Subject(s)
Asclepias/toxicity , Cardiotoxins/toxicity , Fruit/toxicity , Phytosterols/toxicity , Plant Poisoning/physiopathology , Adult , Cardiac Glycosides/blood , Cardiac Glycosides/toxicity , Cardiotoxins/blood , Cooking , Digoxin/blood , Emergency Medical Services , Humans , Internet , Male , Minnesota , Nausea/etiology , Phytosterols/blood , Plant Poisoning/blood , Plant Poisoning/therapy , Severity of Illness Index , Treatment OutcomeSubject(s)
Cyanides/poisoning , Hydroxocobalamin/adverse effects , Renal Dialysis , Fatal Outcome , HumansABSTRACT
Flecainide is a Vaughan Williams Class Ic antidysrhythmic associated with PR, QRS, and QTc prolongation on the electrocardiogram and development of life-threatening cardiac toxicity in overdose. The cornerstone of treatment is fluid resuscitation and the administration of magnesium and sodium bicarbonate. We report a case of flecainide overdose associated with life-threatening hemodynamic compromise successfully treated with intravenous fat emulsion (IFE) therapy. IFE should be considered as a novel adjunctive therapy in patients with life-threatening toxicity following flecainide overdose.
Subject(s)
Anti-Arrhythmia Agents/poisoning , Drug Overdose/therapy , Fat Emulsions, Intravenous/therapeutic use , Flecainide/poisoning , Emergency Treatment , Humans , Male , Middle AgedABSTRACT
Quetiapine overdose is a clinical entity commonly encountered in emergency departments. Quetiapine is a drug with many mechanisms, including antimuscarinic effects. Traditionally, treatment of quetiapine toxicity has been primarily supportive care. Case reports exist documenting improvement in mental status in these patients after administration of physostigmine, a carbamate capable of reversing antimuscarinic toxicity. In this descriptive case series, 3 patients with quetiapine toxicity treated with physostigmine are reported. In each case, the patient had significant altered mental status that was rapidly reversed with administration of physostigmine. In all 3 cases, patient disposition was changed to a lower level of care, requiring less invasive monitoring. In 1 case, intubation was prevented. Because quetiapine toxicity is commonly encountered and the use of physostigmine in this setting is a potentially practice-altering treatment, emergency physicians should be aware of this phenomenon.
Subject(s)
Antipsychotic Agents/adverse effects , Cholinesterase Inhibitors/therapeutic use , Consciousness Disorders/chemically induced , Dibenzothiazepines/adverse effects , Physostigmine/therapeutic use , Adult , Antipsychotic Agents/antagonists & inhibitors , Consciousness Disorders/drug therapy , Dibenzothiazepines/antagonists & inhibitors , Drug Overdose/drug therapy , Emergency Service, Hospital , Female , Glasgow Coma Scale , Humans , Male , Quetiapine Fumarate , Young AdultABSTRACT
Bacterial acetone carboxylase catalyzes the ATP-dependent carboxylation of acetone to acetoacetate with the concomitant production of AMP and two inorganic phosphates. The importance of manganese in Rhodobacter capsulatus acetone carboxylase has been established through a combination of physiological, biochemical, and spectroscopic studies. Depletion of manganese from the R. capsulatus growth medium resulted in inhibition of acetone-dependent but not malate-dependent cell growth. Under normal growth conditions (0.5 microm Mn2+ in medium), growth with acetone as the carbon source resulted in a 4-fold increase in intracellular protein-bound manganese over malate-grown cells and the appearance of a Mn2+ EPR signal centered at g = 2 that was absent in malate-grown cells. Acetone carboxylase purified from cells grown with 50 microm Mn2+ had a 1.6-fold higher specific activity and 1.9-fold higher manganese content than cells grown with 0.5 microm Mn2+, consistently yielding a stoichiometry of 1.9 manganese/alpha2beta2gamma2 multimer, or 0.95 manganese/alphabetagamma protomer. Manganese in acetone carboxylase was tightly bound and not removed upon dialysis against various metal ion chelators. The addition of acetone to malate-grown cells grown in medium depleted of manganese resulted in the high level synthesis of acetone carboxylase (15-20% soluble protein), which, upon purification, exhibited 7% of the activity and 6% of the manganese content of the enzyme purified from acetone-grown cells. EPR analysis of purified acetone carboxylase indicates the presence of a mononuclear Mn2+ center, with possible spin coupling of two mononuclear sites. The addition of Mg.ATP or Mg.AMP resulted in EPR spectral changes, whereas the addition of acetone, CO2, inorganic phosphate, and acetoacetate did not perturb the EPR. These studies demonstrate that manganese is essential for acetone carboxylation and suggest a role for manganese in nucleotide binding and activation.
Subject(s)
Bacteria/enzymology , Carboxy-Lyases/chemistry , Enzymes/chemistry , Manganese/chemistry , Acetone/chemistry , Acetone/pharmacology , Adenosine Monophosphate/metabolism , Adenosine Triphosphate/chemistry , Carbon/chemistry , Carbon Dioxide/chemistry , Catalysis , Electron Spin Resonance Spectroscopy , Electrophoresis, Polyacrylamide Gel , Immunoblotting , Ions , Magnetics , Malates/chemistry , Metals/chemistry , Rhodobacter/enzymology , Spectrophotometry , Temperature , Time Factors , Xanthobacter/enzymologyABSTRACT
Epoxyalkane:CoM transferase (EaCoMT) is a key enzyme of bacterial propylene metabolism, catalyzing the nucleophilic attack of coenzyme M (CoM, 2-mercaptoethanesulfonic acid) on epoxypropane to form the thioether conjugate 2-hydroxypropyl-CoM. The biochemical and molecular properties of EaCoMT suggest that the enzyme belongs to the family of alkyltransferase enzymes for which Zn plays a key role in activating an organic thiol substrate for nucleophilic attack on an alkyl-donating substrate. In the present work, the role of Zn in the EaCoMT-catalyzed reactions is established by removing Zn from EaCoMT, resulting in loss of catalytic activity that was restored upon addition of Zn back to the enzyme, and by expressing an inactive and Zn-deficient form of the enzyme that was activated by addition of ZnCl(2) or CoCl(2). Site-directed mutagenesis of one of the predicted Zn ligands (C220A) resulted in the formation of a largely catalytically inactive protein (0.06% of wild-type activity) that, when purified, contained a substoichiometric complement of Zn. EaCoMT was kinetically characterized and found to follow a random sequential mechanism with kinetic parameters K(m,epoxypropane) = 1.8 microM, K(m,CoM) = 34 microM, and k(cat) = 6.5 s(-1). The CoM analogues 2-mercaptopropionate, 2-mercaptoethanol, and cysteine substituted poorly for CoM as the thiol substrate, with specific rates of epoxyalkane conjugation that were at best 0.6% of the CoM-dependent rate, while ethanethiol, propanethiol, glutathione, homocysteine, and lipoic acid provided no activity. 2-Mercaptoethanol was a weak competitive inhibitor vs CoM with a K(I) of 192 mM. Isothermal titration calorimetry was used to investigate the thermodynamic binding determinants for the interaction of CoM and analogues with holo, Zn-deficient, and C220A EaCoMT variants. The stoichiometry of CoM binding correlated directly with the Zn content rather than monomer content of protein samples, reinforcing the importance of Zn in CoM binding. The binding of CoM to EaCoMT occurred with DeltaG = -7.5 kcal/mol (K(d) = 3.8 microM) and was driven by a large release of enthalpy. The thermodynamic contributors (K(a), DeltaG, DeltaH, DeltaS) to the individual binding of CoM, ethanesulfonate, and ethanethiol were determined and used to assess the contributions of the thiol, alkyl, and sulfonate moieties to total binding energy in the E x CoM binary complex.
