Clinical evaluation of a new preparation combining penicillin with triple sulfonamide.
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Child↗
Biomedical subjects
W A Daniel
Publications and source records attributed to W A Daniel.
Replication of poliovirus in HeLa cells: electron microscopic observations.
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Cell Nucleus↗
Electron microscope observations on the structure and discharge of the stenotele of hydra.
Sections of the stenotele type of nematocyst of Chlorohydra hadleyi have revealed that the stenotele, upon firing, completely everts its stylets and spines and the long, thin tubule, much as the eversion of the tubule of the nematocyst of the jewel anemone (Picken, 1953; Robson, 1953). Alternative mechanisms for supplying the energy necessary to forcefully discharge the stenotele contents are discussed as well as the possible significance of several regions containing highly ordered periodic structure. The origin of nematocysts as kinetosomal derivatives is discussed as a possibility suggested by the symmetry of the stenotele contents and the structure, location, and function of the cnidocil.
Cnidaria↗
Pharmacokinetics of phenothiazine neuroleptics after chronic coadministration of carbamazepine.
The aim of the present study was to assess the influence of carbamazepine on the pharmacokinetics of the two phenothiazine neuroleptics thioridazine and perazine in rats. The obtained results are compared with the results of analogical experiments concerning promazine. Thioridazine or perazine (10 mg/kg i.p.) were administered twice a day for two weeks alone or jointly with carbamazepine (15 mg/kg i.p. during the 1st week, and 20 mg/kg i.p. during the 2nd week of treatment). Concentrations of the neuroleptics and their main metabolites in the plasma and brain were measured at 30 min, 6 and 12 h after the last dose of the drugs. Carbamazepine decreased the concentrations of thioridazine and its metabolites (especially mesoridazine and sulforidazine) in plasma at 30 min and 6 h after the last dose of the drugs. Similar changes in the concentrations of thioridazine and its metabolites were observed at 6 h in the brain. Carbamazepine did not significantly influence the pharmacokinetics of perazine. In vitro studies with liver microsomes of control rats revealed that carbamazepine added to the incubation mixture inhibited N-demethylation of thioridazine via mixed mechanism, but it did not influence significantly 2- or 5-sulfoxidation of the neuroleptic. In the case of perazine, no distinct inhibition of its N-demethylation or sulfoxidation by carbamazepine was observed. Neither carbamazepine nor the neuroleptics, administered separately or jointly for two weeks, significantly influenced the concentrations of cytochromes P-450 and b-5 in the liver. Carbamazepine++ given chronically decreased the rate of N-demethylation and had a tendency to accelerate 2-sulfoxidation of thioridazine, both when given alone (as compared to the control) and when coadministered with thioridazine (as compared to the thioridazine-treated group). In contrast, chronic treatment with carbamazepine alone, significantly increased the rate of perazine N-demethylation. When carbamazepine was coadministered with perazine, the effect was less pronounced. In conclusion, carbamazepine given jointly with thioridazine or promazine at pharmacological doses to rats accelerates the metabolism of the neuroleptics, which is not the case with perazine. The observed induction proceeds by metabolic pathways other than N-demethylation or sulfoxidation. The different effect of carbamazepine on the N-demethylation of thioridazine and perazine in liver microsomes of control and carbamazepine-treated rats implicates that the two reactions are not catalyzed by the same enzyme. Such an induction of neuroleptic metabolism by carbamazepine in patients may worsen psychotic symptoms.
Animals↗
Effects of selective cytochrome P-450 inhibitors on the metabolism of thioridazine. In vitro studies.
The aim of the present study was to determine optimum conditions for the study of thioridazine metabolism in rat liver microsomes and to investigate the influence of specific cytochrome P-450 inhibitors on 2- and 5-sulfoxidation, and N-demethylation of thioridazine. Basing on the developed method, the thioridazine metabolism in liver microsomes was studied at linear dependence of the product formation on time, and protein and substrate concentrations (incubation time was 15 min, concentration of microsomal protein was 0.5 mg/ml, substrate concentrations were 25, 50 and 75 nmol/ml). Dixon analysis of tioridazine metabolism carried out in the control liver microsomes, in the absence and presence of specific cytochrome P-450 inhibitors, showed that quinine (CYP2D1 inhibitor), metyrapone (CYP2B1/B2 inhibitor) and alpha-naphthoflavone (CYP1A2 inhibitor) affected while erythromycin (CYP3A inhibitor) and sulfaphenazole (CYP2C9 inhibitor) did not affect the neuroleptic biotransformation. Thus, quinine and metyrapone inhibited competitively thioridazine N-demethylation and mono-2-sulfoxidation. As reflected by Ki values, N-demethylation was inhibited to a higher degree (Ki = 16.5 and 43 microM, respectively) than mono-2-sulfoxidation (Ki = 25 and 137 microM, respectively). On the other hand, alpha-naphthoflavone inhibited competitively not only N-demethylation and mono-2-sulfoxidation, but also 5-sulfoxidation of thioridazine. The calculated Ki values showed that the highest potency of alpha-naphthoflavone to inhibit thioridazine metabolism was observed for N-demethylation and it descended in the following order: N-demethylation (Ki = 13.8 microM) > mono-2-sulfoxidation (Ki = 34 microM) > 5-sulfoxidation (Ki = 70.4 microM). In conclusion, it can be assumed that N-demethylation and mono-2-sulfoxidation are catalyzed by the isoenzymes 2D1, 2B and 1A2 while 5-sulfoxidation only by 1A2; isoenzymes belonging to the subfamilies 2C and 3A seem not to be involved in the metabolism of thioridazine. The obtained results are discussed in the view of species and structure differences in the enzymatic catalysis of phenothiazines' metabolism as well as in relation to their pharmacological and clinical significance.
Animals↗
Distribution interactions between perazine and antidepressant drugs. In vivo studies.
Perazine belongs to the most frequently chosen neuroleptics for a combination with antidepressants in the therapy of complex or "treatment-resistant" psychiatric illnesses. The aim of the present study was to investigate the effect of the distribution interaction between perazine and antidepressants in vivo. Experiments were carried out on male Wistar rats. Animals received perazine and an antidepressant drug (imipramine or fluoxetine), separately or jointly, at a dose of 10 mg/kg ip. Concentrations of perazine, imipramine, fluoxetine and their metabolites in the blood plasma and tissues were measured at 1 h after administration of the drugs (HPLC). Effects of distribution interactions were estimated on the basis of the calculated tissue/plasma and lysosome-poor/lysosome-rich tissue concentration ratios, considering the heart and muscles as lysosome-poor and the lungs, liver and kidneys as lysosome-rich ones. Both imipramine and fluoxetine diminished the tissue/plasma concentration ratios of perazine for the lungs and kidneys (not for the liver), but elevated those ratios for the brain, muscles and heart. On the other hand, perazine lowered the lungs/plasma concentration ratio of both antidepressants and the liver/plasma concentration ratio of imipramine. Simultaneously, perazine elevated the brain/plasma and heart/plasma concentration ratios of both antidepressants. Consequently, the perazine concentration ratios of lysosome-poor/lysosome-rich tissue significantly increased in the presence of the investigated antidepressants, with an exception of the muscles/liver concentration ratio. At the same time, perazine raised the heart/lysosome-rich tissue concentration ratios of imipramine and fluoxetine, not changing significantly the muscles/lysosome-rich concentration ratios of the antidepressants. In conclusion, the presented results provide evidence that the observed in vitro distributive interactions between perazine and the antidepressants occur also in vivo, leading to a shift of the drugs from organs rich in lysosomes to those poor in these organella, in particular to the heart. Perazine and the antidepressants mutually increased the drug concentration ratios of heart/plasma and heart/lysosome-rich tissue, i.e. the heart/lung, heart/liver and heart/kidneys ratios. Similar results were obtained with lysosome-poor muscles in the case ofperazine. Moreover, the obtained results indicate that, apart from the lysosome density in the investigated tissues, the potential metabolic interactions in the liver and the order of drug circulation in a body have an important impact on the calculated drug concentration ratios.
Animals↗
Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver.
The primary metabolic pathways of caffeine are 3-N-demethylation to paraxanthine (CYP1A2), 1-N-demethylation to theobromine and 7-N-demethylation to theophylline (CYP1A2 and other enzymes), and 8-hydroxylation to 1,3,7-trimethyluric acid (CYP3A). The aim of the present study was to investigate the influence of phenothiazine neuroleptics (chlorpromazine, levomepromazine, thioridazine, perazine) on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that all the investigated neuroleptics competitively inhibited caffeine oxidation in the rat liver, though their potency to inhibit particular metabolic pathways was not equal. Levomepromazine exerted the most potent inhibitory effect on caffeine oxidation pathways, the effect on 8-hydroxylation being the most pronounced. This indicates inhibition of CYP 1 A2 (inhibition of 3-N- and 1-N-demethylation; Ki = 36 and 32 microM, respectively), CYP3A2 (inhibition of 8-hydroxylations; Ki = 20 microM), and possibly other CYP isoenzymes (inhibition of 7-N-demethylation; Ki = 58 microM) by the neuroleptics. The potency of inhibition of caffeine oxidation by perazine was similar to levomepromazine. Thioridazine was a weaker inhibitor of caffeine 3-N- and 7-N-demethylation, while chlorpromazine was weaker in inhibiting caffeine 1-N- and 7-N-demethylation, compared to levomepromazine. In summary, the obtained results showed that all the investigated neuroleptics had a broad spectra of CYP inhibition in the rat liver. The isoenzymes CYP1A2 and CYP3A2 were distinctly inhibited by all the investigated neuroleptics, while other CYP isoenzymes (CYP2B and/or 2E1) by perazine and levomepromazine. The CYP3A2 inhibition was most pronounced. (Ki = 20-40 microM).
Animals↗
Pharmacokinetics of thioridazine and its metabolites in blood plasma and the brain of rats after acute and chronic treatment.
This study was aimed at investigation of the pharmacokinetics of thioridazine and its metabolites after a single and repeated administrations. Male Wistar rats received thioridazine as a single dose (10 mg/kg i.p.) or they were treated chronically with the neuroleptic (10 mg/kg i.p., twice a day for two weeks). Plasma and brain concentrations of thioridazine and its metabolites (N-desmethylthioridazine, mesoridazine, sulforidazine, and the ring sulfoxide) were determined using the HPLC method. The obtained data showed that sulfoxidation in position 2 of the thiomethyl substituent and in the thiazine ring are main metabolic pathways of thioridazine, and showed that, in contrast to humans, in the rat N-desmethylthioridazine is formed in appreciable amount. The biotransformation of thioridazine was rather fast yielding plasma peak concentrations of metabolites lower than that of the parent compound. The maximum concentrations of thioridazine and its metabolites in the brain appeared later than in plasma. The peak concentrations and AUC values of thioridazine and its metabolites were higher in the brain than in plasma and this corresponded well with their longer half-lives in the brain as compared to plasma. The drug was not taken up by the brain as efficiently as other phenothiazines. Chronic treatment with thioridazine produced significant increases (with the exception of thioridazine ring sulfoxide) in the plasma concentrations of the parent compound and its metabolites which was accompanied with the prolongation of their plasma half-lives. The observed plasma levels of thioridazine were within 'therapeutic range' while the concentrations of its metabolites were relatively lower as compared to those observed in psychiatric patients. The increased plasma concentrations of thioridazine and its metabolites observed in plasma after chronic treatment were not followed by parallel changes in the brain.
Animals↗
Promazine pharmacokinetics during concurrent treatment with tricyclic antidepressants.
The aim of the present study was to search for a possible effect of tricyclic antidepressants on the pharmacokinetics of promazine. Male Wistar rats received promazine and/or an antidepressant (amitriptyline, imipramine) at a dose of 10 mg/kg i.p. twice a day for two weeks. Amitriptyline increased the plasma concentrations of promazine and N-desmethylpromazine. The concentration of promazine sulfoxide was lowered after 30 min, but later it was raised after 6 and 12 h. The interaction was pronounced after 6 and 12 h when the concentration of promazine was 3 times as high, that of N-desmethylpromazine 25 times as high, and that of sulfoxide 22 times as high as those observed after administration of promazine alone. Similar results were obtained in the brain. Imipramine produced less distinct changes in promazine pharmacokinetics. It did not produce any significant changes in promazine concentration (a tendency to raise it after 30 min was observed) in plasma, but it significantly increased the concentration of N-desmethylpromazine and decreased that of promazine sulfoxide. Changes in the brain did not follow closely those in the plasma. In the brain, significant increases in the levels of promazine and its metabolites were observed after 6 and 12 h. In vitro studies with liver microsomes showed that chronic co-administration of the antidepressants did not significantly influence the rate of promazine demethylation and sulfoxidation. Instead, the Lineweaver-Burk's analysis showed that both amitriptyline and imipramine competitively inhibited the two metabolic pathways of the neuroleptic. The potency of imipramine to inhibit the promazine metabolism in vitro was lower than that of amitriptyline, which was in line with its weaker effect on the pharmacokinetics of promazine in vivo. The observed increase in the sum of concentrations of the measured compounds (promazine + metabolites) in the plasma suggests additional inhibition by amitriptyline of another, metabolic pathway of promazine (e.g. hydroxylation). It is concluded that amitriptyline and imipramine which interfere with the metabolism (and probably distribution) of promazine produce potent increases in the brain (in the case of amitriptyline also in the plasma) concentrations of the neuroleptic.
Amitriptyline↗