Liliana Rogozea

Benign Ethnic Neutropenia and Clozapine Use: A Systematic Review of the Evidence and Treatment Recommendations

OBJECTIVEnTo evaluate the epidemiology, pathobiology, and management of benign ethnic neutropenia and determine the extent to which these factors should influence measures designed to avoid clozapine-induced agranulocytosis.nnnDATA SOURCESnA structured MEDLINE search with no language limitation was performed from database inception until March 31, 2015, using the terms clozapine and benign ethnic neutropenia. Retrieved articles were cross-checked for additional relevant studies.nnnSTUDY SELECTIONnIncluded in the study were articles that reported on the prevalence, etiology, and complications of benign ethnic neutropenia and the hematologic outcome of clozapine treatment in patients with this condition.nnnDATA EXTRACTIONnStudy results that documented the epidemiology, pathobiology, and clozapine utilization in persons of African, Arabian, and Mediterranean descent with a neutrophil count in the 1,000-1,800/mm³ range.nnnRESULTSnThe search identified 342 publications. Forty-two articles described the epidemiology, pathobiology, and management of benign ethnic neutropenia. Of these, 12 articles described patients with benign ethnic neutropenia whose neutrophil count decreased during treatment with clozapine. Persons with benign ethnic neutropenia do not have signs of impaired phagocytosis, and the frequency, severity, and outcome of their infections are similar to those observed in the general population. These features suggest that a neutrophil count > 1,000/mm³ is safe for initiating and/or resuming clozapine therapy.nnnCONCLUSIONSnThe presence of benign ethnic neutropenia should not prevent treatment with clozapine. Patients with benign ethnic neutropenia who develop a clozapine-induced decrease in the neutrophil count, but have no evidence of infection or impaired phagocytosis, may resume clozapine as soon as they have > 1,000 neutrophils/mm³.

The Discovery of Statins.

Not too long ago, the 1985 Nobel Prize laureates Michael Brown and Joseph Goldstein noted that “When we started out (in 1973), it seemed like our fellow scientists were only interested in 3 areas: neuroscience, development, and cancer. So, we chose cholesterol. None of our superstar contemporaries showed any interest in cholesterol. They used to ask us whywe worked on it—it’s just an amorphous piece of glob, they would say.” The prevailing sentiment in the early 1970’s was easy to understand, because the effect of reducing cholesterol level on the incidence of coronary events had not been demonstrated. In 1965–1967, the World Health Organization undertook the task of performing the first prospective trial of primary prevention of ischemic heart disease. Using a simple, unifactorial, double-blind, placebo-controlled, and randomized study design, the investigators recruited 15,745 clinically healthy males aged 30–59 years residing in the capitals of Hungary, Scotland, and Czechoslovakia. The persons assigned to the intervention group received 1.6 grams of clofibrate daily. The participants were followed for an average of 5.3 years. At the end of the observation period, the incidence of coronary events (fatal and nonfatal myocardial infarction, angina pectoris with and without abnormal electrocardiogram, and abnormal electrocardiograms without chest pain) was 20% lower in the intervention group than in the control patients with high cholesterol levels, a statistically significant difference. Most of the difference was due to a substantial reduction in cases of nonfatal myocardial infarction and correlated with a 9% decrease in the serum cholesterol level. The findings were published in 1979 and suggested that better cholesterollowering interventions were needed to amplify these promising results. The discovery of statins began with the demonstration that certain fungal metabolites decrease cholesterol synthesis in vitro by inhibiting the 3-hydroxy-3 methylglutaryl (HMG)–Coenzyme A reductase, the ratelimiting enzyme in the hepatic cholesterol synthesis. The first experiment was performed in the Fermentation Research Laboratories of Sankyo Company, Ltd, a Japanese pharmaceutical manufacturer, and was published in 1976. The metabolites used, named ML-236A and ML-236B had been isolated from cultures of Penicillium citrinum. The compounds were prepared in lactone and acid forms and their effect tested on HMG-CoA reductase obtained from rat liver microsomes. The sodium salt of the ML-236B was the most effective of the 4 compounds. ML-236B in a dosage range of 50–150 mg/d was used by the same group to treat a group of 11 patients with primary hypercholesterolemia. The data were in print in March, 1980 and indicated that the serum cholesterol levels decreased on average by 27% (range, 11%–37%) after 4–8 weeks. The work performed in Japan was continued a few years later by researchers from Merck Sharp & Dohme Research Laboratories in the United States using a strain of Aspergillus terreus obtained from a Spanish soil isolation program. The final compound, named mevinolin, was obtained in a multistage fermentation process. In a first step, cell propagation occurred in a medium containing tomato paste, oat flour, corn steep liqueur, and dextrose. The second step, leading to product formation, took place in medium peptonized milk, yeast extract, and dextrose. After treatment with ethyl acetate, the slurry was filtered, dried over magnesium sulfate, and stripped of the residual solvent with toluene. After further purification procedures using ethyl acetate and methylene chloride, the process yielded 111 g of mevinolin crystals of the 200 gallon culture of A. terreus. The substance was then converted to a sodium salt and its effect on HMG-CoA reductase and cholesterol levels was compared with that of ML-236, which had been obtained as a gift from Sankyo Co. Mevinolin was shown to have a substantially stronger inhibitor of HMG-coenzyme A reductase than ML-236B in multiple animal experimental models. The clinical testing of mevinolin (soon to be renamed lovastatin) was entrusted by Merck in 1982 to Scott Grundy and David Bilheimer of the University of Texas Southwestern in Dallas and to Roger Illingsworth of Oregon Health Sciences University. Joined by Brown and Goldstein at Southwestern, the Dallas-based group showed that mevinolin stimulates receptor-mediated clearance of low-density lipoprotein from plasma in 5 patients with familial hypercholesterolemia heterozygotes, particularly when combined with interventions that lead to bile acid depletion. At the same time, in 1984, Illingworth reported 12 patients with the same American Journal of Therapeutics 23, e980–e981 (2016)

Multiple Drug-Intolerant Hypertension

Clinical Features: The term multiple drug intolerance (MDI) is attributed to patients who experience adverse drug reactions to more than 3 different classes of medication without a known immunological mechanism. A special attention should be given to multiple drug-intolerant hypertension (MDI-HTN) that is a cause of drop out from treatment and consequent poor blood pressure control. Patients with MDIs account for 2%–5% of all population. The patient we present is a 63-year-old man with third-degree hypertension identified with intolerance to drugs from 4 major classes of antihypertensive medication. Therapeutic Challenge: Patients with MDIs are difficult to treat. They frequently also have numerous comorbidities and high cardiovascular risk. It is recognized that guidelines for the management of hypertension do not include an algorithm of action in situations of MDIs to medication. Solution: We chose to use a recently proposed four-step algorithm for the management of MDI-HTN. A 1-month follow-up program was established. Weekly visits were scheduled to elicit about side effects and measure blood pressure . Ambulatory blood pressure monitoring was performed after a month. The strategy was first to reuse medication from classes the patient was intolerant to, but in smaller doses and in combinations. Among same class members, we have chosen those with less adverse effects. Not all steps within the algorithm were followed since our patient did not need alternative formulation as liquid or transdermal ones. Anxiety medication was prescribed as nonlicensed antihypertensive medication. At the end of the follow-up month, blood pressure control was satisfactory, 24-hour ambulatory blood pressure monitoring was 135.5/83.0 mm Hg, and the patient did not claim any adverse drug reactions.

Vitamin K Antagonists Versus Novel Oral Anticoagulants for Elective Electrical Cardioversion of Atrial Fibrillation

Background: The management strategy for patients with atrial fibrillation (AF) is often very complex, electrical cardioversion (EC) being often used to restore sinus rhythm in those patients. The increased risk of thromboembolic complications was lowered using anticoagulation therapy. Usually, the anticoagulation was achieved using vitamin K antagonists (VKAs), but over the last years we witnessed a wide implementation of the novel oral anticoagulants (NOACs). Study Question: Study question was to compare the efficacy of NOACs versus VKAs in patients undergoing elective EC for persistent AF, by assessing the presence of left atrial spontaneous contrast and left atrial thrombi (LACS), as well as the occurrence of the thromboembolic events in the first month after the procedure. Study Design: A prospective study, including patients with persistent AF enrolled between January 1, 2015 and December 31, 2016, was conducted in 2 tertiary cardiology clinics. In all these patients, a management strategy based on EC was considered for the treatment of the disease. All patients received anticoagulant therapy for at least 3 weeks before cardioversion. The data of 103 patients were analyzed. Results: The patients were divided into 2 groups: group A—VKAs treated—included 45 patients (43.68%), mean age 65.3 ± 12.47, 36% women; group B—NOACs treated—included 58 patients (56.31%), mean age 66.4 ± 9.79, 46% women. There was a trend toward higher incidence of left atrial thrombi in group B (16.28%) versus group A (7.69%), but the difference was not statistically significant (P = 0.5). The incidence of LACS was 40% in group A and 29% in group B, (P = 0.54). Conclusion: There are no statistically significant differences between the transesophageal echocardiography characteristics of left atrium and left atrial appendage examinations in the patients who received anticoagulation with VKAs as compared to patients who received anticoagulation with NOACs.

Penicillin for Pneumococcal Pneumonia.

“In the Mortality Bills,” wrote William Osler in 1905, “pneumonia is an easy second, to tuberculosis; indeed in many cities the death-rate is now higher and it has become, to use the phrase of Bunyan, the captain of the men of death.” The statement remained true for another four decades. Yet, in only a few years, in the 1940s, a new treatment for this frequently fatal disease changed its outcome in a profound and lasting way. The standard of care for pneumococcal pneumonia in the United States in 1943, as defined by Russell Cecil in that year’s edition of his Textbook of Medicine by American Authors, focused on the general care of the patient, relief of symptoms, and specific measures for the treatment of infection. The introduction of sulfonamides was still considered revolutionary on the basis of a report from Birmingham, England, which had indicated a fatality rate of 8% in 100 cases treated with sulfapyridine and 27% in a control group in 1938. The oral administration of the drug was frequently associated with severe nausea, followed sometimes by intractable vomiting. Intravenous dosing did not prove effective, and the concentration of the drug for intramuscular route had not been established. A second molecule, sulfathiazole, had become available in 1939 and produced a significantly lower incidence of nausea. Just 1 year later, trials indicated that a third sulfonamide derivative, sulfadiazine, was just as effective, but less toxic than its predecessors. In the practice of Cecil on the wards of New York Hospital and Bellevue Hospital, the initial oral dose of sulfadiazine ranged from 2 to 4 gm and therapy continued with 1 gm every 4 hours until the patient remained afebrile for 24–72 hours. A soluble form of the drug was also available for “emergency” intravenous administration, usually as a single dose of 5 gm. Sodium bicarbonate was added to the regimen in dosages sufficient to maintain the urine alkaline and thus prevent crystalluria, a common adverse effect of sulfonamides. Cecil described in detail the potential for serious and potentially fatal toxic effects of sulfonamides, such as acute renal failure, leukopenia, hemolytic anemia, hepatitis, and peripheral neuropathy and outlined the principle for their recognition and prevention. He also mentioned his own observations with regard to acquired hypersensitivity, characterized by fever, morbilliform or urticarial rash, angioneurotic edema, and systemic reactions. “Sulfonamide-fast” pneumococci were first identified in the Alexander Fleming’s laboratory in 1939. Of great concern was the demonstration that pneumococci could change from susceptible to resistant during the course of treatment, a phenomenon that contributed to the mortality rate in patients with pneumonia. In the case of a 62year-old patient admitted gravely ill to Bellevue Hospital in New York City with pneumonic consolidations of the right middle and lower lobes and type 1 pneumococcus in blood culture, the fever decreased by the third day during treatment with sulfadiazine intravenously and orally but rose again 1 day later. A blood culture obtained on the eighth hospital day indicated persistent bacteremia despite therapeutic plasma levels of sulfadiazine. The patient remained acutely ill until she was injected with type 1 antipneumococcal rabbit serum. A search for an alternative form of chemotherapy was immediately started, and pioneering animal experiments performed by William Tillett’s group at Bellevue in 1942 indicated that all sulfadiazine-resistant strains of pneumococci were sensitive to penicillin. Systematic laboratory investigations of bacterial inhibition by penicillin were started by Howard Florey in 1929 and concluded successfully at Oxford after Ernst Chain joined this effort in 1938. A small number of victims of the German bombing of England were treated with penicillin in London in the winter of 1940– 1941. As the existing supply was almost immediately exhausted, Florey came to the United States in July 1941 to look for ways of starting large-scale production of the drug. He met with officials from the Department of Agriculture who understood the importance of the project. An agreement was reached with the US Office of Scientific Research and Development to start production of naturally fermented penicillin at the Northern Regional Research Laboratory in Peoria, IL. The facility had already been involved in fermentation experiments using corn-steep liquid, a by-product of corn starch manufacture, which proved to be an adequate medium for the culture of penicillin-producing molds. The results of the first clinical trial of penicillin for pneumococcal pneumonia in the United States were communicated on November 4, 1943 at a meeting of the New York Academy of Medicine. The 46 patients described in the report had been treated with penicillin at Bellevue in the 1942–1943 season. A second group of 61 patients was treated in the 1943–1944 season, and the effect of penicillin in the entire sample (N 5 110) was submitted for publication to the Journal of Clinical American Journal of Therapeutics 23, e326–e327 (2016)

Medical Rapid Response in Psychiatry: Reasons for Activation and Immediate Outcome

Rapid response teams are used to improve the recognition of acute deteriorations in medical and surgical settings. They are activated by abnormal physiological parameters, symptoms or clinical concern, and are believed to decrease hospital mortality rates. We evaluated the reasons for activation and the outcome of rapid response interventions in a 222-bed psychiatric hospital in New York City using data obtained at the time of all activations from January through November, 2012. The primary outcome was the admission rate to a medical or surgical unit for each of the main reasons for activation. The 169 activations were initiated by nursing staff (78.7xa0%) and psychiatrists (13xa0%) for acute changes in condition (64.5xa0%), abnormal physiological parameters (27.2xa0%) and non-specified concern (8.3xa0%). The most common reasons for activation were chest pain (14.2xa0%), fluctuating level of consciousness (9.5xa0%), hypertension (9.5xa0%), syncope or fall (8.9xa0%), hypotension (8.3xa0%), dyspnea (7.7xa0%) and seizures (5.9xa0%). The rapid response team transferred 127 (75.2xa0%) patients to the Emergency Department and 46 (27.2xa0%) were admitted to a medical or surgical unit. The admission rates were statistically similar for acute changes in condition, abnormal physiological parameters, and clinicians’ concern. In conclusion, a majority of rapid response activations in a self-standing psychiatric hospital were initiated by nursing staff for changes in condition, rather than for policy-specified abnormal physiological parameters. The findings suggest that a rapid response system may empower psychiatric nurses to use their clinical skills to identify patients requiring urgent transfer to a general hospital.