Biomedical subjects
Publications and source records attributed to D C Dyer.
The pharmacokinetics of chlortetracycline (CTC) in plasma and bile after intravenous administration in turkeys was ascertained. After a dose of CTC (0.9 mg/kg) was administered IV, 8.5% of the dose appeared in the bile in 4 hours. The peak bile/plasma concentration ratio for CTC was 254 at 2 hours. The bile/plasma concentration ratio was greater than 1 from 10 to 240 minutes after CTC administration.
Twenty healthy ponies were given i.v. 1.1 mg/kg of xylazine from 2 manufacturers and the pharmacokinetic parameters calculated from the disposition curves. The disposition curves for the 2 commercial preparations were not different. Yohimbine, an antagonist of the pharmacologic effects produced by xylazine, did not alter the disposition of xylazine in the plasma. A single i.v. bolus of xylazine was completely described in 17 of 20 animals by the biexponential equation: Cp = 1.30e(-0.3955t) + 0.58e(-0.033t) where Cp represents the concentration of xylazine in the plasma at time t (min). The t1/2 beta was 75 +/- 13 min and whole body clearance was 18.9 +/- 1.5 (ml/min.kg).
Recent investigations have suggested that the alpha 2-adrenoreceptor agonist B-HT 920 is also a dopamine (DA) agonist with a selectivity for presynaptic receptors. In the present study, the emetic effect of B-HT 920 was investigated. Intravenous injections of B-HT 920 (0.32-10.0 micrograms/kg) and a DA2-agonist apomorphine (3.2-100.0 micrograms/kg) caused dose-dependent emesis. The ED50 of B-HT 920 and apomorphine were 3.2 and 12.3 micrograms/kg, respectively. When haloperidol (10.0-24.5 micrograms/kg i.v.), a DA2-antagonist, was given 5 minutes before B-HT 920 (10 micrograms/kg) or apomorphine (32 micrograms/kg), it caused a dose-dependent prevention of B-HT 920- and apomorphine-induced emesis. The ED50 of haloperidol in preventing the emetic effect of both drugs was identical (13.5 micrograms/kg). In contrast, haloperidol (32 micrograms/kg i.v.) did not prevent the emetic effect of ouabain (40 micrograms/kg i.v.). Neither did yohimbine (0.1 mg/kg i.v.), an alpha 2-adrenoreceptor antagonist, prevent the emetic effect of B-HT 920 (10 micrograms/kg). These results suggest that B-HT 920, acting like apomorphine, induces emesis by activating DA2-receptors probably in the chemoreceptor trigger zone of the area postrema.
A physiologically based pharmacokinetic model was developed to describe the absorption and disposition of chlortetracyline (CTC) in the healthy and diseased (fowl cholera) turkey. The CTC was given (with and without citric acid) as an oral (15 mg/kg) or i.v. (1 mg/kg) dose. When minerals (0.3 g/L Ca2+, 0.1 g/L Mg2+) were dissolved in the bird's drinking water, the model indicated that the addition of citric acid (mass ratio of 10 citrate: 1 CTC) increased the fraction of dose absorbed from 0.06 to 0.16; once absorbed, the fractions of drug eliminated by renal excretion, biliary secretion, and chemical decomposition were 50, 46, and 4%, respectively. The presence of fowl cholera appeared to increase plasma levels by increasing the intestinal permeability and lowering the hepatic and/or renal clearance.
Plasma and tissue concentrations, following the oral administration of the antibiotic chlortetracycline (CTC) alone or with citric acid, were determined in healthy and infected (Pasteurella multocida) turkeys. The principal results were: 1) The dose (of CTC) versus plasma level relationship was nearly linear. 2) Addition of citric acid to an oral preparation produced significantly higher plasma levels when divalent cations Ca2+ (.3 g/liter) and Mg2+ (.1 g/liter) were present in the drinking water and dosage solution than when citric acid was omitted. 3) The concentration of CTC was considerably higher in the liver and kidney than in the muscle and brain. 4) Birds infected with P. multocida had significantly higher plasma levels than healthy birds. 5) Oral administration of CTC increased the survival rate of the birds infected with P. multocida.
Serum concentrations of chlortetracycline (CTC) in healthy chickens were determined for the 24-hour period after they were given CTC (with and without citric acid) as an oral (25 mg/kg) or IV (0.9 mg/kg) dose. The oral time-course drug data were fitted adequately by a 2-compartment pharmacokinetic model with absorption. The resulting absorption rate constant (Ka) for the birds orally given CTC with citric acid was nearly equal to that for the birds given CTC alone. Although the uptake of orally administered CTC was rapid, only a small fraction of the dose was absorbed. The administration of citric acid-CTC significantly increased the mean serum concentration of CTC and the fraction of the dose absorbed. The citric acid-CTC mixture also produced significantly higher elimination (Kel) and distribution (K12) rate constants for CTC.
Contractions of isolated strips of human umbilical artery (HUA) induced by arachidonic acid were antagonized by indomethacin at concentrations as low as 1 microgram/ml. Much higher concentrations (25 and 65 microgram/ml) were needed to relax KCl-contracted strips of HUA. These data suggest that indomethacin at 1 microgram/ml inhibits endogenous synthesis of vasoconstrictive prostaglandin-like substances whereas indomethacin at higher concentrations causes nonspecific relaxation. Contractions induced by 5-hydroxytryptamine (5-HT), KCl and prostaglandin F2 alpha (PGF2 alpha) were antagonized by indomethacin at 25 and 65 microgram/ml, but not at 2.5 microgram/ml. These data suggest that the contractile responses to 5-HT, KCl and PGF2 alpha are not mediated by endogenous prostaglandin-like substances. Contractions induced by adenosine triphosphate (ATP), in contrast, were completely inhibited by indomethacin (1 microgram/ml). Therefore, the data suggest that prostaglandin-like substances may mediate contractions to ATP.
A technique allowing the direct measurement of fetal heart rate and blood pressure in the guinea pig is described in detail. The basal heart rate and blood pressure measurements under both pentobarbital and methoxyflurane anesthesia are given. In comparison to the mother, the fetal cardiovascular system was less responsive to norepinephrine. This technique demonstrates the feasibility of using the guinea pig in fetal cardiovascular experimentation.
Mirex kinetics were determined in chickens after a single dose of 30 mg/kg iv or 300 mg/kg orally. The decline in blood concentrations was biphasic and suggested uptake of mirex by "fast" and "slow" tissue compartments, with the greatest accumulation in fat and skin 2 wk after administration. Less than 1% of the dose was excreted in 2 wk. Mirex depletion rates in skin and fat were determined in growing chicks fed 1 or 10 ppm mirex in the diet for 1 wk. Calculated disappearance half-times for mirex were 24.8 in skin and 31.5 d in fat. The decrease in tissue concentrations was attributed to dilution in tissue mass accompanying the rapid growth rate rather than to excretion of mirex. The results do not indicate that avian species eliminate mirex more efficently than mammals.
The enantiomers of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]methyl]-1,4-benzodioxane (4) were prepared from the chiral 2-[(tosyloxy)methyl]-1,4-benzodioxanes [(2S)- and (2R)-5]. The corresponding (2R)- and (2S)-2-(aminoethyl)-1,4-benzodioxanes [2R)- and (2S)-7] were prepared by a modified Gabriel synthesis and converted to the enantiomers of 4 by condensation with 2,6-dimethoxyphenoxyacetaldehyde (8) and reduction of the intermediate imine with NaBH4. The enantiomer (2S)-4 was 40--50 times as potent as the enantiomer (2R)-4 in antagonizing the alpha-adrenergic response of methoxamine-induced contraction of rabbit aortic strips, showing a pA2 = 9.0. This result is consistent with the previous observation that S enantiomers of 2-[(alkylamino)methyl]benzodioxanes are more potent antagonists at a alpha-adrenergic receptors than the R enantiomers.
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Replacement of the 4-methoxy of mescaline with higher alkyl homologues or with bromine led to increased activity at serotonin receptors in a sheep umbilical artery preparation. This activity appears correlated with lipophilicity, as measured by 1-octanol-water partition coefficients, but drops off when the 4-substituent is about five atoms in length. It is suggested that 3,4,5-trisubhe 2,4,5-substitution pattern.
The optical isomers of alpha-adrenergic receptor antagonists prosympal (2), piperoxan (3), and dibozane (4) were prepared by methods establishing the absolute configuration of each. (2S)-3(2'-Hydroxyphenoxy)-1,2-propanediol ditosylate (10) was prepared from (2R)-3-tosyloxy-1,2-propanediol acetonide (6). Intramolecular displacement afforded (2S)-tosyloxymethylbenzodioxan [(2R)-11]. Reaction of (2R)-11 with the appropriate amine (diethylamine, piperidine, or piperazine) afforded the 2S isomers of 2, 3, and 12, respectively. Reaction of (2S)-12 with (2R)-11 afforded the SS isomer of 4. Reaction of (2S)-3-benzyloxy-1,2-propanediol ditosylate (14) with catechol (NaOMe) afforded (2R)-benzyloxymethylbenzodioxan (15). Subjecting 15 to hydrogenolysis, tosylation, and displacement with the appropriate amine afforded 2R isomers of 2, 3, and 12. Reaction of (2R)-12 with (2S)-11 afforded (RR)-4. Reaction of (2R)-12 with (2R)-11 afforded meso-4. The S isomers were more effective antagonists to the alpha-adrenergic response of methoxamine-induced contraction of rabbit aortic strips by twofold in 2 and 18-19-fold in 3 and 4. meso-4 was as effective as the SS isomer of 4. The results are interpreted in terms of a similar conformational distribution of aminoalkyl, oxygen, and aromatic functional groups of the (S)-benzodioxans and (R)-epinephrine.
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Isolated strips of sheep umbilical arteries contracted in the presence of R-(-)-2-amino-1-(2,5-dimethoxy-4-methylphenyl) butane (BL3912A). These contractions faded over an hour period and at this time BL3912A antagonized contractions to R-(-)-DOM, 5-hydroxytryptamine (5-HT) but not to angiotensin. The initial contraction produced by BL3912A was antagonized by cinanserin, a 5-HT antagonist. These experiments indicate that BL3912A can be classified as a partial agonist of 5-HT receptors in sheep umbilical arteries.
A homologous series of 4-alkyl-2,5-dimethoxyphenylisopropylamines (alkyl = H through n-C5H11 and t-C4H9) was synthesized and compared with mescaline as serotonin agonists in a sheep umbilical preparation. The three-carbon homolog 6d was found to be the most potent of the straight-chain series in accordance with its observed psychotomimetic effectiveness in man.
Contractions of sheep umbilical vasculature induced by 5-hydroxytryptamine, mescaline and d-lysergic acid diethylamide (LSD) were antagonized by 1-methyl-1, 2, 5, 6-tetrahydropyridine-N, N-diethyl-carboxamide (THPC) 5 X 10(-4)M. THPC did not block contractile responses to angiotensin. The data are interpreted to support our previous suggestions that certain chemical entities representing portions of the LSD molecule may be effectively studied as antagonists to the hallucinogens. The present data indicate that THPC is a weak 5-hydroxytryptamine receptor antagonist.