bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal outcomes of a cohort of pregnancies affected by non‐immune hydrops fetalis
Authors: Critchlow Elizabeth , Wodoslawsky Sascha , Makhamreh Mona M. , Rice Stephanie M. , Turan Ozhan M. , Firman Brandy , McLaren Rodney , Araji Sara , Al‐Kouatly Huda B.
Published: October 2023

Objective

To describe the maternal outcomes of a prospective cohort of non‐immune hydrops fetalis (NIHF) pregnancies with negative standard‐of‐care evaluations.

Methods

This study was a secondary analysis of a prospective cohort study of NIHF pregnancies with negative work‐ups (infection, alloimmune anemia, fetomaternal hemorrhage, and chromosomal disorders). Outcomes were obstetric complications, including pre‐eclampsia, mirror syndrome, preterm birth, polyhydramnios, postpartum hemorrhage, and maternal mental health.

Results

Forty pregnancies were included. Four patients developed pre‐eclampsia (4/40, 10.0%); three occurred postpartum. None was diagnosed with mirror syndrome. Of the 31 continued pregnancies, 16 (51.6%) resulted in early fetal death or stillbirth and 15 (48.4%) resulted in live births. Of the 15 live births, 8 (53.3%) were delivered by primary cesarean delivery; 5 (62.5%) were for hydrops fetalis. Eleven live births (73.3%) were delivered preterm; 9 (81.8%) were indicated, most commonly for fetal indications (7/9, 77.8%). Polyhydramnios occurred in 14/40 (35.0%) cases. Where EBL was recorded (n=37), there were 5 (13.5%) cases of postpartum hemorrhage and an additional 3 (8.1%) had uterine atony without hemorrhage. Eighteen patients (18/40, 45.0%) had new‐onset or exacerbated depression or anxiety symptoms.

Conclusion

Our study identified several important adverse outcomes of pregnancies complicated by NIHF with negative standard‐of‐care evaluations, including a high rate of postpartum pre‐eclampsia and worsened mental health. We identified a higher rate of cesarean delivery and preterm birth, both primarily for fetal indications. We also observed the known relationship between polyhydramnios, hemorrhage, and atony, but noted that this risk included pregnancies concluding in dilation and evacuation. Counseling after a diagnosis of NIHF should include these adverse outcomes.
Controlling the Growth of Microcystis Using Surged Artificial Aeration
Authors: Lilndenschmidt Karl‐Erich
Published: October 2023

This paper investigates the effect of lake mixing, due to artificial hypolimnetic aeration, on the succession and ecological composition of selected phytoplankton species in Tegeler See, Berlin. Special attention is given to Microcystis, a nuisance bloom‐forming blue‐green algae and its competitor (in this lake) Ceratium, a dinoflagellate. Due to the installation configuration, the aerators frequently destratified the lake, especially when the stratification was weak. Five years representing three different operating schemes of the 15 aerators (continuous aeration, non‐aeration and surge aeration) in this lake were used to determine possible aeration strategies in controlling Microsystis. In order to ease correlation of the mixing status in the lake with its yearly successions of phytoplankton growth a non‐dimensional parameter called the Lake number was utilised. This parameter represents a balance between: i) forcing due to wind and aerator discharge and ii) potential energy acquired from the stratification of the lake. The results indicate that surged operation of the aerators is effective in suppressing massive growth of Microcystis. Due to their ability to adapt to the mixing/stability state of the water column, prolonged aeration or prolonged stable stratified conditions have little effect in controlling this algae.
Impact of Headwater Stream Acidification on the Trophic Structure of Macroinvertebrate Communities
Authors: Dangles Olivier , Guérold François
Published: October 2023

In order to investigate the impact of freshwater acidification on the trophic structure of macroinvertebrate communities, we performed a study on 22 forested headwater streams characterised by different degrees of acidification (mean pH = 4.49 to 6.98). Results showed that in acidic streams all functional feeding groups were affected in terms of taxonomic richness. As far as the population density was concerned, only a few acid‐tolerant taxa of shredders and predators showed an increasing abundance under acidic conditions. Trophic structure of acidified streams appeared to be deeply impacted with a large contribution of shredders and a complete disappearance of scrapers. In contrast, in circumneutral streams, we found that each functional feeding group had an almost equal share of the trophic web.
Vertiquant: A Device for Automatically Recording Vertical Migration of Plankton
Authors: Vareschi Ekkehard , Reuter Rainer , Brandorff Dietmar , Jannsen Manfred , König Edmund , Wübben Dirk L.
Published: October 2023

Vertical migration is a key subject in understanding zooplankton ecology and its influence on aquatic ecosystems. This paper introduces a device for automatically recording vertical plankton migrations to study proximate factors regulating the stimulus, timing and amplitude of these movements under controlled laboratory conditions. The instrument records the light scattered by organisms at their respective depths and processes the signals in real time to a graphic representation of the organisms vertical distribution. Organisms of different taxa from a size of <40 μ, to > 10 000 μm were used for these experiments. Daphnia migrations in response to UV light are used to demonstrate the basic functions of the instrument.
Dynamic Properties of Recruitment, Expansion and Mortality of Macrophyte Patches in Streams
Authors: Sand‐Jensen Kaj , Andersen Karsten , Andersen Tine
Published: October 2023

Streams are physically perturbed habitats with high demands on the dispersal and recruitment to maintain plant populations. Yet, little is known about these important demographic processes for stream plants. Therefore, we studied the monospecific vegetation of Callitriche cophocarpa in a small Danish lowland stream to determine: 1) the importance of drifting shoots and seeds for recruitment of plants, and 2) the influence of water flow, light availability and patch size on recruitment, growth and mortality processes. We found that the majority (about 90%) of new colonising patches of plant stands derived from drifting shoots being caught around protruding stones, while few developed from seeds. Many new patches were lost in the flowing water before roots became well established. Flow exposure of the patches resulted in the main growth taking place in the downstream direction. Combined areal cover of Callitriche patches on the stream bottom reached an upper limit of about 70%, probably because areal expansion above this threshold was constrained by strong shear forces and coarse substrata developing in the flow channels between the patches. We discuss why efficient shoot dispersal and vegetative growth documented here for Callitriche is an optimal plant strategy in flow‐perturbed streams in contrast to the production of numerous small seeds but limited vegetative spread among ruderal plants in perturbed habitats on land.
The Effects of a Developing Biofilm on Chemical Changes across the Sediment‐Water Interface in a Freshwater Environment
Authors: Woodruff Sarah L. , House W. Alan , Callow Maureen E. , Leadbeater Barry S. C.
Published: October 2023

The development of a diatom biofilm on a river sediment was studied using a fluvarium channel with intensive investigations over a total duration of 16 days. The overlying solution was monitored for dissolved calcium, silicon and soluble reactive phosphorus, pH, dissolved oxygen and temperature. The surface of the sediment was sampled for chlorophyll a, algal cell density and porewater profile measurements of calcium concentration, pH and dissolved oxygen were made using microelectrodes. At the end of the experiment the sediment was longitudinally sectioned and porewaters isolated and analysed.

A diatom biofilm developed within approximately 5 days leading to a decrease in the concentrations of dissolved silicon and phosphorus in the overlying solution. After approximately 270 hours, the dissolved silicon concentration remained low (average of 6.7 μM). As the diatom numbers increased, photosynthetic activity was evident from increases in dissolved oxygen and pH at the interface. By the end of the experiment diurnal changes in the overlying solution of dissolved calcium, alkalinity and soluble reactive phosphorus were evident. Vertical concentration gradients in dissolved calcium, phosphorus and silicon in the sediment porewater were found at the end of the experiment.

The results are consistent with the development of a photosynthetically active diatom biofilm that acted as a barrier to the diffusion of silicon from the porewater. It also induced precipitation and dissolution of calcite and co‐precipitation of phosphate with calcite. Chemical fluxes of silicon, calcium and phosphorus were estimated from concentration gradients in the sediment and found to be much smaller than fluxes measured from changes in the bulk solution indicating that processes at the sediment‐water interface and biofilm mainly control the flux to the overlying solution.
Metformin, a Promising Oral Antihyperglycemic for the Treatment of Noninsulin‐Dependent Diabetes Mellitus
Authors: Wildasin Elena M. , Skaar Debra J. , Kirchain William R. , Hulse Michelle
Published: October 2023

Noninsulin‐dependent diabetes mellitus has historically been treated with diet therapy alone or the addition of an oral hypoglycemic agent such as a sulfonylurea, or the two in combination with insulin. Although these medical interventions lower blood glucose concentrations, they may also potentiate hyperinsulinism through increased serum insulin concentrations. Insulin resistance and hyperinsulinism are associated with cardiovascular risk factors such as hypertriglyceridemia, decreased high‐density lipoprotein cholesterol levels, hypertension, and hyperglycemia, among others. Therefore, a desirable therapeutic alternative would lower blood glucose, not result in hyperinsulinism, and have beneficial effects on lipid profiles. Metformin is a biguanide antihyperglycemic agent that provides these effects. When administered to carefully selected patients and monitored appropriately, metformin may prove to be valuable in the treatment of diabetes mellitus and in altering its cardiovascular sequelae.
Antithrombotic Therapy after Intracoronary Stenting
Authors: Spinier Sarah , Cheng Judy
Published: October 2023

Conventional percutaneous transluminal coronary angioplasty may result in complications such as abrupt closure and late restenosis. This has led to increased application of mechanical revascularization techniques including intracoronary stents. In the past, subacute thrombosis after intracoronary stenting mandated anticoagulation with warfarin for a minimum of 1 month, with aspirin (ASA) started before the procedure and continued indefinitely. New information suggests that high‐pressure balloon inflation, with or without intracoronary ultrasound guidance to ensure successful stent placement, may permit reduction in the antithrombotic regimen to ASA, continued indefinitely, and ticlopidine, continued for 1–3 months. However, the majority of trials supporting this practice are primarily small, nonrandomized, observational studies. One randomized study found a lower frequency of cardiac events, including thrombosis, as well as fewer bleeding complications with combined antiplatelet therapy with ticlopidine compared with anticoagulant therapy with phenprocoumon. Intracoronary stenting without anticoagulation would permit shorter hospitalization and lead to cost‐savings. This has led many cardiologists to administer ASA and ticlopidine without benefit of data from randomized, blinded clinical trials. Antithrombotic therapy after coronary artery stenting is in an evolutionary stage, and additional information regarding the safety and efficacy of ASA and ticlopidine is necessary.
Long‐Term Effectiveness of Enalapril plus Extended‐Release Diltiazem in Essential Hypertension
Authors: Applegate William , Cohen Jerome D. , Wolfson Paul , Davis Archie , Green Stephen
Published: October 2023

Study Objective. To evaluate the efficacy and safety of a new combination product, enalapril‐diltiazem ER, when administered over the long term.

Design. Open‐label, titration to response, with treatment lasting 46 weeks after a 6‐week, double‐blind phase.

Setting. Medical clinics in the private and academic sectors.

Patients. Of 265 patients (68% men, 83% Caucasian, mean age 54.9 yrs) with essential hypertension (sitting diastolic blood pressure 95–115 mm Hg) enrolled, 167 completed the trial.

Interventions. Patients received either the dosage of enalapril‐diltiazem ER that they were given during the double‐blind phase, or were prescribed enalapril 5 mg‐diltiazem ER 120 mg once/day. The dosage was increased until blood pressure was controlled or to a maximum of enalapril 10‐diltiazem ER 360 mg/day.

Measurements and Main Results. Combination therapy decreased sitting blood pressures by −11.1/−10.6 mm Hg. Overall, 58% of the patients achieved a sitting diastolic blood pressure of 90 mm Hg or below at the end of the study. There was no evidence of tolerance to the agents' antihypertensive effects. The most common drug‐related adverse events were cough, headache, dizziness, and asthenia or fatigue.

Conclusion. The combination effectively managed essential hypertension when administered on a long‐term basis and was generally well tolerated. It should improve both compliance and management of hypertension.
The Effect of Flurbiprofen on Steady‐State Plasma Lithium Levels
Authors: Hughes Barbara McGee , Small Ralph E. , Brink Douglas , McKenzie Norma D.
Published: October 2023

Study Objective. To evaluate the effects of flurbiprofen therapy on the pharmacokinetics of lithium.

Design. Placebo‐controlled, single‐blind, crossover study.

Setting. University‐affiliated hospital.

Patients. Eleven healthy women with bipolar disorder.

Interventions. The subjects received therapeutic doses of lithium administered as an immediate‐release capsule every 12 hours. In addition, they received one placebo tablet every 12 hours during phase I and flurbiprofen 100 mg every 12 hours during phase II of the study.

Measurements and Main Results. Steady‐state pharmacokinetic parameters were measured for each phase. Lithium trough plasma concentration (Cmin) and area under the curve were statistically significantly increased (p<0.05) when patients received flurbiprofen. Flurbiprofen also caused decreases in lithium clearance and 24‐hour lithium urine excretion, although the changes did not reach statistical significance. Clinically significant increases in Cmin appeared to be associated with a greater than 1000‐μg/24 hour decrease in urinary excretion of prostaglandin E2.

Conclusion. Patients with clinically normal renal function may experience an increase in lithium levels with the initiation of flurbiprofen therapy.
Patient Self‐Reporting of Compliance Does Not Correspond with Electronic Monitoring: An Evaluation Using Isosorbide Dinitrate as a Model Drug
Authors: Straka Robert J. , Fish Jeffrey T. , Benson Steven R. , Suh J. Thomas
Published: October 2023

Study Objective. To assess the accuracy of patient‐kept diaries relative to electronic monitoring of compliance with isosorbide dinitrate prescribed 3 times/day for ischemic heart disease.

Design. Unblinded, prospective, three‐phase study.

Methods. Patients with coronary artery disease prescribed isosorbide dinitrate 3 times/day were asked to record the time of administration of each dose in a pocket diary while being monitored for compliance with a computerized Medication‐Event Monitoring System (MEMS‐4) vial that electronically recorded the date and time the vial was opened.

Results. Sixty‐eight stable outpatients with documented coronary artery disease who were prescribed isosorbide dinitrate 3 times/day were evaluated. Based on a prospectively chosen definition including a nitrate‐free period, the mean (± SD) overall compliance rates were 71% (± 30) versus 55% (± 32) for the patient‐kept diaries and the MEMS vials respectively (p=0.001). The concordance between patient‐kept diaries and MEMS data indicate that 67% of patients overestimate their compliance when using a self‐recording tool. An average of 30% of diary entries were in error compared with the MEMS vial recordings.

Conclusions. Patient‐kept diaries statistically overestimate actual compliance relative to that determined by MEMS devices. Given the prevalence of the use of diaries as the predominant tool on which researchers depend to document compliance with study drugs, our findings suggest that this practice should be reevaluated specifically when the time of the dose and documentation of administration are critical to qualifying the outcome of drug therapy. Such is the case with isosorbide dinitrate use in patients with ischemic heart disease. Furthermore, the overall poor compliance documented in this study suggests that the utility of isosorbide dinitrate prescribed 3 times/day be reevaluated as a clinically effective antianginal drug.
Pharmacology of Leukotriene Receptor Antagonists and 5‐Lipoxygenase Inhibitors in the Management of Asthma
Authors: Drazen Jeffrey M.
Published: October 2023

The leukotrienes (LTs), a family of inflammatory mediators arising from the metabolism of arachidonic acid via the 5‐lipoxygenase pathway, are prominently implicated in the pathobiology of asthma. Two classes of LTs, the cysteinyl LTs (LTC4, LTD4, and LTE4) and the dihydroxy‐LT (LTB4) have been identified, with each class acting via distinct receptors. Inhibition of LT‐mediated inflammation can be achieved by either interruption of 5‐lipoxygenase action, thereby preventing formation of the LTs, or inhibition at specific LT receptor sites in the airway. Both the 5‐lipoxygenase inhibitors and the cysLT receptor antagonists have thus far demonstrated the capacity to improve pulmonary function and reduce symptoms in clinical models of asthma, such as exercise‐, aspirin‐, or antigen‐induced bronchoconstriction, and to improve pulmonary function in patients with mild‐to‐moderate, chronic stable asthma. The LTs are therefore critical effector molecules in some patients with asthma and important targets in the pharmacologic management of this disease.
Use of Allergen Bronchoprovocation to Screen Drugs for Anti‐Asthma Activity
Authors: Hendeles Leslie , Harman Eloise
Published: October 2023

In the atopic patient with asthma, allergens are an important cause of chronic airway inflammation and symptoms. Natural exposure to seasonal allergens, such as grass pollen, may result in exacerbation of asthma, increased airway responsiveness (i.e., increased susceptibility of the airways to constrict), and an increased frequency of emergency room visits. Removal of patients from exposure to indoor allergens, such as dust mites, results in a marked reduction in symptoms, less airway responsiveness, and a decrease in drug requirements. In the pulmonary function laboratory inhalation of increasing doses of allergen, in a safe and controlled manner (allergen bronchoprovocation), produces physiological responses similar to those observed after natural exposure. These include an immediate decrease in the forced expiratory volume in 1 second (FEV1) that is rapid in onset but short in duration (early response), a subsequent gradual decline in FEV1 4–8 hours after allergen inhalation that is sustained (late response), an increase in airway responsiveness, and infiltration of the airway mucosa by inflammatory cells. Drugs that are effective as maintenance therapy for chronic asthma generally attenuate the late response to allergen bronchoprovocation, and those with antiinflammatory effects (e.g., inhaled corticosteroids) also attenuate the allergen‐induced increase in airway responsiveness and cellular infiltration of the airways. However, the magnitude of drug effect in this clinical model does not correlate well with the drug's relative efficacy in chronic asthma. In contrast, drugs that have no effect in this clinical model, such as calcium channel blockers, ketotifen, and antihistamines, are ineffective as maintenance therapy for chronic asthma. Thus, it appears that allergen bronchoprovocation is most useful as a screening tool for excluding drugs that are unlikely to be effective for chronic asthma and for determining whether a drug has antiinflammatory and/or immunomodulatory actions on the airway mucosa.
The Use of 5‐Lipoxygenase Inhibitors and Leukotriene Receptor Antagonists in the Treatment of Chronic Asthma
Authors: Sorkness Christine A.
Published: October 2023

With the elucidation of asthma as a chronic inflammatory disease, therapeutic approaches have shifted from treatment of symptoms with bronchodilators to treatment of the underlying disease with antiinflammatory agents. Along with concerns about corticosteroid side effects on the part of both physicians and patients, this shift has motivated researchers to develop and test new agents with antiinflammatory capabilities. The leukotrienes are endogenous mediators with three inflammatory effects: they increase vascular permeability, recruit other inflammatory leukocytes, and induce bronchoconstriction. A number of antileukotriene agents are in various stages of development. Zileuton, a lukotriene synthesis inhibitor, has been shown to improve airway function and reduce asthma symptoms, although there is some concern over liver toxicity. Zafirlukast, montelukast, and pranlukast, three new leukotriene receptor antagonists, have similar benefits and have not been associated with serious increases in liver enzymes. It is hoped that new antiinflammatory drugs will provide clinicians with targeted and effective asthma treatments that do not bear the potential risks of corticosteroid therapy.
Advanced Cardiac Life Support Controversy: Where Do Antiarrhythmic Agents Fit In?
Authors: Chow Moses S.S.
Published: October 2023

Approximately half of all cardiovascular fatalities are attributable to sudden cardiac death, and the majority of sudden cardiac deaths result from ventricular fibrillation (VF). Antiarrhythmic agents are needed to manage refractory VF and ventricular tachycardia (VT); the primary reason for their administration is to prevent recurrence of VF and to abolish VT. The American Heart Association recommends lidocaine hydrochloride as a first‐line antiarrhythmic agent in the advanced cardiac life support (ACLS) setting, followed by bretylium tosylate. Although the newly approved intravenous antiarrhythmic agent, amiodarone hydrochloride, may potentially be effective in ACLS, studies are needed to document its clinical benefit in this setting. Such studies are currently under way to document this potential use.
An Overview of Cyclophosphamide and Ifosfamide Pharmacology
Authors: Fleming Ronald A.
Published: October 2023

Cyclophosphamide and ifosfamide are alkylating agents administered to treat malignant disease. They are prodrugs and require activation by hepatic microsomal enzymes before being metabolized to their respective cytotoxic species, phosphoramide mustard and ifosfamide mustard. These species alkylate DNA, forming DNA‐DNA cross‐links that result in inhibition of DNA synthesis and cell death. Resistance to oxazaphosphorines is poorly understood, although increased aldehyde dehydrogenase activity may be a significant factor. Although both compounds share a common metabolic pathway, 4‐hydroxylation of ifosfamide occurs at a slower rate and to a lesser extent than that of cyclophosphamide. This difference significantly alters the toxicity profile of ifosfamide. Leukopenia is the dose‐limiting toxicity of cyclophosphamide, and neurotoxicity is the dose‐limiting toxicity of ifosfamide when preventive measures are taken to reduce urotoxicity. With recent findings concerning their basic and clinical pharmacology, the therapeutic index of these compounds can be improved.
Pharmacokinetics of Pyrazinamide under Fasting Conditions, with Food, and with Antacids
Authors: Peloquin Charles A. , Bulpitt Amy E. , Jaresko George S. , Jelliffe Roger W. , James Gordon T. , Nix David E.
Published: October 2023

Study Objectives. To determine intrasubject and intersubject variability in, and the effects of food and antacids on, the pharmacokinetics of pyrazinamide (PZA).

Design. Randomized, four‐period, crossover phase I study.

Subjects. Fourteen healthy men and women volunteers.

Interventions. Subjects ingested single doses of PZA 30 mg/kg under fasting conditions twice, without a high‐fat meal and with an aluminum‐magnesium antacid. They also received standard dosages of isoniazid, rifampin, and ethambutol.

Measurements and Main Results. Serum was collected for 48 hours and assayed by gas chromatography with mass selective detector. Data were analyzed by noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: mean PZA Cmax 53.4 ± 10.4 μg/ml, Tmax 1.43 ± 1.06 hours, and AUC0‐∞, 673 ± 79.7 μg·hr/ml. Fasting results are similar to those in previous reports. In the presence of antacids, subjects had a mean Cmax of 55.6 ± 9.0 μg/ml, Tmax of 1.43 ± 1.23 hours, and AUC0‐∞ of 628 ± 88.4 μg·hr/ml. In the presence of the high‐fat meal, mean Cmax was 45.6 ± 9.44 μg/ml, Tmax 3.09 ± 1.74 hours, and AUC0‐∞ 687 ± 116 μg·hr/ml.

Conclusions. These small changes in Cmax. Tmax, and AUC0‐∞. can be avoided by giving PZA on an empty stomach whenever possible.

Conclusion: Serum concentrations in this study were consistent with those described previously. In addition, PZA's kinetic behavior was consistent between fasting treatments. Antacids and food had minimal effects on the agent's absorption. Samples drawn between 0.5 and 3 hours after dosing approached Cmax for most subjects, with 1 hour being closest. Samples drawn as early as day 2 of daily PZA therapy will produce serum concentrations that approach steady‐state values.
Acute Effects of Prechemotherapy Filgrastim Administration on Late Hematopoietic Progenitor Cells
Authors: Higa Gerald M.
Published: October 2023

Administration of filgrastim influences the proliferative kinetics of myeloid progenitor cells. Even after it is discontinued, increased levels of cycling of granulocyte precursors are sustained for approximately 4 days. Beginning chemotherapy during this period of enhanced marrow activity can cause great damage to late, and possibly early, progenitor cell pools. Peripheral blood samples were collected from two research study patients who were prospectively randomized to receive filgrastim by different schedules after chemotherapy. The mononuclear cell fraction was analyzed by clonogenic progenitor cell assay and flow cytometry. Ex vivo and clinical findings were correlated with filgrastim and chemotherapy administration times. Although quantitative recovery of circulating neutrophils occurred, a substantial decrease in peripheral blood progenitor cells was observed when chemotherapy was started 72 hours after cessation of filgrastim therapy. Neutrophil recovery alone is not a precise index of short‐term marrow granulocyte progenitor status. Starting chemotherapy within 72 hours of filgrastim therapy is biologically, and possibly, clinically relevant.
A Multicenter, Investigator‐Blinded, Randomized Comparison of Oral Levofloxacin and Oral Clarithromycin in the Treatment of Acute Bacterial Sinusitis
Authors: Adelglass Jeffrey , Jones Terry M. , Ruoff Gary , Kahn James B. , Wiesinger Barbara A. , Rielly‐Gauvin Katie , Siu Cynthia O.
Published: October 2023

A multicenter, investigator‐blinded, randomized, parallel‐group study was conducted to compare oral levofloxacin 500 mg once/day for 14 days with clarithromycin 500 mg twice/day for 14 days in the treatment of acute bacterial sinusitis. Of 216 adult outpatients randomized to treatment, 190 were evaluable for efficacy. The primary efficacy measure was clinical response, based on resolution of signs and symptoms 2–5 days after therapy. A secondary efficacy measure was relapse rate 1 month after therapy. Among evaluable patients, clinical success rates (cured or improved) were 96.0% and 93.3% for levofloxacin (L) and clarithromycin (C), respectively (95% CI −9.2%, 3.7%). The confidence interval (CI) for treatment difference (C‐L) included zero and its upper limit was less than 15%, indicating that levofloxacin was as effective as clarithromycin. In all, 4.1% of patients receiving levofloxacin and 7.2% receiving clarithromycin had a relapse of symptoms 1 month after therapy (95% CI −12.2%, 3.2%). Long‐term success (initial success, absence of relapse at 1 month, no further antibacterial therapy 2–5 days after therapy) was 79.2% in the levofloxacin group and 76.4% in the clarithromycin group (95% CI −14.7%, 9.0%). Based on investigator‐assessed treatment‐emergent adverse events, overall tolerability of the drugs was similar, except for a higher frequency of taste perversion and diarrhea in the clarithromycin group. Levofloxacin had an advantage over clarithromycin based on two quality‐of‐life (QOL) parameters: number of times taking other drugs for targeted medical conditions and mean total cost of these drugs. No statistical significance was found in other QOL variables. These findings suggest that the efficacy and tolerability of levofloxacin 500 mg once/day are comparable with those of clarithromycin 500 mg twice/day in the treatment of acute bacterial sinusitis.
Safety of GM‐CSF in Patients with AIDS: A Review of the Literature
Authors: Ross Susan D. , DiGeorge Angela , Connelly Janet E. , Whiting Gregory W. , McDonnell Neil
Published: October 2023

We performed a literature search for all clinical studies reporting outcomes in patients with the acquired immunodeficiency syndrome (AIDS) receiving granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) for any indication. Safety outcomes included human immunodeficiency virus replication, immune status, and frequency of opportunistic infections and neoplasms. Data were synthesized qualitatively. We identified 22 studies (274 patients): 12 addressed AIDS neutropenia, 8 AIDS cancer therapy, and 2 opportunistic infections. Viral burden was assessed by serum p24Ag in 15 studies. Nine reported no change in levels, three net decreases, and three net increases. All studies showing net increases involved patients receiving GM‐CSF without a concurrent antiretroviral. The CD4 counts were unchanged in 5 studies, increased in 3, and not reported in 14. The incidence of neoplasms or new opportunistic infections was low. The literature suggests no increased risk of viral replication or clinical deterioration in patients with AIDS who take GM‐CSF concurrently with zidovudine.
Safety Issues in the Pharmacologic Management of Chronic Pain in the Elderly
Authors: Shimp Leslie A.
Published: October 2023

Chronic pain is commonly encountered in elderly patients. About 20–50% of community‐dwelling elderly experience it, and 45–80% of nursing home residents may be affected. Selection of pharmacologic therapy for the management of chronic pain must take into consideration the increased potential for adverse effects in this population. Major classes of drugs used to treat chronic pain (nonsteroidal antiinflammatory drugs, opioids, antidepressants) have adverse effects that occur more frequently in elderly than in younger patients. Given the often prolonged duration of therapy, optimal management requires minimizing the risk of adverse reactions.
Interaction Between Tacrolimus and Nefazodone in a Stable Renal Transplant Recipient
Authors: Olyaei Ali J. , DeMattos Angelo M. , Norman Douglas J. , Bennett William M.
Published: October 2023

Tacrolimus (FK‐506) is an important immunosuppressive agent most often given for maintenance immunosuppression to prevent acute cellular organ rejection. A 57‐year‐old woman with end‐stage renal disease presumed secondary to chronic glomerulonephritis underwent a living related renal allograft transplantation. She tolerated the surgery well and was discharged on postoperative day 5. She was stabilized with prednisone, azathioprine, and tacrolimus. Two years after transplantation, nefazodone 50 mg twice/day orally was prescribed due to depression. After 1 week of nefazodone therapy the patient experienced headache, confusion, and “gray areas” in her vision, without abnormal ophthalmologic findings. Her serum creatinine was elevated to 2.2 mg/dl (baseline 1.5 mg/dl), and trough tacrolimus level was markedly elevated (> 30 ng/ml). Both tacrolimus and nefazodone are metabolized by the cytochrome P450 (CYP) 3A4 system. We suspect that nefazodone inhibits metabolism of tacrolimus. Coadministration of antidepressant agents such as nefazodone, or any other drug that inhibits the CYP3A4 isoenzyme subfamily, should be anticipated to interfere with tacrolimus metabolism. Monitoring blood concentrations of tacrolimus is vital, and appropriate dosage adjustments are required when the two drugs are administered concurrently to avoid serious interactions such as nephrotoxicity and neurotoxicity.
Peripheral Blood Progenitor Cell Transplantation: Economic Issues
Authors: Yee Gary C.
Published: October 2023

High‐dose chemotherapy with autologous hematopoietic stem cell rescue is an expensive procedure. It is associated with improved long‐term survival in many patients with cancer, but concern is growing about its cost and cost‐effectiveness. The cost‐effectiveness of high‐dose chemotherapy depends largely on the magnitude of the difference in survival between it and standard‐dose chemotherapy. Several economic analyses reported that the cost‐effectiveness ratio of high‐dose chemotherapy in the treatment of breast cancer is in the range of or slightly higher than that reported for other widely accepted medical interventions. Most centers are evaluating new strategies to reduce the overall cost of this therapy, including using peripheral blood progenitor cells rather than bone marrow‐derived stem cells, optimizing the collection of peripheral blood progenitor cells, and shifting care from the inpatient to the outpatient setting.
Peripheral Blood Progenitor Cell Transplantation: Impact on the Pharmacy Workload and Budget
Authors: Davis Thomas L.
Published: October 2023

Due to reduced engraftment times and significantly shortened hospitalizations, peripheral blood progenitor cell (PBPC) transplantation has reduced the costs associated with autologous transplantation. Several institutions reported a reduction of 20–50% in transplantation cost using PBPCs and an aggressive outpatient program. These savings could be offset by hospital readmissions, but improvements in supportive care such as administration of colony‐stimulating factors and broad‐spectrum oral antibiotics, and assigning a 24‐hour caregiver as a prerequisite for transplantation enable safe performance of outpatient transplantation and limit readmission rates to about 20–40%. At this institution, the effect of this program on the pharmacy has been a shift in staff and drug costs to outpatient cost centers. The transition from inpatient to outpatient care did not necessitate a greater investment in pharmacy staffing, but did require cross‐training for inpatient and outpatient pharmacists. Future management of outpatient transplantation will apply a cooperative care philosophy that will rely to a large extent on patient care by family members and on a multidisciplinary model of seamless care.
Population Pharmacokinetics of Carbamazepine in Adults with Epilepsy
Authors: Graves Nina M. , Brundage Richard C. , Wen Yandong , Cascino Greg , So Elson , Ahman Peter , Rarick John , Krause Sandra , Leppik Ilo E.
Published: October 2023

Study Objective. To conduct a population pharmacokinetic analysis of carbamazepine (CBZ).

Design. Retrospective chart review.

Setting. Ambulatory neurology clinics at three medical centers.

Patients. Patients diagnosed with epilepsy from 1991–1995. The index set included 829 adults receiving CBZ. A separate validation set consisted of 50 patients.

Interventions. None.

Measurements and Main Results. Final regression equations were apparent oral clearance (Cl/F) (L/hr) = (0.0134 • TBW + 3.58), • 1.42 if receiving phenytoin only; • 1.17 if receiving phenobarbital or felbamate; • 1.62 if receiving phenytoin and phenobarbital or felbamate; • 0.749 if age ≥ 70 years; apparent volume of distribution (Vd/F) (L) = 1.97 • total body weight; absorption rate constant (hr−1) = 0.441. Interindividual variability in Cl/F and Vd/F was 26% and 82%, respectively. Residual variability was 1.8 mg/L. Predictive performance analysis of the validation set provided a mean prediction error of 0.6 mg/L and median absolute error of 2.4 mg/L.

Conclusions. These routinely collected data provided quantitative estimates of changes in CBZ Cl/F due to comedication and an age‐related decrease in Cl/E The derived regression equations reasonably predicted concentrations in a separate validation set.
Cyclosporine Trough Concentrations in Predicting Allograft Rejection and Renal Toxicity up to 12 Months after Renal Transplantation
Authors: Min David I. , Perry Paul J. , Chen Hsiang‐Yin , Hunsicker Lawrence G.
Published: October 2023

Study Objective. To evaluate the utility of cyclosporine (CsA) trough concentrations as a monitoring tool for acute graft rejections and CsA nephrotoxicity.

Design. Retrospective chart review.

Setting. University‐affiliated teaching hospital.

Patients. One hundred thirty‐seven adults who had undergone kidney transplantation.

Measurements and Main Results. Clinical data extracted from the charts were CsA dosage, CsA trough levels (whole blood, HPLC method), biopsy findings to confirm acute rejections, and serum creatine to determine clearance by the Jelliffe method. Data were collected at up to 1 month, between 1 month and 3 months, and between 3 and 12 months after transplantation. For each time period, receiver's operating characteristics curves were generated to identify the optimum CsA concentration for avoiding acute rejection and CsA nephrotoxicity. At up to 1 month, the CsA therapeutic response threshold was 182 ng/ml (sensitivity 69%, specificity 84%, p < 0.0001) and toxicity threshold for CsA nephrotoxicity was 204 ng/ml (sensitivity 89%, specificity 56%, p < 0.0001). Between 1 month and 3 months, the respective figures were 175 ng/ml (sensitivity 58%, specificity 89%, p < 0.0002) and 189 ng/ml (sensitivity 87%, specificity 65%, p < 0.0001). Between 3 and 12 months, the CsA therapeutic response threshold decreased to 135 ng/ml (sensitivity 56%, specificity 40%, p > 0.1) and the toxicity threshold for CsA nephrotoxicity remained relatively static at 204 ng/ml (sensitivity 100%, specificity 14%, p < 0.0001).

Conclusion. Early in CsA therapy it is essential to prevent graft rejection. Drug concentrations exceeding approximately 182 ng/ml threshold accomplish this goal. Later, successful therapy demands that CsA nephrotoxicity be avoided. This goal is accomplished by not exceeding a CsA concentration of 204 ng/ml.
Relative Bioavailability of Ondansetron 8‐mg Oral Tablets versus Two Extemporaneous 16‐mg Suppositories: Formulation and Gender Differences
Authors: Jann Michael W. , ZumBrunnen Troy L. , Tenjarla Srini N. , Ward Earl S. , Weidler Donald J.
Published: October 2023

Study Objective. To compare the relative bioavailability of two 16‐mg extemporaneously prepared suppository formulations with that of an 8‐mg commercially available oral tablet.

Design. Prospective, crossover bioavailability study.

Setting. Inpatient clinical research center.

Subjects. Sixteen young, nonsmoking, healthy volunteers.

Interventions. Blood samples were obtained 24 and 48 hours after administration of an 8‐mg oral ondansetron tablet and 16‐mg suppository, respectively. Two 16‐mg suppository formulations were compounded using commercially available Fattibase and Polybase.

Measurements and Main Results. Ondansetron was well absorbed by both routes of administration. The following pharmacokinetic parameters (mean ± SEM) were obtained for the 8‐mg tablet, 16‐mg Fattibase suppository, and 16‐mg Polybase suppository, respectively: area under the curve (AUC) in men 154.2 ± 21.77, 253.4 ± 72.3, 304.8 ± 62.2 ng·hr/ml; AUC in women 353.6 ± 32.7, 561.6 ± 103.6, and 768.7 ± 117.9 ng·hr/ml; maximum concentration (Cmax) in men 45.5 ± 7.0, 40.6 ± 10.4, and 51.2 ± 6.7 ng/ml; Cmax in women 51.4 ± 4.8, 47.1 ± 3.9, and 82.9 ± 6.6 ng/ml. Times to Cmax (Tmax; mean ± SEM) for men were 1.5 ± 0.3, 4.4 ± 0.5, and 2.9 ± 0.3 hours; Tmax for women were 1.8 ± 0.3, 4.1 ± 0.4, and 4.4 ± 0.6 hours for the three formulations, respectively. Women had a consistently higher AUC for all three formulations than men (p < 0.05).

Conclusion. With the exception of the 16‐mg Polybase formulation in women, the two suppositories closely approximated the pharmacokinetics of the 8‐mg oral tablet. These results suggest that gender may be a significant factor in ondansetron's disposition.
The Cost‐Effectiveness of a Clinical Pharmacist Intervention Among Elderly Outpatients
Authors: Cowper Patricia A. , Weinberger Morris , Hanlon Joseph T. , Landsman Pamela B. , Samsa Gregory P. , Uttech Kay M. , Schmader Kenneth E. , Lewis Ingrid K. , Cohen Harvey J. , Feussner John R.
Published: October 2023

We estimated the cost and cost‐effectiveness of a clinical pharmacist intervention known to improve the appropriateness of drug prescribing. Elderly veteran outpatients prescribed at least five drugs were randomized to an intervention (105 patients) or control (103) group and followed for 1 year. The intervention pharmacist provided advice to patients and their physicians during all general medicine visits. Mean fixed and variable costs/intervention patient were $36 and $84, respectively. Health services use and costs were comparable between groups. Intervention costs ranged from $7.50–30/patient/unit change in drug appropriateness. The cost to improve the appropriateness of drug prescribing is thus relatively low.
Rifampin, a Useful Drug for Nonmycobacterial Infections
Authors: Vesely Josef J. K. , Pien Francis D. , Pien Brian C. T.
Published: October 2023

Rifampin has clinical efficacy against a wide variety of organisms, including Staphylococcus aureus, Legionella pneumophila, group A Streptococcus, Brucella sp, Haemophilus influenzae, and Neisseria meningitidis, as well as in vitro activity against penicillin‐resistant Streptococcus pneumoniae, Neisseria gonorrhoeae, Chlamydia trachomatis, Haemophilus ducreyi, and many gram‐negative rods. Rifampin is a useful drug for several types of bacterial infections because of its broad spectrum of activity, excellent tissue penetration, and low side effect profile. In combination with other antibiotics, it may be effective when conventional therapies are not.
Serotonin Syndrome Secondary to Phenelzine‐Venlafaxine Interaction
Authors: Weiner Laura A. , Smythe Maureen , Cisek James
Published: October 2023

A 44‐year‐old woman accidentally ingested phenelzine along with venlafaxine. Thirty minutes after the ingestion the woman began to feel nauseous and anxious. Approximately 45 minutes later a friend noted that the woman had lower extremity shaking and increasingly rapid respirations. The friend brought the woman to the emergency department and she was subsequently diagnosed with serotonin syndrome. Serotonin syndrome is usually precipitated by combinations of serotonin‐potentiating agents and can lead to devastating outcomes. When using combinations of drugs that elevate serotonin levels in the central nervous system, the possibility of serotonin syndrome should be considered.
Famotidine‐Associated Mental Status Changes
Authors: Rodgers Philip T. , Brengel George R.
Published: October 2023

A 77‐year‐old man who had taken ranitidine for several years for dyspepsia was prescribed alternative therapy with famotidine 20 mg twice/day. He subsequently developed mental status changes, with confusion, disorientation, and nightmares. The symptoms dissipated after he discontinued famotidine for 2 days. He rechallenged himself and experienced return of the symptoms shortly thereafter, with additional visual hallucinations. His therapy was changed to lansoprazole, and his symptoms again disappeared and have not recurred. Case reports of central nervous system effects with other histamine2 antagonists have been published. Eight cases occurred with famotidine, all of which were in hospitalized patients receiving intravenous famotidine. We believe this is the first report of mental status changes in an ambulatory patient taking oral famotidine. The elderly may be particularly susceptible to such changes.
Octreotide‐Induced Bradycardia
Authors: Herrington Annie M. , George Kevin W. , Moulds Christine C.
Published: October 2023

Because of deleterious hemodynamic effects of octreotide in a nonacromegalic patient with a pancreatic fistula, we conducted a MEDLINE search of English‐language journal articles to extract information on this complication of octreotide or somatostatin therapy. Few data are available regarding patients with disease states other than acromegaly. We believe octreotide should be considered when determining the cause of bradycardia.
Metrifonate: Overview of Safety and Efficacy
Authors: Cummings Jeffrey L.
Published: October 2023

Metrifonate is a cholinesterase inhibitor with a long‐lasting inhibition that raises brain acetylcholine levels. It is well‐absorbed and has limited binding to serum proteins. In preliminary studies of its utility in the treatment of Alzheimer disease's (AD), it led to improvements of cognition or reduced the rate of decline of cognition compared with placebo. It also benefited the global function of these patients. Side effects include nausea, cramping, and diarrhea. Metrifonate has promise as a well‐tolerated treatment of the symptoms of AD.
Pharmacokinetics and Drug Interactions of Cholinesterase Inhibitors Administered in Alzheimer's Disease
Authors: Crismon M. Lynn
Published: October 2023

Cholinesterase inhibitors are the first agents to be successfully developed specifically for the treatment of cognitive decline associated with Alzheimer's disease. Basic knowledge of their pharmacokinetics is important to their appropriate administration. Their pharmacokinetics help determine the magnitude and duration of their pharmacologic effects, and also the manner in which they affect the degree of cholinesterase inhibition and recovery. The clinical utility of measuring these values in daily practice awaits further research. Drug interactions with cholinesterase inhibitors may occur by pharmacokinetic or pharmacodynamic mechanisms. For the most part, interactions that are mediated by the hepatic cytochrome P‐450 system have been inadequately evaluated.
The High Cost of Stroke to Society, the Family, and the Patient
Authors: Horner Ronald D.
Published: October 2023

Stroke is the third leading cause of mortality in the United States, after heart disease and cancer, and is a major cause of adult disability. Stroke‐related neurologic deficits affect language, cognition, and motor function. They are often persistent, exerting a negative effect on the patient's quality of life. Besides affecting the patient, stroke also places a heavy emotional burden on the caregivers of patients with stroke. In the United States, the medical and nonmedical costs of caring for patients with stroke during the first year after their stroke are $30 billion/year, or approximately $50,000/patient. Many strokes are preventable, however, through judicious medical or surgical therapies. In addition, emerging thrombolytic and neuroprotective drugs, administered early after stroke onset, may minimize or eliminate some of the residual deficits associated with stroke. A massive educational effort is needed to raise public and professional awareness about stroke and emerging stroke therapies.