bluuebunny/crossref_metadata_2025 huggingface dataset:
In Unfractionated Heparin Dosing, the Combination of Patient Age and Estimated Plasma Volume Predicts Initial Antifactor Xa Activity Better than Patient Weight Alone
Authors: Rosborough Terry K.
Published: October 2023

Study Objective. To determine whether patient factors other than body weight would better predict patients' initial antifactor Xa heparin activity (HA) after start of unfractionated heparin (UFH) therapy.

Design. Case series.

Setting. A 625‐bed, adults‐only private, tertiary care teaching hospital.

Patients. Ninety‐two patients requiring UFH therapy.

Interventions. Patients received initial UFH bolus doses of 72–80 U/kg ideal weight and initial UFH infusions of 19.1–21.2 U/kg ideal weight.

Measurements and Main Results. Fifty‐five percent of the first 6‐hour HA measurements were supratherapeutic (> 0.7 U/ml antifactor Xa activity). Patient weight was inferior to a combination of age and estimated plasma volume in predicting initial HA. A predictive model including these two factors accounted for 38.5% of variation in first HA levels compared with 17.7% with actual weight alone.

Conclusion. Weight‐based UFH dosing may frequently result in nontherapeutic initial HA levels. Initial UFH dosing might be improved if protocols based on patient age and estimated plasma volume were developed.
The Pharmacokinetics and Pharmacodynamics of Fludarabine in Rheumatoid Arthritis
Authors: Knebel William , Davis John C. , Sanders William D. , Fessler Barri , Yarboro Cheryl , Pucino Frank , Boumpas Dimitrios T.
Published: October 2023

Study Objective. To describe the pharmacokinetics and pharmacodynamics of fludarabine in patients with rheumatoid arthritis (RA).

Design. Open‐label, staggered trial conducted in conjunction with a phase I‐II clinical trial.

Setting. Government research hospital.

Patients. Twenty‐six patients with refractory RA.

Intervention. Fludarabine 20 or 30 mg/m2/day was administered as a 0.5‐hour infusion for 3 consecutive days (1 cycle) for 6 months (1 cycle/mo).

Measurements and Main Results. Serial plasma samples were collected for pharmacokinetic analysis on day 2 of the first cycle of therapy. Relationships between pharmacokinetic parameters and hematologic and efficacy parameters were examined. The disposition of fludarabine was characterized by a two‐compartment model. There were no differences in pharmacokinetics between the low‐ and high‐dose groups. The mean ± SD total clearance, volume of distribution at steady state, and β‐half‐life were 13.68 ± 5.1 L/hour, 170.08 ± 86.5 L, and 10.9 ± 3.1 hours, respectively. The volume of the peripheral compartment was approximately twice as large as the volume of the central compartment, indicating a significant amount of tissue distribution. No significant pharmacodynamic relationships were observed between pharmacokinetic parameters and hematologic and efficacy parameters.

Conclusion. Fludarabine pharmacokinetics in patients with RA are characterized by an intermediate‐length distribution phase (∼ 40 min), terminal half‐life of 10.9 hours, and significant amount of tissue distribution.
Pharmacokinetics of Dexamethasone and Valspodar, a P‐glycoprotein (mdr1) Modulator: Implications for Coadministration
Authors: Kovarik John M. , Purba Harpal S. , Pongowski Michele , Gerbeau Christophe , Humbert Henri , Mueller Edgar A.
Published: October 2023

Study Objective. To assess the potential for a drug‐drug interaction between valspodar, a P‐glycoprotein (mdr1) modulator used as a chemotherapy adjunct, and dexamethasone, widely included in oncology antiemetic regimens.

Design. Randomized, open‐label, three‐period crossover study.

Setting. Clinical pharmacology research center.

Subjects. Eighteen healthy men volunteers (age 25.8 ± 3.5 yrs, weight 71.6 ± 10.3 kg).

Interventions. Subjects received single fasting oral doses of valspodar 400 mg, dexamethasone 8 mg, and both drugs concomitantly with 2‐ to 3‐week washout phases between administrations.

Measurements and Main Results. Lack of a pharmacokinetic drug‐drug interaction with respect to valspodar was conclusively demonstrated for both Cmax,b (2.3 ± 0.4 vs 2.4 ± 0.5 μg/ml) and AUCb (19.8 ± 4.8 vs 19.6 ± 4.9 μg·hr/ml) inasmuch as bioequivalence criteria were satisfied when comparing administration alone with coadministration, respectively. Although no changes in the rate of dexamethasone absorption were noted on coadministration with valspodar (Cmax 88 ± 23 vs 91 ± 20 ng/ml), overall exposure was significantly increased by 24% on average (AUC 400 ± 87 vs 494 ± 90 ng·hr/ml). Regression analysis of valspodar Cmax,b and AUCb during coadministration versus the extent of the interaction (percentage increase in dexamethasone AUC) did not reveal a concentration‐effect relationship (p=0.7299 and 0.9718, respectively).

Conclusion. Given dexamethasone's wide therapeutic index and the short duration of coadministration foreseen for these drugs in a clinical setting (maximum 1 wk/chemotherapy cycle), the 24% increase in dexamethasone's AUC is unlikely to be relevant. Thus no alterations in valspodar or dexamethasone dosages appear warranted when the two drugs are coadministered. Multiple‐dose experience in patients would be desirable to confirm these conclusions.
Cytochrome P450 3A4 Activity in Premenopausal and Postmenopausal Women, Based on 6‐β‐Hydroxycortisol:Cortisol Ratios
Authors: Burstein Aaron H. , Reiss William G. , Kantor Eric , Anderson Gail D.
Published: October 2023

Study Objective. To characterize cytochrome P450 (CYP) 3A4 activity in premenopausal and postmenopausal women by evaluating the urinary 6‐β‐hydroxycortisokcortisol ratio.

Design. Prospective study.

Subjects. Thirteen premenopausal and 13 postmenopausal women who were healthy and not receiving drugs known to affect CYP3A4 activity.

Interventions. Beginning on day 2 of menses, premenopausal women collected first morning urine samples every other day for a complete menstrual cycle. Postmenopausal women collected first morning urine every other day for 28 days.

Measurements and Main Results. Mean weekly 6‐β‐hydroxycortisol:cortisol ratios did not differ during the phase (week) of the menstrual cycle. Daily ratios did not differ in postmenopausal women. No difference between premenopausal and postmenopausal women was found on comparing overall median ratios.

Conclusion. Cytochrome P450 3A4 activity as measured by 6‐β‐hydroxy cortisol:cortisol ratio did not differ by week of menstrual cycle, suggesting no menstrual cycle‐related changes. Menopause does not appear to be associated with differences in CYP3A4 activity, compared with premenopause.
Antiepileptics and Blood Dyscrasias: A Cohort Study
Authors: Blackburn Stella C. F. , Oliart Alberto Duque , Rodríguez Luis A. García , Gutthann Susanne Pérez
Published: October 2023

We conducted a cohort study to investigate the frequency of serious blood dyscrasias in patients age 10–74 years, taking antiepileptic drugs between January 1, 1990, and October 31, 1994. Main outcome measures were validated diagnoses of neutropenia, agranulocytosis, hemolytic anemia, thrombocytopenia, bicytopenia, pancytopenia, or aplastic anemia. A total of 29,357 recipients of antiepileptic therapy received 684,706 prescriptions. Among them there were 21 cases of serious blood dyscrasia of which only 18 could be considered to have a temporal relationship to drug use. Seventeen cases occurred in current users of carbamazepine, phenobarbital, phenytoin or valproate, and 7 in patients taking two or more drugs. Twenty of the 21 patients recovered. The overall rate of blood dyscrasias was 3–4/100,000 prescriptions. The rate in those age less than 60 years was 2.0 (range 0.9‐3.6)/100,000 prescriptions compared with 4.0 (range 1.6–8.2) for those age 60 or older. The overall rate of neutropenia was 1.2 (0.5‐2.3)/100,000 prescriptions, compared with 0.9 (0.3‐1.9) for thrombocytopenia and 0.4 (0.1‐1.3) for hemolytic anemia. Rates did not differ among the four drugs. Serious blood dyscrasias are rare in patients taking antiepileptic agents.
Pharmacokinetic Drug Interactions of Vinca Alkaloids: Summary of Case Reports
Authors: Chan Jeannie D.
Published: October 2023

Involvement of the cytochrome P450 (CYP) 3A subfamily in the metabolism of vincristine is well established. However, information is limited regarding vincristine's drug interaction profile. All the substrates and inhibitors of CYP3A4 such as the azole antifungals (itraconazole, ketoconazole), cyclosporine, isoniazid, and nifedipine have very high propensity to interfere with vincristine metabolism. The proposed mechanism is most likely attributed to either inhibition of 3A4 enzymes or blockade of P‐glycoprotein pumps. These interactions are clinically significant and can lead to severe vincristine toxicity if not detected. Although case reports discussed here exclusively involve vincristine, it is important to assume that all vinca alkaloids interact in the same manner until proved otherwise, because they share similar metabolism pathways.
Withdrawal after Narcotic Therapy: A Survey of Neonatal and Pediatric Clinicians
Authors: Scott Christy S. , Decker Jodi L. , Edwards Melanie L. , Freid Eugene B.
Published: October 2023

Pharmacists at the 1995 American College of Clinical Pharmacy Pediatric Practice and Research Network meeting volunteered to act as coordinators at their sites and survey pediatric and neonatal nurses, pharmacists, and physicians regarding dependency in neonatal and pediatric patients after therapeutic administration of narcotics. Thirteen (60%) of 21 coordinators returned 244 surveys. Primary symptoms of withdrawal reported by clinicians were agitation (100%), irritability (100%), inconsolability (100%), crying (99%), tremors (98%), high heart rate (98%), fidgets (98%), high blood pressure (97%), less sleep (96%), and sweating (94%). Most clinicians considered narcotic withdrawal to be a problem (74%) that should be treated (87%). A dependency scale is being developed and will include symptoms reported by more than 75% of respondents.
Ticlopidine‐Induced Thrombotic Thrombocytopenic Purpura
Authors: Muszkat Mordechai , Shapira Michael Y. , Sviri Sigal , Linton David M. , Caraco Yoseph
Published: October 2023

Thrombotic thrombocytopenic purpura (TTP) occurs in association with a wide variety of disorders including infections, connective tissue diseases, and solid organ tumors. It also may coincide with administration of drugs such as mitomycin, metronidazole, oral contraceptives, cyclosporine, and many others. We report the occurrence of TTP in a patient shortly after the initiation of ticlopidine.
Statins in the Prevention of Coronary Heart Disease
Authors: Williamson David R. , Pharand Chantal
Published: October 2023

Although epidemiologic studies proved that a causal relationship exists between elevated serum cholesterol levels and coronary heart disease, it is only recently that cholesterol‐lowering strategies have shown significant reductions in total mortality. In the last few years, three landmark coronary artery disease‐reduction trials with HMG‐coenzyme A reductase inhibitors (statins) showed significant reductions in coronary heart disease and mortality. Statins have beneficial effects on coronary heart disease and overall mortality in primary and secondary prevention, including in women and the elderly. Angiographic studies reveal the potential mechanisms through which statins exert their clinical benefits.
Low‐Molecular‐Weight Heparins in Coronary Arterial Thrombus Disease: A Review of the Literature
Authors: Rodman Daniel P.
Published: October 2023

Popularity of low‐molecular‐weight heparins (LMWH) continues to grow. Clinical trials established their efficacy for various venous thromboembolic disease states. Their use in arterial disorders is also becoming widespread. Unfortunately, clinical trials in this population subgroup are either lacking or show little or no benefit of LMWH. Specifically, they appear to offer no benefit over antiplatelet agents, such as aspirin and ticlopidine, after percutaneous transluminal coronary angioplasty. Conversely, they may have a role in the management of unstable angina. At this time, however, their efficacy appears equivalent only to therapeutic dosages of unfractionated heparin.
1995 National Clinical Pharmacy Services Study
Authors: Raehl Cynthia L. , Bond C. A. , Pitterle Michael E.
Published: October 2023

To determine the extent of hospital‐based clinical pharmacy services in 1995, we surveyed 1109 United States acute care, general, medical‐surgical, and pediatric hospitals with 50 or more licensed beds. Fifteen clinical pharmacy services were assessed to determine pharmacists' specific patient care responsibilities. The percentage of hospitals offering services grew between 1992 and 1995: pharmacokinetic consultations (16% increase), drug therapy protocol management (15%), drug therapy monitoring (8%), drug counseling (13%), and parenteral‐enteral nutrition team (6%). All other services increased 0–5%. Pharmacists conducted clinical research in 14% of hospitals, averaging 6.3 ± 22.1 protocols/department annually; total budget $96,219 ± $262,026. Patient‐focused care predominated in 20% of hospitals, although most pharmacists reported to directors of pharmacy through traditional pharmacy department channels. Clinical pharmacy services continue to expand, with pharmacists providing higher‐level direct patient care activities related to drug therapy management and monitoring.
Impact of Patient Knowledge, Patient‐Pharmacist Relationship, and Drug Perceptions on Adverse Drug Therapy Outcomes
Authors: O'Neil Christine K. , Poirer Therese I.
Published: October 2023

The purpose of this project was to determine the relationship between adverse drug outcomes and knowledge of drugs, quality of a counseling relationship, and perceptions about drugs in an ambulatory clinic population. The presence of these three factors and other indicators of adverse outcomes were identified through a structured interview of 78 patients. Medical records were reviewed 3, 6, and 12 months after the initial interview to determine the presence of adverse drug outcomes. Four outcomes—hospitalizations, unscheduled clinic visits, emergency room visits, and changes in drug regimen—were assessed and categorized according to drug‐related problem. Demographics of the group were recorded. Responses to the interview were analyzed to determine differences in counseling relationships between pharmacists and other health professionals. Logistic regression analysis was performed to determine the influence of independent variables on outcome. Relative risks for developing adverse outcomes given the presence of certain independent variables were calculated for significant associations. Significant relationships between predictor variables and adverse drug outcomes were identified for the following independent variables: female gender (RR = 5.2, CI 1.11, 24.31), three or more diseases (RR = 3.3, CI 1.13, 9.75), more drug knowledge and better perceptions (RR = 0.29, CI 0.10, 0.84), perception of no or low drug interference (RR = 0.18, CI 0.044, 0.745), and inadequate data collection by nurses and physicians as perceived by the patient (RR = 3.08, CI 1.09, 8.70). More knowledge and better perceptions about drugs were associated with a reduced risk of therapy changes due to drug‐related problems. No association was found between the quality of the pharmacist‐patient counseling relationship and adverse drug outcomes.
Patient Recall of Therapeutic Paralysis in a Surgical Critical Care Unit
Authors: Wagner Bertil K.J. , Zavotsky Kathleen Evanovich , Sweeney Janet B. , Palmeri Barbara A. , Hammond Jeffrey S.
Published: October 2023

Study Objective. To investigate patient recall of therapeutic paralysis (TP) in a surgical critical care unit.

Design. Prospectively applied structured interview of patients undergoing TP over 18 months.

Setting. Surgical critical care unit with 27 beds at a tertiary care university teaching hospital.

Patients. Forty patients admitted for postoperative care after coronary artery bypass graft surgery, trauma, or gastrointestinal surgery.

Interventions. Patients received TP and concurrent sedation with benzodiazepines, propofol, and narcotics.

Measurements and Main Results. After the end of TP patients were asked to recall the experience, and their responses were ranked on a four‐point ordinal scale. Four of 11 patients recalled mostly negative events and experiences with TP, such as sleeplessness, discomfort, pain, anxiety, and inconsistent caregiver communication. All patients with recall experienced fear, anxiety, and sleeplessness. Single‐drug therapy with propofol and inadequate benzodiazepine dosing were linked to patient recall.

Conclusions. Patient recollection from TP may be more common than appreciated and is generally unpleasant. Adequate dosing with benzodiazepines and narcotics is warranted to prevent recall and discomfort.
Effect of Pharmacokinetic Sampling Methods on Aminoglycoside Dosing in Critically Ill Surgery Patients
Authors: Mann Henry J. , Wittbrodt Eric T. , Baghaie Ali A. , Cerra Frank B.
Published: October 2023

We compared pharmacokinetic parameters derived from three aminoglycoside serum concentration sampling methods and evaluated their effects on recommended aminoglycoside dosing regimens in 60 critically ill surgery patients. Patients had presumed or documented gram‐negative sepsis, and had at least 4 aminoglycoside serum concentrations measured. We used a one‐compartment model for peak and trough, 3‐point series, and 4‐point series sampling methods. Dosing regimens were calculated for each patient based on values derived from each method. We found differences in regimens for nearly 50% of patients if either 4‐ or 3‐point series sampling was used to calculate the recommended dosage rather than peak and trough sampling. However, the 3‐point method required a clinically significant change in regimen in only 12% of patients compared with 4‐point sampling. The variability of all values derived from 3‐point sampling were well accounted for by the 4‐point method (r2 > 0.80). In addition, we noted significantly greater relative precision for 3‐point sampling than peak and trough sampling for estimates of clearance, elimination rate, recommended daily dosage, and recommended dosing frequency. We recommend three optimally timed samples be drawn instead of peak and trough levels in dosing aminoglycosides in critically ill surgery patients.
Prolongation of the QT Interval Related to Cisapride‐Diltiazem Interaction
Authors: Thomas Audra R. , Chan Lingtak‐Neander , Bauman Jerry L. , Olopade Christopher O.
Published: October 2023

Cisapride, a cytochrome P450 3A4 (CYP3A4) substrate, is widely prescribed for the treatment of gastrointestinal motility disorders. Prolongation of QT interval, torsades de pointes, and sudden cardiac death have been reported after concomitant administration with erythromycin or azole antifungal agents, but not with other CYP3A4 inhibitors. A possible drug interaction occurred in a 45‐year‐old woman who was taking cisapride for gastroesophageal reflux disorder and diltiazem, an agent that has inhibitory effect on CYP3A4, for hypertension. The patient was in near syncope and had QT‐interval prolongation. After discontinuing cisapride, the QT interval returned to normal and symptoms did not recur. We suggest that caution be taken when cisapride is prescribed with any potent inhibitor of CYP3A4, including diltiazem.
Delayed Elevation of International Normalized Ratio with Concurrent Clarithromycin and Warfarin Therapy
Authors: Oberg Kristin C.
Published: October 2023

Clarithromycin is rarely reported to cause disturbances in anticoagulation. Theoretically, clarithromycin administered concurrently with warfarin could result in enhanced anticoagulation, since many properties of clarithromycin are similar to those of erythromycin, which interacts with warfarin. A search of the National Library of Medicine produced no published reports of an interaction between the drugs. Erythromycin competitively inhibits hepatic metabolism of warfarin, specifically the R‐warfarin enantiomer, by the cytochrome P450 3A3 and 3A4 pathways, resulting in increased prothrombin time and international normalized ratio (INR). Two men, age 61 and 70 years, who received stable warfarin regimens, experienced supratherapeutic elevations in prothrombin time (98.4 and 26.8 sec) and INR (90.3 arid 5.6), respectively. While taking warfarin, both patients experienced dramatically increased anticoagulation effects 5 days after starting clarithromycin for atypical pneumonia. They were similarly managed for overanticoagulation by discontinuing clarithromycin, holding warfarin, and receiving intravenous phytonadione. Neither man suffered from medical complications related to anticoagulation. Until clear documentation of the exact mechanism and temporal relationship of this interaction is known, patients receiving warfarin who require the concurrent clarithromycin should have prothrombin time and INR closely monitored.
A Multidisciplinary Team Approach to Managing Alzheimer's Disease
Authors: Beck Cornelia K. , Cody Marisue , Zhang Mingliang
Published: October 2023

Patients with Alzheimer's disease experience a range of symptoms that may overwhelm the patients, their families, and the people responsible for their care. With today's drive to reduce health care costs, any plan for managing these patients must produce maximum effectiveness at the lowest possible cost. A multidisciplinary team potentially offers both effective and efficient dementia care by eliminating duplicative or ineffective services and maintaining the optimum health of the patient and family.
Preclinical Pharmacology of Metrifonate
Authors: Jann Michael W.
Published: October 2023

Alzheimer's disease is a chronic neurodegenerative disorder that is characterized by memory impairment, cognitive dysfunction, behavioral disturbances, and deficits in activities of daily living. A consistent observation in these patients is that cholinergic neurons are affected and deteriorate over time, leading to decreased levels of acetylcholine (ACh). Acetylcholinesterase (AChE) inhibitors, which attempt to prevent the breakdown of ACh, may be classified as short acting, intermediate acting, and long acting based on AChE regeneration time. Metrifonate is converted by a nonenzymatic process to the long‐acting cholinesterase inhibitor 2,2‐dichlorovinyl dimethyl phosphate (DDVP). Acetylcholinesterase inhibition produced by metrifonate occurs rapidly, is dose dependent, can be detected by inhibition measured in red blood cells, and can be reversed by oxime administration. Metrifonate and DDVP improved performance in young rats; cognitive improvement in aged rats also was observed. Both agents were well tolerated and did not have significant effects on various preclinical pharmacologic safety tests.
Prospects of Developing Interventions to Prevent Alzheimer's Disease
Authors: Khachaturian Zaven S.
Published: October 2023

Based largely on recommendations of scientists from around the world, it is possible to discover treatments designed to maintain independent functioning of patients with Alzheimer's disease. It is hoped that discussion of critical targets for intervention, and possible strategies for altering the degenerative course of the disease will spur interested groups into action.
Advancing the Battle Against Acute Ischemic Syndromes: A Focus on the GP IIb‐IIIa Inhibitors
Authors: Dobesh Paul P. , Latham Keith A.
Published: October 2023

Platelet aggregation and thrombus formation, resulting from disruption of a coronary artery plaque, play a critical role in the pathology of acute coronary syndromes. Currently, aspirin and heparin are administered to decrease platelet aggregation. The discovery of the platelet integrin receptor αIIbβ3, also known as the platelet glycoprotein (GP) IIb‐IIIa receptor, is a breakthrough in antiplatelet therapy. The GP IIb‐IIIa receptor is responsible for the crucial binding of fibrinogen to platelets, leading to cross‐links between platelets and further platelet aggregation. Since the introduction of abciximab, the first GP IIb‐IIIa‐receptor antagonist, several other nonantibody agents have been studied for use in percutaneous transluminal coronary angioplasty and also in stent placement, treatment of unstable angina, and myocardial infarction.
Carvedilol: Therapeutic Application and Practice Guidelines
Authors: Bleske Barry E. , Gilbert Edward M. , Munger Mark A.
Published: October 2023

Current knowledge of the mechanisms contributing to progression of heart failure suggests that therapies that limit or interfere with the consequences of neurohormonal activation and improve myocardial energetics appear to be most beneficial. Carvedilol, a nonselective β‐adrenergic blocker with peripheral vasodilating properties, reduces mortality, slows progression of disease, and improves quality of life in patients with heart failure when added to standard therapy. When administered according to recommended guidelines, carvedilol is well tolerated. Clinical guidelines on the use of carvedilol in heart failure are provided.
Current Strategies for the Prevention and Treatment of Disseminated Mycobacterium avium Complex Infection in Patients with AIDS
Authors: Wright Julie
Published: October 2023

Disseminated Mycobacterium avium complex (MAC) infection is a common opportunistic disease in patients with acquired immunodeficiency syndrome and is associated with significant morbidity and mortality. Macrolides effectively prevented and treated the disease in clinical trials. In general, prophylaxis with clarithromycin or azithromycin is indicated for patients with CD4 cell counts below 50 cells/mm3. Treatment of disseminated MAC infection is lifelong and must include two agents with antimycobacterial activity. Clarithromycin plus ethambutol is considered the standard regimen. Potential alternatives are azithromycin, rifabutin, ciprofloxacin, clofazamine, and amikacin. Several factors influence drug selection, such as the patient's immune status, evidence of treatment safety and efficacy, drug interactions, and potential for resistance.
Low‐Molecular‐Weight Heparin for the Treatment of Deep Vein Thrombosis
Authors: Thompson‐Ford Julie K.
Published: October 2023

Low‐molecular‐weight heparin has been studied for the treatment of deep vein thrombosis in the inpatient setting and more recently in the outpatient setting. It is as safe and effective as unfractionated heparin and is effective when administered subcutaneously once or twice a day. Its bioavailability nears 100% and it has a longer half‐life than unfractionated heparin, resulting in a prolonged anticoagulant effect. A reduction in thrombocytopenia and bleeding complications with low‐molecular‐weight heparin has been reported. Laboratory monitoring is unnecessary. Low‐molecular‐weight heparin provides the opportunity for home therapy.
Hepatic Drug Metabolism in Critical Illness
Authors: McKindley David S. , Hanes Scott , Boucher Bradley A.
Published: October 2023

Hepatic drug metabolism is altered in critically ill patients. The etiology and mechanisms of the alterations are not clearly understood and are difficult to address in clinical studies. For this reason, in vitro and animal models were developed to investigate the effects of critical illness on hepatic drug metabolism. Specifically, those with sepsis, septic shock, hemorrhagic shock, trauma, neurotrauma, and burns are populations that have been studied. Most of this research, however, has not led to established guidelines for the administration of drugs in these populations.
The Role of H2‐Receptor Antagonists in the Pathogenesis of Nosocomial Pneumonia in Mechanically Ventilated Patients
Authors: Trofe Jennifer , Peterson Andrew M.
Published: October 2023

We conducted a computerized MEDLINE search and selected controlled studies and meta‐analyses correlating the frequency of nosocomial pneumonia (NP) with the administration of histamine2‐receptor antagonists (H2RAs) as stress ulcer prophylaxis in critically ill patients. Although such a correlation does exist, the literature supports the theory that gastric bacterial overcolonization through alkalinization by H2RAs is not a risk factor for NP in critically ill patients. Further well‐designed studies are necessary to resolve the issue and clarify the role of H2RAs in the pathogenesis of NP
Effect of Oral H2‐Receptor Antagonists on Left Ventricular Systolic Function and Exercise Capacity in Patients with Chronic Stable Heart Failure
Authors: Lucas B. Daniel , Williams Mark A. , Mohiuddin Syed M. , LaMadrid Lance J. , Schroeder Lisa J. , Hilleman Daniel E.
Published: October 2023

Study Objective. To evaluate the effect of cimetidine, famotidine, ranitidine, and placebo on left ventricular systolic function, aerobic metabolic performance, and exercise capacity in patients with chronic, stable heart failure.

Design. Double‐blind, randomized, placebo‐controlled, four‐way crossover study.

Setting. Outpatient, university‐affiliated cardiology clinic.

Patients. Twelve men with stable New York Heart Association class II or III heart failure secondary to ischemic heart disease or hypertension.

Interventions. Patients received in random sequence cimetidine 400 mg twice/day, famotidine 40 mg/day, ranitidine 150 mg twice/day, and placebo. Each treatment was administered for 7 days, and the periods were separated by a 1‐week washout.

Measurements and Main Results. Before and after each treatment, patients underwent a bicycle stress echocardiogram with aerobic metabolic assessment. Left ventricular function was evaluated by calculating ejection phase indexes from Doppler echocardiographic measurements. All 12 patients successfully completed the study. No patient reported any adverse effect attributed to study drugs. None of the treatments was associated with significant changes in any measure of left ventricular systolic function, aerobic metabolic performance, or exercise capacity, nor were placebo‐subtracted differences for the agents significantly different for any of the three measures.
A Comparison of Fluvastatin 40 mg Every Other Day versus 20 mg Every Day in Patients with Hypercholesterolemia
Authors: Rindone Joseph P. , Hiller Debra , Arriola Greg
Published: October 2023

Study Objective. To assess the efficacy of fluvastatin administered every other day versus an equivalent dose given daily in patients with hypercholesterolemia.

Design. Randomized, nonblinded, crossover study.

Setting. Veterans Affairs Medical Center.

Patients. Twenty‐three patients with low‐density lipoprotein (LDL) levels above 160 mg/dl despite diet therapy.

Intervention. Patients received fluvastatin 40 mg every other day or 20 mg/day, all doses taken at bedtime. Each treatment arm was 6 weeks in duration.

Measurements and Main Results. A lipid profile was determined at baseline and after each regimen. Both regimens significantly lowered total cholesterol and LDL versus baseline. The LDL levels were lowered by 24% and 21% by fluvastatin 20 mg/day and 40 mg every other day, respectively. There was no statistically significant difference in lipid components between regimens.

Conclusion. Fluvastatin 40 mg every other day is effective in lowering total cholesterol and LDL in patients with hypercholesterolemia.
Pharmacokinetic Profile and Variability of Cyclosporine versus Neoral in Patients with Cystic Fibrosis after Lung Transplantation
Authors: Kesten Steven , Scavuzzo Masina , Chaparro Cecilia , Szalai John‐Paul
Published: October 2023

Various factors may influence bioavailability and blood concentrations of cyclosporine, a problem that may be compounded by diseases such as cystic fibrosis in which impaired absorption through the gastrointestinal tract is common. Neoral, a microemulsion formulation of cyclosporine, has improved bioavailability and more stable blood concentrations than earlier formulations. We conducted a prospective, open, crossover study to examine whether these findings held true in 12 clinically stable patients with cystic fibrosis who had undergone lung transplantation at least 6 months earlier. In the first arm, patients continued their usual dosage of cyclosporine twice/day. In the second arm they received Neoral for at least 1 week before having blood studies. For each arm whole blood trough concentrations were drawn for 7–10 successive days, together with a pharmacokinetic study with concentrations drawn at times zero, 1, 2, 3, 4, 6, 12, and 24 hours. Variance was assessed from morning concentrations. Area under the curve from zero to 12 hours (AUC12), maximum concentration (Cmax), and time to Cmax (Tmax) were calculated for each arm. Eleven subjects completed the protocol. The daily variance for Neoral was significantly less than for cyclosporine (p=0.04). The AUC12 for Neoral and cyclosporine were 4164 ± 1467 and 5318 ± 1670 μg·L/hour (p=0.09), respectively. Respective Cmax were 613 ± 242 and 931 ± 458 μg/L (p=0.08) and relative Cmax and AUC12 were 1.91 and 1.47 (p<0.05). Thus Neoral had a superior pharmacokinetic profile and less day‐to‐day variability in patients with cystic fibrosis who had undergone lung transplantation.
Determination of Fluoxetine and Norfluoxetine Concentrations in Cadaveric Allograft Skin
Authors: Neudeck Brien L. , Taddonio Thomas E. , Garner Warren L. , Welage Lynda S.
Published: October 2023

Fluoxetine hydrochloride is the sixth most prescribed drug in the United States and is administered to treat major depression. A cadaveric skin donation was obtained from a 46‐year‐old woman who died as a result of a fluoxetine overdose. Due to the potential penetration of the drug and its major metabolite, norfluoxetine, into skin, the safety of using the skin as an allograft was questioned. Our evaluation showed that mean concentrations in skin were 2304 ± 175 and 1353 ± 102 ng/g of skin, respectively. The skin:plasma ratio was 0.41. Clinically, the amount of fluoxetine that can be transferred to an allograft recipient depends on many factors. Based on penetration of drug and metabolite into skin, one would have to evaluate carefully the risk:benefit ratio of using allografts from a donor who died from a fluoxetine overdose.
Warfarin Sensitivity after Mechanical Heart Valve Replacement
Authors: Rose John P. , Rihn Thomas L. , Long Scott F.
Published: October 2023

We performed a retrospective chart review of 60 patients after mechanical heart valve replacement to assess warfarin sensitivity. The overall international normalized ratio (INR) on day 3 of therapy was 4.1 ± 3.9 (range 1.1–17.1). In a control group of 100 patients who received anticoagulation for atrial fibrillation, pulmonary embolism, and deep vein thrombosis, the overall mean INR at day 3 was 1.9 ± 0.7 (range 1.0–4.9). The difference between groups was statistically significant (p<0.05). We conclude that patients receiving warfarin after mechanical heart valve replacement are more sensitive to the drug than those receiving it for other indications, and reduced dosages may be necessary during the first 3 days after valve replacement.
Suspected Chromium Picolinate‐Induced Rhabdomyolysis
Authors: Martin William R. , Fuller Robert E.
Published: October 2023

Rhabdomyolysis results from skeletal muscle injury and release of muscle cell contents into plasma. A number of etiologic factors have been reported for the condition, including strenuous exercise, weight lifting, trauma, seizure, sepsis, and alcohol and drug abuse. Hundreds of drugs also reportedly cause rhabdomyolysis. A 24‐year‐old body builder developed the disease after ingesting 1200 μg of chromium picolinate (6–24 times the daily recommended allowance of 50–200 μg) over 48 hours. We believe this to be the first reported case of chromium‐induced rhabdomyolysis.
Intravaginal Morphine: An Alternative Route of Administration
Authors: Ostrop Nikola J. , Lamb Jeanne , Reid Gwynneth
Published: October 2023

The availability of various dosage forms allows morphine to be administered in a number of ways. However, if the oral and rectal routes are not feasible, the parenteral one may appear to be the only viable option. Morphine was administered by the intravaginal route in a 44‐year‐old woman as an alternative to intravenous patient‐controlled analgesia. The dosage forms included sustained‐ and immediate‐release tablets as well as regular suppositories. The initial dosage was calculated according to guidelines for switching to oral administration and titrated to response. Adequate pain control was achieved, but due to unpredictable bioavailability, close monitoring was essential.
Erythematous Bullous Lesions on the Dorsa of the Hands Due to Contact Exposure to Ibutilide Fumarate for Injection
Authors: Dodds Elizabeth S. , Oberg Kristin C.
Published: October 2023

While waiting to observe the response to ibutilide fumarate by a patient with atrial fibrillation, a nurse preparing the intravenous solution inadvertently spilled the drug on the hands of a medical resident. The resident immediately wiped his hands dry with disposable paper towels. Several hours later he sensed tingling and itching over the area, and the next day two erythematous bullous lesions were present on the dorsal surfaces of both hands. A single application of topical steroid was applied to the affected areas. The lesions were kept clean and dry, and healed completely in approximately 10 days. This is an unusual allergic reaction due to contact with ibutilide fumarate.
Current and Future Perspectives on Inhaled Anesthetics
Authors: II Edmond I. Eger
Published: October 2023

The discovery of ether anesthesia made modern surgery possible. Successive improvements produced today's inhaled anesthetics, compounds that allow precise control over the anesthetic state without compromising safety. Such control extends to induction and maintenance of, and recovery from, anesthesia. The greatest emphasis is on the last, particularly the rapid recovery obtained with anesthetics with low solubility in blood and tissues. The lowest solubility is produced by halogenation with fluoride to the exclusion of other halogens. The safety of anesthesia has many components. Important among these is molecular stability that permits elimination of the unchanged anesthetic molecule in expired air and provides resistance to degradation by metabolism and by carbon dioxide absorbents. Halogenation with fluorine produces more stable, safer anesthetics. Greater stability, lower solubility, and rapid recovery can decrease direct and indirect costs.
Perioperative Hypertension
Authors: Goldberg Michael E. , Larijani Ghassem E.
Published: October 2023

Increased activity or inadequate inhibition of the autonomic nervous system is often the cause of perioperative hypertension. The goal of treatment is to maintain an adequate balance between myocardial oxygen supply and demand. Newer agents, such as nicardipine and fenoldopam, may offer potential advantages over older agents. The cost:benefit ratio of therapy with these newer agents must also be considered. Despite the fact that perioperative hypertension is aggressively treated, there are no long‐term, large‐scale study data indicating that this treatment affects long‐term patient outcomes.
Venous Thromboembolism in Multiple Trauma Patients
Authors: Erstad Brian L.
Published: October 2023

Thromboembolic complications are frequent in patients with multiple trauma. The efficacy of unfractionated heparin for venous thrombosis prophylaxis has not been established. Based on limited prospective data, low‐molecular‐weight heparin appears to be more effective than unfractionated heparin and at least as effective as compression devices for preventing thromboembolic complications in these patients. Vena cava filters should be considered in high‐risk patients who cannot receive anticoagulant therapy, but long‐term filter use without concomitant anticoagulant therapy is associated with a substantial risk of recurrent thromboembolism.
Restenosis, the Achilles' Heel of Coronary Angioplasty
Authors: Wurdeman Richard L. , Hilleman Daniel E. , Mooss Aryan N.
Published: October 2023

Coronary angioplasty is widely performed for the management of symptomatic coronary artery disease. With improvements in technique, operator experience, and tools, more complex lesions are being treated. Unfortunately, luminal renarrowing continues to limit the long‐term success of the procedure, resulting in the need for repeat revascularization in approximately 30% of patients within 6 months. As the pathophysiologic process of restenosis is better defined, various pharmacologic and mechanical interventions have been tried to attenuate the process. Some agents are antithrombotics, antiplatelets, angiotensin‐converting enzyme inhibitors, lipid‐lowering drugs, and calcium channel blockers. Improvement has been noted with the newer glycoprotein IIb‐ and IIIa‐blocking agents, mechanical stents, and radioactive materials. Whether these new compounds will withstand the test of time is unknown.
Comparison of Bactericidal Activities of Intermittent and Continuous Infusion Dosing of Vancomycin against Methicillin‐Resistant Staphylococcus aureus and Enterococcus faecalis
Authors: Klepser Michael E. , Patel Kalpana B. , Nicolau David P. , Quintiliani Richard , Nightingale Charles H.
Published: October 2023

Study Objective. To describe the pharmacokinetic profiles of vancomycin administered by continuous infusion and intermittent dosing and compare the duration of activity of the regimens.

Design. Randomized, open‐label, cross‐over study.

Setting. Clinical research center at an academic medical center.

Subjects. Twelve healthy, nonpregnant volunteers age 27.6 ± 2.3 years.

Intervention. Subjects received the following intravenous vancomycin regimens: 1 g every 12 hours; 2 g continuous infusion over 24 hours; and 1 g continuous infusion over 24 hours. Dosages were administered with and without gentamicin 2 mg/kg.

Measurements and Main Results. Serum samples were collected, drug concentrations determined, and bactericidal activity measured against two isolates each of methicillin‐resistant Staphylococcus aureus and Enterococcus faecalis. Subjects had poor tolerability for continuous infusions. Trough concentration for the intermittent regimen was 5.5 ± 1.9 mg/ml, and steady‐state concentrations were 8.8 ± 1.6 and 16.9 ± 1.9 mg/ml for 1 and 2 g continuous infusions, respectively. In general, all regimens provided bactericidal activity throughout the study interval. Against one isolate of E. faecalis, 2 g continuous infusion plus gentamicin provided cidal activity for a significantly greater percentage of the dosing interval (p<0.001).

Conclusion. Continuous infusion does not greatly improve the activity of vancomycin and should not be routinely administered. However, it may prove useful against isolates with reduced susceptibility to the agent.
Vancomycin Pharmacokinetics in Neonates Receiving Extracorporeal Membrane Oxygenation
Authors: Buck Marcia L.
Published: October 2023

Vancomycin is administered as both prophylaxis and treatment in neonates receiving extracorporeal membrane oxygenation (ECMO), typically after surgery. An open‐label, retrospective study was conducted to determine dosing strategies in all neonates who received vancomycin during ECMO and compare pharmacokinetic values with those of matched controls not receiving ECMO. Fifteen neonates receiving ECMO were given vancomycin infused into the circuit, with dosages based on weight and gestational age. Blood for serum concentrations was drawn around the third dose, for trough concentrations immediately before the dose, and for peak concentrations 1 hour after infusion. Samples were analyzed by fluorescence polarization immunoassay. The most frequent regimen for both groups (8 ECMO, 13 controls) was 10 mg/kg every 8 hours. It produced peak and trough concentrations of 27.5 ± 4.3 and 13.7 ± 2.7 μg/ml, and 23.0 ± 5.4 and 13.2 ± 4.5 μg/ml, respectively. Pharmacokinetic analysis using a one‐compartment model revealed volume of distribution of 0.45 ± 0.18 L/kg, half‐life of 8.29 ± 2.23 hours, and total body clearance of 0.65 ± 0.28 ml/min/kg in ECMO recipients. Volume of distribution and clearance were not significantly different in controls (0.39 ± 0.12 L/kg, 0.79 ± 0.41 ml/min/kg), but half‐life was shorter (6.53 ± 2.05 hrs, p = 0.02). Based on long volume of distribution in neonates receiving ECMO, we recommend that empiric vancomycin regimens incorporate a longer dosing interval than the 6–8 hours commonly recommended for term infants. The effects of severity of illness on drug elimination require additional study.
Case‐Control Study of Amphotericin B in a Triglyceride Fat Emulsion versus Conventional Amphotericin B in Patients with AIDS
Authors: Manfredi Roberto , Chiodo Francesco
Published: October 2023

We evaluated the efficacy and tolerability of amphotericin B triglyceride emulsion in 16 patients with acquired immunodeficiency syndrome‐related candidal esophagitis and cryptococcosis, compared with standard amphotericin B in 24 patients. Compared with the conventional formulation, the fat emulsion was administered in a significantly greater daily dose, and required shorter induction period and infusion time (p<0.001‐<0.03). Although the two drugs had similar clinical and microbiologic efficacy, the fat emulsion had a better safety profile with respect to frequency of flu‐like symptoms, other local and systemic adverse events, and treatment discontinuation (p<0.02‐<0.05). Because it is easily available and inexpensive, it may have a number of advantages over the conventional formulation. Further similar comparisons are warranted, in addition to investigations to assess whether reduced toxicity can be obtained with fat emulsion without impairing (or possibly improving) the efficacy of this key antifungal agent.
Cost Avoidance, Acceptance, and Outcomes Associated with a Pharmacotherapy Consult Clinic in a Veterans Affairs Medical Center
Authors: Galt Kimberly A.
Published: October 2023

A pharmacist‐directed pharmacotherapy consult clinic (PCC) was established in an interdisciplinary primary care medicine continuity clinic. The pharmacist initiated or modified patient care plans in collaboration with primary care physicians and maintained care plans for 336 (32.8%) of 1023 patients enrolled in the continuity clinic. Clinical outcomes were positive in 88.3% of patient visits, with 95.7% attendance at the PCC clinic and 95% physician acceptance of pharmacist recommendations. Average reductions of 2.4 prescriptions/patient and 6.9 doses/day were achieved. Actual and potential cost avoidance totaled $54,730.56, with actual and potential savings realized compared with dollars spent at a ratio of 5.8:1. The pharmacist provided value‐added services and contributed to decreased costs associated with care.
Postmarketing Surveillance of the Safety of Cyclic Etidronate
Authors: Van Staa Tjeerd P. , Leufkens Hubert , Abenhaim Lucien , Cooper Cyrus
Published: October 2023

To evaluate the safety of cyclic etidronate in routine clinical practice, we obtained information from 550 general practices in the United Kingdom that provide the medical records to the General Practice Research Database. A group of 7977 patients taking cyclic etidronate and two age‐, gender‐, and practice‐matched control groups, one with osteoporosis and one without, were analyzed. For the group taking cyclic etidronate, the average age was 71.6 years and follow‐up was 10,328 person‐years. Conditions that do not induce osteoporosis generally occurred in these patients at a rate comparable to that in the control groups. The incidence of osteomalacia was low and comparable between patients taking cyclic etidronate and controls with osteoporosis. No medically significant increases in frequency were observed among patients taking cyclic etidronate for a broad group of diseases that may potentially be induced by exposure to the drug. These data support the favorable risk:benefit ratio of cyclic etidronate.