The pharmacokinetics and pharmacodynamics of thiopental as used in lethal injection

This paper will concentrate on the pharmacokinetics and pharmacodynamics of thiopental. As applied here, pharmacokinetics is the study of the concentration of thiopental as a function of time in tissues (particularly brain), while pharmacodynamics is the study of the effects of thiopental (particularly the production of unconsciousness and impairment of the heart’s ability to circulate blood). By using generally accepted computer modeling techniques, and considering the wealth of published studies on the pharmacology of thiopental, we can prepare predictions of such relevant parameters as the onset (how long it takes for the inmate to become unconscious) and duration (how long the inmate would remain unconscious) of the pharmacological effects of thiopental

Treatment of Cancer Pain

Pain is one of the first concerns most cancer patients express when newly diagnosed or meeting a new physician. They are concerned about how much pain they presently have, how much pain they are likely to experience, and their physicians’ commitment to treating cancer pain. The reality is that many cancer patients will never experience pain during their course and for those that do, the great majority can be well-managed with the tools described in this chapter in Cancer Concepts: A Guidebook for the Non-Oncologist. It is incumbent on every physician to understand the mechanisms of cancer pain and the fundamentals of treating it.https://escholarship.umassmed.edu/cancer_concepts/1024/thumbnail.jp

A case of malignant hyperthermia during anesthesia induction with sevoflurane -A case report-

We experienced a case of malignant hyperthermia (MH) in 6-year-old boy during anesthesia induction for strabismus surgery. It has been generally reported that sevoflurane can induce the delayed onset of MH in the absence of succinylcholine. Our case of MH was elicited after about 2-3 min of sevoflurane administration with N2O, O2 and rocuronium. However, we successfully treated the patient by early recognition of his condition and administering symptomatic treatment and dantrolene

Scottish and Newcastle antiemetic pre-treatment for paracetamol poisoning study (SNAP)

BACKGROUND: Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen. METHODS/DESIGN: We designed a double-blind trial using a 2 × 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4 mg IV was compared against placebo on nausea and vomiting following the standard (20.25 h) regimen, or a novel 12 h NAC regimen in paracetamol poisoning. Each delivered 300 mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course. DISCUSSION: This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30 years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk. TRIAL REGISTRATION: EudraCT number 2009-017800-10, ClinicalTrials.gov IdentifierNCT0105027

Morphine Postconditioning Attenuates ICAM-1 Expression on Endothelial Cells

The purpose of this study is to determine 1) whether morphine postconditiong (MPostC) can attenuate the intercellular adhesion molecules-1 (ICAM-1) expression after reoxygenation injury and 2) the subtype(s) of the opioid receptors (ORs) that are involved with MPostC. Human umbilical vein endothelial cells (HUVECs) were subjected to 6 hr anoxia followed by 12 hr reoxygenation. Three morphine concentrations (0.3, 3, 30 µM) were used to evaluate the protective effect of MPostC. We also investigated blockading the OR subtypes' effects on MPostC by using three antagonists (a µ-OR antagonist naloxone, a κ-OR antagonist nor-binaltorphimine, and a δ-OR antagonist naltrindole) and the inhibitor of protein kinase C (PKC) chelerythrine. As results, the ICAM-1 expression was significantly reduced in the MPostC (3, 30 µM) groups compared to the control group at 1, 6, 9, and 12 hours reoxygenation time. As a consequence, neutrophil adhesion was also decreased after MPostC. These effects were abolished by coadministering chelerythrine, nor-binaltorphimine or naltrindole, but not with naloxone. In conclusion, it is assumed that MPostC could attenuate the expression of ICAM-1 on endothelial cells during reoxygenation via the κ and δ-OR (opioid receptor)-specific pathway, and this also involves a PKC-dependent pathway

Is droperidol safe? Probably…

As of this writing, anesthesiologists have been living with the “black box” warning (or the “boxed warning” in FDA parlance) for droperidol for over two years. The response by clinicians and institutions has ranged from little change in practice (as in my own institution) to complete removal from the formulary. Clinicians who have described in letters to the editor or public lectures abandoning droperidol usually give as the reason their concerns about the liability of continuing to use a drug with a boxed warning. In addition, these writers and speakers (including myself) have castigated the FDA for taking too drastic an action without adequate supporting data. It is clear to me that, although the FDA was successful in informing anesthesiologists about the change in the droperidol label, including the boxed warning, they were quite unsuccessful in explaining why they took the action they did. For example, it was not until November 18, 2003 that the FDA held a meeting with anesthesiologists to discuss droperidol safety. At this meeting of the Anesthetic and Life Support Drugs Advisory Committee, one of the Human Drug Advisory Committees within the Center for Drug Evaluation and Research, the attendees were charged by the FDA with recommending what was currently known about the safety of droperidol and what studies should be done to remedy the gaps in knowledge. The minutes and transcript of this meeting are major sources for this article

Investigations of Metalloproteins by Purification and Unlabeled Nitrogen NMR

The first half of this study concerns the fungal oxidoreductase Chloroperoxidase, and the possibility of its modification towards a model system for the newly-discovered class of enzymes, Aromatic Peroxidases. CPO was synthesized in transgenic bacteria first as the wild-type protein, then again after directed mutagenesis, with the goal of incorporating the heme prosthetic group into the apoprotein and regenerating function. Unfortunately, despite promising extant results in the literature, every attempt ultimately failed at the reconstitution step. The second half of this study concerns $^{14}$N NMR spectroscopy. While this nucleus is usually dismissed outright as useless, an initial survey of the field suggested that it may be of more use than previously thought. While the end goal was to perform unlabeled nitrogen NMR experiments on proteins, and that particular tangent failed under the conditions available, a great deal of promising data was gathered.$^{14}$N NMR experiments successfully probed a number of organic small molecules and peptides, and in particular a binding isotherm for interactions between lysine's amine nitrogens and hydrogen was developed. These findings served to validate $^{14}$N NMR as a worthwhile paradigm, and highlighted a number of paths for further study

Droperidol: should the black box be light gray

In December 2001, the United States Food and Drug Administration (FDA) added a black box warning to the labeling for droperidol stating that all doses, even those typically used for postoperative nausea and vomiting, were potentially associated with malignant ventricular dysrhythmias, including torsade de pointes. The 19 cases in which droperidol doses less than 10 mg were allegedly associated with such dysrhythmias are reviewed in detail. Confounding issues present in a majority of the cases make it difficult to incriminate droperidol as the likely cause of the reported adverse events

Methanobactin biosynthesis and redox activity

Methanobactins are low-molecular-mass (<1,300 Da), ribosomally synthesized and posttranslationally modified copper-binding peptides excreted by some methanotrophs as the extracellular component of a copper acquisition system. Structurally, methanobactins are characterized by the presence of a C-terminal oxazolone group with a C2-associated thioamide and by the presence of an N-terminal oxazolone, imidazolone or pyrazinedione group with an associated thioamide. Some methanobactins also contain a sulfate group in-place of the hydroxyl group on a Tyr adjacent to the C-terminal oxazolone group. The two nitrogens on the rings and the two thioamide sulfurs are the four atoms that coordinate with copper and are the source of methanobactins’ copper-binding ability. Methanobactins with two oxazolone groups are classified as Group I, while those with only one are classified as Group II. Group I methanobactins bind copper to form a stable tetrahedral structure, while Group II methanobactins form a more dynamic hairpin structure. These structural differences give rise to the two groups’ physical and functional differences. The first part of this dissertation focuses on a methanobactin-catalyzed redox reaction in which O2 is generated from H2O, the difference in activity between different methanobactins, and the functional and ecological implications of this reaction. Specifically, in methanotrophs that produce methanobactins, their ability to generate their own oxygen could allow them to perform aerobic methane oxidation in a range of environments in which that reaction would otherwise not be possible. The second part of this dissertation focuses on the biosynthesis of methanobactin from Methylosinus trichosporium OB3b. As ribosomally synthesized and posttranslationally modified peptides, methanobactins have an entire operon dedicated to the transport, chaperoning and modification of the proto-methanobactin gene product from the mbnA gene. Several of the genes in this operon were and are unannotated, including mbnC. To that end a ΔmbnC knockout mutant was created and the structure of its resulting methanobactin was solved by metal-free NMR in order to determine that mbnC is not required for the formation of the N-terminal oxazolone the methanobactin from M. trichosporium OB3b. Finally, to elucidate the function of mbnF from Methylocystis strain SB2, the gene product was isolated, a crystal structure of the protein was solved, and preliminary enzymology was performed. From this work it was determined that mbnF encodes a NADPH-dependent flavin monooxygenase. The results and methods in this research advance our understanding of the function and biosynthesis of methanobactin. In light of methanobactins’ utility as a copper chelator for the treatment of Wilson’s disease in a rat model, and methanotrophs’ critical importance in the global carbon cycle, a better understanding of methanobactins’ biosynthesis and catalytic activity could have far-reaching consequences for society