bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect-Directed Analysis Based on Transthyretin Binding Activity of Per- and Polyfluoroalkyl Substances in a Contaminated Sediment Extract
Authors: Langberg Håkon A. , Choyke Sarah , Hale Sarah E. , Koekkoek Jacco , Cenijn Peter H. , Lamoree Marja H. , Rundberget Thomas , Jartun Morten , Breedveld Gijs D. , Jenssen Bjørn M. , Higgins Christopher P. , Hamers Timo
Published: October 2023

Only a fraction of the total number of per- and polyfluoroalkyl substances (PFAS) are monitored on a routine basis using targeted chemical analyses. We report on an approach toward identifying bioactive substances in environmental samples using effect-directed analysis by combining toxicity testing, targeted chemical analyses, and suspect screening. PFAS compete with the thyroid hormone thyroxin (T4) for binding to its distributor protein transthyretin (TTR). Therefore, a TTR-binding bioassay was used to prioritize unknown features for chemical identification in a PFAS-contaminated sediment sample collected downstream of a factory producing PFAS-coated paper. First, the TTR-binding potencies of 31 analytical PFAS standards were determined. Potencies varied between PFAS depending on carbon chain length, functional group, and, for precursors to perfluoroalkyl sulfonic acids (PFSA), the size or number of atoms in the group(s) attached to the nitrogen. The most potent PFAS were the seven- and eight-carbon PFSA, perfluoroheptane sulfonic acid (PFHpS) and perfluorooctane sulfonic acid (PFOS), and the eight-carbon perfluoroalkyl carboxylic acid (PFCA), perfluorooctanoic acid (PFOA), which showed approximately four- and five-times weaker potencies, respectively, compared with the native ligand T4. For some of the other PFAS tested, TTR-binding potencies were weak or not observed at all. For the environmental sediment sample, not all of the bioactivity observed in the TTR-binding assay could be assigned to the PFAS quantified using targeted chemical analyses. Therefore, suspect screening was applied to the retention times corresponding to observed TTR binding, and five candidates were identified. Targeted analyses showed that the sediment was dominated by the di-substituted phosphate ester of N-ethyl perfluorooctane sulfonamido ethanol (SAmPAP diester), whereas it was not bioactive in the assay. SAmPAP diester has the potential for (bio)transformation into smaller PFAS, including PFOS. Therefore, when it comes to TTR binding, the hazard associated with this substance is likely through (bio)transformation into more potent transformation products. Environ Toxicol Chem 2024;43:245–258. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
Conformational features and chemical behavior of 5H, 7H‐dibenzo[B,g][1,5] dithiocin oxides: 1,5‐Oxygen shift via a dithiodication intermediate
Authors: Ohkata Katsuo , Okada Keiji , Akiba Kin‐Ya
Published: October 2023

Some 5H,7H‐dibenzo[b,g][1,5]dithiocin oxides (4–8) and their related compounds 9–13 were prepared and the assignment of the most favorable conformation was carried out on the basis of the characteristic 1H NMR spectral data. Only a single conformer (BC: boatchair form) exists for 4,5, and 8–13, while two conformers (BC and TB: twist‐boat form) are apparent for 6 and 7. Oxidation and methylation of 4 gave exclusively a single geometrical isomer (8 and 13, respectively). These results are interpreted as a sterically preferential attack of electrophiles on the BC conformer of the starting material. A 1,5‐oxygen shift of 4 occurred smoothly to give 6 in the presence of trifluoroacetic acid in CDCl3 solution. The mechanistic investigation is described briefly. Differences in chemical behavior between dibenzodithiocin 12‐oxide 4 and dibenzothiazocine 12‐oxide 2 are also discussed on the basis of the conformational features.
The European Convention on Bioethics
Authors: de Wachter Maurice A. M.
Published: October 2023

Nearly fifteen years after the Council of Europe first called for a pan‐European convention on issues in bioethics to harmonize disparate national regulations, in November 1996 the council's Committee of Ministers approved the Convention on Human Rights and Biomedicine for formal adoption. The draft convention, released in July 1994, provoked strong public, professional, and governmental debate among European nations, particularly regarding provisions for biomedical research with subjects unable to give informed consent. If ratified, the “bioethics convention” will become the first such document to have binding force internationally.
Is It Time to Abandon Brain Death?
Authors: Truog Robert D.
Published: October 2023

Despite its familiarity and widespread acceptance, the concept of “brain death” remains incoherent in theory and confused in practice. Moreover, the only purpose served by the concept is to facilitate the procurement of transplantable organs. By abandoning the concept of brain death and adopting different criteria for organ procurement, we may be able to increase both the supply of transplantable organs and clarity in our understanding of death.
Effects of Nicotinic Acid on Poloxamer 407‐Induced Hyperlipidemia
Authors: Nash Virginia J. , Johnston Thomas P. , Palmer Warren K.
Published: October 2023

We attempted to determine the mechanism(s) of poloxamer (P)‐407‐induced hyperlipidemia in rats by administering a lipid‐lowering drug with a known mechanism of action. Five weight‐matched animals were assigned to each of four treatment groups. Two groups received P‐407 300 mg/ml and two received saline 1 ml. One of the P‐407 and one of the saline groups were administered nicotinic acid 100 mg/kg by intraperitoneal injection at 6–96 hours after blood sampling. Blood samples were collected at 7 points from time zero to 120 hours and analyzed for triglyceride and cholesterol concentrations. The detergent produces hypertriglyceridemia (HTG) increasing from 53.4 ± 7.0 mg/dl (time zero) to 4026.9 ± 42.1 mg/dl by 24 hours. The HTG response was significantly attenuated by nicotinic acid (at t = 24 hrs). This, however, was followed by an average triglyceride concentration increase of 2.8‐fold from 72 to 120 hours. The detergent produces a dramatic hypercholesterolemia (HCHO), increasing cholesterol from 47.5 ± 1.8 mg/dl to 468.5 ± 27.9 mg/dl by 48 hours. The HCHO was significantly affected by nicotinic acid administration during the accumulation phase. Nicotinic acid reduced cholesterol concentration from 364.4 ± 16.1 mg/dl to 276.8 ± 16.4 mg/dl at 24 hours (p<0.05). It is a potent antilipolytic agent, limiting the free fatty acids available for the synthesis of triglyceride and cholesterol. These data suggest that P‐407 may act by stimulating the release of free fatty acids from the adipocyte for at least 24 hours after injection.
Alopecia Associated With Zidovudine Therapy
Authors: Geletko Sandra M. , Segarra Marisel , Mikolich Dennis J.
Published: October 2023

Alopecia has been described in patients infected with the human immunodeficiency virus (HIV). Zidovudine reportedly influences hair growth in these patients, causing regrowth or thickening. A 33‐year‐old HIV‐infected man developed alopecia areata after beginning zidovudine therapy. The alopecia reversed after the drug was discontinued.
Is There a Fountain of Youth? A Review of Current Life Extension Strategies
Authors: Bernarducci Marc P. , Owens Norma J.
Published: October 2023

Life expectancy has dramatically increased in industrialized countries since the 1900s due to advances in disease prevention and treatment, and improvements in nutrition and infant mortality. Thus, as a society we are living longer and experiencing more of the changes and declines associated with aging. Although the factors that cause our bodies to age are unknown, various medical interventions have been proposed and explored to prevent the process. Published research on aging conducted during the past 10 years was retrieved through MEDLINE and critically evaluated. Animal and human studies suggest potential benefits of dietary modification, exercise, antioxidants, hormones, and deprenyl. Due to the interrelationships between disease and older age and the limitations of existing research in this area, most life extension strategies are untested hypotheses. Many strategies merit scientific inquiry, but they cannot be recommended for use. More extensive research is necessary to assess their safety, effectiveness, and socioeconomic impact, and to resolve ethical controversies before they can be considered applicable in humans.
In Vitro Testing of Antibiotics
Authors: Ackerman Bruce H. , Buono Felicia A. Dello
Published: October 2023

To enhance knowledge in the area of in vitro testing of antibiotics and to understand the limitations of available methods for susceptibility testing, we conducted a MEDLINE literature search in the English language to accumulate relevant articles. Headings searched included microbial sensitivity tests; Kirby‐Bauer; laboratory tests; antiinfective agents; antibiotics, combined; microbiological techniques; blood bactericidal assay; and pharmacology, clinical. The management of patients with serious life‐threatening infections can be complicated by recent changes in organism nomenclature, newly marketed antibiotics, and new isolation and sensitivity testing methods. With the addition of formulary constraints, many problems and controversies arise regarding interpretation of antibiotic sensitivity results. Comprehensive care for infected patients requires assessment of current antibiotic therapy and options for alternative therapy. By applying pharmacodynamic and pharmacokinetic knowledge to known limits of in vitro testing results, the clinician is able to select the most efficient antibiotic or antibiotic combination.
Comparison of Measured and Estimated Creatinine Clearance in Patients With Advanced HIV Disease
Authors: Huang Eric , Hewitt Ross G. , Shelton Mark , Morse Gene D.
Published: October 2023

Study Objective. To assess the accuracy of five creatinine clearance equations in predicting measured creatinine clearance in hospitalized patients with human immunodeficiency viral (HIV) infection.

Design. Prospective evaluation over a 6‐month period.

Setting. Erie County Medical Center, a 550‐bed teaching institution.

Patients. Forty‐seven HIV‐positive patients (39 men, 8 women) who were admitted for a variety of HIV‐related illnesses and judged clinically to have stable renal function. Of the 47 original patients, 44 were evaluable based on exclusion criteria.

Interventions. Serum creatinine and 24‐hour measured creatinine clearance were performed in each patient.

Measurements and Main Results. The estimated creatinine clearance from each of the equations (Cockcroft‐Gault, two Jeliffe equations, Mawer et al, and Hull et al) was compared with the measured creatinine clearance. Statistical analysis of these comparisons was performed and all of the equations were found to overestimate the measured creatinine clearance (mean error 34–45%).

Conclusions. Many HIV‐infected patients have a decreased creatinine clearance despite a serum creatinine concentration within the normal range. Each of the equations overestimated the measured creatinine clearance.
Chemical Pleurodesis With Doxycycline 1 g
Authors: Herrington Jon D. , Gora‐Harper Mary Lea , Salley Robert K.
Published: October 2023

We evaluated the utility of a single 1‐g dose of doxycycline in the treatment of malignant and nonmalignant pleural effusions and refractory pneumothoraces in 27 consecutive patients requiring pleurodesis. After the evacuation of all retained air or fluid, and premedication with intravenous narcotic analgesics and intrapleural lidocaine 200 mg, the patients received doxycycline 1 g in 50 ml normal saline instilled through the chest tube. This was followed by instillation of 100–200 ml of air to facilitate dispersion. The chest tube was removed when the drainage was less than 150 ml/day. Twenty‐three of 27 patients were evaluated at 30 days. Six (67%) of the nine patients with pneumothoraces achieved a response, and both patients with nonmalignant pleural effusions had a complete response. Of the 12 patients with malignant pleural effusion, 8 (67%) achieved a complete response, 2 had a partial response, and 2 had no response. Twenty‐two (81%) of 27 patients experienced adverse effects with pleurodesis, with pain (81%) and fever (11%) being the most prevalent. In this limited number of patients, doxycycline 1 g appeared to be safe and effective for the treatment of pleural effusions and pneumothoraces. The 1‐g dose must be compared with the standard 500‐mg dose and with other established agents.
Failure of Prostatitis Treatment Secondary to Probable Ciprofloxacin‐Sucralfate Drug Interaction
Authors: Spivey J. Michael , Cummings Doyle M. , Pierson Noah R.
Published: October 2023

Metal cations such as aluminum, magnesium, ferrous sulfate, and zinc are thought to form chelation complexes with fluoroquinolone antibiotics and prevent the drugs from being absorbed. Sucralfate, which has a high aluminum content, reduces the bioavailability of ciprofloxacin to approximately 4%. The concomitant administration of ciprofloxacin and sucralfate resulted in treatment failure for a patient with prostatitis and a subsequent 5‐day hospitalization. Fluoroquinolone antibiotics should be administered at least 2 hours before agents containing metal cations to allow for their absorption. In addition, sucralfate should not be administered less than 6 hours before fluoroquinolone antibiotic administration.
Evolving Role of Calcium Channel Blockers in Heart Failure
Authors: Pieper John A.
Published: October 2023

Calcium channel blockers are theoretically effective in the treatment of chronic systolic heart failure because of their actions as arteriolar dilators, antiischemic agents, and relaxants of diastolic left ventricular function, and because they may prevent progression of myocardial dysfunction. The first‐generation calcium channel blockers nifedipine, verapamil, and diltiazem cause hemodynamic and clinical deterioration and may increase the frequency of cardiac events in postmyocardial infarction patients with heart failure. These drugs depress left ventricular contractility in the short term, and can activate neurohormonal systems due to their hypotensive effects. The second‐generation calcium channel blocker felodipine does not activate the sympathetic nervous and renin‐angiotensin systems, but has no effect on exercise capacity or mortality. Amlodipine increases exercise time and reduces symptoms and plasma norepinephrine concentration in heart failure. It also reduces morbidity and mortality in New York Heart Association class IV patients with nonischemic dilated cardiomyopathy, and appears to be effective as primary therapy for patients with dilated cardiomyopathy.
Effect of Food on the Pharmacokinetics of a New Hydroxypropyl‐β‐Cyclodextrin Formulation of Itraconazole
Authors: Van de Velde Vera J.S. , Van Peer Achiel P. , Heykants Joseph J.P. , Woestenborghs Robert J.H. , Van Rooy Patricia , De Beule Karel L. , Cauwenbergh Geert F.M.J.
Published: October 2023

Study Objective. To compare the pharmacokinetics of a single 100‐mg oral dose of itraconazole administered as 10 ml of a 10‐mg/ml itraconazole solution in hydroxypropyl‐β‐cyclodextrin under fasting versus postprandial conditions.

Design. Open‐label, two‐way, randomized, crossover study.

Setting. Janssen Research Foundation, Belgium.

Patients. Twelve healthy volunteers.

Interventions. Blood samples were obtained for pharmacokinetic analyses immediately before dosing and at regular intervals up to 96 hours after each dose. Blood and urine samples were obtained for hematologic, biochemical, and urinary safety analyses at baseline and at the end of the study.

Measurements and Main Results. The mean peak plasma concentrations of both itraconazole and its active metabolite hydroxy‐itraconazole were significantly higher under fasting conditions than under postprandial conditions. The mean times to peak concentration for both the parent compound and its metabolite were significantly shorter under fasting than under nonfasting conditions. The mean areas under the curve (AUC0–∞ and AUC0–24 hrs) were also significantly higher under fasting than under postprandial conditions.

Conclusions. Our findings suggest that the higher bioavailability of this new formulation of itraconazole may be of benefit in seriously ill patients who are not able to ingest adequate quantities of food. The fact that the solution was also well tolerated and was not associated with clinically significant changes in any laboratory value further underscores the potential utility of this dosing form.
A New Class of Antihypertensive Therapy: Angiotensin II Receptor Antagonists
Authors: Ellis Melissa L. , Patterson J. Herbert
Published: October 2023

Despite the availability of safe and efficacious antihypertensive agents, hypertension continues to be a major source of morbidity and mortality in the United States. Losartan, the first of a new class of agents, the angiotensin II receptor antagonists, can be administered as monotherapy in the treatment of hypertension or to complement existing therapy. The angiotensin II receptor antagonists block the effects of angiotensin II through preferential binding to angiotensin II receptor subtype AT1 on the cell membrane. Compared with angiotensin‐converting enzyme inhibitors, they may provide more complete blockade of the renin‐angiotensin system and be associated with a lower frequency of cough as a side effect.
Viral Infectivity of Albumin and Plasma Protein Fraction
Authors: Erstad Brian L.
Published: October 2023

Original research, reviews, and case reports discussing viral infectivity of blood‐ and plasma‐derived products were reviewed to determine the potential viral infectivity of human serum albumin (HSA) and plasma protein fraction (PPF). Data concerning viral infectivity, viral screening and inactivation procedures, and viral outbreaks associated with blood and plasma products were extracted and evaluated for pertinence to HSA and PPF. The starting material used for fractionation, the manufacturing process, postmanufacturing handling, and immunocompetence of HSA or PPF recipients were assessed to determine risk of symptomatic viral disease after transfusion. Both HSA and PPF are manufactured with pasteurization procedures that have led to an excellent viral safety record based on 50 years of clinical use. One outbreak of hepatitis B was associated with PPF as a result of an unreliable manufacturing process that has been corrected. The pasteurization process is effective in eradicating known viral pathogens when good manufacturing practices are followed. Continued surveillance of such products is warranted for viruses not included in routine screening procedures and for those that are resistant to current inactivation methods.
Serum Iron Concentrations and Symptoms of Acute Iron Poisoning in Children
Authors: Chyka Peter A. , Butler Adrianne Y. , Holley Joseph E.
Published: October 2023

Study Objective. To determine whether serum iron concentrations correlate with the development of symptoms of iron poisoning in children.

Design. A retrospective study of medical records from January 1976 through June 1992.

Setting. A tertiary care children's medical center.

Patients. Criteria for patient selection included an acute ingestion of iron‐containing drugs, measurement of serum iron prior to deferoxamine administration, and a serum iron concentration (obtained within 2–9 hours of exposure) that was greater than 150 μg/dl (27 μmol/L). Of the 128 children who were hospitalized for acute iron poisoning, 92 patients (mean age 2.3 ± 2.2 years) met the selection criteria.

Interventions. None.

Measurements and Main Results. The mean (± SD) serum iron concentrations (μg/dl) of patients who exhibited cardiovascular instability (725 ± 555, n = 6; p < 0.001) differed from those categorized with central nervous system changes (373 ± 77, n = 30), gastrointestinal symptoms (334 ± 83, n = 44), and no symptoms (368 ± 102, n = 12). Serum iron concentrations in patients with cardiovascular instability ranged from 205–500 μg/dl (37–269 μmol/L), whereas those with no symptoms ranged from 170–513 μg/dl (30 to 92 μmol/L) demonstrating considerable overlap of ranges.

Conclusions. Serum iron concentrations do not necessarily relate to acute toxicity, and further study is needed to demonstrate the value of serum iron concentrations and to identify alternative strategies in the emergency assessment of the acutely poisoned child.
The Perceived Influence of Clinical Pharmacy Services on Physician Prescribing Behavior: A Matched‐Pair Comparison of Pharmacists and Physicians
Authors: Sulick Judith A. , Pathak Dev S.
Published: October 2023

In contrast with cross‐sectional designs used in previous studies, this exploratory study compared survey data from 127 matched pairs of clinical pharmacists and physicians working together. Physicians' perceptions of the importance of clinical pharmacy activities for patient care and the competence of pharmacists performing the activities were examined for their influence on prescribing behavior in an institutional setting. Data from a national survey showed that physicians rated pharmacists higher regarding recommendations based on drug use evaluations (p = 0.004) and competency to provide all clinical pharmacy services. Scores for pharmacokinetics ratings were similar between pharmacists and physicians (p = 0.168). Pharmacists rated the importance of recommendations based on cost‐effectiveness higher than physicians (p = 0.012). Overall, physicians' perceptions of activity importance for patient care and pharmacist competency appear to dictate pharmacists' influence on physician prescribing behavior (R = 0.723).
Assessing Pharmacotherapy Outcomes: A Model for Clinicians
Authors: Gleason Patrick P. , Schulz Richard
Published: October 2023

Health‐related quality of life (HQL) has become an important therapeutic end point of pharmacologic therapy. As a result, clinicians will be increasingly called on to assess HQL outcomes associated with medication use. The review of HQL measures and the model described here should provide clinicians with the necessary framework to assess medication outcomes more globally so that they can identify and quantify medication‐induced changes and guide management decisions, use resources efficiently, and improve patient satisfaction with care.
Use of Novel Antipsychotic Drugs
Authors: Raleigh Fred
Published: October 2023

The atypical antipsychotic agents clozapine and risperidone bring new insight into the care and treatment of patients with schizophrenia. Since their introduction, several names (e.g., novel, atypical, serotonergic‐dopaminergic antagonist) have been used to describe the nature of these compounds. The agents are unique in a number of ways compared with conventional neuroleptics. In particular, they have the distinction of having achieved separation between the effective dosage and the dosage that causes extrapyramidal symptoms, which has significant implications for patient care. On the whole, the advent of atypical agents is changing treatment protocols for patients with schizophrenia.
Prolonged Quinidine Half‐life with Associated Toxicity in a Patient with Hepatic Failure
Authors: Stanek Eric J. , Simko Robert J. , DeNofrio David , Pavri Behzad B.
Published: October 2023

A markedly prolonged quinidine elimination half‐life due to hepatic failure and resultant quinidine toxicity occurred in a 57‐year‐old man with a history of atrial fibrillation. A prolonged QT interval, development of torsades de pointes, and a serum quinidine concentration of 3.1 μg/ml contributed to a decision favoring permanent pacemaker implantation. The apparent quinidine half‐life ranged from 66–99 hours and was associated with QT prolongation and persistent U waves. On discontinuing quinidine, all signs associated with toxicity resolved as serum quinidine concentrations decreased, which resulted in reversal of the decision to implant a permanent pacemaker. This case reports an extremely long quinidine elimination half‐life and reillustrates the importance of drug pharmacokinetics in patient care.
New Drug Interactions with Zidovudine
Authors: Robertson‐Dallas Shannon , Read Stanley E. , Bendayan Reina
Published: October 2023

Polypharmacy is commonly encountered in human immunodeficiency virus (HIV)‐positive patients, and the risk and frequency of drug‐drug interactions are significant in this patient population. Most HIV‐positive patients receive the antiretroviral drug zidovudine (3′‐azido‐3′‐deoxythymidine, ZDV), the first drug to be approved for the treatment of HIV Many drug interactions with ZDV have already been reported. As HIV pharmacotherapy becomes more complex, the potential for drug‐drug interactions is likely to increase significantly.
Effect of Infusing Fat Emulsion into Extracorporeal Membrane Oxygenation Circuits
Authors: Buck Marcia L. , Ksenich Roberta A. , Wooldridge Peggy
Published: October 2023

Our objectives were to identify problems associated with the administration of fat emulsion by extracorporeal membrane oxygenation (ECMO) circuits, and gather information from other institutions on standards of practice and the complications associated with infusion of fat emulsion by ECMO to infants and children. In vitro analysis was performed using six circuits. Fat emulsion was infused into a prereservoir port at 3 ml/hour. Circuits and blood samples collected distal to the oxygenator were inspected visually for layering (separation of fat emulsion from blood), agglutination, and phase separation (formation of an oil layer) at 0.5, 1, 2, 4, 6, 12, and 24 hours. At 24 hours, samples were reevaluated and circuits dissected. All circuits showed layering and agglutination. Blood clots were present in five circuits during the simulation. There was no evidence of phase separation in the samples. Adhesion of emulsion to the equipment was present in all circuits. Five of the membrane oxygenators contained clots. One contained long strands of fat; separation of its mesh revealed an oily residue indicating disruption of the stability of the emulsion. Survey responses from 54 centers found that 78% used fat emulsion routinely in neonatal or pediatric patients receiving ECMO. Most used both ECMO and separate venous access for the infusion, depending on availability. Twenty‐two (52%) of the 42 centers using fat emulsion had a policy in place regarding site selection. Of those, 73% preferred central venous access, another 18% used a prereservoir port of the ECMO circuit. The most frequently reported problems with administration through the circuit were cracking of stopcocks, clogging and malfunction of the membrane oxygenator, agglutination of the emulsion, and increase in blood clot formation. Our results suggest that fat emulsion should be infused through a separate intravenous site whenever possible. Based on these results and current practices of most ECMO centers, a clinical trial is currently being conducted to provide additional information.
Bradycardia Associated with Intravenous Administration of Tacrolimus in a Liver Transplant Recipient
Authors: Cox Toby H. , Baillie G. Mark , Baliga Prabhakar
Published: October 2023

Cardiotoxicity due to tacrolimus is documented infrequently in the medical literature. Sinus bradycardia associated with intravenous tacrolimus occurred in a 15‐year‐old orthotopic liver transplant recipient. The mechanism of this adverse effect is unknown; however, it does not appear to be concentration dependent, and in this patient it resolved on changing to oral therapy. Practitioners should be aware that intravenous administration of tacrolimus may be associated with adverse cardiac events including sinus bradycardia.
Reemergence of Positive Symptoms after Initial Response to Risperidone
Authors: Cung Donna D. , Stimmel Glen L.
Published: October 2023

Risperidone was effective in successfully treating a patient's negative symptoms of schizophrenia as well as reducing adverse effects from typical antipsychotic drugs. Auditory hallucinations reemerged after 8 months, however, and again after 24 months of risperidone therapy. Reemergence of psychotic symptoms after initial response might be explained by inadequate dosage, by the natural course of the patient's schizophrenia independent of drug therapy, or by the possibility that, for this patient, risperidone was less effective than chlorpromazine for the positive symptom of auditory hallucinations.
Diffuse Pulmonary Hemorrhage after Streptokinase Administration for Acute Myocardial Infarction
Authors: Swanson George A. , Kaeley Gurjit , Geraci Stephen A.
Published: October 2023

Fibrinolytic drug therapy has markedly reduced morbidity and mortality from acute myocardial infarction. As with any other drug therapy, however, benefits are maximal when patients at higher risk for complications can be identified and treatment decisions modified to reduce the chance of adverse events. Streptokinase, a commonly used and inexpensive thrombolytic, is known to cause both bleeding and immunologic complications, and coexistent conditions predisposing to either are considered relative or absolute contraindications to its use. We report an unusual case of immune‐mediated diffuse pulmonary hemorrhage following streptokinase administration for acute myocardial infarction in a patient with pulmonary infection and concurrent cutaneous infection. We propose that these infections constitute additional risk factors and may be used to identify patients at higher risk of this complication from streptokinase.
The Overregulation of Pharmacy Practice
Authors: Cacciatore Gary G.
Published: October 2023

Many professions are highly regulated, yet few are regulated to the degree pharmacy is. Not only are there large numbers of regulations, but the regulations are so detailed they dictate precisely how pharmacists are to perform both dispensing and clinical services. As a result, pharmacists end up trying to meet the requirements of the regulations rather than exercising professional judgment and providing true pharmaceutical care. Many of the regulations are unnecessary intrusions into the practice of pharmacy and tend to diminish its professionalism.
A Review of Epidemiologic Research on Drug‐Induced Acute Liver Injury Using the General Practice Research Data Base in the United Kingdom
Authors: Rodriguez Luis A. Garcia , Ruigómez Ana , Jick Hershel
Published: October 2023

Drug hepatotoxicities have been evaluated in case histories, surveys based on retrospective record reviews, and spontaneous adverse drug reactions reported to national pharmacovigilance systems, but in relatively few epidemiologic studies. To identify and quantify the risk of acute liver injury associated with individual drugs, we reviewed and integrated all the published epidemiologic research on the subject. The source population for the eight studies was general population registered on a single large general practice‐based computerized data base. All were retrospective cohort studies, but some had a case‐control design nested within the source cohort. Participants were selected according to their use of selected agents (nonsteroidal antiinflammatory drugs [NSAIDs], antibiotics, acid‐suppressing drugs, other drugs suspected of being hepatotoxic) during the study period. Among the agents, we found a group of important hepatotoxic drugs with an associated incidence rate of acute liver injury greater than 100/100,000 users, including chlorpromazine and isoniazid. Agents with less risk but greater than 10/100,000 users were amoxicillin‐clavulanic acid and cimetidine. A third group of drugs had an associated incidence rate of acute liver injury of less than 10/100,000 users. Our results provide evidence of relative safety for commonly administered agents such as NSAIDs, amoxicillin, omeprazole, and ranitidine. We also quantified important suspected liver toxicity, providing a reasonable precise risk estimate of clinical liver injury associated with chlorpromazine, isoniazid, and amoxicillin‐clavulanic acid.
Symptomatic Cardiotoxicity Associated with 5‐Fluorouracil
Authors: Meyer Christine C. , Calis Karim Anton , Burke Laurie B. , Walawander Cynthia A. , Grasela Thaddeus H.
Published: October 2023

A prospective cohort study was conducted in 35 hospitals with oncology units to determine the incidence of symptomatic cardiotoxicity in patients receiving continuous infusions of 5‐fluorouracil (5‐FU), and to identify risk factors that could contribute to the development of 5‐FU‐associated cardiotoxicity. A sample of 483 patients [197 (41%) women, overall average age ± SD 60.9 ± 11.9 yrs] were followed for one cycle of 5‐FU infusion. Thirty‐eight (7.9%) patients had abrupt termination of the infusion. There were 9 (1.9%) cases of suspected or documented cardiotoxic events. Cardiotoxicity occurred in 7 (3.35%) of 209 patients receiving their first course of 5‐FU and in 2 (0.73%) other patients (p=0.044). Based on univariate analysis, the following patient groups were at elevated risk of cardiotoxicity: those with preexisting cardiac disease (RR=6.83, p=0.0023); patients receiving calcium channel blockers (RR=4.75, p=0.014); those receiving nitrates (RR=9.18, p=0.007); and patients receiving concomitant etoposide (RR=10.32, p=0.022). Patients with underlying cardiac disease require close monitoring while receiving continuous infusions of 5‐FU. They should be observed for signs and symptoms of cardiotoxicity, and vital signs should be measured frequently. Continued reporting of 5‐FU‐associated cardiotoxicity is necessary to identify other patients at risk.
Impact of a Pharmacist‐Based Consult Service on Nutritional Rehabilitation of Nonambulatory Patients with Severe Developmental Disabilities
Authors: Brown Rex O. , Dickerson Roland N. , Hak Emily B. , Matthews J. Barret , Hak Lawrence J.
Published: October 2023

A pharmacist consult service was developed to evaluate the appropriateness of enteral feeding through a permanent ostomy in 24 nonambulatory patients with severe developmental disabilities. Several problems with enteral nutrition were identified. Policies to improve them were instituted, and several educational presentations were made. Pharmacists' actions were implemented, including assessment of energy needs by indirect calorimetry and rearrangement of enteral feeding schedules to achieve optimal nutrition support and pharmacotherapy administration. By the fourth month of the consult service, body weight in these patients increased from 101 ± 6% of baseline to 109 ± 7% (p<0.05). Weight continued to increase through the seventh month of the consult service to 116 ± 12% of baseline (p<0.0001). Measured resting energy expenditure for the group was 889 ± 170 kcal/day compared with the predicted 1055 ± 163 kcal/day.
Ticlopidine‐Induced Elevated Liver Enzymes
Authors: Klepser Teresa B. , Jogerst Gerald J.
Published: October 2023

Ticlopidine is a reasonable alternative to prevent stroke and myocardial infarction when aspirin is intolerable or ineffective. It can be limited, however, by its severe adverse effect profile. The most worrisome of these is neutropenia, although clinicians must be mindful of other adverse events that may be caused by this drug. A patient experienced elevated liver function tests probably due to ticlopidine.
Precipitous Fall in Platelet Count with Anagrelide: Case Report and Critique of Dosing Recommendations
Authors: McCune Jeannine S. , Liles Dark , Lindley Celeste
Published: October 2023

Thrombotic and hemorrhagic events may result from high circulating concentrations of platelets (> 1,000,000/mm3), and measures to reduce the platelet count are indicated in symptomatic or extreme thrombocytosis. The platelet count can be decreased quickly by plasmapheresis, but the effect is transient. Patients with thrombocytosis secondary to a myeloproliferative disease, such as chronic myelogenous leukemia (CML), frequently require more sustained suppression of the platelet count. Hydroxyurea, busulfan, and interferon are used to maintain a lower platelet count but are occasionally ineffective or intolerable. An alternative to these therapies is anagrelide, a quinazolin derivative that was approved by the Food and Drug Administration in March 1997. Because current dosing guidelines for anagrelide are scarce, the dosing method of the Anagrelide Study Group that published the largest study to date on the drug's efficacy in thrombocytosis was followed. Two unexpected episodes of anagrelide‐induced thrombocytopenia occurred despite following these dosing methods. This prompted a critical evaluation of the pharmacodynamic response and the appropriateness of anagrelide dosage recommendations. A case of thrombocytosis treated with anagrelide in a patient with CML is described.
Evaluation of the Total Cost of Treating Elderly Hypertensive Patients with ACE Inhibitors: A Comparison of Older and Newer Agents
Authors: Small Ralph E. , Freeman‐Arnold Susan B. , Goode Jean‐Venable R. , Pyles Michael A.
Published: October 2023

We compared total costs and adherence to the regimen of older versus newer angiotensin‐converting enzyme (ACE) inhibitors for the treatment of elderly patients with hypertension. A computer search using the data base of a health care insurer identified 6176 subjects age 65 years or older who had ICD‐9 coding for hypertension only and had a new prescription for an ACE inhibitor dispensed between April 1, 1992, and January 31, 1993. Subjects receiving concurrent antihypertensive drugs were included. Total cost of therapy included acquisition costs for the ACE inhibitors and concurrent antihypertensive agents, and nondrug costs. Other costs were laboratory tests, hospitalization, and clinic visits associated with monitoring outcomes of antihypertensive therapy. Total median cost per month was greater for older than for newer agents, $59.82 versus $53.09 (p<0.0009). The mean percentage of patients complying with therapy as determined by refill data was greater with newer than with older agents, 66% versus 58% (p<0.0001). Based on our results, newer ACE inhibitors should be first‐line antihypertensive therapy in elderly patients. They also should be considered for elderly patients who are unresponsive to older ACE inhibitors.
Methemoglobinemia Caused by Topical Benzocaine
Authors: Guerriero Stephanie E.
Published: October 2023

Benzocaine‐induced methemoglobinemia is a rare but life‐threatening event. The use of topical benzocaine spray in a 77‐year‐old woman during endoscopic retrograde cholangiopancreatogram produced marked cyanosis and mrthemoglobin levels consistent with methemoglobinemia. Immediate recognition and prompt treatment of the disorder are essential to decrease morbidity and mortality.
Mechanical Ventilation and Pharmacologic Strategies for Acute Respiratory Distress Syndrome
Authors: Cawley Michael J. , Skaar Debra J. , Anderson Harry L. , Hanson C. William
Published: October 2023

Acute or adult respiratory distress syndrome (ARDS) contributes to mortality and morbidity in the intensive care environment. Appropriate application of microprocessor‐controlled mechanical ventilatory support, pathophysiology of the disease, and new pharmacologic modalities are currently being investigated. Mechanical ventilation is usually begun when respiratory failure is caused by alveolar hypoventilation or hypoxia. Primary choices for this therapy are control‐mode ventilation, assist‐control ventilation, pressure‐control ventilation, intermittent mandatory ventilation, and synchronized intermittent mandatory ventilation with the addition of positive end‐expiratory pressure. Patients who deteriorate despite these interventions may require alternative modes of ventilation. Pharmacologic agents in ARDS is important due to the multifactorial pathophysiologic and pharmacodynamic processes that are part of the disease. Clinical studies will continue to determine advantageous agents. Unfortunately, no convincing data exist that any pharmacologic or nonpharmacologic strategy is superior for the support of these patients or results in a better outcome than others.
Changes in Luminal Fluid Protein Composition in the Rat Cauda Epididymidis Following Partial Sympathetic Denervation
Authors: RICKER DEBORAH D. , CHAMNESS SHELLY L. , HINTON BARRY T. , CHANG THOMAS S. K.
Published: October 2023

ABSTRACT: Sympathetic denervation of the rat cauda epididymidis by surgical removal of the inferior mesenteric ganglion (IMG) results in an excessive accumulation of sperm in the cauda epididymidis as well as significant changes in cauda sperm motility and cauda epididymal gross histology. The objective of the present study was to determine if the cauda‐specific changes in sperm storage, sperm motility, and epididymal histology following the loss of sympathetic innervation were accompanied by changes in the protein composition of epididymal fluid. One and 4 weeks after surgical IMG removal or sham operations, luminal fluid obtained from the caput and cauda epididymidis and cauda epididymal sperm‐associated proteins were subjected to two‐dimensional polyacrylamide gel electrophoresis (2‐D PAGE) and silver‐stained proteins were quantitated. One week after IMG removal, two cauda epididymal fluid (CEF) proteins (2 and 13) had increased 43% and 49%, respectively, whereas four CEF proteins (5, 8, 9, and 19) had decreased between 30% and 73% compared to controls. Four weeks after IMG removal, changes in CEF proteins observed 1 week following surgery were no longer present, but the staining intensities of three additional CEF proteins (11, 12, and 18) were reduced an average of 70% compared to control CEF proteins. By obstructing the cauda epididymidis, we confirmed that the changes in CEF protein composition observed following IMG removal were not the result of sperm accumulation but were due directly to the loss of innervation; the staining intensity of CEF protein 2 increased as a result of excessive sperm accumulation in the cauda epididymidis both in the presence and absence of innervation from the IMG. No significant changes in caput epididymal fluid proteins or cauda epididymal sperm‐associated proteins were detected following IMG removal. These data show that the protein composition of rat CEF is significantly affected by the loss of sympathetic innervation and suggest that neuronal input may play an important role in the maintenance of epididymal function.
Breakthroughs in Andrology Chloride Efflux during the Progesterone‐Initiated Human Sperm Acrosome Reaction Is Inhibited by Lavendustin A, a Tyrosine Kinase Inhibitor
Authors: MEIZEL STANLEY , TURNER KENNETH O.
Published: October 2023

ABSTRACT: Previous studies showed that progesterone (P) can initiate the mammalian sperm acrosome reaction (AR) in vitro and that a sperm GABAA‐like receptor/CI− channel is involved in an essential Cl− efflux mediated by P during the AR. Here, we show that lavendustin A, a potent, specific inhibitor of tyrosine kinase activity, strongly inhibits the P‐initiated human AR and the essential P‐me‐diated Cl− efflux. Lavendustin B, a weak tyrosine kinase inhibitor, had no significant effect. These results suggest that, as part of AR initiation, P mediates tyrosine phosphorylation of the sperm GABAA‐like receptor/Cl− channel.
Expression of c‐KIT and Its Ligand, Stem Cell Factor, in Normal and Subfertile Human Testicular Tissue
Authors: SANDLOW JAY I. , FENG HUAI‐LIANG , COHEN MICHAEL B. , SANDRA ALEXANDER
Published: October 2023

ABSTRACT: The c‐KIT proto‐oncogene encodes for a transmembrane receptor and is associated with maturation of several cell types, including germ cells. The ligand of the receptor has been identified as stem cell factor (SCF). Loss or alteration of the expression of either of these factors leads to anemia, albinism, and/or sterility in mice. We examined the expression of c‐KIT and SCF by immunohistochemistry in specimens from normal and infertile human testis. All specimens were obtained in the evaluation of male subfertility. We were able to demonstrate staining for c‐KIT in Leydig cells in all specimens. Normal testis stained for c‐KIT in the cytoplasm of early spermatogenic cells, as well as the acrosomal granules of the round spermatids and the acrosome of testicular spermatozoa. However, staining in testis demonstrating maturation arrest failed to demonstrate acrosomal staining, and Sertoli‐only specimens demonstrated staining for c‐KIT in Leydig cells only. The results for SCF demonstrated an overall uniform staining of Leydig cells in all specimens. The intensity of staining of Sertoli cells increased from normal to maturation arrest to Sertoli‐only specimens. Germ cell staining was consistently negative. We hypothesize that these staining patterns for SCF are due to either lack of staining of the receptor‐ligand complex or overexpression of the kit ligand in tissue that does not express the kit receptor. It appears that the c‐kit receptor is expressed in the acrosome of developing germ cells, as well as in Leydig cells and early spermatogenic cells, suggesting a role in the acrosome reaction, as well as germ cell maturation and differentiation.
Current Perspectives on Hematospermia: A Review
Authors: MUNKELWITZ ROBERT , KRASNOKUTSKY SVETLANA , LIE JACKY , SHAH SOVRIN M. , BAYSHTOK JULIA , KHAN S. ALI
Published: October 2023

ABSTRACT: Hematospermia is a disconcerting symptom that produces extreme anxiety in sexually active male patients. To understand the pathophysiology of hematospermia, the anatomy of the ejaculatory system and neurophysiology of emission and ejaculation is essential. Emission and ejaculation must be present for hematospermia to occur. Hematospermia may be the result of inflammation, infection, ductal obstruction or cysts, neoplasms, vascular abnormalities, and systemic or iatrogenic factors. Most patients promptly consult a urologist after an episode of hematospermia. History and physical examination are often unrevealing and the judicious use of imaging modalities, such as transrectal ultrasound, MRI, and rigid or flexible endoscopy, may be diagnostic. Unless the specific etiology is defined, most cases are managed expectantly. We review the etiology of hematospermia and an algorithm is provided for the diagnosis and management.