Local anaesthetic effect of oxyfedrin in animals.
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Administration, Topical↗
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Anidoxime: a clinical trial of an oral analgesic agent.
The new oral analgesic drug anidoxime was compared with dihydrocodeine. There were no side-effects, and no significant differences between the effects of dihydrocodeine 50 mg, anidoxime 75 mg or anidoxime 100 mg.
Administration, Oral↗
Inhibition of 12-O-tetradecanoylphorbol-13-acetate-mediated epidermal ornithine decarboxylase induction and skin tumor promotion by new lipoxygenase inhibitors lacking protein kinase C inhibitory effects.
Both 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861) and 3,4,2',4'-tetrahydroxychalcone inhibited 12-lipoxygenase of mouse epidermis. The IC50 of AA861 and 3,4,2',4'-tetrahydroxychalcone for epidermal 12-lipoxygenase were 1.9 and 0.2 microM, respectively. These agents showed very weak inhibitory actions on epidermal cyclooxygenase, with the potency of inhibition for cyclooxygenase less than 1/50 of that for lipoxygenase. Induction of epidermal ornithine decarboxylase by 12-O-tetradecanoylphorbol-13-acetate (TPA; 10 nmol/mouse) was potently inhibited by these agents in a dose-dependent manner (1-30 mumol/mouse). TPA (5 nmol/mouse)-induced skin tumor formation was also strongly suppressed by these agents (15 mumol/mouse). Both AA861 and 3,4,2',4'-tetrahydroxychalcone failed to inhibit partially purified epidermal protein kinase C activity. These results support the proposed involvement of lipoxygenase product(s) of arachidonic acid in TPA-induced skin tumor promotion.
Animals↗
Rapid and sensitive liquid chromatography-electrospray ionization-mass spectrometry method for the determination of eperisone in human plasma: method and clinical applications.
A sensitive liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method for determination of eperisone in human plasma using buflomedil as the internal standard (IS) is established. After being made alkaline with saturated sodium bicarbonate solution, plasma samples are extracted with a mixture of diethyl ether-cyclohexane (1:1, v/v) and separated by high-performance liquid chromatography on a reversed-phase C(18) column with a mobile phase of 10mM ammonium acetate buffer (adjusted the pH to 3.9 with acetic acid)-methanol (20:80, v/v). Eperisone is determined using ESI in a single-quadrupole MS. LC-ESI-MS is performed in the selected ion monitoring mode using target ions at m/z 260 for eperisone and m/z 308 for the IS. Calibration curves are linear over the ranges 0.02-20 ng/mL for eperisone. The intra- and interassay variability values are less than 9.0% and 11.5%, respectively. The mean plasma extraction recovery of eperisone is 91.7 +/- 6.6%. The method has been successfully applied to study the pharmacokinetics of eperisone in healthy, male, Chinese volunteers. Pharmacokinetic parameters of the reference and test tablets have been compared.
Chromatography, High Pressure Liquid↗
High-performance liquid chromatographic determination of xanthohumol in rat plasma, urine, and fecal samples.
Xanthohumol (XN) is the major prenylated flavonoid in hop plants and as such a constituent of beer. Pharmacological studies have shown that XN possesses marked antioxidant and antiproliferative effects. In order to study the resorption and metabolism of this compound, reversed-phase high-performance liquid chromatography is used for the determination of XN in rat plasma, urine, and feces. In session one, rats receive either oral or intravenous (iv) administration (20 mg/kg body weight) of XN. In session two, rats receive oral administration of 50, 100, 200, 400, and 500 mg/kg body weight XN for bioavailability studies at various dose levels. Plasma, urine, and feces are collected at varying time points and assayed for their XN content. Plasma levels of XN fell rapidly within 60 min after iv administration; no XN is detected in plasma after oral administration in either session. XN and its metabolites are excreted mainly in feces within 24 h of administration. The method is a reliable tool for performing studies of XN in different biological material.
Animals↗
Chromatographic and mass spectral studies on methoxymethcathinones related to 3,4-methylenedioxymethamphetamine.
The methoxymethcathinones are uniquely regioisomeric with the controlled drug substance 3,4-methylenedioxymethamphetamine (3,4-MDMA) or Ecstacy. The various isomeric forms of the methoxymethcathinones have mass spectra essentially equivalent to 3,4-MDMA. They all have a molecular weight of 193 and major fragment ions in their electron ionization mass spectra at m/z 58 and 135/136. Differentiation by mass spectrometry was only possible after formation of the perfluoroacyl derivatives, pentafluoropropionylamides (PFPA), and heptafluorobutrylamides (HFBA). Gas chromatographic separation on nonpolar stationary phases successfully resolved the three methcathinones from 2,3- and 3,4-MDMA as the PFPA and HFBA derivatives.
Gas Chromatography-Mass Spectrometry↗
Effects of oxyfedrin: a beta-adrenoreceptor stimulant, on infarct size following acute coronary artery ligation.
Regional left ventricular blood flow and the extent of myocardial ischaemia were studied after acute coronary artery occlusion in open-chest dogs before and after infusion of oxyfedrin, a beta-adrenergic stimulant. Regional blood flow was measured with radioactive tracer microspheres and local tissue injury was estimated by the S-T segment elevation in epicardial electrocardiograms. Animals receiving oxyfedrin were divided into two groups: 1 and 2. Oxyfedrin was infused intravenously in a dose of 0.80 to 0.94 mg.kg-1 in dogs of group 1 and 1.45 to 1.60 mg.kg-1 in dogs of group 2. The rate of infusion in the animals of both groups was 0.61 mg.min-1. Oxyfedrin caused further S-T segment elevation over ischaemic myocardium and increased the extent of ischaemic injury in group 1 dogs. Conversely, in this same group of dogs, the blood flow was unchanged in low flow regions ( less than 0.3 cm3.g-1.min-1) and increased in higher flow areas, inside the ischaemic region. In the animals of group 2, oxyfedrin caused further S-T segment elevation over ischaemic myocardium and increased the extent of ischaemic injury. Concomitantly, blood flow was significantly reduced both inside and outside the ischaemic region. These observations in dogs of group 1 (ie increased blood flow inside the ischaemic region by infusion of oxyfedrin, in flow zones higher than 0.3 cm3.g-1.min-1, with a further S-T segment elevation over ischaemic myocardium, and an increase in the extent of ischaemic injury) may be explained by a primary effect of oxyfedrin on oxygen demands with secondary changes in blood flow.
Animals↗
Regional myocardial blood flow and segmental wall function after oxyfedrine administration in the ischaemic porcine heart.
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Animals↗
Evaluation of the antirhinovirus chalcone Ro 09-0415 given orally to volunteers.
Ro 09-0415, a phosphorylated 'pro-drug' of the potent antirhinovirus compound, 4' ethoxy-2'-hydroxy-4, 6' dimethoxy-chalcone (Ro 09-0410) was tested in a double-blind placebo-controlled trial for its protective effect against experimental rhinovirus infection. The maximum dose, 1200 mg bd, based on considerations of practicality and tolerance was given orally both before and after challenge with a sensitive rhinovirus, type 9. Plasma concentrations of active compound in excess of those required for the inhibition of rhinovirus type 9 in vitro were achieved, but there was no evidence to suggest that treatment with Ro 09-0415 had a beneficial effect. It is concluded that Ro 09-0415 given orally is unlikely to be of value in the prophylaxis or therapy of human rhinovirus infection.
Administration, Oral↗
Intranasal chalcone, Ro 09-0410, as prophylaxis against rhinovirus infection in human volunteers.
The antirhinovirus agent chalcone Ro 09-0410 was tested in double-blind place-controlled volunteer trials for its protective efficacy against experimental rhinovirus infection. Fifty volunteers received either drug (26 volunteers) or placebo (24 volunteers) both before and after challenge with 20-40 tissue culture infecting dose (TCID50) of human rhinovirus 2 (RV2). There was no evidence that medication significantly reduced the incidence of infection or illness, indeed there was some increase in the nasal secretion produced.
Administration, Intranasal↗
Cathinone (Khat) and methcathinone (CAT) in urine specimens: a gas chromatographic-mass spectrometric detection procedure.
A gas chromatographic-mass spectrometric procedure for detection of cathinone (Khat) and methcathinone (CAT) in urine was developed. The compounds were detected as 4-carboethoxyhexafluorobutyryl derivatives. Three ions for the drugs and two ions for the internal standards were monitored. The drugs were identified by comparing retention times and ion ratios with that of reference compounds. The concentrations were measured by using amphetamine-d6 as internal standard for cathinone and methamphetamine-d9 as internal standard for methcathinone, and were linear over the range of 25-5000 ng/mL for cathinone and 12.5-5000 ng/mL for methcathinone. The overall recoveries of cathinone and methcathinone were 86 and 78%, respectively. Intrarun and inter-run variations were < 20%. To verify that the drugs are not metabolites of over-the-counter medications, cathinone and methcathinone were tested in urine specimens collected from individuals who ingested phenylpropanolamine and pseudoephedrine. None of the specimens showed the keto-amines as the metabolic products. When the procedure was applied to test 66 amphetamine-immunoassay-positive specimens containing no amphetamine or methamphetamine, two specimens were found positive for cathinone (118 and 3266 ng/mL) and six specimens were found positive for methcathinone (13-91 ng/mL).
Alkaloids↗
The chalcone xanthohumol inhibits triglyceride and apolipoprotein B secretion in HepG2 cells.
The present study examined the role of xanthohumol (XN), a plant chalcone, on apolipoprotein B (apoB) and triglyceride (TG) synthesis and secretion, using HepG2 cells as the model system. The data indicated that XN decreased apoB secretion in a dose-dependent manner under both basal and lipid-rich conditions (as much as 43% at 15 micromol/L). This decrease was associated with increased cellular apoB degradation. To determine the mechanism underlying this effect, we examined triglyceride availability, a major factor in the regulation of apoB secretion. XN inhibited the synthesis of TG in the microsomal membrane and the transfer of this newly synthesized TG to the microsomal lumen (decreases of 26 and 64%, respectively, under lipid-rich conditions), indicating that TG availability is a determining factor in the regulation of apoB secretion under the experimental conditions. The inhibition of TG synthesis was caused by a reduction in diacylglycerol acyltransferase (DGAT) activity, which corresponded to a decrease in DGAT-1 mRNA expression, but not DGAT-2 expression. Microsomal triglyceride transfer protein (MTP) may also control the rate of TG transfer from the microsomal membrane to the active lumenal pool. XN decreased MTP activity in a dose-dependent manner (as much as 30%). Whether the reduction in TG accumulation in the microsomal lumen is predominantly due to DGAT and/or MTP activity remains unknown. In summary, the data suggest that xanthohumol is a potent inhibitor of apoB secretion.
Acyltransferases↗
The prenylflavonoid isoxanthohumol from hops (Humulus lupulus L.) is activated into the potent phytoestrogen 8-prenylnaringenin in vitro and in the human intestine.
Hops, an essential beer ingredient, are a source of prenylflavonoids, including 8-prenylnaringenin (8-PN), one of the most potent phytoestrogens. Because 8-PN concentrations in beers are generally low, its health effects after moderate beer consumption were considered negligible. However, human intestinal microbiota may activate up to 4 mg/L isoxanthohumol (IX) in beer into 8-PN. Depending on interindividual differences in the intestinal transformation potential, this conversion could easily increase the 8-PN exposure 10-fold upon beer consumption. Here, we present a further investigation of the process both in vitro and in vivo. In vitro experiments with the dynamic SHIME model showed that hop prenylflavonoids pass unaltered through the stomach and small intestine and that activation of IX into 8-PN (up to 80% conversion) occurs only in the distal colon. In vitro incubations of 51 fecal samples from female volunteers with IX enabled us to separate the fecal microbiota into high (8 of 51), moderate (11 of 51) and slow (32 of 51) 8-PN producers, clearly illustrating an interindividual variability. Three women, selected from the respective groups, received a daily dose of 5.59 mg IX for 4 d. Intestinal IX activation and urinary 8-PN excretion were correlated (R(2) = 0.6417, P < 0.01). These data show that intestinal conversion of IX upon moderate beer consumption can lead to 8-PN exposure values that might fall within the range of human biological activity.
Adult↗
Propafenone--a new antiarrhythmic drug.
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Anti-Arrhythmia Agents↗
Electrophysiological effects of propafenone studied with programmed electrical stimulation of the heart in patients with recurrent paroxysmal supraventricular tachycardia.
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Administration, Oral↗
The multiple modes of action of propafenone.
Previous studies of widely different concentrations of propafenone in various species have reported that in addition to having class 1 antiarrhythmic action, the drug was a beta adrenoceptor blocker and a calcium antagonist. High concentration shortened action potential duration in animal experiments, but Q-T interval was reported as being lengthened in man. It was thought desirable to study the effects of propafenone over a range of concentrations equivalent to those used clinically in various cardiac tissues of a single species, the rabbit. It was concluded that although the primary action of propafenone was on fast inward current, the drug being categorised as of group 1c, its potency as a beta blocker was sufficient for the effect to be of clinical significance. Its potency as a calcium antagonist was relatively weak. Action potential duration and effective refractory period were lengthened in both atrium and ventricle, the effects being long-lasting and persisting on wash-out of the drug when other measurements had returned to control values.
Action Potentials↗
Efficacy of oral propafenone in chronic ventricular arrhythmias: a placebo controlled cross-over exercise study.
The efficacy of propafenone, a new class I C antiarrhythmic drug, on ventricular premature contractions (VPCs) during rest and exercise was assessed during a two-phase protocol: phase 1, an initial two week placebo controlled double blind cross-over assessment; phase 2, an open 3 month follow-up. Twelve consecutive patients with symptomatic chronic ventricular arrhythmias and fulfilling other inclusion criteria underwent an exercise test and were allocated to either propafenone or placebo. During the double blind phase, oral propafenone significantly reduced the number of VPCs at rest with the patient supine or sitting, during the bicycle ergometer test, and after the exercise test. After 3 months of treatment a 90 to 100% reduction of VPCs was achieved in 11 patients continuing on 600 to 900 mg of propafenone daily. Treatment was stopped in one patient during the double blind phase because of drug induced LBBB. A prolongation of the PR interval and QRS duration occurred in all patients with propafenone doses exceeding 450 mg day-1. Subjective side effects were slight and consisted of abnormal taste sensations and minor central nervous symptoms. The results suggest that propafenone is an effective drug for the treatment of ventricular arrhythmias in selected patients. A-V or intraventricular conduction disturbances contraindicate its use.
Administration, Oral↗
Malignant ventricular tachyarrhythmias in association with propafenone treatment.
During treatment with the class Ic antiarrhythmic agent propafenone, the drug appeared to cause malignant ventricular tachyarrhythmias in five patients. Sudden cardiac death occurred in two of them. Three patients exhibited a transition from non-self-terminating ventricular tachycardia to ventricular fibrillation. In the other two patients electrocardiography during syncope revealed ventricular fibrillation. The observed malignant arrhythmias occurred within the first three days of treatment for chronic complex ventricular ectopic activity. Two of the five patients had markedly impaired left ventricular function. All patients received digoxin and low dose diuretic therapy. In contrast to drug induced arrhythmias encountered with other type I antiarrhythmic agents, the proarrhythmic effects of propafenone were not associated with marked QT prolongation. QRS duration was only slightly affected.
Adult↗