No description available.

No description available.

No description available.

An investigation was undertaken to study the kinetics and possible cellular control mechanisms for imipramine HCl metabolism in the isolated perfused rat liver. The isotope ¹⁴C-imipramine was used and quantification was done by liquid scintillation counting. Analysis for imipramine (IMI), desmethylimipramine (DMI), free hydroxy (OH), glucuronide (G) and N-oxide (N-0) metabolites was done on the perfusate, bile and liver. The rate of IMI metabolism was found to be dependent on two major enzymatic routes, N-demethylation (formation of DMI) and aromatic hydroxylation (formation of G, OH) of imipramine and one minor enzymatic route, N-oxidation (N-O). The rate of aromatic hydroxylation of IMI was found to be inhibited after thirty minutes, with IMI concentration 2 X 10 ⁻⁵M. This inhibition of aromatic hydroxylation could not be detected if the perfusate half-life for IMI (t½=18.5 minutes) was the only parameter monitored. After incubation periods of fifteen, thirty and sixty 80 per cent and the remainder of IMI was in the perfusate. The dose of IMI was varied (0.5 X 10⁻⁵ M, 1 X 10⁻⁵ M and 2 X 10⁻⁵ M) for metabolism by the perfused rat liver. The incubation time was kept constant at fifteen minutes. The rate of imipramine metabolism (formation of DMI and GOH) followed first order kinetics when the dose of IMI was 0.5 X 10⁻⁵ M or 1 X 10⁻⁵ M. Increasing the dose of IMI to 2 X 10⁻⁵ M slightly suppressed the formation of DMI and the formation of GOH followed zero order kinetics. It was found that the endogenous DMI formed from IMI metabolism inhibited the formation of GOH after fifteen minutes and thirty minutes of IMI metabolism as shown by the following results. DMI (1.65, 3.33, 6.66 or 13.32 X 10⁻⁶ M) was preincubated prior to addition of IMI. DMI (1.65 or 3.33 X 10⁻⁶ M) was found to specifically inhibit aromatic hydroxylation of IMI. Higher concentration of DMI (6.66 or 13.32 X 10⁻⁶ M) inhibited the formation of GOH and DMI. Ethyl alcohol (1 mM) preincubated prior to addition of 1 X 10⁻⁵ M of IMI specifically inhibited DMI formation. No inhibition of GOH occurred. Ethyl alcohol (1 mM) caused inhibition of formation of DMI from IMI metabolism when the dose of IMI was 2 X 10⁻⁵ M. The incubation time for IMI metabolism was fifteen and sixty minutes. With this decrease of DMI formation, the formation of GOH increased after fifteen or sixty minutes of incubation time. From these experiments it was concluded that suppression of aromatic hydroxylation of imipramine was due to the formation of endogenous DMI formed from IMI metabolism. Optimal conditions were found to study possible cellular control mechanisms for IMI metabolism in the isolated perfused rat liver. The dose of IMI was 1 X 10⁻⁵ M and the incubation time was fifteen minutes. Dibutyryl cyclic AMP (2 X 10⁻⁶ M) caused inhibition of IMI metabolism. DMI formation was inhibited 28 per cent while GOH formation was inhibited 29 per cent. NADPH (1.1 X 10⁻⁶ M) or NADH (1.3 X 10⁻⁶ M) was found to inhibit imipramine metabolism. GOH and DMI were both inhibited. Succinic acid (1.6 X 10⁻³ M) was found to inhibit DMI formation but not GOH. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

No description available.

No description available.

The synthesis of 1-methyl-promazine, 4-hydroxymethyl-iminodibenzyl, and 4-bromo-5-trimethylsilyl-iminodibenzyl via dilithiation and ¹H-NMR's are described. Molecular modeling was done for the latter compound. The heat of dissociation was 30.6 kcal/mole for the lowest energy conformer. Rotational energies were examined for three bonds. The IC₅₀ values for inhibition of neurotransmitter uptake by rat brain synaptosomes were determined for a series of 1-substituted promazines, and 4-substituted imipramines. 1-Substituted promazines were fair inhibitors of serotonin uptake with an average IC₅₀ of 2000 nm. Their potency for inhibiting norepinephrine uptake was difficult to assess due to poor assay reproducibility, and the average IC₅₀ was estimated at 200 to 1700 nm. Serotonin, but not norepinephrine, uptake inhibition was increased with additional ring substitution at C(2) with a trifluoromethyl group. The 4-substituted imipramines were equal or slightly decreased in potency to unsubstituted imipramine for uptake inhibition of both neurotransmitters. IC₅₀'s were also reported for imipramine and desipramine.

Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2008. / Vita. Bibliography: p.184-192

This project was divided into two studies. The first investigated the pharmacokinetics of imipramine hydrochloride (IMI) in bulls. IMI was administered intravenously to three bulls (600-705.5 kg) at a dose of 2mg/kg body weight (BW). Intravenous plasma concentrations of IMI over time were determined by fluorescence polarization immunoassay (FPIA). IMI plasma concentration versus time profile was best described by a two compartmental open model with first-order rate constants. IMI distributed rapidly, (t½<font face="symbol">a</font>) at 7.2 ± 4.2 min, exhibited a very large apparent steady state volume of distribution (Vdss) of 4.2 ± 0.9 <font face="symbol">l</font>/kg BW, had a very short terminal elimination half-life (t½<font face="symbol">b</font>) of 140 ± 15 min and showed a rapid total body clearance (C<font face="symbol">l</font>) of 22.7 ± 7 m<font face="symbol">l</font>/min/kg. Both IMI and the pharmacologically active metabolite, desipramine was negligible in serum at 24 hours. All three bulls treated with IMI showed pronounced central nervous system signs immediately post injection. Signs of generalised weakness and ataxia were evident. All CNS signs dissipated 15-20 minutes post injection and should therefore not influence the treatment interval. An interval of at least 23 hours between repeat treatments of IMI, representing a period of at least 10 half-lives, is recommended. The dose of 2 mg/kg BW used in this study was similar to that routinely used in stallions without fatal side effects. One of the three bulls exhibited spontaneous emission and ejaculation with this dose. The second study investigated the effects of IMI on ampullar strips of bulls in organ baths. Vasa deferentia were collected from 16 freshly slaughtered post-puberal bulls of various breeds. Longitudinal ampullar strips were prepared and placed into 20 ml modified Krebs bicarbonate solution, aerated with a mixture of 02 (95 %) and CO2 (5 %) in water-jacketed organ baths. The effect on the smooth muscle tissue of noradrenaline (NA) alone, NA in combination with IMI and IMI alone was evaluated. NA alone consistently produced dose-dependant smooth muscle tissue contractions. IMI doses equivalent to <1 mg/kg BW (body weight equivalent; bwe) had NA potentiating effects. Doses of <0.1 mg/kg bwe were consistently potentiating while doses of >0.1 mg to <1 mg/kg bwe partially blocked NA stimulating effects. Amplitude of rhythmic contractions increased while contraction frequency decreased at this level. This study supports the adrenergic potentiating effects of IMI at doses of 0.05-0.2 mg/kg bwe with higher doses having paradoxical effects. Doses of IMI < 2 mg/kg bwe completely blocked NA effects. Tissue response to NA, after IMI blockade, started to recover 146-186 minutes after application of IMI at <2 mg/kg bwe. In the absence of NA, IMI had no effect on smooth muscle activity. The time to an IMI effect on NA initiated smooth muscle activity was 8 minutes. On the basis of the results of this in vitro study, we propose that IMI can be used to enhance semen collection by means of electro-stimulation in domestic bulls and immobilised wildlife species such as buffalo, provided that the correct dose is used. / Dissertation (MMedVet (Gyn))--University of Pretoria, 2005. / Production Animal Studies / unrestricted

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A cocaÃna à reconhecida por produzir marcantes alteraÃÃes sobre o humor e comportamento humanos. Este trabalho teve como objetivo estudar as alteraÃÃes neuroquÃmicas, comportamentais e histopatolÃgicas promovidos pela administraÃÃo repetida (7 dias) de cocaÃna isoladamente ou em associaÃÃo com imipramina, um antidepressivo tricÃclico, topiramato, um antiepilÃptico, e pentoxifilina, um vasodilatador, em ratos. Ratos Wistar machos (200-250 g) foram tratados diariamente com cocaÃna isoladamente (Coc, 10 e 20 mg/kg, i.p.) ou em associaÃÃo com imipramina (Imi, 12.5 ou 25 mg/kg, v.o.), topiramato (TPM, 50mg/kg, v.o.), pentoxifilina (Pent, 50mg/kg, i.p.) durante 7 dias. CocaÃna causou um aumento significativo da atividade locomotora, e sua combinaÃÃo com Imipramina, topiramato e pentoxifilina bloqueou os efeitos promovidos pela cocaÃna. No teste de esquiva passiva, a cocaÃna reduziu a memÃria de curto e de longo prazo enquanto que a imipramina reverteu parcialmente os efeitos da cocaÃna. Pentoxifilina bloqueou completamente os efeitos da cocaÃna. No labirinto aquÃtico, a cocaÃna aumentou o tempo para encontrar a plataforma, efeito revertido totalmente pela imipramina e pentoxifilina e parcialmente pelo topiramato. No teste de labirinto em cruz elevada, cocaÃna e imipramina diminuÃram o numero de entradas e o tempo de permanÃncia nos braÃos abertos. A combinaÃÃo das duas drogas reverteu parcialmente estes efeitos. No teste de nado forÃado, cocaÃna e imipramina diminuÃram significativamente o tempo de imobilidade do animal. CocaÃna promoveu aumento dos nÃveis de dopamina (DA) e diminuiÃÃo de HVA em corpo estriado, efeitos estes bloqueados por imipramina e topiramato. CocaÃna tambÃm aumentou Noradrenalina (NA), efeito bloqueado pelo topiramato. Contudo, cocaÃna nÃo alterou os nÃveis de serotonina (5-HT). Imipramina aumentou os nÃveis de 5-HT. A exposiÃÃo de cultura primÃria de cÃlulas mesencefÃlicas de ratos a cocaÃna reduziu a morte celular causada pela 6-OHDA (10ÂM). CocaÃna diminuiu o fluxo sanguÃneo cerebral e este efeito foi completamente revertido pelo topiramato. CocaÃna aumentou os nÃveis de nitrito no cÃrebro dos animais e este efeito foi bloqueado pela imipramina e topiramato. Nos estudos histolÃgicos, cocaÃna promoveu um dano significativo no cÃrtex e giro denteado do hipocampo, efeito revertido pela imipramina. Estes resultados sÃo de grande importÃncia, especialmente em relaÃÃo a atenuaÃÃo do prejuÃzo cognitivo, a reduÃÃo do fluxo sanguÃneo cerebral, a formaÃÃo de nitrito e a morte celular induzidos pela cocaÃna.