bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding Disturbance Regimes from Patterns in Forest Biomass
Authors: Wang Siyuan , Yang Hui , Koirala Sujan , Forkel Matthias , Reichstein Markus , Carvalhais Nuno
Published: October 2023

Natural and anthropogenic disturbances are important drivers of tree
mortality, shaping the structure, composition, and biomass distribution
of forest ecosystems. Differences in disturbance regimes, characterized
by the frequency, extent, and intensity of disturbance events, result in
structurally different landscapes. Characterizing different disturbance
regimes through landscape-scale forest structure provides a unique
perspective for diagnosing the impacts and potential carbon-climate
feedbacks from terrestrial ecosystems. In this study, we design a
model-based experiment to investigate the links between disturbance
regimes and spatial biomass patterns. We generate over 850 thousand
biomass patterns, from 2,142 combinations of μ, α, and
β under different primary productivity and background mortality
scenarios. We characterize the emergent biomass patterns via synthesis
statistics, including central tendency statistics; different moments of
the distribution; information-based and texture features. We further
follow a multi-output regression approach that takes the biomass
synthesis statistics and gross primary production (GPP) as independent
variables to retrieve the three disturbance regimes parameters. Results
show confident inversion of all three “true” disturbance parameters,
with Nash-Sutcliffe efficiency of  94.8% for μ, 94.9% for
α, and 97.1% for β. Overall, these results demonstrate
the association between biomass patterns and disturbance statistics that
emerge from different underlying disturbance regimes. By doing so, it
overcomes the known issue of equifinality between mortality rates and
total biomass. Given the increasing availability of Earth observation of
biomass, our findings open a new avenue to better understand and
parameterize disturbance regimes and their links with vegetation
dynamics under climate change. Ultimately, at a large scale, this
approach would improve our current understanding of controls and
feedback at the biosphere-atmosphere interface in the current Earth
system models.
A cross‐layer routing approach for MANET‐assisted IoT applications
Authors: Quy Vu Khanh , Van Anh Dang , Ban Nguyen Tien , Quy Nguyen Minh , Jeon Gwanggil
Published: October 2023

The Internet of things (IoT) is a concept that allows all things such as sensors, actuators, humans, platforms, and software to interact with others relying on Internet infrastructure. The launch of the 5th generation communication networks allows providing network services with extremely high performance aiming to realize IoT concepts and forming a series of other smart IoT ecosystems. Nowadays, IoT is emerging as a dominant technology in almost domain. One of the most crucial technologies forming IoT networks is device‐to‐device (D2D) communication. D2D technology allows mobile nodes self‐setup, and self‐config to identify optimal paths for data transmission without relying on pre‐installed infrastructure, which is the principle of forming mobile ad‐hoc networks (MANETs). The fusing of MANETs and IoT technologies forming MANET‐assisted IoT networks architecture to provide abilities and novel unpredict services. However, mobility and network structure often change are the main limitations of this architecture, hence, identifying the optimal route is a significant challenge. In this study, we propose a cross‐layer routing approach for MANET‐assisted IoT networks. Our routing mechanism is based on considering three factors, including number of hops, link quality, and queue length. The simulation results show that our proposed solution improves performance compared to the traditional solutions. We hope that our simple and efficient solution will be applied popular for future MANET‐assisted IoT networks.
Assessing the environmental impacts of copper cathode production based on life cycle assessment
Authors: Shahraki Hamed , Einollahipeer Fatemeh , Abyar Hajar , Erfani Malihe
Published: October 2023

The demand for copper is growing considerably in parallel with economic and technological development. The rate increase in copper consumption in Iran increases pressure on the numerous unexploited mines in southeast Iran and causes the environmental crisis alongside the northern Levar wind in this area. Given this, this study systematically explored the environmental impacts of a one-ton copper cathode processing operation from a cradle-to-gate perspective, using life cycle assessment (LCA). Moreover, the release of greenhouse gases and the energy consumption during the copper cathode production were also assessed. The results indicated that sulfuric acid use in the smelting and extraction stages, metal leaching from tailings, and CO2 dominated more than 50% of contributions to freshwater and marine ecotoxicity, human toxicity, and global warming. The energy analysis revealed 88.92% of crude oil use especially for the electrowinning stage, which should be promoted technologically. For global warming, the indirect CO2 emission from electricity consumption using fossil fuels was the main contributor (94.56%). Therefore, shifting from conventional energy systems to renewable energy systems could alleviate the overall environmental impact. For a 0.57-ton sulfuric acid effluent per one ton of copper cathode production, its treatment and reuse in the process is recommended. Summing up, the results of this study provide the environmental hot spots for copper cathode production for further investigation. Integr Environ Assess Manag 2024;20:1180–1190. © 2023 SETAC

Key Points

Copper cathode production was analyzed from life cycle assessment (LCA) and energy perspectives. Sulfuric acid use in the smelting and extraction stages was the main contributor. Most environmental impacts applied to water ecotoxicity and human toxicity. The indirect CO2 emission from electricity consumption intensified global warming.
Overview of Cost‐Consequence Modeling in Outcomes Research
Authors: Stergachis Andy
Published: October 2023

Outcomes research has developed in response to the need for information on costs, risks, and benefits of clinical treatments, including data regarding the effectiveness of prescription drugs. It attempts to consider more than the biologic effects of pharmaceuticals, that is, to encompass wider measures of the results of their use, issues that are not routinely addressed during clinical trials. Cost‐effectiveness analysis compares the outcome of different treatment options in terms of monetary cost per unit of effectiveness. Examples of measures of effectiveness are years of life saved, number of days of hospitalization avoided, and number of treatment successes. Cost‐consequence models, also referred to as cost‐outcome models, deal with costs and a variety of outcomes ranging from clinical to humanistic. Direct medical costs are those for prevention, detection, treatment, and rehabilitation; they are amounts spent to treat an illness, including hospitalization, professional services, pharmaceuticals, and medical supplies. Indirect medical costs are associated with changes in productivity, such as earnings lost because of illness. Humanistic outcomes deal primarily with functional status, quality of life, and satisfaction, and may include pain, anxiety, self‐esteem, ability to carry out normal activities, and overall impressions. Since it is not possible to study all effects of treatments with clinical trials, modeling techniques are useful in making therapeutic decisions.
Insights into Mechanisms of Cisplatin Resistance and Potential for Its Clinical Reversal
Authors: Gosland Michael , Lum Bert , Schimmelpfennig Julia , Baker James , Doukas Michael
Published: October 2023

Cisplatin in combination with other cytotoxic agents is the backbone for a potential cure of testicular germ cell neoplasms and is a critical factor in the substantial activity observed in the treatment of small cell lung cancer, bladder cancer, and ovarian germ cell tumors. Resistance to cisplatin at the onset of treatment or at relapse limits its curative potential, however. Laboratory studies using both cells selected for cisplatin resistance by exposure to sublethal concentrations and biopsy specimens from patients' tumors provide insights for the potential mechanisms of resistance. The mechanisms identified in vitro include a complex and wide array of related and unrelated pathways such as alterations in cellular drug transport, enhanced DNA repair dependent and independent of signal transduction pathways, and enhanced intracellular detoxification such as glutathione and metallothionein systems. Studies of these mechanisms have identified a number of agents with known potential for administration to humans and that reverse cisplatin resistance in vitro; for example, reversal of cellular accumulation defects by dipyridamole; inhibition of DNA repair by hydroxyurea, pentoxifylline, and novobiocin; inhibition of the glutathione system by ethacrynic acid and buthionine sulfoximine; and inhibition of signal transduction pathways by cyclosporine, tamoxifen, and calcium channel‐blocking agents. Current phase I clinical trials are focusing on the most effective doses and schedules to administer these agents in combination with cisplatin. Initial uncontrolled trials in limited numbers of patients suggest that the addition of modulators of cisplatin has the potential to reverse resistance in patients previously failing therapy. Another promising avenue for circumventing cisplatin resistance is the development of noncross‐resistant platinum analogs.
Active Immunization in HIV‐infected Patients
Authors: Pau Alice K. , McNicholl Ian R. , Pursell Kenneth J.
Published: October 2023

Patients infected with human immunodeficiency virus (HIV) are at risk for various viral and bacterial infections. Active immunization with currently available vaccines may reduce the risk of some vaccine‐preventable diseases in this population. Based on available data, most vaccines used in the United States are safe in HIV‐infected adults and children. Their clinical efficacy in these individuals is not well defined, although it appears that patients in the earlier stages of infection are more likely to mount a protective antibody response than those in the later stages. Current guidelines for vaccination in HIV‐infected children and adults in the United States have been recommended by the Advisory Committee on Immunization Practices.
Therapeutic Options for the Management and Prevention of Mycobacterium Avium Complex Infection in Patients With the Acquired Immunodeficiency Syndrome
Authors: Tartaglione Teresa A.
Published: October 2023

Atypical mycobacteria that cause disseminated disease result in significant morbidity and mortality among patients with advanced human immunodeficiency viral infection. Although significant progress has been made with respect to our understanding of the epidemiology, microbiology, and pathogenesis of Mycobacterium avium complex (MAC) infections in patients with the acquired immunodeficiency syndrome (AIDS), treatment and prevention strategies are still emerging. A series of case‐controlled studies and clinical trials evaluated various combinations of traditional and investigational antimycobacterial agents, and demonstrated modest clinical and microbiologic success in the treatment of disseminated MAC infection. Prevention studies proved rifabutin and clarithromycin to be rational prophylaxis agents. Continued identification of optimum combination regimens remains essential to curtail the increasing frequency of disseminated MAC disease in patients with AIDS.
Metformin in Noninsulin‐Dependent Diabetes Mellitus
Authors: Lee Audrey Jade
Published: October 2023

Metformin is an oral antihyperglycemic agent that is approved by the Food and Drug Administration for the treatment of noninsulin‐dependent diabetes mellitus. It differs from the sulfonylureas in that it is does not enhance insulin secretion and normally does not produce hypoglycemia. Metformin acts to decrease preprandial and postprandial blood glucose concentrations by increasing skeletal muscle uptake of glucose, decreasing gluconeogenesis, and decreasing absorption of glucose. The addition of metformin to maximum dosages of a sulfonylurea may synergistically improve glucose control. The drug may offer other potential benefits, such as weight loss or minimal weight gain, improved blood flow in patients with peripheral vascular disease, reduction of tissue plasminogen activator inhibitor, and improved lipid profiles. It is relatively safe if taken appropriately. Its most common side effects are gastrointestinal (nausea, diarrhea, anorexia), metallic taste, and vitamin B12 malabsorption. Lactic acidosis may also occur, but it is rare if metformin is avoided in patients with contraindications to its use. With careful monitoring, the agent may be considered for the initial treatment of obese patients who fail dietary measures, and those whose disease is refractory to maximum dosages of sulfonylureas or who do not tolerate them.
The Effect of Cocaine on Ventricular Fibrillation Threshold in the Normal Canine Heart
Authors: Tisdale James E. , Shimoyama Hisashi , Sabbah Hani N. , Webb Charles R.
Published: October 2023

We determined the effect of cocaine on ventricular vulnerability to fibrillation, as measured by ventricular fibrillation threshold (VFT), and cardiac electrophysiology in 20 anesthetized dogs with normal hearts. Animals were randomized in blinded fashion to receive a continuous 3‐hour infusion of cocaine 0.11 mg/kg/minute (total dose 20 mg/kg) or placebo (lactose dissolved in normal saline). The VFT, systolic and diastolic blood pressures, ventricular effective refractory period (ERP), and electrocardiographic intervals were measured at baseline and every 30 minutes during infusion. Baseline mean ± SE VFT in cocaine and placebo groups was 57.0 ± 7.8 and 51.8 ± 7.6 må, respectively (p=0.64). Cocaine did not significantly decrease VFT, but actually increased it (i.e., reduced ventricular vulnerability to fibrillation) compared with placebo (84.6 ± 10.4 vs 55.8 ± 7.2 må, respectively, at 150 minutes, p=0.04). Cocaine prolonged ERP and PR, QRS, QT, QTc, JT, and JTc intervals. Cocaine does not increase ventricular vulnerability to fibrillation in anesthetized dogs with normal intact hearts. Its electrophysiologic effects are similar to those of class I antiarrhythmic agents in this model.
Electrophysiologic and Electrocardiographic Pharmacodynamics of Cocaine
Authors: Tisdale James E. , Ducharme Murray P. , Shimoyama Hisashi , Webb Charles R. , Sabbah Hani N. , Edwards David J.
Published: October 2023

To determine and describe relationships between plasma cocaine concentrations and electrophysiologic and electrocardiographic effects, 10 anesthetized dogs with normal intact hearts received a continuous 3‐hour infusion of cocaine 0.11 mg/kg/minute (total dose 20 mg/kg). Data were collected as part of a randomized, blinded, placebo‐controlled study investigating the effects of cocaine on ventricular fibrillation threshold. Every 30 minutes during infusion of cocaine or placebo and for 3 hours after discontinuation of the infusion, heart rate and mean arterial pressure were determined, effective refractory period (ERP) was measured, and QRS duration and PR, QTc, and JTc intervals were recorded. At the time of each 30‐minute measurement, arterial blood was obtained to determine plasma cocaine concentrations. Hysteresis curves were observed for cocaine‐induced increases in ERP and PR interval. The effects of cocaine on QRS duration and QTc and JTc intervals were not well described by tested models. Pharmacodynamic modeling techniques may be used to describe relationships between plasma cocaine concentrations and specific cardiovascular effects of cocaine. Further study is required to determine applicability of this model for prediction of cocaine's cardiovascular effects in humans.
Clearance of Ticarcillin‐Clavulanic Acid by Continuous Venovenous Hemofiltration in Three Critically Ill Children, Two With and One Without Concomitant Extracorporeal Membrane Oxygenation
Authors: Lindsay Christine A. , Bawdon Roger , Quigley Raymond
Published: October 2023

Three children were receiving ticarcillin‐clavulanic acid by continuous venovenous hemofiltration (CVVH). Two of them were also receiving concomitant extracorporeal membrane oxygenation (ECMO). We collected ultrafiltrate hourly to determine the clearance of ticarcillin‐clavulanic acid by CVVH. Serum concentrations were also determined at the midpoint of each ultrafiltrate collection. All samples were collected over one dosing interval. The volume of distribution of ticarcillin and clavulanic acid was 0.26. ± 0.01 and 0.69 ± 0.23 L/kg, respectively. Total body clearance of ticarcillin, determined from the elimination rate constant and volume of distribution, was 0.038 ± 0.003 L/kg/hour and for clavulanic acid was 0.18 ± 0.03 L/kg/hour. The sieving coefficients for ticarcillin and clavulanic acid were 0.83 ± 0.11 and 1.69 ± 0.19, respectively. We attempted to estimate the clearances by ECMO, but the result was uninterpretable.
Effective Treatment of Narcolepsy with Codeine in a Patient Receiving Hemodialysis
Authors: Benbadis Selim R.
Published: October 2023

A 64‐year‐old man with narcolepsy could not take stimulant drugs due to coronary heart disease. In the past he noted improvement in alertness when taking codeine for pain, but this was eventually discontinued. After he developed end‐stage renal disease, and because the use of stimulants in this setting may be difficult, treatment with codeine was again initiated. This resulted in dramatic improvement in alertness and substantial reduction of cataplexy. Because it is simple to use and familiar to most physicians, codeine may be the drug of choice for narcoleptic patients who are undergoing hemodialysis.
The Pharmacologic Effects of Recombinant, Human Colony‐Stimulating Factors and Their Modulation by Theophylline
Authors: Petros William P. , Rosner Gary L. , Rabinowitz Josh , Gilbert Colleen J. , Coniglio David , Vredenburgh James J. , Ross Maureen , Peters William P.
Published: October 2023

Study Objectives. To investigate the effect of colony‐stimulating factors (CSFs) on drug metabolism using theophylline as a substrate (phase I), and to evaluate the influence of theophylline on endogenous serum cytokine concentrations (phase II).

Design. Open‐label, prospective study.

Setting. The bone marrow transplant unit of a tertiary university teaching hospital.

Patients. Thirty‐seven women with breast cancer (28 phase I, 9 phase II).

Interventions. Patients received aminophylline 0.58 mg/kg either as a 30‐minute intravenous infusion before receiving recombinant CSFs or after several days of CSF therapy, just before high‐dose chemotherapy (phase I) or as a continuous intravenous infusion after bone marrow transplantation (phase II).

Measurements and Main Results. Clearance of theophylline was significantly higher after CSF administration (0.76 vs 0.99 ml/min/kg, p=0.019). Continuous infusion of aminophylline resulted in elevations of serum macrophage‐CSF and interleukin‐6.

Conclusions. Administration of CSFs before autologous bone marrow transplantation for priming progenitor cells may alter drug metabolism. Studies should be conducted to evaluate the potential effects of CSFs on the disposition of chemotherapeutic agents.
Prospective Evaluation of Two Dosing Equations for Theophylline in Premature Infants
Authors: Bhatt‐Mehta Varsha , Donn Steven M. , Schork M. Anthony , Reed Susan , Johnson Cary E.
Published: October 2023

Study Objectives. To evaluate prospectively the ability of two equations that we previously derived to predict maintenance theophylline dosages that provide a serum theophylline concentration (STC) of 8 μg/ml, the midtherapeutic range for treating apnea of prematurity; and to determine the number of further dosage adjustments and STC determinations required to achieve the target concentration in infants in whom it was not achieved initially.

Design. Prospective study.

Setting. A 37‐bed neonatal intensive care unit.

Patients. Fifty‐four infants 27–34 weeks' gestational age requiring intravenous hydrous aminophylline.

Interventions. Patients received a loading dose of 6 mg/kg intravenous aminophylline, followed by a maintenance dosage calculated using one of the two derived equations. The basis for equation selection was the gestational age of the patient.

Measurements and Main Results. Patients were stratified into two age groups: 27–30 weeks' gestational age (34 infants) and 31–34 weeks' gestational age (20 infants). The overall success rate for both equations in achieving the target concentration was 74%. When infants were stratified by gestational age, those dosed by Equation 1 had a 76% success rate and those dosed by Equation 2 had a 65% success rate. Overall, 14 of 54 infants received an average of 1.2 dosage adjustments. This represents more than a 50% reduction in the number of adjustments made before introduction of these equations.

Conclusions. The ability of our previously derived equations to produce an STC within the midtherapeutic range for treating apnea of prematurity was demonstrated in the majority of patients studied (74%). Further, the number of subsequent dosage adjustments required to attain the target STC in infants who had failed to achieve this STC initially was significantly less than using older, more traditional regimens.
New Pharmacologic Strategies for Acute Neuronal Injury
Authors: Luer Mark S. , Rhoney Denise H. , Hughes Melody , Hatton Jimmi
Published: October 2023

The number of new drugs for treating neurotrauma is rapidly expanding. Emerging theories regarding the mechanisms of secondary neuronal injury provide the scientific basis for evaluating these new agents. Some of the most promising mechanisms for intervention are ionotropic channel antagonism, inhibition of lipid peroxidation, and neurotrophic factor augmentation. Many of these new agents are undergoing clinical trials to establish their roles in therapy.
Treating Allergic Rhinitis with Second‐Generation Antihistamines
Authors: Nightingale Charles H.
Published: October 2023

Allergic rhinitis afflicts close to 40% of the nation's population and costs more than $1.8 billion a year. The toll exacted by this disorder has been greatly alleviated by nonsedating second‐generation antihistamines loratadine, terfenadine, and astemizole. The three agents effectively reduce symptoms without the sometimes intolerable adverse effects of older drugs, but they are not completely equivalent. For example, terfenadine requires twice/day dosing, whereas the others can be given once/day. Astemizole has a slow onset and extremely prolonged duration of action. Both terfenadine and astemizole may have cardiotoxic effects (e.g., torsades de pointes) when serum concentrations rise due to overdosing or drug interactions. Cetirizine, a recently approved second‐generation antihistamine, has sedative and anticholinergic effects, although to a lesser degree than the first‐generation antihistamines.
Pharmacoeconomics of Aztreonam‐Clindamycin versus Gentamicin‐Clindamycin in the Treatment of Penetrating Abdominal Injury
Authors: Fabian Timothy C. , Boucher Bradley A. , Croce Martin C.
Published: October 2023

Study Objective. To evaluate the pharmacoeconomic implications of using aztreonam‐clindamycin (A‐C) versus gentamicin‐clindamycin (G‐C) from the perspective of the hospital and pharmacy directors.

Design. Pharmacoeconomic analysis performed at one of the sites participating in the prospective, randomized, double‐blind, comparative, multicenter efficacy study.

Setting. Referral hospital with level 1 trauma center.

Patients. Eight‐five adults with a suspected penetrating intraabdominal injury requiring laparotomy.

Interventions. Patients were randomized to receive aztreonam 2 g intravenously every 8 hours or gentamicin 2 mg/kg intravenous load followed by 5 mg/kg/day intravenously initially adjusted to peak concentrations of 6–8 μg/ml. All patients received clindamycin 900 mg intravenously every 8 hours.

Measurements and Main Results. Charge data were gathered from the hospital billing system and converted to cost data using an institutional cost:charge ratio of 0.6. Study drug and aminoglycoside monitoring costs were also calculated. Overall, 43 (97%) of 44 patients receiving A‐C had a favorable clinical response compared with 35 (85.4%) of 41 receiving G‐C (p=0.052). The mean hospital cost of $66,336 for 7 infected patients was significantly higher than that of $8014 in 78 noninfected patients (p>0.0001). Mean hospital costs of $12,058 and $13,742 for A‐C and G‐C groups, respectively, were not significantly different (p<0.05) despite having only a single failure (total cost $162,666) in the A‐C group. Similarly, mean pharmacy costs of $1411 and $1604, respectively, were not significantly different (p>0.05).

Conclusions. Hospital costs for infected patients with penetrating abdominal trauma exceed those of noninfected patients by 5‐fold. Despite a lower infection rate in the A‐C group, neither hospital nor pharmacy costs were significantly different compared with those in the G‐C group.
Influence of Grapefruit Juice on Caffeine Pharmacokinetics and Pharmacodynamics
Authors: Maish William A. , Hampton Edward M. , Whitsett Thomas L. , Shepard Jack D. , Lovallo William R.
Published: October 2023

The influence of grapefruit juice (GFJ) on caffeine's metabolism and the hemodynamic effects of this potential food interaction were studied in 10 normotensive volunteers. In this crossover study, caffeine (3.3 mg/kg) and water or caffeine and GFJ were given to participants. Nine serum caffeine concentrations were determined within 24 hours of each phase. In another phase of this study, caffeine was given with multiple GFJ doses to 6 of the 10 participants. Ambulatory blood pressure (BP) monitors were used for 12 hours to assess treatment hemodynamic effects. The mean area under the serum caffeine concentration‐time curve (AUC0–∞) values ± SD for the caffeine with water group, caffeine with GFJ group, and caffeine with multiple GFJ group were 47.0 ± 10.8, 48.7 ± 15.2, and 49.6 ± 7.0 μg/ml · hr, respectively (NS). There was no significant difference on the ambulatory systolic BP, diastolic BP, percentage of the time with a diastolic BP greater than 90 mm Hg, or heart rate area under the effect curves. We conclude that grapefruit juice had no effect on caffeine pharmacokinetics or hemodynamic effects.
A Pharmacokinetic Study to Determine the Drug Interaction between Valproate and Propranolol
Authors: Nemire Ruth E. , Toledo Cynthia A. , Ramsay R. Eugene
Published: October 2023

A 40‐year‐old female receiving divalproex sodium (VPA) monotherapy for epilepsy developed a tremor secondary to the drug. Propranolol treatment was initiated. While receiving propranolol 40 mg, VPA clearance was reduced from 1.66 L/hr to 1.19 L/hr and dropped to 1.08 L/hr on propranolol 80 mg. The mechanism of this interaction is unknown. To evaluate the potential for a drug interaction between these two agents, 12 patients on VPA monotherapy, ages 19–55, were studied. The subjects were maintained on a constant dose of VPA. Each was then randomly assigned to receive placebo, or long‐acting propranolol 60 mg/day or 120 mg/day. Mean VPA serum concentrations did not change among the three groups. Plasma half‐life of VPA ranged from 7.3–18 hours and did not change with coadministration of propranolol. We concluded that VPA metabolism is not affected by coadministration of propranolol in this group of patients.
Comparison of Two Methods for INR Determination in a Pharmacist‐Based Oral Anticoagulation Clinic
Authors: Yamreudeewong Weeranuj , Johnson James V. , Cassidy Thomas G. , Berg Jean T.
Published: October 2023

Warfarin is a commonly used oral anticoagulant that is usually initiated after the definitive diagnosis of a certain thromboembolic disorder or disease. Warfarin therapy will usually be prescribed for 6–12 weeks or more, and some patients may continue therapy throughout life, depending on the type of thromboembolic disorder. Major problems associated with warfarin therapy include adverse effects such as bleeding complications and drug‐drug or drug‐food interactions. In addition, thromboembolic complications may occur due to subtherapeutic dosages of warfarin. The laboratory reference standards for monitoring warfarin therapy are the prothrombin time (PT) and the International Normalized Ratio (INR). While both the PT or INR will reflect the clinical response in the patient, results reported as INR values have been shown to be more accurate than those reported as PT values. Thirty‐two patients were enrolled in this study. Our objectives were to compare INR values measured by both the Coumatrak and conventional laboratory method, and to demonstrate the effects of pharmacist intervention on managing patients receiving warfarin therapy. Results from our study reveal that INR monitoring by Coumatrak is similar to the conventional laboratory method. In addition, our study indicates that patients receiving warfarin therapy can be monitored and managed effectively by pharmacists.
Biochemical and Pharmacologic Comparison of Thrombolytic Agents
Authors: Stringer Kathleen A.
Published: October 2023

The number of thrombolytic drugs for the management of acute myocardial infarction is rapidly expanding. New agents, some of which are biochemically modified versions of currently available thrombolytics, will soon arrive in the marketplace. The pharmacologic differences of the new drugs are the basis for clinical differences such as enhanced clot lysis and prolonged elimination half‐life. Ultimately, these features may result in improved infarct artery patency and patient survival.
Benzodiazepines in Schizophrenia
Authors: Stimmel Glen L.
Published: October 2023

Benzodiazepines have a checkered history in the United States; public and professional attitudes about them have ranged from their being wonder drugs in the 1970s to being virtually purged from many formularies as addictive and dangerous in the 1980s. The attitude today is that they are useful for specific indications. In the last 20 years they have been investigated as adjunctive agents to conventional antipsychotic drugs in the treatment of schizophrenia. Benzodiazepines may be effective in schizophrenia because stress is one mediator of relapse in these patients. In addition, inhibition of dopamine neurotransmission through γ‐aminobutyric acid‐enhancing activity may provide a direct antipsychotic effect. As monotherapy or adjuncts to antipsychotic agents, benzodiazepines produced antipsychotic effects in schizophrenia in approximately 50% of controlled trials. Although there is no particular benzodiazepine of choice, low‐potency compounds with long elimination half‐lives are recommended. Adverse effects of concern include sedation and cognitive impairment, behavioral disinhibition, exacerbation of psychotic symptoms, and the potential for dependence, withdrawal, and abuse. The recent arrival of atypical antipsychotic drugs has significantly slowed research and interest in benzodiazepines in schizophrenia beyond their initial beneficial sedative effects for acute psychotic episodes.
4‐Aminopyridine Improves Pulmonary Function in Quadriplegic Humans with Longstanding Spinal Cord Injury
Authors: Segal Jack L. , Brunnemann Sherry R.
Published: October 2023

Study Objective. To test the hypothesis that 4‐aminopyridine (4‐AP) might cause clinically evident improvement in pulmonary function in humans with chronic spinal cord injury (chronic SCI).

Design. Balanced, open‐label study with subjects consecutively enrolled.

Setting. Spinal Cord Injury Service, university‐affiliated tertiary level care Department of Veterans Affairs Medical Center.

Patients. Seventeen healthy men and women suffering from traumatic SCI (11 quadriplegic, 6 paraplegic patients) for more than 1 year.

Interventions. Each subject was given a single dose of 4‐AP 10 mg orally in an immediate‐release formulation.

Measurements and Main Results. Significant increases in mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) that persisted for at least 12 hours were demonstrated in quadriplegic patients beginning 6 hours after 4‐AP administration. Tests of pulmonary function that demonstrated statistically significant increases at any time were also numerically, if not statistically, increased at 24 hours compared with pretreatment values obtained in 4‐AP‐naive subjects.

Conclusions. The administration of a single dose of an immediate‐release formulation of 4‐AP to humans with longstanding, traumatic quadriplegia is associated with sustained, clinically meaningful, and statistically significant improvements in pulmonary function. We suggest that the administration of 4‐AP may have a salutary effect in patients suffering from SCI and appears to be associated with potentially clinically significant reductions in the pathophysiologic pulmonary sequelae of SCI.
The Fluconazole Era: Management of Hematogenously Disseminated Candidiasis in the Nonneutropenic Patient
Authors: Kramer Katherine M. , Skaar Debra J. , Ackerman Bruce H.
Published: October 2023

Hematogenously disseminated candidiasis arising from nosocomial fungal infection is a life‐threatening complication in critically ill, nonneutropenic patients. The overall nosocomial fungal infection rate in United States hospitals doubled from 1980–1990. Until recently, amphotericin B was the only agent available for the treatment of life‐threatening candidal infections, but its use is plagued by toxicities including nephrotoxicity and infusion‐related reactions such as rigors and hypotension. The availability of fluconazole, which is regarded as much less toxic than amphotericin B, prompted a surge in research to determine if it is as efficacious in the management of candidemia and hematogenously disseminated candidiasis. Complicating the interpretation of studies is the broad range of infection severity, from candidemia that may be transient and self‐limiting to life‐threatening hematogenously disseminated candidiasis. Clinical trials comparing fluconazole and amphotericin B demonstrate the efficacy of fluconazole for catheter‐associated candidemia in critically ill patients when the likely pathogen is Candida albicans. Amphotericin B should remain the first‐line agent for the management of candidemia and hematogenously disseminated candidiasis in all other patients.
Female Sexual Stimulation During Antidepressant Treatment
Authors: Elmore James L. , Quattlebaum James T.
Published: October 2023

Three women with several diagnoses, including depression and psychosis, personality disorder, attention deficit hyperactivity disorder, alcohol abuse, and physical disease, were treated with selective serotonin reuptake inhibitors (fluoxetine, paroxetine, fluvoxamine). One patient was prescribed paroxetine in addition to methylphenidate. While receiving these agents, two women experienced undesirable sexual arousal and the third had increased sexual desire, arousal, and hypersexuality.
Mycophenolate Mofetil
Authors: Sievers Theodore M. , Rossi Stephen J. , Ghobrial Rafik M. , Arriola Edgar , Nishimura Pamela , Kawano Marv , Holt Curtis D.
Published: October 2023

Mycophenolate mofetil is the morpholinoethylester prodrug of mycophenolic acid, an agent that inhibits the proliferation of B and T lymphocytes through noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, a key enzyme in the de novo synthetic pathway of guanine nucleotides. Currently, mycophenolate mofetil is approved for the prevention of acute renal allograft rejection when given in combination with cyclosporine and steroids. Several studies also demonstrated that the agent is effective in the treatment of refractory rejection in renal, heart, and liver transplant recipients, and may have efficacy in the treatment of chronic rejection as well.
Cost Analysis of the American College of Chest Physicians Guidelines for Deep Vein Thrombosis Prophylaxis in Patients Undergoing Orthopedic Arthroplastic Surgery
Authors: Wade William E. , Spruill William J.
Published: October 2023

Guidelines for prophylaxis of deep vein thrombosis secondary to orthopedic surgery have been developed. In selecting a specific drug for formulary inclusion, it is ideal for an individual institution to determine the cost of therapy, as well as the frequency of adverse events and the cost of treating them for each agent undergoing consideration. Cost‐effectiveness analysis using incremental cost‐effectiveness ratios and sensitivity analyses are useful for determining which drug may be most cost effective.
N‐Desmethylclozapine, an Insensitive Marker of Clozapine‐Induced Agranulocytosis and Granulocytopenia
Authors: Combs Michael D. , Perry Paul J. , Bever Kristine A.
Published: October 2023

We reviewed the charts of 58 patients with treatment‐refractory schizophrenia who were receiving clozapine, to determine if the drug's active metabolite, N‐desmethylclozapine, is a biologic marker for impending clozapine‐induced granulocytopenia and agranulocytosis. No significant correlation between granulocyte counts and patient demographic variables of clozapine and N‐desmethylclozapine steady‐state plasma concentrations, clozapine: N‐desmethylclozapine ratio, age, gender, clozapine dosage, smoking status, and race were found. We believe N‐desmethylclozapine is not a clinically useful marker for monitoring the effect of clozapine on granulocyte integrity On the contrary, its plasma concentrations correlated positively with granulocyte counts.
Paradoxic Excitation with Diphenhydramine in an Adult
Authors: Cheng Kit L. , Dwyer Patrick N. , Amsden Guy W.
Published: October 2023

Although paradoxic excitation may rarely occur in children and adults with conventional dosages of antihistamines, few case reports have appeared in the literature. We cared for a 46‐year‐old patient who became extremely agitated after receiving a dose of intravenous diphenhydramine.
Delayed Hypersensitivity Reaction to Vancomycin
Authors: Marik Paul E. , Ferris Nan
Published: October 2023

The use of vancomycin has increased dramatically in recent years with the emergence of methicillin‐resistant Staphylococcus aureus and coagulase‐negative staphylococci as important hospital pathogens. A patient receiving vancomycin 1.75 g intravenously as a single daily dose developed a syndrome characterized by high fever, erythema multiforme, eosinophilia, and presumed interstitial nephritis. This delayed hypersensitivity reaction resolved with discontinuation of the drug and treatment with methylprednisolone.
The Place of Selective Serotonin Reuptake Inhibitors in the Treatment of Panic Disorder
Authors: DeVane C. Lindsay
Published: October 2023

Panic disorder is a frequently chronic condition with extensive patterns of psychiatric comorbidity. Optimum pharmacotherapy with traditional agents is limited by side effects, long‐term tolerability, and other problems. Recent research findings support the characterization of panic disorder as an illness involving derangements of central serotonergic function. Selective serotonin reuptake inhibitors could become first‐line treatment of the disorder, as they seem to have fewer side effects than tricyclic antidepressants and benzodiazepines.
Comparison of Valaciclovir and Acyclovir for the Treatment of Herpes Zoster in Immunocompetent Patients over 50 Years of Age: A Cost‐Consequence Model
Authors: Grant David M. , Mauskopf Josephine A. , Bell Larry , Austin Randall
Published: October 2023

A method was developed for modeling the costs and consequences of treating varicella zoster viral infections to clinical data generated in a pivotal phase III clinical trial of valaciclovir versus acyclovir for the treatment of acute herpes zoster in immunocompetent patients over 50 years of age. Direct medical costs and indirect costs (productivity losses) were modeled using unit costs applicable in the United States. Compared with acyclovir, valaciclovir reduced average direct medical costs per patient by 17% ($60.01) and indirect costs by an average of 25% ($46.54). Median duration of pain was reduced by 13 days for valaciclovir compared with acyclovir in the intent‐to‐treat population or by 19 days in patients with pain after rash healing. The cost variables described in the model (drug costs, cost of treating long‐term pain, physician visits, hospitalization, treatment of severe ocular involvement, productivity losses) were tested by sensitivity analysis. Total costs associated with valaciclovir treatment remained lower than those with acyclovir over the range of the analysis.
The Effect of Pravastatin on Hepatic 3‐Hydroxy‐3‐methylglutaryl CoA Reductase Obtained from Poloxamer 407‐Induced Hyperlipidemic Rats
Authors: Johnston Thomas P. , Palmer Warren K.
Published: October 2023

A single 300‐mg intraperitoneal injection of poloxamer 407 (P‐407) to rats produces a marked hypercholesterolemia for a minimum of 96 hours and increases the activity of hepatic 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase compared with the enzyme activity found in microsomal homogenates of control animals. We attempted to determine whether inhibition of microsomal HMG‐CoA reductase by pravastatin sodium would yield similar values for the maximum reaction in velocity (Vmax) and the HMG‐CoA reductase‐pravastatin dissociation constant (Ki) when the enzyme was in the activated state compared with the control state. Knowledge of the respective values for Vmax and Ki would allow us to determine whether P‐407‐induced hypercholesterolemia in the rat was refractory to pravastatin treatment. Over a pravastatin concentration range of 0.5–50 nM, enzyme activity in vitro decreased as the drug's concentration increased. A standard Dixon plot of mean values of reciprocal reaction velocity versus pravastatin concentration yielded Ki of 3.7 and 4.1 nM for the control and activated states, respectively. The Vmax for conversion of HMG‐CoA to mevalonate in vitro in the presence of pravastatin was 3.5‐fold greater when assayed in microsomal homogenates obtained from P‐407‐injected rats compared with control animals. Dixon plot analysis of the data resulted in Vmax of 58.1 and 202 pmol•min−1•mg−1 for the control and activated states, respectively. These data suggest that whereas the Vmax is affected, injection of P‐407 to rats does not alter the binding affinity of pravastatin for receptor(s) contained in HMG‐CoA reductase as reflected by similar Ki values. This experimental animal model may be an additional screen with which to rank order the relative potency of HMG‐CoA reductase inhibitors by determining the drug's effectiveness when HMG‐CoA reductase is in an activated state.
T Lymphocyte β2‐Adrenergic Receptor Function and Density after Acute Myocardial Infarction
Authors: McCoy Randall A. , Clifton G. Dennis , Booth David C. , Bartels Laura A. , Chandler Mary H.H.
Published: October 2023

The T lymphocyte β2‐adrenergic receptor (β2AR) density and function were compared in 15 patients suffering acute myocardial infarction and 10 patients with stable coronary artery disease (CAD). Density was determined using radioligand binding with 125IPIN, and function by in vitro cyclic adenosine 3′,5′‐monophosphate (cAMP) production. In patients suffering acute myocardial infarction, T lymphocyte β2AR density (823.8 ± 480 sites/cell) was slightly but not significantly different from that in patients with stable CAD (629 ± 301 sites/cell). There was no difference in T lymphocyte cAMP production at baseline (1.11 ± 0.70 vs 1.04 ± 0.49 pM/106 cells) or after isoproterenol stimulation (2.53 ± 1.63 vs 2.62 ± 2.05 pM/106 cells), respectively. Further study is necessary to determine if β2AR numbers on T lymphocytes are significantly increased after acute myocardial infarction.
Miconazole‐Induced Fatal Dysrhythmia
Authors: Coley Kim C. , Crain Judy L.
Published: October 2023

Miconazole is an imidazole antifungal agent that is available in topical, vaginal, and parenteral formulations. Indications for the parenteral product have become rare with the development of newer, more effective agents. A 54‐year‐old man who had undergone orthotopic heart transplantation developed a widespread subcutaneous Scopulariopsis infection that progressed despite treatment with amphotericin B and itraconazole. Intravenous miconazole was added to his regimen. During the infusion he developed a bradyarrhythmia that resolved after miconazole was discontinued. On rechallenge with a lower dosage, bradyarrhythmia recurred and progressed to ventricular fibrillation. The patient died despite full resuscitation efforts. Only a few case reports exist of miconazole‐induced cardiac arrhythmias, and these events were attributed to rapid intravenous administration, insufficient dilution, and the drug's vehicle. We believe that intravenous miconazole should be given with caution to patients with underlying heart disease.
Drug Interaction Potential with Inhibitors of HIV Protease
Authors: Van Cleef Gwendolyn F. , Fisher Evelyn J. , Polk Ron E.
Published: October 2023

We conducted a retrospective chart review to estimate the potential for drug interactions in subjects infected with the human immunodeficiency virus‐1 when a protease inhibitor was added to existing therapy. Medical records of 50 patients in each of three immunologic strata (CD4 cell counts/μl < 100, 100–199, 200–500) were randomly selected from records of all patients receiving care at the clinic; 114 records were evaluable. The probabilities of one interaction or more were 31%, 42%, and 77% of patients if treated with indinavir, saquinavir, and ritonavir, respectively, across all CD4 groups; when the CD4 count was below 100 cells/μl, the probabilities were 55%, 63%, and 93%. Many of these interactions, however, resulted from administration of rifabutin, a drug likely to decrease in importance as less toxic alternatives become more widely administered. The potential for drug interactions is high when starting protease inhibitor therapy, especially in patients with low CD4 cell counts who receive ritonavir. Concurrent therapy must be evaluated before treatment, as many agents are either contraindicated or require dosage modification.