Migraine: pharmacotherapy in the emergency department.
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Migraine can be a disabling condition for the sufferer. For the small number of patients who fail home therapy and seek treatment in an emergency department, there are a number of therapeutic options. This paper reviews the evidence regarding the effectiveness and safety of the following therapies: the phenothiazines, lignocaine (lidocaine), ketorolac, the ergot alkaloids, metoclopramide, the "triptans", haloperidol, pethidine and magnesium. Based on available evidence, the most effective agents seem to be prochlorperazine, chlorpromazine and sumatriptan, each of which have achieved greater then 70% efficacy in a number of studies. (+info)
Disposition of ethopropazine enantiomers in the rat: tissue distribution and plasma protein binding.
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PURPOSE: To determine the in vitro plasma protein binding, and the in vivo brain, heart and plasma concentrations of ethopropazine (ET) enantiomers in the rat after iv doses. METHODS: For in vivo assessment of ET enantiomer concentrations, rats with implanted jugular vein cannulae were injected with 10 mg/kg of (+/-)-ET HCl. At selected times after dosing, rats were sacrificed and heart, brain, and plasma were collected. Equilibrium dialysis was used to determine the unbound fraction of ET in rat plasma over a concentration range of 150 to 4000 ng/mL of each enantiomer. A stereospecific assay was used to measure concentrations of ET enantiomer. RESULTS: No stereoselectivity was observed in plasma or tissues after iv dosing. Area under the concentration vs. time curves indicated that highest uptake of ET occurred in brain tissue, followed by heart tissues, then plasma. There was no noticeable difference between concentrations of ET enantiomers in different parts of brain (substantia nigra, cortex, or striatum). There was no observed stereoselectivity in plasma protein binding of ET enantiomers in rat plasma. Saturation of binding to plasma proteins was observed between 500 and 2000 ng/mL of each ET enantiomer, but unbound fraction was constant at concentrations below and above that range. CONCLUSION: Ethopropazine displays nonstereoselectivity in its pharmacokinetics. The drug shares distribution features similar to those of other phenothiazine derivatives. Based on the in vitro plasma protein binding results, there appears to be saturation of some, but not all, plasma binding proteins of ET within the range of concentrations studied. (+info)
A phenothiazine derivative in the treatment of spasticity.
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The efficacy of a selective fusimotor suppressant, the phenothiazine (+/-)-10-3-dimethylamino-2-methylpropyl)-2-valeroylphenothiazine, has been assessed in a double-blind crossover trail in eight patients suffering from cerebral spasticity and one patient suffering from spinal spasticity. Dosage was 40 mg daily. Independent clinical and electromyographic methods of assessment were used. The active agent produced a small but significant reduction in spasticity, although this was of clinical value in only a few patients. There were few side-effects. It is recommended that further studies using higher dosages be undertaken. (+info)
Active acetyl-CoA synthase from Clostridium thermoaceticum obtained by cloning and heterologous expression of acsAB in Escherichia coli.
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Acetyl-CoA synthase from Clostridium thermoaceticum (ACS(Ct)) is an alpha(2)beta(2) tetramer containing two novel Ni-X-Fe(4)S(4) active sites (the A and C clusters) and a standard Fe(4)S(4) cluster (the B cluster). The acsA and acsB genes encoding the enzyme were cloned into Escherichia coli strain JM109 and overexpressed at 37(o)C under anaerobic conditions with Ni supplementation. The isolated recombinant His-tagged protein (AcsAB) exhibited characteristics essentially indistinguishable from those of ACS(Ct), from which Ni had been removed from the A cluster. AcsAB migrated through nondenaturing electrophoretic gels as a single band and contained a 1:1 molar ratio of subunits and 1.0-1.6 Ni/alphabeta and 14-22 Fe/alphabeta. AcsAB exhibited 100-250 units/mg CO oxidation activity but no CO/acetyl-CoA exchange activity. Electronic absorption spectra of thionin-oxidized and CO-reduced AcsAB were similar to those of ACS(Ct), with features typical of redox-active Fe(4)S(4) clusters. Partially oxidized and CO-reduced AcsAB exhibited EPR signals with g values and low spin intensities indistinguishable from those of the B(red) state of the B cluster and the C(red1) and C(red2) states of the C cluster of ACS(Ct). Upon overnight exposure to NiCl(2), the resulting recombinant enzyme (ACS(Ec)) developed 0. 06-0.25 units/mg exchange activity. The highest of these values is typical of fully active ACS(Ct). When reduced with CO, ACS(Ec) exhibited an EPR signal indistinguishable from the NiFeC signal of Ni-replete ACS(Ct). Variability of activities and signal intensities were observed among different preparations. Issues involving the assembly of these metal centers in E. coli are discussed. (+info)
Extrapyramidal effects of neuroleptics.
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A study was conducted on 66 psychiatric inpatients who took major tranquilizers for periods of four to 16 years. The frequency of signs of Parkinsonism and the effects of orphenadrine on these were studied in a double-blind crossover method. Sixty-one per cent of the patients showed signs of Parkinsonism. Female patients and those with organic brain pathology more frequently exhibited Parkinsonism (although the difference was not statistically significant). No correlation was found between duration of treatment and extrapyramidal effects. Of the 40 patients who developed Parkinsonism, 25 responded favourably to orphenadrine, while six (15%) had more marked manifestations on orphenadrine than on placebo. (+info)
Catalytic selenols couple the redox cycles of metallothionein and glutathione.
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Co-ordination of zinc to the thiol group of cysteine allows mobilization of zinc through oxidation of its ligand. This molecular property links the binding and release of zinc in metallothionein (MT) to the cellular redox state [Maret W. & Vallee B.L. (1998) Proc. Natl Acad. Sci. USA 95, 3483-3488]. Biological disulfides such as glutathione disulfide (GSSG) oxidize MT with concomitant release of zinc, while glutathione (GSH) reduces the oxidized protein to thionein, which then binds to available zinc. Neither of these two redox processes is very efficient, even at high concentrations of GSSG or GSH. However, the GSH/GSSG redox pair can efficiently couple with the MT/thionein system in the presence of a selenium compound that has the capacity to form a catalytic selenol(ate). This coupling provides a very effective means of modulating oxidation and reduction. Remarkably, selenium compounds catalyze the oxidation of MT even under overall reducing conditions such as those prevailing in the cytosol. In this manner, the binding and release of zinc from zinc-thiolate co-ordination sites is linked to redox catalysis by selenium compounds, changes in the glutathione redox state, and the availability of either a zinc donor or a zinc acceptor. The results also suggest that the pharmacological actions of selenium compounds in cancer prevention and other antiviral and anti-inflammatory therapeutic applications, as well as unknown functions of selenium-containing proteins, may relate to coupling between the thiol redox state and the zinc state. (+info)
Behavior of haloperidol and various phenothiazines on several alkyl bonded phases.
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Haloperidol and phenothiazines are present in psychiatrical treatments. An analysis in body fluids is tedious because of the presence of demethylated (DM) derivatives of phenothiazines. The behavior of some interfering solutes on alkyl bonded phases has been studied. Phenothiazines and DM derivatives exhibit a very similar behavior with a binary eluent (phosphate buffer-acetonitrile), which precludes an optimization with this system. When a ternary phase is used (phosphate buffer-acetonitrile-methanol), haloperidol and reduced haloperidol behave differently as compared with phenothiazines. In this mode it is possible to unambiguously detect haloperidol that would otherwise interfere. Phenothiazine peaks are characterized by a large tailing. An interesting feature is the comparison between cyclohexyl bonded and octadecyl bonded phases, the former being much more efficient. (+info)
Concentrations of cis(Z)-clopenthixol and trans(E)-clopenthixol in a lethal case involving zuclopenthixol, diazepam, and cyamemazine.
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cis(Z)-Clopenthixol and trans(E)-clopenthixol were determined by gas chromatography-mass spectrometry and high-performance liquid chromatography-diode-array detection in necropic samples from a postmortem case. The peripheral blood concentrations of cis(Z)-clopenthixol and trans(E)-clopenthixol were 278 and 177 ng/mL, respectively. The level of the active cis(Z)-isomer is within the toxic range. Other associated drugs' concentrations were within their therapeutic ranges. Postmortem redistribution of the drug and instability of the drug due to trans-isomerization were discussed. (+info)