenytoin sodium at intravenous infusion rates of 100–150 mg PE/minute and 50 mg/minute, respectively. In clinical studies to date, fosphenytoin is safe and significantly better tolerated than phenytoin sodium when administered intravenously. It is also well tolerated when given intramuscularly, and this is a valuable alternative route of administration when intravenous access or cardiographic monitoring is unavailable. Its pharmacoeconomic advantages over phenytoin have not been documented in formal studies to date, although the likelihood of savings based on cost‐effectiveness analyses is high. Hence, fosphenytoin has the potential as a safe, well‐tolerated, and effective means of delivering phenytoin parenterally in a variety of clinical settings.
Vancomycin‐Resistant Enterococci
Authors: Palmer Shirley M. , Rybak Michael J.
Published: October 2023

Vancomycin‐resistant enterococci (VRE) are a major problem in numerous institutions in the United States. Most VRE are resistant to all available antimicrobial agents, resulting in serious therapeutic dilemmas. The resistance genes are transmitted on transposons, so the potential for dissemination to other species is significant. Risk factors associated with VRE infection and colonization are vancomycin and cephalosporin use, but numerous patient‐related factors also contribute. Although resistant strains appear to arise from the patient's endogenous flora, VRE may be spread through direct contact with contaminated environmental surfaces and hands of caregivers. Published guidelines for preventing such spread suggest implementing infection‐control practices and vancomycin restrictions. The ideal drug regimen for the treatment of VRE is unknown. Various drug combinations have been studied in the laboratory, but patient treatment data are scarce. There is an urgent need for new antimicrobial agents.
Overview of Health‐Related Quality‐of‐Life Measures for Pediatric Patients: Application in the Assessment of Pharmacotherapeutic and Pharmacoeconomic Outcomes
Authors: Marra Carlo A. , Levine Marc , McKerrow Ron , Carleton Bruce C.
Published: October 2023

Health‐related quality of life (HRQOL) is an important dimension in assessing health care. Several methodologic considerations are related to the manner in which these data are obtained in children. Few multidimensional generic measures of quality of life (QOL) have been developed for children and adolescents. Most published research concerns the development of tools to be used in a disease‐specific manner for clinical trials. Although several authors point out numerous advantages in assessing HRQOL in clinical practice, several barriers must be overcome for this to occur. In the current era of economic restraint, HRQOL measures must be integrated into pharmacoeconomic analyses to assess fully the impact of a drug on health care resources and outcomes.
Practice Functions Necessary for the Delivery of Pharmaceutical Care
Authors: Winslade Nancy E. , Strand Linda. M. , Pugsley John. A. , Perrier Don. G.
Published: October 2023

Pharmaceutical care is a concept outlining the responsibilities of individual pharmacists to individual patients. Although widely accepted on a philosophical basis, there is a lack of comprehensive information about the functions and responsibilities pharmacists undertake when providing pharmaceutical care. Pharmacy educators and practitioners at the faculty of pharmacy, University of Toronto, developed and informally tested a process that details the practice functions required of pharmacists when providing pharmaceutical care as originally defined.
Renal Drug Transport: A Review
Authors: Bendayan Reina
Published: October 2023

Renal drug elimination involves three major processes: glomerular filtration, tubular secretion, and tubular reabsorption. Drug filtration is a simple unidirectional diffusion process. Renal tubular secretion and reabsorption are bidirectional processes that often involve both passive diffusion and carrier‐mediated membrane processes. Various in vivo and in vitro techniques are available to study renal drug elimination and renal drug transport. The complete renal handling of a drug is best understood from data obtained from a combination of in vivo and in vitro methodologies. At the membranes of the renal proximal tubule, a number of carrier systems are involved in the tubular secretion and/or reabsorption of various drugs. Organic acid and base transporters are two major carrier systems important in the tubular transport of a number of organic acid and base drugs, respectively. Nucleoside and P‐glycoprotein transporters appear to play an important role in renal tubular transport of dideoxynucleosides (e.g., zidovudine, dideoxyinosine) and digoxin, respectively. Clinically, these transporters are not only necessary for the renal tubular secretion and reabsorption of various drugs, but are also responsible in part for the drug's pharmacologic response (e.g., furosemide), drug‐drug interactions of therapeutic or toxic importance, and drug nephrotoxicity.
Warfarin Resistance: Diagnosis and Therapeutic Alternatives
Authors: Hulse Michelle L.
Published: October 2023

Warfarin resistance is a rare phenomenon, and most of the related literature obtained in a MEDLINE search from 1964–1995 consists of case reports. Warfarin resistance may develop as a result of noncompliance, exogenous consumption of vitamin K, and concurrent ingestion of other agents known to decrease warfarin's effects. There are three documented cases of hereditary resistance and one case of loose documentation of hereditary resistance with confirmation of similar resistant patterns in family members. Data on two of the three cases may support the postulation that hereditary resistance may be caused by the presence of an abnormal receptor or enzyme that has an increased affinity for vitamin K. To date, this receptor or enzyme has not been identified. To assess a subtherapeutic dose response to oral anticoagulation, the clinician must consider many possible causes of resistance, such as noncompliance, drug interactions, laboratory error, or pharmacokinetic changes. Once these have been ruled out, it is possible to consider that a tissue resistance to warfarin may be responsible.
Effects of Restricting Levothyroxine Dosage Strength Availability
Authors: Ain Kenneth B. , Pucino Frank , Csako Gyorgy , Wesley Robert A. , Drass Jan A. , Clark Charles , Ketteridge Paul , Crawford Keith , Banks Steve M. , Dorworth Thomas E.
Published: October 2023

We conducted a prospective, randomized, controlled trial to assess whether hospital formulary restrictions involving limiting dosage strengths of levothyroxine affect physicians' ability to manage patients effectively and provide pharmacy cost savings in a tertiary care federal government research hospital. Thirty‐three endocrinologists were randomly assigned to prescribe levothyroxine from a restrictive (dosage strengths of 25, 50, 100, 125, and 150 μg) or a nonrestrictive (dosage strengths of 25, 50, 75, 100, 112, 125, 150, 175, 200, and 300 μg) formulary through a central computer system. Their 241 respective outpatients' laboratory results and drug compliance were outcome measures. Achievement of treatment objectives was measured by thyroid function tests (free and total thyroxine, total triiodothyronine, thyrotropin), number of clinic visits, and compliance (survey method). Additional measures were drug distribution patterns, drug costs, and pharmacy inventory costs. Restriction of levothyroxine's dosage strength did not significantly alter therapeutic outcomes. However, the restricted formulary was associated with more complex dosing regimens, and resulted in no significant cost savings. It is not known whether such restriction would adversely affect the care of patients of nohspecialists. Prospective studies are required to verify presumed cost‐containment measures before such measures are adopted for widespread application.
Variability in Zidovudine Serum Concentrations
Authors: Fletcher Courtney V. , Balfour Henry H.
Published: October 2023

This study explored the variability of zidovudine concentrations with computer simulations and measured concentrations. A one‐compartment oral absorption model was selected to characterize zidovudine disposition. Mean (± standard deviation) values for the pharmacokinetic parameters were taken from the literature. Five different Monte Carlo simulations (50 each) were performed of zidovudine concentrations following repetitive administration of 100‐mg oral doses 6 times/day in patients weighing 45–85 kg. A sixth simulation considered a weight‐adjusted regimen. Predicted concentrations were compared with those measured in 30 HIV‐infected persons receiving 100 mg/dose. Predicted concentrations 1 hour after 100 mg was administered fell in the range of 0.52–5.18 μM; measured values in 30 patients were 0.54–3.07 μM. This study confirms substantial variability in zidovudine serum concentrations. The simulation study of a weight‐adjusted regimen suggests one possibility to reduce this variability. These observations provide a basis to explore dosing strategies that control for pharmacokinetic and perhaps pharmacodynamic sources of interpatient variability.
Strategies in the Management of Acute Myocardial Infarction
Authors: Talbert Robert L.
Published: October 2023

Clinical trials continue to evaluate the pharmacologic management of myocardial infarction for benefits in mortality, degree of infarct artery patency, and frequency of reocclusion. The discovery of thrombus formation in the development of the myocardial infarction renewed interest in thrombolytic therapy. In appropriate candidates, timely administration of thrombolytics after myocardial infarction restores coronary artery patency, reduces myocardial ischemic damage, and improves left ventricular function. Adjunct therapy for thrombolysis typically includes aspirin, heparin, β‐blockers, nitroglycerin, and angiotensin‐converting enzyme inhibitors, if not contraindicated. To reduce cardiac risk, postthrombolysis management generally includes aspirin, β‐blockers, and angiotensin‐converting enzyme inhibitors together with efforts to reduce known cardiovascular risk factors.
The Neurobiology of Schizophrenia
Authors: Littrell Robert A. , Schneiderhan Mark
Published: October 2023

The hypothesis that altered dopamine function is a major factor in the etiology of schizophrenia has persisted for some time, and changes in other neurochemical systems are strongly implicated as well. These findings are supported by the recent development of new, effective antipsychotic agents, such as clozapine and risperidone, whose actions are attributed to their combined serotonin and dopamine antagonism. In addition to their clinical efficacy, these agents are associated with substantially fewer extrapyramidal adverse effects. Continued research to identify the neurochemical alterations of psychotic diseases will undoubtedly have a favorable impact on the development of improved therapeutic regimens.
Sedation in Acute and Chronic Agitation
Authors: Levy Robert H.
Published: October 2023

Agitation is a nonspecific constellation of symptoms seen in a variety of psychiatric disorders, ranging from psychotic exacerbations in patients with schizophrenia to behavioral disturbances associated with organic factors. Its treatment must be individualized and based on the etiology of the psychomotor disturbance. Certain categories of drugs are broadly effective. Sedation and control of disruptive and dangerous behavior are the initial goals in stabilizing acutely agitated patients. Sedation is necessary during the lag period before antipsychotic and mood‐stabilizing drugs take effect. Barbiturates and chlorpromazine, initially given to control agitated behavior, are largely supplanted by higher‐potency antipsychotics, benzodiazepines, and, recently, a combination of these two agents. Agitation is generally controlled within hours to days, whereas remission of affective or psychotic symptoms often requires weeks to months. Once remission is obtained, sedation is no longer desired and may be a barrier to optimal patient function and compliance. Thus, for long‐term treatment, strategies are used to minimize sedation, such as reducing dosages, changing administration to bedtime, or adding antidepressants or stimulants where appropriate.
Evaluation of an Open‐Loop, Computer‐Based Infusion System Designed to Achieve a Series of Constant, Targeted Plasma Procainamide Concentrations in Patients Undergoing Electrophysiologic Testing
Authors: Coyle James D. , Carnes Cynthia A. , Schaal Stephen F.
Published: October 2023

Study Objective. To evaluate the performance of a computer‐based procainamide infusion system in patients undergoing electrophysiologic testing.

Design. Prospective case series.

Setting. Electrophysiology laboratory in a university hospital.

Patients. Thirty‐four patients with inducible sustained ventricular tachycardia.

Interventions. Intravenous infusion of procainamide to achieve and maintain targeted plasma concentrations.

Measurements and Main Results. System performance was assessed by comparing targeted and observed plasma concentrations. The population median absolute performance error (size of typical miss) was 12.6% (95% CI 11.2–14.1%). The population median performance error (system bias) was not significantly different from zero. A small but statistically significant improvement in performance over time was observed (population absolute performance error divergence −0.125%/min). Population wobble (overall system stability) was 7.6% (95% CI 6.8–8.3%). Population‐based estimates of central compartment volume and volume of distribution at steady state were significantly higher and lower, respectively, than estimates used by the infusion system.

Conclusion. The computer‐based infusion system is capable of achieving and maintaining a series of targeted procainamide concentrations in patients undergoing electrophysiologic testing.
Time‐Dependent Disposition of Tacrolimus and Its Effect on Endothelin‐1 in Liver Allograft Recipients
Authors: Min David I. , Chen Hsiang‐Yin , Lee Myung‐Koo , Ashton Kay , Martin Maureen F.
Published: October 2023

Study Objective. To characterize a time‐dependent disposition of oral tacrolimus and its relationship with plasma endothelin‐1 concentrations.

Design. Randomized, crossover study.

Setting. Clinical research center of a university‐affiliated hospital.

Patients. Twelve stable liver transplant recipients.

Interventions. In the steady state, 23 blood samples were taken from each patient before and after tacrolimus administration over 24 hours.

Measurements and Main Results. Whole blood samples for tacrolimus and plasma endothelin‐1 were analyzed by enzyme immunoassay. The relationship of their concentrations and their pharmacokinetic parameters between morning and evening doses were compared. The area under the curve (AUC) of tacrolimus in the morning dose was significantly larger than that in the evening dose (219 ± 54 ng•hr/ml and 188 ± 57 ng•hr/ml, respectively, p=0.004). The mean time to peak concentration (Tmax) was significantly shorter for the morning dose than for the evening dose (1.6 ± 0.7 hrs and 3.5 ± 2.9 hrs, respectively, p=0.01). The mean peak concentration (Cmax) was significantly higher in the morning dose than in the evening dose (32.2 ±9.1 ng/ml and 21.6 ± 8.3 ng/ml, respectively, p=0.008). However, the mean trough concentration (Cmin) was not significantly different between doses. Endothelin‐1 concentrations followed the same pattern as tacrolimus, with AUC and Cmax for the morning significantly higher than those for the evening dose of tacrolimus (AUC 13.8 ± 3.7 pg•hr/ml, morning, and 11.0 ± 3.5 pg•hr/ml, evening, p=0.005; Cmax 2.4 ± 1.1 pg/ml morning, and 1.5 ± 0.6 pg/ml evening, p=0.02). Tacrolimus levels did not correlate with endothelin‐1 levels (r2=0.06, p=0.001).

Conclusions. Tacrolimus disposition in liver transplant patients is determined by time of administration. Plasma endothelin‐1 concentrations follow the same pattern as blood tacrolimus concentrations.
Effect of Pharmaceutical Care on Optimum Colestipol Treatment in Elderly Hypercholesterolemic Veterans
Authors: Konzem Sherri L. , Gray David R. , Kashyap Moti L.
Published: October 2023

We conducted a prospective trial to determine whether a formal, integrated pharmaceutical care plan can enhance patient acceptance and compliance with colestipol therapy and improve outcomes. Forty patients with hypercholesterolemia were equally divided and assigned to either a usual care or pharmaceutical care group. In the pharmaceutical care group compared with the usual care group, after 52 weeks, colestipol therapy resulted in a greater reduction in total cholesterol (12.5% vs 7.3%), low‐density lipoprotein cholesterol (LDL‐C; 16% vs 9.4%), and LDL‐C:high‐density lipoprotein cholesterol (HDL‐C) ratio (24.4% vs 12.2%, p<0.05). The percentage of patients who achieved their LDL‐C goal at week 52 was much greater in the pharmaceutical care group (29.4%) than in the usual care group (5.0%, p<0.05). Comanagement by a physician and a pharmacist of hypercholesterolemic veterans treated with colestipol can enhance patient acceptance of the drug, LDL‐C reduction, and achievement of therapeutic goals.
Atorvastatin Calcium: An Addition to HMG‐CoA Reductase Inhibitors
Authors: Chong Pang H. , Seeger John D.
Published: October 2023

Atorvastatin calcium is an HMG‐coenzyme A (CoA) reductase inhibitor that was approved by the Food and Drug Administration on December 17, 1996. Like other such agents, it inhibits the action of HMG‐CoA reductase and thereby decreases endogenous cholesterol synthesis, leading to a decrease in circulating low‐density lipoprotein cholesterol. In addition to its effect on lipoprotein profile, atorvastatin reduces triglycerides to a greater extent than other HMG‐CoA reductase inhibitors. These actions occur in a dose‐dependent fashion. The adverse effect profile is similar to that of other agents in this class. Indications for atorvastatin include primary hypercholesterolemia as well as other lipid disorders.
A Systematic Review and Meta‐analysis of the Incidence of Cancer in Randomized, Controlled Trials of Verapamil
Authors: Dong Esther W. , Connelly Janet E. , Borden Susan P. , Yorzyk William , Passov David G. , Kupelnick Bruce , Luo Donghan , Ross Susan D.
Published: October 2023

We conducted a systematic review of all published randomized, controlled trials to assess the risk of cancer or death in patients receiving verapamil for hypertension, angina pectoris, or cardiac arrhythmias. Meta‐analysis comparing the risk of new cancers, cancer deaths, and all deaths was performed. Thirty‐nine trials comprising 11,201 patients were eligible. Study durations ranged from 8 days‐6 years (mean 29.5 wks). Nine trials (6507 patients) were 24 weeks in duration or longer. For cancer and cancer death, OR was 1.20 (95% CI = 0.60–2.42) for verapamil versus active controls and 0.73 (95% CI = 0.39–1.39) for verapamil versus placebo. For all deaths, OR was 1.13 (95% CI = 0.70–1.82) for verapamil versus active controls and 0.85 (95% CI = 0.71–1.00) for verapamil versus placebo. Sensitivity analysis for the 9 trials 24 weeks' duration or longer gave similar results. There is no statistically significant increased risk of cancer or deaths with verapamil compared with active controls or placebo.
Drug‐Induced Neuromuscular Blockade and Myasthenia Gravis
Authors: Barrons Robert W.
Published: October 2023

Myasthenia gravis is an uncommon disorder of the neuromuscular junction resulting in weakness of all striated voluntary muscles. Therapeutic advances have increased patients' age and survival. Older patients with myasthenia gravis may have additional medication needs. Numerous drugs have experimental and clinical evidence of neuromuscular blockade. A MEDLINE search of the English literature from 1966 to the present pertinent to drug‐induced myasthenia gravis was performed. Additional literature was obtained from reference citations of relevant articles. Drugs with several reports of neuromuscular blockade were assessed for causality by a recognized probability scale. Prednisone was most commonly implicated as aggravating myasthenia gravis, and D‐penicillamine was most commonly associated with myasthenic syndrome. The greatest frequency of drug‐induced neuromuscular blockade was seen with aminoglycoside‐induced postoperative respiratory depression. However, drugs most likely to impact myasthenic patients negatively are those used in the treatment of the disease. These include overuse of anticholinesterase drugs, high‐dose prednisone, and anesthesia and neuromuscular blockers for thymectomy.
Acetaminophen‐Related Acute Renal Failure without Fulminant Liver Failure
Authors: Eguia Luis , Materson Barry J.
Published: October 2023

Background. Our patient experienced acute renal failure but not fulminant hepatic failure from acetaminophen toxicity.

Objective. To review the clinical and laboratory characteristics of similar cases of acetaminophen nephrotoxicity.

Methods. A MEDLINE search and medical record search at two large teaching hospitals.

Results. We reviewed our index case, a patient at Jackson Memorial Hospital, and 34 additional patients with acetaminophen nephrotoxicity reported in the literature. Oliguria was present in 23 of 31 patients. There was no difference in peak serum creatinine levels between patients treated with N‐acetylcysteine and those not treated. The onset of acute renal failure was from 2–5 days after overdose, and peak serum creatinine levels occurred 3–16 days (average 7.3 days) after overdose. Thirteen patients required hemodialysis; all but one were oliguric. Renal failure was spontaneously reversible in all patients.

Conclusion. Although uncommon, it is possible to have acute renal failure due to acetaminophen toxicity in the absence of fulminant hepatic failure.
A Review of the Effects of Plasmapheresis on Drug Clearance
Authors: Kale‐Pradhan Pramodini B. , Woo Michael H.
Published: October 2023

Plasmapheresis (PP) is being increasingly performed to treat a number of infectious, immunologic, metabolic, and inherited illnesses. In this procedure, plasma and cellular components of blood are separated, and all solutes in plasma, including drugs, can be removed. The effects of PP on the pharmacokinetics of drugs administered therapeutically and taken in overdose are evolving. As the procedure becomes more widely performed, it is important that these effects be understood.
Prevention and Treatment of Hemorrhagic Cystitis
Authors: West Nina J.
Published: October 2023

Hemorrhagic cystitis is a syndrome associated with certain disease states as well as exposure to drugs, viruses, and toxins. It manifests as diffuse bleeding of the endothelial lining of the bladder. Treatment includes intravesical, systemic, and nonpharmacologic therapies, all of which have advantages and disadvantages.
Effects of Terbinafine on the Pharmacokinetics of Digoxin in Healthy Volunteers
Authors: Tarral Antoine , Francheteau Patrice , Guerret Madeleine
Published: October 2023

Study Objective. To assess the potential effects of terbinafine, a new synthetic allylamine antifungal agent, on the pharmacokinetics of a single 0.75‐mg oral dose of digoxin.

Design. Randomized, double‐blind, placebo‐controlled, crossover study consisting of two treatment periods.

Subjects. Sixteen healthy men and women volunteers.

Interventions. During treatment A, placebo was administered once/day for 12 days; during treatment B, terbinafine 250 mg was administered orally once/day for 12 days. The washout period between treatments was at least 2 weeks. A single 0.75‐mg oral dose of digoxin was administered on day 8 of each period. Blood samples were collected after administration of digoxin to determine pharmacokinetics.

Measurements and Main Results. Compared with placebo, terbinafine did not alter the time course of the digoxin serum levels. Although the time to maximum peak concentration with terbinafine was slightly reduced, the maximum concentration and area under the serum drug concentration‐time curve from time zero to 120 hours were not significantly different with terbinafine than with placebo. No drug‐related side effects were reported with either active treatment, and no clinically significant changes in vital signs, physical examination results, electrocardiograms, or clinical laboratory results were observed.

Conclusions. No special dosage adjustments for digoxin appear to be necessary during concomitant therapy with terbinafine.
Torsades de Pointes with Administration of High‐Dose Intravenous d‐Sotalol to a Patient with Congestive Heart Failure
Authors: Gottlieb Stephen S. , Cines Michelle , Marshall Joanne
Published: October 2023

A patient with heart failure was administered d‐sotalol 3.0 mg/kg infused over 2 minutes. The patient had normal electrolytes and baseline QT. Six minutes after drug administration the QT prolonged to 600 msec, and the patient developed torsades de pointes and required electrical cardioversion. This emphasizes the need to consider both rate of administration and the dosage when evaluating the safety and efficacy of a new class III antiarrhythmic drug.
Double‐Blind, Randomized, Placebo‐Controlled Evaluation of Atropine to Prevent Vasovagal Reaction During Removal of Femoral Arterial Sheaths
Authors: Rama Bhola N. , Mohiuddin Syed M. , Mooss Aryan N. , Khemani Anil K. , Ryschon Kay L. , Lucas B. Daniel , Hilleman Daniel E.
Published: October 2023

Study Objective. To evaluate the efficacy and safety of atropine in preventing vasovagal reactions (VVRs) during removal of femoral arterial sheaths after diagnostic left heart catheterization.

Design. Prospective, double‐blind, randomized, placebo‐controlled study.

Setting. University‐affiliated, 450‐bed teaching hospital.

Patients. One hundred sixty‐five patients undergoing left heart catheterization.

Interventions. Eighty‐eight patients were assigned to receive atropine 0.5 mg intravenously and 77 received placebo 5 minutes before sheath removal.

Measurements and Main Results. The frequency of VVRs was significantly reduced in the atropine group compared with the placebo group, 2.3% and 10.4%, respectively (overall relative risk in the atropine group 0.22, 95% CI 0.12‐0.41, p=0.03). Significant decreases in systolic (35.2 ± 5.8 mm Hg, p<0.001) and diastolic blood pressures (12.6 ± 12.6 mm Hg, p=0.002) occurred in the 10 patients with VVRs compared with those without VVR. No cardiac arrhythmias occurred after atropine administration. Dry mouth was the only side effect reported with atropine (8/88, 9%).

Conclusion. Atropine significantly reduced the frequency of VVRs associated with removal of femoral arterial sheaths after diagnostic left heart catheterization. The drug should be studied in a larger series of patients to assess its ability to decrease the morbidity and costs associated with VVR. (Pharmacotherapy 1997;17(5):867–873)
Pharmacokinetics of Azithromycin after Single‐ and Multiple‐Doses in Children
Authors: Stevens Robert C. , Reed Michael D. , Shenep Jerry L. , Baker Donald K. , Foulds George , Luke David R. , Blumer Jeffrey L. , Rodman John H.
Published: October 2023

Study Objective. To characterize the disposition and tolerance of azithromycin after single and multiple oral doses of 12 mg/kg in children with and without cancer.

Design. Open‐label, nonrandomized pharmacokinetic study.

Setting. Two pediatric hospitals.

Patients. Twelve children with cancer admitted to the inpatient unit for empiric antibiotic treatment of febrile neutropenia, and 16 hospitalized patients receiving antibiotic therapy.

Interventions. Patients received azithromycin suspension either as a single dose or daily dose every morning for 5 consecutive days. Serial blood samples were collected up to 120 hours after a single dose or during and after multiple doses to characterize the pharmacokinetic parameters estimated for a two‐compartment absorption model.

Measurements and Main Results. All 28 patients were evaluable for safety. Azithromycin was well tolerated except in one patient with cancer who experienced abdominal cramps and withdrew from the study. Pharmacokinetic results were not determined in five patients because of insufficient concentration‐time data. The mean ± SD estimates of oral clearance, terminal half‐life, maximum concentration in serum (Cmax), and time to achieve Cmax in the 23 evaluable patients were 4.83 ± 3.59 L/hour/kg, 54.5 ± 36.4 hours, 318.2 ± 174.5 μg/L, and 2.4 ± 1.1 hours, respectively. These estimates did not differ between single‐dose (14 patients) and multiple‐dose (9 patients) groups. Pharmacokinetic parameters were not different between the 11 children with cancer and the 12 without cancer.

Conclusion. Azithromycin 12 mg/kg results in proportionately higher serum concentrations than previously published results for lower doses (5 mg/kg). Variability in concentration profiles among patients is substantial, and age or other yet unidentified clinical factors may explain some of the differences observed. (Pharmacotherapy 1997;17(5):874–880)

In conclusion, Cmax, Clo, and terminal half‐life in these pediatric patients were consistent after single and multiple doses of azithromycin. Moreover, pharmacokinetic parameters were not different between patients with cancer and those with no major concurrent illness. Variability in concentration profiles among patients is substantial, and age or other yet unidentified clinical factors may explain a portion of the differences. The higher dose of azithromycin (12 mg/kg) in this study was well tolerated, and did result in proportionately higher serum concentrations than those reported for lower doses.
Microbiologic Effect of Bovine Cerebrospinal Fluid and Azithromycin Against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae
Authors: Destache Christopher J. , Pakiz Catherine B. , Kersting Karl
Published: October 2023

Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of azithromycin against reference strains of Streptococcus pneumoniae ATCC 49619, Neisseria meningitidis ATCC 13090, and Haemophilus influenzae ATCC 49247 were determined by the macrodilution broth method with and without 10% bovine cerebrospinal fluid (CSF) supplementation. The MICs and MBCs were within one to two dilutions for N. meningitidis and S. pneumoniae, and no difference was observed for H. influenzae. Time‐kill curves demonstrated enhanced killing by azithromycin when 10% bovine CSF was added to media for N. meningitidis. The minimum azithromycin concentration for a greater than 3 log10 reduction in inoculum with bovine CSF was 0.03 μg/ml and without CSF was 0.12 μg/ml, a 3‐fold difference. Killing was not significantly different for either H. influenzae nor S. pneumoniae. (Pharmacotherapy 1997;17(5);985–989)
Evaluation of a Noninstrumented Disposable Method for Quantifying Serum Theophylline Concentrations
Authors: Asmus Michael J. , Milavetz Gary , Teresi Mary E. , Weinberger Miles M.
Published: October 2023

Study Objective. To compare the performance of a new point‐of‐care theophylline assay (AccuMeter) with that of a standard laboratory assay (TDx), and another point‐of‐care method (AccuLevel).

Design. Prospective evaluation of consecutive patients receiving theophylline.

Setting. University‐based, ambulatory, allergy‐pulmonary clinic.

Patients. Forty subjects receiving maintenance theophylline therapy for asthma.

Interventions. Theophylline concentrations obtained from AccuMeter, TDx and AccuLevel were compared.

Measurements and Main Results. The error, or difference, between TDx and AccuMeter results in 40 subjects on maintenance theophylline described accuracy. Mean error, an estimate of bias, was 1.1 (95% CI 0.72–1.5), 0.67 (0.34–1.0), and 0.98 (0.79–1.2) μg/ml for AccuMeter capillary, serum, and heparinized blood samples. Square root of the mean squared error, an estimate of precision, was 1.6 (1.2–2.0), 1.22 (0.90–1.5), and 1.14 (0.96–1.3) μg/ml for AccuMeter capillary, serum, and heparinized samples. Difference between AccuMeter and AccuLevel ME, an estimate of relative bias, was 0.59 (0.04–1.1) μg/ml. The difference in mean squared errors, an estimate of relative precision, was 0.86 (‐0.54–2.3) μg/ml.

Conclusions. AccuMeter demonstrated good precision and minimal bias compared with TDx and AccuLevel. Method of sample collection had no effect on its accuracy.
Effect of Hepatic Disease on the Pharmacokinetics and Plasma Protein Binding of Eprosartan
Authors: Tenero David , Martin David , Chapelsky Martha , Ilson Bernard , Boike Steven , Patterson Scott , Keogh John , Rodriguez Sheila , Jorkasky Diane
Published: October 2023

Study Objective. To evaluate the pharmacokinetics and plasma protein binding of eprosartan in hepatic disease.

Design. Single‐dose, parallel‐group study.

Setting. Oklahoma Foundation for Digestive Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Patients. Eight healthy subjects with normal hepatic function and eight patients with hepatic disease.

Intervention. All subjects received a single oral dose of eprosartan 100 mg.

Measurements and Main Results. Eprosartan plasma concentrations were quantified by high‐performance liquid chromatography; plasma protein binding was determined by ultrafiltration. Using analysis of variance, point estimates (PE) and 90% CIs were calculated. Total and unbound maximum concentrations and degree of plasma protein binding were similar for both groups. Total area under the plasma concentration‐time curve (AUC0‐t) was approximately 40% higher for the group with hepatic disease (PE 1.42, 90% CI 0.94–2.14). Similarly, unbound AUC0‐t was approximately 50% higher (PE 1.53, 90% CI 0.98–2.39).

Conclusion. Eprosartan was safe and well tolerated by both groups. Based on the increase in AUC in patients with hepatic disease compared with those with normal hepatic function, the dosage of eprosartan in patients with hepatic disease should be individualized based on tolerability and response.
Therapeutic Considerations in the Management of Agitated or Delirious Critically 111 Patients
Authors: Hassan Erkan , Fontaine Dorrie K. , Nearman Howard S.
Published: October 2023

Agitation and delirium in the critical care unit are common problems that at times are difficult to treat. The difficulty stems from few placebo‐controlled or even blinded trials evaluating various therapies. In addition, the literature in these areas is scattered through various journals in a variety of disciplines. Pharmacologic and nonpharmacologic techniques may achieve the therapeutic objective for these patients. Since no one drug will achieve the goals in every patient, therapy must be tailored to the characteristics and needs of each individual.
Effects of Two Non‐Steroidal Antiandrogens on Testicular Function in Prepubertal Rats
Authors: Rulli Susana B. , Gonzalez‐Calvar Silvia I. , Campo Stella , Calandra Ricardo S.
Published: October 2023

ABSTRACT: The effects of two non‐steroidal antiandrogens, flutamide and casodex, were evaluated in prepubertal male rats. Animals (23 days old) were subcutaneously administered vehicle or 1, 2,5, or 10 mg/day of flutamide or casodex for 10 days. Testis weights were diminished at the 10 mg/day dose of both antiandrogens. A significant increase in serum luteinizing hormone (LH) and folliclestimulating hormone (FSH) levels was detected. Notwithstanding, flutamide influenced LH/FSH levels more severely than casodex. No changes were observed in serum prolactin. Serum testosterone, dihydrotestosterone, and 3α‐androstanediol levels were increased in flutamide‐treated rats from the 2 mg/day dose, whereas only 3α‐androstanediol was modified at 10 mg/day of casodex, suggesting a differential effect on androgen metabolism. An elevation of testicular concentration and basal production of androgens was found, indicating that flutamide and casodex administration are capable of stimulating testicular steroidogenesis, as well as 5α‐reduction. However, the in vitro maximal responsiveness of the gonads to human chorionic gonadotropin was preserved. Antiandrogen administration did not modify testicular androgen binding protein concentration. In conclusion, the blockade of androgen action during sexual maturation caused profound changes on the pituitary‐gonadal axis in male rats.
Release of Angiotensin‐Converting Enzyme (ACE) From Human Spermatozoa During Capacitation and Acrosome Reaction
Authors: KÖHN FRANK‐M. , MISKA WERNER , SCHILL WOLF‐B.
Published: October 2023

ABSTRACT: The present study examines the release of angiotensin‐converting enzyme (ACE) from human spermatozoa during capacitation conditions and in correlation to acrosome reaction and cell death. The ACE content of spermatozoa was measured by treating the cells with different detergents. Glass wool‐filtered and washed human spermatozoa were incubated for 3 hours at 37°C. Percentages of acrosome‐reacted and dead spermatozoa did not change significantly, but the ACE release increased from 0 to 2.93 ± 0.44 mU/100 × 106 spermatozoa after 180 minutes (P < 0.001). In order to study the influence of acrosome reaction on ACE release, the acrosome reaction of noncapacitated spermatozoa was induced by 10 μM calcium ionophore A23187. The percentages of acrosome reaction and viability in noncapacitated spermatozoa as well as the ACE release were compared to corresponding data from experiments using capacitated spermatozoa (3 hours, 37°C) from the same donors. Although the number of living acrosome‐reacted spermatozoa after ionophore treatment (30.5 ± 4.0%) was significantly higher than after capacitation (13.3 ± 2.8%, P 0.001), ACE release from ionophore‐treated, noncapacitated spermatozoa was lower P < 0.05). The data indicate that ACE release from human spermatozoa during capacitation is independent of acrosome reaction. Measurement of ACE release may be a clinically useful assay for human sperm capacitation.
Cryopreservation Extenders Affect Calcium Flux in Bovine Spermatozoa During a Temperature Challenge
Authors: ZHAO YUYUAN , BUHR MARY M.
Published: October 2023

ABSTRACT: Bovine spermatozoa are commercially cryopreserved by diluting the cells in media, known as extenders, followed by slow cooling and freezing. Previous work has shown that this process of cryopreservation alters the cells' ability to control divalent calcium (Ca2+) movement. This study evaluated the effect of a brief exposure to common extenders on bovine spermatozoa during subsequent cooling and rewarming. Three fresh ejaculates from each of three bulls were each split and incubated for 30 minutes at 25°C in milk extender or phosphate‐buffered saline (PBS) (control); three other fresh ejaculates from each of three bulls were similarly incubated in egg yolk‐Tris extender (EYT) or PBS. Spermatozoa were washed and the fluorescent Ca2+ indicator, indo‐1 acetoxymethyl ester, was used to monitor the internal Ca2+ in the spermatozoa in Ca2+‐free PBS over a continuous temperature gradient of 25°C (15 minutes), cooling to 5°C (32 minutes), at 5°C (15 minutes), rewarming to 25°C (25 minutes), and at 25°C (15 minutes). Milk exposure reduced the initial percentage of missing acrosomes and EYT exposure improved the initial viability and acrosome morphology compared to the controls; only milk immediately increased internal Ca2+. The initial rate of Ca2+ uptake at 25°C was greater for milk or EYT‐exposed spermatozoa than controls (P < 0.05). During cooling, the rate of Ca2+ uptake in all spermatozoa increased (P < 0.01), and it continued to increase during the 15 minutes at 5°C. During rewarming to 25°C, the internal Ca2+ in all spermatozoa declined. The rate of decline of Ca2+ in control exceeded that of EYT‐exposed spermatozoa. Addition of 1 mM Ca2+ during the final 25°C incubation caused internal Ca2+ to increase for 1 minute in all samples. The rate of increase in the milk samples was greater than that of its control (P < 0.05). There was no further change over the subsequent 35 minutes except for an increase of free intracellular Ca2+ in the EYT control sample. The percentage of either viable or intact spermatozoa had decreased in all samples at the end of the temperature gradient. The brief exposure of spermatozoa to milk and egg yolk increased free intracellular Ca2+ in spermatozoa, perhaps initiating the early stages of capadtation. Milk and EYT differed in their effect on Ca2+ flux; this result may have implications for fertility.