Michael Schachter

Bio: Michael Schachter is an academic researcher from Imperial College London. The author has contributed to research in topics: Vascular smooth muscle & Cholesterol. The author has an hindex of 31, co-authored 100 publications receiving 4663 citations. Previous affiliations of Michael Schachter include National Institutes of Health & St Mary's Hospital.

Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update

Abstract: Statins are the treatment of choice for the management of hypercholesterolaemia because of their proven efficacy and safety profile. They also have an increasing role in managing cardiovascular risk in patients with relatively normal levels of plasma cholesterol. Although all statins share a common mechanism of action, they differ in terms of their chemical structures, pharmacokinetic profiles, and lipid-modifying efficacy. The chemical structures of statins govern their water solubility, which in turn influences their absorption, distribution, metabolism and excretion. Lovastatin, pravastatin and simvastatin are derived from fungal metabolites and have elimination half-lives of 1-3 h. Atorvastatin, cerivastatin (withdrawn from clinical use in 2001), fluvastatin, pitavastatin and rosuvastatin are fully synthetic compounds, with elimination half-lives ranging from 1 h for fluvastatin to 19 h for rosuvastatin. Atorvastatin, simvastatin, lovastatin, fluvastatin, cerivastatin and pitavastatin are relatively lipophilic compounds. Lipophilic statins are more susceptible to metabolism by the cytochrome P(450) system, except for pitavastatin, which undergoes limited metabolism via this pathway. Pravastatin and rosuvastatin are relatively hydrophilic and not significantly metabolized by cytochrome P(450) enzymes. All statins are selective for effect in the liver, largely because of efficient first-pass uptake; passive diffusion through hepatocyte cell membranes is primarily responsible for hepatic uptake of lipophilic statins, while hydrophilic agents are taken up by active carrier-mediated processes. Pravastatin and rosuvastatin show greater hepatoselectivity than lipophilic agents, as well as a reduced potential for uptake by peripheral cells. The bioavailability of the statins differs greatly, from 5% for lovastatin and simvastatin to 60% or greater for cerivastatin and pitavastatin. Clinical studies have demonstrated rosuvastatin to be the most effective for reducing low-density lipoprotein cholesterol, followed by atorvastatin, simvastatin and pravastatin. As a class, statins are generally well tolerated and serious adverse events, including muscle toxicity leading to rhabdomyolysis, are rare. Consideration of the differences between the statins helps to provide a rational basis for their use in clinical practice.

Prescribing errors in hospital inpatients: their incidence and clinical significance

Abstract: Background: It has been estimated that 1–2% of US inpatients are harmed by medication errors, the majority of which are errors in prescribing. The UK Department of Health has recommended that serious errors in the use of prescribed drugs should be reduced by 40% by 2005; however, little is known about the current incidence of prescribing errors in the UK. This pilot study sought to investigate their incidence in one UK hospital. Methods: Pharmacists prospectively recorded details of all prescribing errors identified in non-obstetric inpatients during a 4 week period. The number of medication orders written was estimated from a 1 in 5 sample of inpatients. Potential clinical significance was assessed by a pharmacist and a clinical pharmacologist. Results: About 36 200 medication orders were written during the study period, and a prescribing error was identified in 1.5% (95% confidence interval (CI) 1.4 to 1.6). A potentially serious error occurred in 0.4% (95% CI 0.3 to 0.5). Most of the errors (54%) were associated with choice of dose. Error rates were significantly different for different stages of patient stay (p<0.0001) with a higher error rate for medication orders written during the inpatient stay than for those written on admission or discharge. While the majority of all errors (61%) originated in medication order writing, most serious errors (58%) originated in the prescribing decision. Conclusions: There were about 135 prescribing errors identified each week, of which 34 were potentially serious. Knowing where and when errors are most likely to occur will be helpful in designing initiatives to reduce them. The methods developed could be used to evaluate such initiatives.

What is a prescribing error

Abstract: N Barber, professor of the practice of pharmacy M Schachter, senior lecturer and honorary consultant physician Objective—To develop a practitioner led definition of a prescribing error for use in quantitative studies of their incidence. Design—Two stage Delphi technique. Subjects—A panel of 34 UK judges, which included physicians, surgeons, pharmacists, nurses and risk managers. Main outcome measures—The extent to which judges agreed with a general definition of a prescribing error, and the extent to which they agreed that each of 42 scenarios represented a prescribing error. Results—Responses were obtained from 30 (88%) of 34 judges in the first Delphi round, and from 26 (87%) of 30 in the second round. The general definition of a prescribing error was accepted. The panel reached consensus that 24 of the 42 scenarios should be included as prescribing errors and that five should be excluded. In general, transcription errors, failure to communicate essential information, and the use of drugs or doses inappropriate for the individual patient were considered prescribing errors; deviations from policies or guidelines were not. Conclusions—Health care professionals are in broad agreement about the types of events that should be included and excluded as prescribing errors. A general definition of a prescribing error has been developed, together with more detailed guidance regarding the types of events that should be included. This definition allows the comparison of prescribing error rates among different prescribing systems and different hospitals, and is suitable for use in both research and clinical governance initiatives. (Quality in Health Care 2000;9:232–237) Key Words: prescribing errors; medication errors; definition of error

Statin-fibrate combination therapy for hyperlipidaemia: a review

Abstract: Statins and fibrates are well-established treatments for hyperlipidaemias and the prevention of vascular events. However, fibrate + statin therapy has been restricted following early reports of rhabdomyolysis that mainly involved gemfibrozil, originally with bovastatin, and recently, with cerivastatin. Despite this limitation, several reports describing combination therapy have been published. This review considers these studies and the relevant indications and contraindications. Statin + fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids ornicotinic acid) did not achieve lipid targets or is impractical. Combination therapy should be hospital-based and reserved for high-risk patients with a mixed hyperlipidaemia characterised by low density lipoprotein cholesterol (LDL) >2.6 mmol/l(100 mg/dl, high density lipoprotein cholesterol (HDL) 5.6 mmol/l (500 mg/dl. These three 'goals' are individually mentioned in guidelines. Patients should have normal renal, liver and thyroid function tests and should not be receiving therapy with cyclosporine, protease inhibitors or drugs metabolised through cytochrome P450 (especially 3A4). Combination therapy is probably best conducted using drugs with short plasma half-lives; fibrates should be prescribed in the morning and statins at night to minimise peak dose interactions. Both drug classes should be progressively titated from low doses. Regular (3-monthly) monitoring of liver function and creatine kinase is required. In conclusion, fibrate + statin therapy remains an option in high-risk patents. However, long-term studies involving safety monitoring and vascular endpoints are required to demonstrate the efficacy of this regimen.

Dopamine Receptors: From Structure to Function

Abstract: Missale, Cristina, S. Russel Nash, Susan W. Robinson, Mohamed Jaber, and Marc G. Caron. Dopamine Receptors: From Structure to Function. Physiol. Rev. 78: 189–225, 1998. — The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2 , D3 , and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine s...

Regulatory functions of the vascular endothelium.

Abstract: William harvey, when studying the circulation of the blood, must have recognized that "In sound and living vessels the blood remains fluid, but it coagulates in dead ones" (Ernst Brucke, 1857). Joseph Lister (1909) provided further evidence for an active role of blood vessels in maintaining the liquidity of blood. The vascular endothelium, which envelops the circulating blood in a continuous monolayer, is mainly responsible for this function. Over the past 20 years numerous other important functions have been discovered. For instance, the outer surface of the endothelial cell contains angiotensin-converting enzyme, which catalyzes the formation of the vasoconstrictor angiotensin . . .

A Comprehensive Review on Metabolic Syndrome

Abstract: Metabolic syndrome is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increases the risk of cardiovascular disease, type 2 diabetes mellitus, and all cause mortality. Insulin resistance, visceral adiposity, atherogenic dyslipidemia, endothelial dysfunction, genetic susceptibility, elevated blood pressure, hypercoagulable state, and chronic stress are the several factors which constitute the syndrome. Chronic inflammation is known to be associated with visceral obesity and insulin resistance which is characterized by production of abnormal adipocytokines such as tumor necrosis factor α , interleukin-1 (IL-1), IL-6, leptin, and adiponectin. The interaction between components of the clinical phenotype of the syndrome with its biological phenotype (insulin resistance, dyslipidemia, etc.) contributes to the development of a proinflammatory state and further a chronic, subclinical vascular inflammation which modulates and results in atherosclerotic processes. Lifestyle modification remains the initial intervention of choice for such population. Modern lifestyle modification therapy combines specific recommendations on diet and exercise with behavioural strategies. Pharmacological treatment should be considered for those whose risk factors are not adequately reduced with lifestyle changes. This review provides summary of literature related to the syndrome's definition, epidemiology, underlying pathogenesis, and treatment approaches of each of the risk factors comprising metabolic syndrome.

A circadian gene expression atlas in mammals: Implications for biology and medicine

Abstract: To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional “rush hours” preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spliceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.