bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmaceutical Marketing: Implications for Medical Residency Training
Authors: Anastasio Geraldine D. , Little John M.
Published: October 2023

An educational intervention was developed to improve family practice residents' ability to obtain useful information from pharmaceutical representatives. The curriculum is based on the traditional one‐on‐one drug detail. The objectives are to develop residents' skills in controlling the interview, promote skills for critically analyzing drug‐promotional material, and discuss ethical issues. The contents include an assessment tool, suggested readings, and interview questions with rationale. After 5 years, residents' confidence in all areas of the curriculum improved significantly.
Piperacillin‐Tazobactam: A New β‐Lactam‐β‐Lactamase Inhibitor Combination
Authors: Daniel Karen P. , Krop Lynne C.
Published: October 2023

We reviewed the spectrum of activity, pharmacokinetics, clinical efficacy, adverse effects, and relative advantages of piperacillin‐tazobactam, a new β‐lactam‐β‐lactamase inhibitor. Piperacillin‐tazobactam has a wide spectrum of activity that includes gram‐positive organisms such as staphylococci and streptococci, as well as many gram‐negative aerobic and anaerobic bacteria. The combination distributes rapidly after parenteral administration and penetrates well into skin, lung, and intestinal mucosa. Compared with other β‐lactam‐β‐lactamase inhibitor combinations, piperacillin‐tazobactam has comparable efficacy in the treatment of intraabdominal infections, skin and soft tissue infections, and upper and lower respiratory tract infections. It may have better in vitro activity than the currently available combinations against selective bacteria that produce class I β‐lactamases (Richmond‐Sykes classification). The combination is well tolerated, with diarrhea being the most common reported adverse effect. Additional controlled trials and clinical experience are required to define its role in clinical practice.
Acute Encephalopathy Attributed to 5‐FU
Authors: Langer Corey J. , Hageboutros Alex , Kloth Dwight D. , Roby David , Shaer Andrew H.
Published: October 2023

Acute encephalopathy attributable to 5‐fluorouracil (5‐FU) is rare. A patient experienced this reaction associated with a continuous 5‐FU infusion. The etiology of the event remains uncertain, but it is generally reversible and does not preclude retreatment with 5‐FU at reduced dosages. Steroids and thiamine may expedite neurologic recovery.
Is There a Role for Digoxin in Patients With Systolic Dysfunction?
Authors: Williamson Kristin M.
Published: October 2023

In early placebo‐controlled trials in patients with heart failure who were in sinus rhythm, digoxin improved hemodynamics, signs and symptoms of heart failure, and exercise capacity, and decreased functional deterioration and the need for pharmacologic cointervention. A more recent trial showed that withdrawing digoxin from patients who were clinically stable while receiving diuretics and angiotensin‐converting enzyme (ACE) inhibitors often resulted in clinical deterioration, whereas continuing the agent maintained stability. Which patients should initially be treated with digoxin remains to be determined. The effects of digoxin on mortality in patients who are receiving ACE inhibitors must also be established.
Angiotensin II Receptor Blockers: Novel Therapy for Heart Failure?
Authors: Munger Mark A. , Furniss Shawn M.
Published: October 2023

Heart failure is a severe, disabling disease that portends a short life expectancy. This grave prognosis may be explained by growth‐promoting effects of angiotensin II implicated in heart failure that mediate a genetic response called programmed cell death. The effects of angiotensin II are inhibited by angiotensin‐converting enzyme (ACE) inhibitors, which improve exercise performance and quality of life, attenuate disease progression, and modestly lengthen survival. Unfortunately, mortality remains exceedingly high and may be partly attributable to augmented production of angiotensin II from a non‐ACE chymase pathway. Angiotensin II production may therefore increase despite treatment with ACE inhibitors. The angiotensin II receptor antagonists are a new class of nonpeptide‐reversible inhibitors that may offer clinical promise in heart failure through blockade of angiotensin II actions, whether produced from ACE or non‐ACE chymase pathways.
Evolving Concepts in the Treatment of Heart Failure: Should New Inotropic Agents Carry Promise or Paranoia?
Authors: Young James B.
Published: October 2023

Heart failure is a common disorder caused by many different diseases. At the root of the problem is diminished myocyte contractility, which ultimately results in failure of the pump to generate adequate peripheral flow. An interplay of hemodynamic, neurohumoral, and inflammatory perturbations initially improves cardiac flow and cellular respiration, but ultimately worsens the syndrome. Inotropic drug therapy was an attractive option in patients with heart failure even before the pump failure aspect of the disease was recognized. Increased contractility should lead to increased cardiac output, which would likely ameliorate hemodynamic and metabolic derangements. Although inotropes increase cardiac contractility at least transiently, this effect does not generally translate into improved survival in clinical trials. Indeed, in patients with advanced heart failure, these drugs frequently increase death rates. It is important to put the issue of inotropic therapeutics into perspective when considering treatment options for these patients. It may well be that certain inotropes in yet to be defined dosages will substantially improve morbidity and mortality when combined with drugs designed to interdict metabolic and neurohumoral components of the syndrome.
Drug‐Cytokine Interactions: Focus on Cyclosporine
Authors: Liao Janice S. , Reiss William G.
Published: October 2023

The immune system is a complex network that regulates and maintains the host's defense system. Changes and alterations in the immune system precipitate a series of reactions to prevent further damage as well as initiate repair. The systems cellular component relies on cytokines (interleukins, tumor necrosis factor, interferons, etc.) to facilitate communication in response to a foreign antigen. Cytokine concentrations are therefore elevated during times of inflammation, such as rejection of a transplanted organ. Recent research suggests that interleukin‐6 may have an inhibitory effect on cytochrome P‐450 3A and thus affect drug metabolism. Cyclosporine, which is administered to prevent rejection of transplanted organs, is metabolized primarily by the P‐450 3A system. Thus, the inhibitory effect of interleukin‐6 may alter cyclosporine concentrations, which in turn may increase its adverse effects, such as nephrotoxicity.
Thrombosis Resulting from Heparin Therapy
Authors: Gottschling Lisa L. , Alaniz Cesar
Published: October 2023

Heparin is widely used in current practice for a variety of indications. It is well known that it can cause thrombocytopenia, but not that thrombosis may also develop in thrombocytopenic patients and cause significant morbidity and mortality. A 56‐year‐old woman developed heparin‐induced thrombocytopenia with thrombosis that resulted in the amputation of her leg. It is proposed that the reaction has an immune‐mediated mechanism. Several ways of diagnosing the condition are available, specifically the serotonin‐release assay and an enzyme‐linked immunosorbent assay. The investigational agent danaproid may be effective in the treatment of heparin‐induced thrombocytopenia with thrombosis.
Drug and Poison Information Resources on the Internet, Part 2: Identification and Evaluation
Authors: Marra Carlo A. , Carleton Bruce C. , Lynd Larry D. , Marra Fawziah , McDougal Al R. , Chow Douglas , McKerrow Ron
Published: October 2023

The Internet is a potential source of information for practitioners and researchers of pharmaceutical sciences. Despite its explosive growth and popularity, pharmacists and other health care providers have been slow to use the Internet as a source of clinical information. We have identified and evaluated several sites available on the Internet that are devoted to providing information related to professional practice, pharmacotherapy, and toxicology. We have concerns, however, regarding the quality of the available information and advise users to be cautious in using the data they obtain.
Cytogenetic Observations After Meglumine Antimoniate Therapy for Visceral Leishmaniasis
Authors: Hantson Philippe , Léonard Eliane D. , Crutzen‐Fayt Marie‐Christine , Léonard Alain , Vandercam Bernard , Delaere Benedicte , Mahieu Paul
Published: October 2023

Few data are available concerning the genotoxic effects of antimonial salts therapy in humans. A patient suffering from visceral leishmaniasis was treated for 15 days with a cumulative dose meglumine antimoniate 42.5 g. Peripheral blood lymphocytes sampled before treatment, 7 days later, and at the end of therapy (day 15) were examined for the presence of structural chromosome aberrations, sister chromatid exchanges (SCEs), and micronuclei in binucleated cells. The treatment resulted in an increase of binucleated cells carrying micronuclei, with no changes in chromosome structural aberrations or in mean SCE frequency. On the basis of these observations and of experimental results reported in the literature, we conclude that therapy with meglumine antimoniate apparently does not represent a mutagenic or carcinogenic risk to humans.
The Impact of Practice Guidelines on Prescribing Patterns of Nondepolarizing Neuromuscular Blocking Agents
Authors: Tschida Suzanne J. , Hoey Lori L. , Vance‐Bryan Kyle
Published: October 2023

Guidelines for selecting nondepolarizing neuromuscular blocking agents (NNMBAs) were developed and implemented by an interdisciplinary team for use in our intensive care units. They suggest pancuronium as the drug of choice if the patient does not have renal insufficiency and is hemodynamically stable. If either of these criteria is not met and hepatic function is normal, vecuronium is recommended. Atracurium is reserved for patients not meeting either criterion. A 12‐month retrospective chart review was performed for 24 patients 18 years of age or older who received continuous infusion of an NNMBA beginning 7 months after the guidelines were implemented. Before the guidelines, atracurium, vecuronium, and pancuronium were prescribed for 68% (17), 24% (6), and 8% (2) of patients, respectively. Their use was inappropriate based on organ function and hemodynamic stability in 88% (15), 83% (5), and 0% of patients, respectively. After guideline implementation, atracurium, vecuronium, and pancuronium were prescribed for 33% (8), 21% (5), and 46% (11) of patients, respectively, and use was inappropriate in 38% (3), 60% (3), and 0% of patients, respectively. Overall, the prevalence of inappropriate NNMBA selection decreased from 80% (20) to 25% (6). Further analysis is necessary to determine the associated pharmacoeconomic impact of decreased inappropriate NNMBA prescribing.
Effects of Age and Gender on Venlafaxine and O‐Desmethylvenlafaxine Pharmacokinetics
Authors: Klamerus Karen J. , Parker Vernon D. , Rudolph Richard L. , Derivan Albert T. , Chiang Soong T.
Published: October 2023

This single‐ and multiple‐dose, nonrandomized, inpatient study was conducted to determine the effects of age and gender on the pharmacokinetic profiles of the antidepressant venlafaxine and its equally active metabolite, O‐desmethylvenlafaxine. The subjects were 18 elderly (age 60–80 yrs) and 18 young (age 21–44 yrs) subjects, 9 men and 9 women per age group. They received a single 50‐mg venlafaxine dose followed by 50‐mg doses every 8 hours for 5 days. No significant differences in venlafaxine single‐dose pharmacokinetics were seen between age groups, but the steady‐state half‐life increased 24% in the elderly. For O‐desmethylvenlafaxine, single doses had a significantly lower apparent clearance in the elderly (0.29 vs 0.38 L/hr/kg), longer half‐life (13.2 vs 10.3 hrs), and 14% greater steady‐state half‐life. For the composite (venlafaxine + O‐desmethylvenlafaxine), there was a nonsignificant 16% increase in elderly steady‐state area under the curve (AUC* = AUC + activity factor • AUCm), and AUC* was linear between doses and age groups. We conclude that venlafaxine dosage adjustments for age or gender are not necessary based on pharmacokinetics.
Treatment of Opioid‐Induced Pruritus with Ondansetron: Report of Four Patients
Authors: Larijani Ghassem E. , Goldberg Michael E. , Rogers Kenneth H.
Published: October 2023

Pruritus is a common side effect after neuraxial administration of the opioids; particularly morphine sulfate. Ondansetron has been used to treat the pruritus in patients with cholestatic diseases or renal insufficiency, suggesting that pruritus may be mediated by serotonin. We administered ondansetron to four patients suffering from pruritus due to the perioperative administration of opioids. Pruritus disappeared within few minutes in three of these patients. Future studies are necessary to evaluate the efficacy of ondansetron for the treatment as well as the prevention of this opioid‐induced effect.
Hemodynamic Response to Intentionally Altered Flow Continuity of Dobutamine and Dopamine by an Infusion Pump in Infants
Authors: Stowe Cindy D. , Storgion Stephanie A. , Lee Kelley R. , Phelps Stephanie J.
Published: October 2023

Study Objective. To evaluate the effect of an intentional alteration in infusion pump flow continuity on the hemodynamic stability of infants receiving either dobutamine or dopamine.

Design. Prospective, open‐label study.

Setting. A university‐affiliated children's hospital.

Patients. Ten hemodynamically stable infants (age 2 wks–10 mo) in intensive care receiving dobutamine (5) or dopamine (5). Three patients received both agents and were studied at independent times.

Interventions. Dobutamine and dopamine were administered using the Flo‐Gard VP pump that delivers an intentional alteration of flow continuity (rate pulse). Heart rate and mean arterial pressure (MAP) were recorded every second. Analysis was based on the measurements obtained from the first 5 minutes on the study pump and the 2 minutes before and after the rate pulse.

Measurements and Main Results. Although hemodynamic changes in pre‐ and post‐rate pulses were statistically significant (p < 0.05) in some individuals, only one infant had a greater that 10% change in MAP 2 minutes after the rate pulse. Alterations in hemodynamics were not consistent among or within patients.

Conclusion. In infants requiring dobutamine or dopamine, no clinically significant pharmacodynamic effects were associated with alteration in continuity of drug delivery caused by the single positive rate pulse. Therefore, we conclude there is no contraindication to the use of this infusion pump in hemodynamically stable infants receiving these drugs.
Suppression of Herpes Simplex Virus Infections with Oral Lithium Carbonate—A Possible Antiviral Activity
Authors: Amsterdam Jay D. , Maislin Greg , Hooper Mary B.
Published: October 2023

In vitro studies have shown an inhibitory effect of lithium salts on herpes simplex virus (HSV) replication by mechanisms that interfere with viral DNA synthesis. Moreover, clinical studies have shown that oral lithium carbonate and topical lithium succinate can suppress genital HSV infections in humans. We conducted a randomized, double‐blind, placebo‐controlled trial of oral lithium carbonate in 11 healthy subjects age 28–65 years (mean ± SD age 38 ± 11 years) who had at least four recurrent HSV infections in the year preceding the study. Six patients completed at least 5 months of, lithium therapy at a mean (± SD) average daily lithium dose of 437 ± 185 mg (range, 150–900mg) and an average serum lithium level of 0.56 ± 0.20 mmol/L. Overall, lithium treatment resulted in a consistent reduction in the mean number of episodes/month, the average duration of each episode, the total number of infection days/month, and the maximum symptom severity. In contrast, treatment with placebo resulted in an increase in three out of the four severity measures. Although the comparisons between the treatment groups did not achieve statistical significance due to the limited sample size, there was a clear “trend” for a reduction in the total monthly duration of all HSV infections with lithium (p = 0.08). Lithium treatment was well tolerated and produced no deleterious effects on renal or thyroid function. These observations lend support to prior observations of an antiviral activity of lithium, and suggest the possibility that oral lithium may represent a safe prophylactic agent in patients with recurrent HSV infections.
Mega‐Analysis of Meta‐Analysis: An Examination of Meta‐Analysis with an Emphasis on Once‐Daily Aminoglycoside Comparative Trials
Authors: Freeman Collin D. , Strayer Andrew H.
Published: October 2023

Meta‐analysis is increasingly performed to try and answer clinical questions around which controversy exists. We performed meta‐analyses using three different methods as examples to illustrate problems and points to consider when doing such work. The questions of interest were comparing frequency of nephrotoxicity and clinical effectiveness with once‐daily aminoglycoside regimens versus multiple‐daily dose aminoglycoside regimens. Inclusion and exclusion criteria were established. Studies were obtained from literature searches, and included published studies and abstracts. The overall odds ratio (95% confidence interval) for nephrotoxicity and clinical effectiveness metaanalyses of these studies using the Mantel‐Haenszel‐Peto method were 0.70 (0.51–0.94, p = 0.042) and 0.79 (0.59–1.07, p = 0.09), respectively. Analyzing the data by Fisher's combined test and the Mean‐P method showed agreement with the other methods' conclusions for nephrotoxicity but not for clinical effectiveness. Meta‐analysis is not an exact procedure and contains various problems and inconsistencies. Combining studies of poor quality is not ideal for answering unresolved clinical questions.
Thromboembolic Prophylaxis in Moderate‐Risk Patients Undergoing Elective Abdominal Surgery: Decision and Cost‐Effectiveness Analyses
Authors: Mamdani Muhammad M. , Weingarten Cindy M. , Stevenson James G.
Published: October 2023

We conducted a retrospective, literature‐based decision analysis to compare the cost‐effectiveness of conventional low‐dose heparin, dalteparin, and intermittent pneumatic compression (IPC) as thromboembolic prophylaxis to a no‐prophylaxis option in patients at moderate risk of developing thromboembolic complications after major elective abdominal surgery. The analysis was conducted through an institutional perspective. Probability and incidence rate data were summarized from the literature. Cost data were obtained from the Detroit Medical Center's cost accounting systems and from national diagnosis‐related group estimates. Mortality and complications avoided were the main outcome measures on which cost‐effectiveness was based. Overall costs associated with conventional low‐dose heparin, dalteparin, intermittent pneumatic compression, and no prophylaxis were $84, $122, $102, and $112, respectively, in the primary analysis, which included costs of labor. Corresponding cost‐effectiveness ratios in terms of costs/complication‐free patient were $86, $124, $103, and $118, respectively. Compared with no prophylaxis, incremental cost‐effectiveness analysis in terms of cost/mortality avoided involved savings of $6087 and $3125 with conventional low‐dose heparin and IPC, respectively, and expenses of $2857 with dalteparin. A secondary analysis excluding costs of labor showed similar results. The results of the study consistently showed conventional low‐dose heparin to provide the most cost‐effective thromboembolic prophylaxis of the methods considered in terms of reducing both morbidity and mortality in the patient population studied.
A Pilot Pharmacokinetic‐Pharmacodynamic Study of Benzodiazepine Antagonism by Flumazenil and Aminophylline
Authors: Bonfiglio Mark F , Fisher‐Katz Lynn E. , Saltis Lawrence M. , Traeger Sheldon M. , Martin Bradley R. , Nackes Nicholas A. , Perkins Thomas A.
Published: October 2023

Study Objectives. To develop a pharmacokinetic‐pharmacodynamic model using quantitative electroencephalographic (EEG) analysis to compare two separate benzodiazepine antagonists and generate data concerning response variability.

Design. A pilot study using a randomized, blinded, crossover design.

Setting. The Neurology Laboratory at the Akron City Hospital campus of SUMMA Health System.

Patients. Four healthy volunteers completed the protocol.

Interventions. Subjects received midazolam 0.1–0.2 mg/kg by intravenous bolus on 3 study days, separated by a minimum washout period of 1 week. Subjects participated in an initial open‐label response phase followed by a randomized, crossover trial of each benzodiazepine antagonist.

Measurements and Main Results. Venous blood samples were obtained to characterize the pharmacokinetics of all study compounds. The EEG parameter of total number of waves/second (recorded from FP1‐F3 and FP2‐F4 electrodes) in the frequency of 12–30 Hz was used to quantify effect. Flumazenil appeared to prolong the elimination half‐life of midazolam significantly (p < 0.05). Theophylline (aminophylline) also appeared to prolong the half‐life of flumazenil (p < 0.05). Despite considerable variability, flumazenil resulted in reversal of sedation at concentrations achieved by routine dosing. Resedation was apparent for all subjects following flumazenil reversal. Only partial reversal of sedation by theophylline was achieved by an aminophylline dose of 1–2 mg/kg.

Conclusions. Flumazenil was consistently effective in reversing sedation by midazolam at routinely recommended dosing. Further investigation of aminophylline as a reversal agent should use an estimated dose of 6–8 mg/kg aminophylline. To achieve adequate reversal, some patients may require aminophylline dosages that exceed safe clinical administration.
Pharmacokinetic‐Pharmacodynamic Relationships of Bromfenac in Mice and Humans
Authors: Chiang Soong T. , Ermer James C. , Osman Mohamed , Chau Thuy , Hicks David , Wheeler Sarah , Vavra Ivan
Published: October 2023

The relationship between pharmacodynamic effect and plasma concentrations of the analgesic bromfenac was assessed retrospectively. The drug was administered in single doses of 5, 10, 25, 50, or 100 mg to patients with oral surgery pain. Concentration‐effect curves were generated by a semiparametric pharmacokinetic‐pharmacodynamic procedure. The bromfenac EC50 (the effect site concentration giving 50% of the maximum effect) was estimated to be 0.36 μg/ml in patients when all five dose groups were combined, and an Emax model was used for pharmacodynamic response. A similar EC50 value, 0.40 μg/ml, was obtained when bromfenac was tested in a mouse pain model. On the basis of combined‐dose data, effect site concentrations were predicted to be above the analgesic EC50 for approximately 7–8 hours after a 50‐mg bromfenac dose was taken in the fasting state. Predictions based on a pharmacokinetic‐pharmacodynamic modeling procedure were in reasonable agreement with the clinical observations.
Controlled Trials Comparing Reteplase with Alteplase and Streptokinase in Patients with Acute Myocardial Infarction
Authors: Amsterdam Ezra A.
Published: October 2023

Although the ability of a thrombolytic agent to lyse a clot has been recognized for over 50 years, it was not until recently that this form of therapy was used to treat acute myocardial infarction. The need for rapid diagnosis and timely treatment to provide optimum outcomes and prognosis is now well established. Numerous clinical trials continue to examine alternative therapeutic regimens as well as the efficacy and safety of new agents to improve short‐ and long‐term outcomes further. Reteplase is a new recombinant tissue‐type plasminogen activator with potential advantages over currently available agents.
Pharmacometric Analysis of the Effect of Furosemide on Suramin Pharmacokinetics
Authors: Piscitelli Stephen C. , Forrest Alan , Lush Richard M. , Ryan Nathan , Whitfield Lloyd R. , Figg William D.
Published: October 2023

Study Objective. To characterize the effects of furosemide on the pharmacokinetics of suramin, a renally eliminated investigational antineoplastic agent.

Design. Retrospective population pharmacokinetic analysis.

Setting. Government biomedical research facility.

Patients. Twenty‐six men with hormone‐refractory prostate cancer and one with adrenocortical carcinoma.

Interventions. Patients received suramin by continuous or intermittent infusion with and without concomitant furosemide.

Measurements and Main Results. Optimum suramin regimens were achieved by adaptive feedback control, and pharmacokinetic data were collected both in the presence and absence of furosemide. Suramin concentrations were determined by high‐performance liquid chromatography (coefficient of variation < 8%). Suramin concentrations were fit to a three‐compartment linear model with six coefficients and two rate inputs, which allowed furosemide to affect suramin pharmacokinetics. Individual and population parameter estimates were determined using the iterative two‐stage approach. Concomitant furosemide was associated with a median decrease in total body clearance of suramin by 36% (range 0–63%, p<0.0001). No other parameter was significantly altered, and there was no trend for change in any pharmacokinetic value with time. Suramin plasma concentrations were simulated with and without prolonged furosemide therapy in 26 patients for 12 weeks. The average suramin concentration increased by greater than 33% in 12 patients; 2 patients had a greater than 67% increase in this extreme case model.

Conclusion. Coadministration of furosemide with suramin can cause an increase in suramin concentrations; however, due to suramin's long half‐life, its rate of accumulation is very slow. Nonetheless, in individuals receiving suramin by nonadaptive control, appropriate precautions should be taken when prolonged furosemide therapy is begun.
Venlafaxine and Nefazodone, Two Pharmacologically Distinct Antidepressants
Authors: Augustin Bruce G. , Cold Julie A. , Jann Michael W.
Published: October 2023

Venlafaxine, a phenylethylamine, and nefazodone, a phenylpiperazine compound, are the newest antidepressants to receive approval of the Food and Drug Administration and to be marketed in the United States. Both strongly inhibit serotonin (5‐HT) reuptake; venlafaxine also inhibits norepinephrine reuptake, and nefazodone also exhibits 5‐HT2‐receptor antagonism. Venlafaxine inhibits the cytochrome P‐450 2D6 isozyme to a lesser extent than the selective serotonin reuptake inhibitors (SSRIs) and is 27% protein bound. Structurally, the drugs are unrelated to SSRIs and have some clinically important differences in side effect profiles. Nausea, headache, somnolence, and dry mouth are the most frequently reported side effects with both. Sustained hypertension was reported by a limited number of venlafaxinetreated patients.
Conduction Disturbances Associated with Administration of Butyrophenone Antipsychotics in the Critically Ill: A Review of the Literature
Authors: Lawrence Kenneth R. , Nasraway Stanley A.
Published: October 2023

Droperidol and haloperidol have demonstrated efficacy and safety in the treatment of acute delirium in critically ill patients. We conducted MEDLINE and manual searches of literature published from 1966–1996 to identify articles describing conduction disturbances associated with the drugs. The objectives were to describe the proposed mechanisms of acquired long QTc interval syndrome and torsades de pointes, and to recommend how critically ill patients receiving these agents should be monitored. We found 11 published reports of conduction disturbances associated with intravenous administration of droperidol or haloperidol. The majority of cases occurred in critically ill patients prescribed more than 50 mg/24 hours of either agent. Of the 18 patients described, 13 (72%) had a history of cardiovascular disease. Based on the small number of available case reports, it seems reasonable to suggest that the incidence of adverse cardiovascular effects due to droperidol and haloperidol is small. The mechanism of butyrophenone‐induced QTc interval prolongation is not known, but is presumed to involve abnormal ventricular repolarization and the development of early after‐depolarizations. Before initiating therapy with droperidol or haloperidol in critically ill patients, a baseline QTc interval and serum magnesium and potassium concentrations should be measured. If the baseline QTc interval is 440 msec or longer, and they are receiving other drugs that may prolong the QTc interval or they have electrolyte disturbances, a butyrophenone antipsychotic should be prescribed with caution. All critically ill patients receiving droperidol or haloperidol should undergo electrocardiogram monitoring and QTc interval measurement; special attention should be given to those receiving doses greater than 50 mg/24 hours, as these patients appear to be at greatest risk for development of conduction disturbances. Based on the currently available literature, in any critically ill patient receiving droperidol or haloperidol therapy whose QTc interval lengthens by 25% or more over baseline, therapy should be discontinued or the dosage reduced.
Aminoglycoside Adaptive Resistance
Authors: Karlowsky James A. , Zelenitsky Sheryl A. , Zhanel George G.
Published: October 2023

Aminoglycoside adaptive resistance is defined as reduced antimicrobial killing in originally susceptible bacterial populations after initial incubation with aminoglycoside. It is observed in vitro and in vivo, most commonly with Pseudomonas aeruginosa. It appears to correlate with a marked reduction in intracellular aminoglycoside accumulation, although its specific mechanism and the cellular structures responsible remain unknown in P. aeruginosa. Recent work suggests that adaptive resistance develops coincident with cytoplasmic membranes protein changes and regulated expression of genes in the anaerobic respiratory pathway of the organism. It is clinically most relevant in immunocompromised patients and in those with serious infections, especially infections due to gram‐negative rods. Treatment of these patients by targeting high peak concentration:minimum inhibitory concentration ratios with once‐daily dosing may result in the best outcome. A major unresolved issue concerns the effect of combination therapy on the development of aminoglycoside adaptive resistance.
Octreotide and Potassium Homeostasis
Authors: Brown Rex O. , Dickerson Roland N. , Mouser Jay F. , Hak Emily B. , Methvin J. Travis , Hak Lawrence J.
Published: October 2023

Somatostatin infusion causes hyperkalemia in healthy subjects and in some animal models. The purpose of this investigation was to determine what effect octreotide has on potassium homeostasis during serious illness and if there is a dose‐response relationship. Sixty‐six male Sprague‐Dawley rats (185–225 g) were randomized to receive parenteral nutrition (PN) only, PN plus continuous infusion of Escherichia coli lipopolysaccharide (LPS), or PN plus LPS plus octreotide 10, 100, or 1000 μg/kg/day for 48 hours. Before randomization all animals received isocaloric, isonitrogenous, isokalemic PN. A 24‐hour urine was collected and a blood sample was taken at the end of the study immediately before euthanization. Data were analyzed by ANOVA and Duncan's multiple range test. Nonhemolyzed serum samples from 50 rats were available for study. Serum potassium concentrations were in the normal range for rats and did not differ significantly among the groups: 5.97 ± 0.86, 5.96 ± 1.58, 5.78 ± 1.48, 5.79 ± 1.67, 5.35 ± 0.78 mEq/L, respectively. No differences among groups were found for fractional excretion of potassium or serum creatinine concentration. Octreotide administration in escalating dosages does not cause hyperkalemia in endotoxemic rats given intravenous potassium at a constant rate by PN.
Salary Survey of Ambulatory Care Clinical Pharmacists
Authors: Anastasio Geraldine D. , Shaughnessy Allen E
Published: October 2023

To determine salary and selected fringe benefits of members of the Ambulatory Care Practice and Research Network of the American College of Clinical Pharmacy, we developed a self‐administered questionnaire that surveyed demographic information, schooling and training, academic appointments, yearly salary (as of February 1, 1995), source of salary, outside income, annual raise, vacation time, financial support for continuing education, and board certification. Ninety‐nine surveys were returned (return rate 46%). Respondents were mostly women (58%), their average age was 34 years (range 25–51 yrs), and they had a median of 5 years in the work force. Most respondents (67%) had residency training, whereas only 21% had fellowship experience. Board certification was reported by 46%. The median salary was $53,500 (average $55,861, range $35–90k), with progression for academic rank. The last salary increase averaged 3.7%. Most (93%) respondents received an average of $1509 for travel. The survey represents a young work force. The salaries vary but show progression for accomplishment.
Sirolimus, a New, Potent Immunosuppressive Agent
Authors: Kelly Patrick A. , Gruber Scott A. , Behbod Fariba , Kahan Barry D.
Published: October 2023

Sirolimus (SRL), a potent immunosuppressant, is currently being investigated in phase III trials for prophylaxis of renal transplant rejection. The mechanism of action of SRL is a blockade of the response of T and B cells to cytokines, thereby preventing cell cycle progression in G1 and consequently cell proliferation. There seems to be a good correlation between SRL concentrations, estimated as exposure by the area under the concentration versus time curve, and trough whole blood concentration, so that therapeutic monitoring may be done by trough levels only. Because of the low frequency of allograft rejection, there has been no documented correlation between trough concentrations and efficacy. Trough SRL concentrations of 15 ng/ml or higher seem to be associated with an increased frequency of adverse effects. Drug‐associated toxicities include thrombocytopenia, leukopenia, and increases in cholesterol and triglyceride levels. The drug has synergy with cyclosporine (CsA) in vitro as well as in animal and clinical studies. In phase II trials the combination of SRL‐CsA therapy reduced the frequency of acute rejection episodes, permit withdrawal of concomitant corticosteroid therapy, and allowed reduction of CsA dosages in nonblack patients.
Is Oral Sotalol Effective in Converting Atrial Fibrillation to Sinus Rhythm?
Authors: Ferreira Ema , Sunderji Rubina , Gin Kenneth
Published: October 2023

d,l‐Sotalol is a noncardioselective β‐blocker that has class III antiarrhythmic activity. It is often used to convert atrial fibrillation (AF) to normal sinus rhythm. Since class III agents increase action potential duration and refractoriness in atrial tissue without affecting conduction, they are theoretically considered ideal agents for the treatment of reentrant arrhythmias such as AF. We reviewed the literature evaluating the efficacy of Sotalol for restoring sinus rhythm in patients with acute or chronic AF. Articles indexed on MEDLINE (1966–1996) and referenced articles not identified by MEDLINE that compared Sotalol with placebo or another antiarrhythmic agent were included. Sotalol was significantly inferior to quinidine in converting AF of recent onset (< 48 hrs) to sinus rhythm. In patients with duration of AF of more than 48 hours, Sotalol was significantly less effective than quinidine and comparable with placebo. Conversion rates for Sotalol in all studies combined ranged from 8–49%. Published studies do not support the drug for conversion of AF to sinus rhythm. Larger well‐designed studies are required to evaluate its efficacy and optimum dosage for this indication. Until further data are available, pharmacologic cardioversion with traditional class I antiarrhythmic agents may be preferable as they are effective particularly for recent‐onset AF.
Evidence for Negative Feedback of Extracellular Methotrexate on Blasts of Acute Lymphoblastic Leukemia in Vitro
Authors: Hum Martina C. , Smith Angela K. , Lark Richard H. , Winick Naomi J. , Kamen Barton A.
Published: October 2023

Study Objective. To explore the value of high‐dose methotrexate (MTX).

Subjects. Blast cells from 15 patients with acute lymphoblastic leukemia.

Interventions. We compared uptake and polyglutamation of [3H]‐MTX by freshly isolated leukemic blasts in vitro after 24‐hour exposure to 1, 10, and 50 μM [3H]‐MTX.

Measurements and Main Results. Mean MTX uptake (pmol/106 cells) was 0.78 ± 0.19, 2.3 ± 0.54, and 5.9 ± 1.9, respectively, and mean polyglutamation was 82%, 66%, and 46%. Consequently, mean MTX polyglutamates were 0.68 ± 0.18, 1.5 ± 0.47, and 2.2 ± 0.67 pmol/106 cells. Three of 15 patient samples had no detectable polyglutamation of MTX at 50 μM but MTX polyglutamates were detectable at 1 μM. Two of these three had a decrease in MTX polyglutamates at 10 versus 1 μM. In eight precursor B cell samples there was a significant difference in median MTX polyglutamates at 1 versus 10 μM but not 10 versus 50 μM.

Conclusion. Increasing extracellular MTX concentrations may be counterproductive for some patients with acute lymphoblastic leukemia. If MTX polyglutamates are important for efficacy, optimal delivery of MTX may have to be determined by individual metabolism rather than by targeting a specific drug concentration.
Lidocaine Does Not Affect Myocardial Electrical Heterogeneity: Implications for Low Proarrhythmic Actions
Authors: Sims J. Jason , Winecoff Allison P. , Ujhelyi Michael R.
Published: October 2023

An area of unidirectional conduction block is one requirement for reentrant arrhythmias to occur. Functional block caused by dispersion of repolarization and refractoriness is the most probable mechanism of drug‐induced unidirectional conduction block. We assessed the effects of lidocaine on spatial dispersion of myocardial repolarization and refractoriness in the intact porcine heart. Monophasic action potential duration at 90% repolarization, effective refractory period (ERP), and ventricular fibrillation cycle length (VFCL) were measured at two endocardial and one epicardial sites at baseline and during a treatment phase with D5W (n=11) or lidocaine 10 mg/kg/hour (n=12). Dispersion was calculated as the difference between the maximum and minimum values of the three recording sites. Lidocaine produced significant changes in ERP, VFCL, paced QRS duration, and intraventricular conduction time. It did not change basal levels of dispersion in repolarization and refractoriness. Lidocaine produced changes in myocardial electrophysiology that are uniform across the myocardium and thus did not change myocardial electrical heterogeneity. This may be a mechanism of the agent's lower proarrhythmic effects compared with other sodium channel blockers that increase myocardial electrical heterogeneity.
Evaluation of Hypertensive Patients after Care Provided by Community Pharmacists in a Rural Setting
Authors: Carter Barry L. , Barnette Debra J. , Chrischilles Elizabeth , Mazzotti Gordon J. , Asali Ziad J.
Published: October 2023

We evaluated blood pressure control, quality of life, quality of care, and satisfaction of patients who were monitored by specially trained community pharmacists in a group medical practice. After participating in an intensive skill development program, pharmacists performed in an interdisciplinary team in a rural clinic. The primary objective was assessed by evaluating outcome variables at 6 months compared with baseline in 25 patients randomly assigned to a study group. A control group of 26 patients was also evaluated to determine if outcome variables remained constant from baseline to 6 months. Systolic blood pressure was reduced in the study group (151 mm Hg baseline, 140 mm Hg at 6 mo, p<0.001) and diastolic blood pressure was significantly lower at 2, 4, and 5 months compared with baseline. Ratings from a blinded peer review panel indicated significant improvement in the appropriateness of the blood pressure regimen, going from 8.7 ± 4.7 to 10.9 ± 4.5 in the study group (p<0.01), but they did not change in the control group. Several quality of life scores improved significantly in the study group after 6 months (p<0.05). These included physical functioning (61.6 vs 70.7), physical role limitations (56.8 vs 72.8), and bodily pain (60.0 vs 71.7) at baseline and 6 months, respectively. There were no significant changes in the control group. Patient satisfaction scores were consistently higher in the study group at the end of the study. Our results indicate that when community pharmacists in a clinic setting are trained and included as members of the primary care team, significant improvements in blood pressure control, quality of life, and patient satisfaction can be achieved.
Impact of CYP2D6 Poor Metabolizer Phenotype on Propranolol Pharmacokinetics and Response
Authors: Sowinski Kevin M. , Burlew Brad S.
Published: October 2023

We conducted an open‐label study to determine the impact of cytochrome P‐4502D6 (CYP2D6) on propranolol pharmacokinetics and response in 12 healthy men with CYP2D6 extensive metabolizer (EM) phenotype and 3 healthy men with CYP2D6 poor metabolizer (PM) phenotype. Subjects received R,S‐propranolol hydrochloride 80 mg every 8 hours for 16 doses. After the sixteenth dose, blood and urine samples were collected for 24 hours, and serum propranolol and urine metabolite concentrations were determined by chiral high‐performance liquid chromatography. Heart rate response to treadmill exercise was measured serially over 24 hours. Apparent oral clearance of propranolol and partial metabolic clearance values of propranolol to 4‐hydroxypropranolol (HOP), propranolol glucuronide, and naphloxylactic acid (NLA) were estimated. Apparent oral clearance and elimination half‐life of propranolol were not different between EMs and PMs. Partial metabolic clearance of propranolol to HOP was significantly higher and to NLA was significantly lower in EMs than in PMs. No differences in percentage reductions in exercise heart rate were observed between EMs and PMs. The CYP2D6 PM phenotype has no effect on propranolol blood concentrations and does not alter response to propranolol. Our data also suggest that CYP2D6 mediates approximately 65% and 70% of S‐ and R‐propranolol's 4‐hydroxylation, respectively.
Elevation of the Erythrocyte Sedimentation Rate Precedes Exacerbation of Bleomycin‐Induced Pulmonary Toxicity: Report of Two Cases and Review of Literature
Authors: Higa Gerald M. , AlKhouri Nabiel , Auber Miklos L.
Published: October 2023

Bleomycin is included in a number of potentially curative chemotherapy regimens. It is associated with distinct forms of pulmonary toxicity, with interstitial pneumonitis the most common. Early detection of pulmonary toxicity is not always predictable by monitoring serial chest radiographs and pulmonary function tests. Even newer serum markers are not useful indicators of bleomycin‐induced pulmonary damage. Two patients developed bleomycin pulmonary toxicity, in both of whom increases in erythrocyte sedimentation rate (ESR) preceded clinical deterioration and radiographic changes. The ESR may have potential significance as a monitoring test in patients receiving bleomycin.
Cross‐Resistance to Both Atracurium‐ and Vecuronium‐Induced Neuromuscular Blockade in a Critically Ill Patient
Authors: Fish Douglas N. , Singletary Tony J.
Published: October 2023

A previously healthy 33‐year‐old woman received neuromuscular blocking agents during treatment of severe adult respiratory distress syndrome secondary to pneumococcal pneumonia and septic shock. Atracurium infusion rates were progressively increased, preceded by repeated loading doses up to a maximum of 3.57 mg/kg/hour, but produced inadequate neuromuscular blockade as assessed by clinical and ventilatory parameters as well as train‐of‐four (TOF) monitoring. Atracurium was discontinued and vecuronium infusions of 2.3 mg/kg/hour finally produced adequate paralysis for 7 days. Increasing vecuronium requirements then prompted discontinuation of neuromuscular blockade. Atracurium was reinstituted 2 days later because of worsening pulmonary function. Infusion rates of 3.04 mg/kg/hour were again required, together with high‐dose midazolam and fentanyl, to achieve adequate oxygenation with acceptable airway pressures; however, TOF monitoring showed an unacceptable level of paralysis. Cross‐resistance among chemically dissimilar neuromuscular blocking agents poses a difficult patient management problem and supports a pharmacodynamic basis of resistance to these agents.
Warfarin Resistance Associated with Intravenous Lipid Administration: Discussion of Propofol and Review of the Literature
Authors: MacLaren Robert , Wachsman Bruce A. , Swift D. Kyle , Kuhl David A.
Published: October 2023

Intravenous lipids are often required for parenteral nutritional (PN) support in critically ill patients and are administered with continuous sedation if patients are receiving propofol, which contains soybean oil 10% as an emulsified preparation. High‐dose propofol infusion was associated with reversal of enteral and intravenous warfarin anticoagulation in a 39‐year‐old woman with severe Crohn's disease. Despite increasing the daily dose of warfarin to 30 mg, anticoagulation was not achieved until propofol was discontinued. Reversal of anticoagulation recurred when PN support was supplemented with Liposyn II 20%. Lipid emulsions may interfere pharmacodynamically with warfarin activity by enhancing the production of clotting factors, facilitating platelet aggregation, or supplying vitamin K. They also may facilitate warfarin binding to albumin. Until further information regarding the mechanism of interference is elucidated, heparin therapy should be considered for initial anticoagulation in patients with intestinal absorptive deficiencies who receive high‐dose lipid emulsions and require reliable anticoagulation. If warfarin is given, the international normalized ratio should be monitored daily to ensure adequate anticoagulation.
Diltiazem‐Associated Thrombocytopenia
Authors: Michalets Elizabeth Landrum , Jackson Don V.
Published: October 2023

Nine days after starting diltiazem therapy for new‐onset atrial fibrillation, a patient's platelet count had diminished to 61 × 103/mm3, and 2 weeks later the nadir was reached at 23 × 103/mm3. No hypersensitivity reaction otherwise was noted, and other hematologic values were unaffected. The patient's platelet counts were not affected by platelet transfusions. Bone marrow examination showed normal to increased numbers of megakaryocytes, suggesting peripheral destruction. After discontinuing diltiazem and administering high‐dose immunoglobulin infusions, the platelet count returned to normal. This case suggests an immune‐mediated cause for thrombocytopenia after exposure to diltiazem.