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PubMed1986

Evaluation of the percutaneous absorption and metabolism of some aminopropiophenones.

The absorption of diethylpropion (DEP I), dimethylpropion (DMP I) and some of their basic metabolites into and passage through the skin was investigated and a comparison of their metabolism following oral and percutaneous administration made. High percentages (60-80%) of DEP I and its metabolites and a small percentage of DMP I and its metabolites were taken up into the skin in less than 2 min--the remaining percentages of the compounds were absorbed into the skin by a first order process. The rate of appearance of the compounds in the blood, which reflects their rate of passage through the skin, did not correlated with their rate of absorption into the skin. More metabolism occurred with all the compounds after their oral administration than after their percutaneous application.

Biotransformation↗
PubMed1990

Phenytoin-bupropion interaction: effect on plasma phenytoin concentration in the rat.

The effect of coadministration of bupropion (50 mg kg-1, p.o.) on the disposition profile of phenytoin has been studied in the rat. Plasma phenytoin concentration was measured serially for 10 h by HPLC. Bupropion had little or no effect on the pharmacokinetic parameters of an acutely administered dose of phenytoin. Following multiple doses of phenytoin however (i.e. steady state) the coadministration of bupropion resulted in significant increases in the elimination half-life (t 1/2), the area under the plasma concentration-time curve (AUC) and the time to maximum plasma concentration (tmax). Allowing for the limitations of single dose studies, these results point to a possible pharmacokinetic interaction between bupropion and phenytoin--the clinical significance of which needs to be assessed.

Administration, Oral↗
PubMed1992

Influence of inhibition of extraneuronal uptake and of O-methylation on the hyperglycaemia caused by sympathomimetic amines in depancreatized rats.

This study aimed at testing whether the O-methylating system (extraneuronal uptake + O-methylation) modulates, in-vivo, beta-adrenoceptor-mediated responses. The influences of U-0521 (3,4-dihydroxymethylpropiophenone, an inhibitor of catechol-O-methyl transferase (COMT)) and hydrocortisone (an inhibitor of extraneuronal uptake) on the hyperglycaemia evoked by isoprenaline and adrenaline were compared. Both inhibitors enhanced the increase of the plasma glucose level induced by either isoprenaline (0.36 nmol kg-1 min-1) or adrenaline (0.55 nmol kg-1 min-1). The enhancement caused by U-0521 developed faster than that caused by hydrocortisone, but was of the same magnitude. This is the first report of supersensitivity to sympathomimetic amines caused by inhibition of either COMT or extraneuronal uptake in-vivo and for a response not involving smooth muscle cells.

Analysis of Variance↗
PubMed1997

Pharmacokinetics and kinetic-dynamic modelling of aminophenones as methaemoglobin formers.

Methaemoglobin, the oxidized form of haemoglobin, can be formed by a variety of agents, most of which act to oxidize haemoglobin directly or indirectly. Cyanide has a higher affinity for methaemoglobin than for mitochondrial cytochromes, making methaemoglobin formation a basis for the treatment of cyanide poisoning. We used the beagle dog model to investigate the relationship between drug concentration and methaemoglobin levels for two candidate anti-cyanide compounds. The compounds studied were the aminophenones p-aminopropiophenone (PAPP) and p-aminoheptylphenone (PAHP). Both PAPP and PAHP were given as intravenous boluses and as two different oral formulations. The kinetics of both compounds appeared to follow a three-compartment open model for intravenous bolus administration and a two-compartment open model for oral administration. The first distribution phase seen with the intravenous administration was obscured by the absorption phase during oral administration. Bioavailability for all formulations varied between 20 and 47%. For both compounds there was a delay between the appearance of drug in the plasma and the appearance of methaemoglobin (counter-clockwise hysteresis) which is suggestive of an active metabolite causing methaemoglobin formation. The pharmacodynamics were fit with an effect-compartment kinetic-dynamic model linked to a sigmoid Emax pharmacodynamic model. Maximum amounts of methaemoglobin occurred between 2 and 4 h for PAHP and between 1 and 3 h for PAPP. When administered intravenously estimates of EC50 were lower than the estimates of EC50 from oral administration for both compounds. This might be because of oral first-pass inactivation or a 'first-pass' activation through the lungs contributing to the formation of an active metabolite. The phenones as a class appear to have the drug cleared and methaemoglobin return to near baseline within 12 h. Both compounds seem to produce sufficient methaemoglobin to treat acute cyanide poisoning and to serve as prophylactic agents against acute cyanide poisoning in a military setting.

Administration, Oral↗
PubMed1998

Synthesis of novel derivatives of aroylaminoalcohols and 3-amino-substituted 1-phenylpropanols with potential anti-inflammatory and immunomodulating activities.

The synthesis of aroylaminoalcohols and 3-amino-substituted 1-phenylpropanols is described. These novel basic compounds have potent anti-inflammatory activity, significantly inhibiting rat paw oedema induced by a variety of phlogistic agents as a result of the release of inflammatory mediators such as histamine, 5-hydroxytryptamine, kinins, prostaglandins or leukotrienes. The biological activity of a selected, representative number of these compounds was examined on adjuvant-induced arthritis, a good animal model for rheumatoid arthritis in man. The results show that 3-(1-hydroxymethylpropylamino)-1-phenylpropan-1-one hydrochloride (2) and 3-(3-hydroxypiperidin-1-yl)-1-phenylpropan-1-one hydrochloride (4) effectively suppress the secondary lesions of adjuvant arthritis. 2-(3-Hydroxy-3-phenylpropylamino)-butan-1-ol hydrochloride (6) had no preventive activity in this animal model. In addition, several of the compounds suppressed the mitogenic responses of T-lymphocytes to concanavalin A, suggesting direct or indirect action on lymphocytes and therefore possible immunosuppressive properties. Finally, we investigated the in-vitro effects of compounds 2 and 4 on production of interleukins 1 and 2 (IL-1 and IL-2). We found that compound 4 suppressed the in-vitro production or action of IL-2 and IL-1. In contrast, compound 2 significantly increased the IL-1 activity of arthritic macrophages while reducing the ability of normal and arthritic splenocytes to produce or release IL-2. Our data suggest that compounds 2 and 4 have immunomodulatory properties that influence T lymphocyte functions.

Adjuvants, Immunologic↗
PubMed1966

The placental transfer of hexoses and polyols in the guinea-pig, as shown by umbilical perfusion of the placenta.

1. Experiments involving polyol and sugar transfer across the guineapig placenta have been described.2. Regarding the former, sorbitol, dulcitol and mannitol are all transferred at approximately the same rate and more slowly than meso-inositol. Erythritol is not transferred.3. Concerning the hexose transfers, glucose and galactose are transferred at approximately the same rate and more rapidly than fructose.4. With regard to glucose transfer, there appears to be a mechanism with the following properties: (a) It tends towards saturation under certain conditions. (b) It favours saturation rather than diffusion kinetics for forward flows. (c) It exhibits competition with fructose and with galactose. Glucose/galactose competition has been used to demonstrate uphill transport by counterflow. (d) Competitive inhibition by phlorrhizin or phloretin could not be demonstrated.

Alcohols↗
PubMed1968

The effect of temperature on the competitive inhibition of glucose transfer in human erythrocytes by phenolphthalein, phloretin and stilboestrol.

1. Phenolphthalein, like other diphenols, has been shown to be a competitive inhibitor of the facilitated transfer system for glucose in the human erythrocyte.2. The concentration producing 50% inhibition is lower at low temperatures and increases steadily over the temperature range 10-40 degrees C. An Arrhenius plot of the results gives a slope of 19,300 cal/mole.3. The effect of temperature on inhibition by phloretin and stilboestrol has also been studied. The temperature variation of the concentration of phloretin giving 50% inhibition is similar to that for phenolphthalein, but that for stilboestrol is much less.4. There is a high cell/medium distribution ratio for stilboestrol, and the possibility that this may affect the temperature dependence of the aqueous concentrations required to give 50% inhibition is discussed.

Animals↗
PubMed2003

Identification of cytochrome p450 enzymes involved in the metabolism of 4'-methyl-alpha-pyrrolidinopropiophenone, a novel scheduled designer drug, in human liver microsomes.

4'-Methyl-alpha-pyrrolidinopropiophenone (MPPP) is a new drug of abuse. It is believed to have an abuse potential similar to that of amphetamines. Previous studies with Wistar rats had shown that MPPP was metabolized mainly by hydroxylation in position 4' followed by dehydrogenation to the corresponding carboxylic acid. The aim of the study presented here was to identify the human hepatic cytochrome p450 (p450) enzymes involved in the biotransformation of MPPP to 4'-hydroxymethyl-pyrrolidinopropiophenone. Baculovirus-infected insect cell microsomes and human liver microsomes were used for this purpose. Only CYP2C19 and CYP2D6 catalyzed this hydroxylation. The apparent Km and Vmax values for the latter were 9.8 +/- 2.5 microM and 13.6 +/- 0.7 pmol/min/pmol p450, respectively. CYP2C19 was not saturable over the tested substrate range (2-1000 microM) and interestingly showed a biphasic kinetic profile with apparent Km,1 and Vmax,1 values of 47.2 +/- 12.5 microM and 8.1 +/- 1.4 pmol/min/pmol p450, respectively. Experiments with pooled human liver microsomes also revealed biphasic nonsaturable kinetics with apparent Km,1 and Vmax,1 values of 57.0 +/- 20.9 microM and 199.7 +/- 59.7 pmol/min/mg of protein for the high affinity enzyme, respectively. Incubation of 2 microM MPPP with 3 microM of the CYP2D6-specific inhibitor quinidine resulted in significant (p < 0.01) turnover inhibition (11.8 +/- 1.6% of control). Based on kinetic data corrected for the relative activity factors, CYP2D6 is the enzyme mainly responsible for MPPP hydroxylation, confirmed by CYP2D6 inhibition studies.

Animals↗
PubMed1993

Controlling chemical reactivity with antibodies.

The remarkable specificity of an antibody molecule has been used to accomplish highly selective functional group transformations not attainable by current chemical methods. An antibody raised against an amine-oxide hapten catalyzes the reduction of a diketone to a hydroxyketone with greater than 75:1 regioselectivity for one of two nearly equivalent ketone moieties. The antibody-catalyzed reaction is highly stereoselective, affording the hydroxyketone in high enantiomeric excess. Similarly, the reduction of ketones containing branched and aryl substituents, including the highly symmetrical 1-nitrophenyl-3-phenyl-2-propanone, was enantioselective. The simple strategy presented herein may find general applicability to the regio- and stereoselective reduction of a broad range of compounds.

Antibodies, Catalytic↗
PubMed1959

Molecular structural factors in competitive inhibition of sugar transport.

The high potency of phloretin as a competitive inhibitor of the human red cell's monosaccharide transport system is not shared by any of several molecular fragments of phloretin, but is duplicated in certain artificial estrogens resembling phloretin in respect to the spacing between terminal phenolic -OH groups. Related molecules which are slightly less extendible are comparatively inactive.

Biological Transport↗
PubMed1971

Prostaglandins.

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Abortion, Induced↗
PubMed1982

Direct and specific inactivation of rhinovirus by chalcone Ro 09-0410.

Studies of various analogs related to the antipicornavirus agent, 4',5-dihydroxy-3,3',7-trimethoxyflavone (Ro 09-0179), led to the identification of 4'-ethoxy-2'-hydroxy-4,6'-dimethoxychalcone (Ro 09-0410), a new and different type of antiviral agent. Ro 09-0410 had a high activity against rhinoviruses but no activity against other picornaviruses. Of 53 rhinovirus serotypes so far tested, 46 were susceptible to Ro 09-0410 in HeLa cell cultures. The concentration of Ro 09-0410 inhibiting 50% of the types of rhinovirus was about 0.03 micrograms/ml, whereas the 50% cytotoxic concentration was 30 microgram/ml. Ro 09-0410 inactivated rhinoviruses in direct dose-, time-, and temperature-dependent fashion. Since infectivity, reduced by exposure to the agent, completely regained the original level by extraction of the agent with chloroform, the inactivation may be associated with the binding of the agent to some specific site of the rhinovirus capsid.

Antiviral Agents↗
PubMed1990

Pathogenicity for humans of human rhinovirus type 2 mutants resistant to or dependent on chalcone Ro 09-0410.

Mutants of human rhinovirus type 2 (HRV-2) resistant to and dependent on the antirhinoviral compound chalcone Ro 09-0410 were selected in cell culture under clean laboratory conditions. A total of 42 volunteers were challenged with either the drug-resistant mutant [SR2-410(r)] (15 volunteers), the drug-dependent mutant [SR2-410(d)] (15 volunteers), or a wild-type HRV-2 which had a similar passage level in vitro as the mutants but without the drug (12 volunteers). Of volunteers challenged with the wild-type HRV-2, 33, 67, and 82% developed cold symptoms, shed virus, and showed serological evidence of infection, respectively. In contrast, only 13, 27, and 23% of volunteers challenged with the drug-resistant mutant developed colds, shed virus, and showed serological evidence of infection, respectively. None of the volunteers challenged with the drug-dependent virus became infected or had symptoms of colds. These results demonstrate that a drug-resistant rhinovirus was capable of infecting humans and producing disease, although its infectivity was reduced when compared with that of the wild type. In contrast, a drug-dependent virus had lost its ability to infect humans.

Adolescent↗
PubMed1969

Metabolism of phloridzin by Erwinia herbicola: nature of the degradation products, and the purification and properties of phloretin hydrolase.

Erwinia herbicola Y46 degrades phloridzin to yield phloretin, phloroglucinol, and phloretic acid, when grown on defined medium containing phloridzin as the sole source of carbon. The identities of the intermediates isolated from culture filtrates were established by co-chromatography and by ultraviolet absorption spectra. Only 3 of 11 strains of this species, and none of the 12 species of bacterial phytopathogens tested could effect this breakdown. Some of the latter organisms possessed beta-glucosidase activity which liberated d-glucose from phloridzin. The enzyme phloretin hydrolase was purified from cells of E. herbicola Y46 grown on Yeast Beef Broth, by treatment of crude extracts with protamine sulfate, ammonium sulfate precipitation, elution from calcium phosphate gel, elution from diethylaminoethyl-cellulose, and concentration by ultrafiltration. The final preparation was free of beta-glucosidase, had a specific activity of 213 units per mg of protein, and represented a 142-fold purification over the crude extract. The enzyme had a pH optimum of 6.7 to 6.8, and produced only phloroglucinol and phloretic acid as products of phloretin breakdown, there being an equimolar relationship between the cleavage of phloretin and the formation of the products. The Michaelis constant (K(m)) for the enzyme with phloretin as substrate was 3.8 x 10(-5)m, and the enzyme was sensitive to Hg(2+) and Cu(2+) ions. Phloroglucinol, phloretic acid, p-chloromercuribenzoate and iodoacetamide were without effect on the activity. The enzyme did not react with phloridzin, naringin, or naringenin. The physiological significance of the results is discussed.

Chromatography, Thin Layer↗