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Biomedical subjects

D N Wade

Publications and source records attributed to D N Wade.

72 records · Page 4Linked to original sources
PubMed1970

Vascular resistance in the perfused isolated rat tail.

1. A constant flow perfusion system using the isolated rat tail has been developed to facilitate the study of resistance vessel behaviour and the action of vasoactive drugs.2. Baseline resistance remains stable for several hours and dose response curves to bolus injections of pressor agents are reproducible when dialysed bovine serum albumen is used in the perfusion medium to maintain osmotic pressure.3. Noradrenaline, adrenaline, serotonin, vasopressin, angiotensin II, high potassium concentrations and sympathetic nerve stimulation constricted the vascular bed.4. Angiotensin I, bradykinin, histamine, acetylcholine and isoprenaline did not alter vascular resistance under baseline conditions.5. Maximal sensitivity to noradrenaline occurred at 32 degrees to 34 degrees C. Below 30 degrees C, resting tone increased and the pressor effect of noradrenaline was prolonged.6. Low concentrations of (+/-)-propranolol in the perfusate enhanced adrenaline and noradrenaline vasoconstriction, high concentration of (+/-)-propranolol had a direct pressor effect and did not affect catecholamine responses.7. The preparation is a simple and relatively inexpensive adjunct to established methods of studying resistance vessel behaviour under varying experimental conditions.

Acetylcholine↗
PubMedDate not supplied

The pharmacokinetics and metabolism of 14C-carprofen in man.

Three healthy male subjects received single 100 mg oral doses of carprofen containing 20 microCi of 14C-carprofen. Venous blood samples were drawn during the first 48 h after the dose and urine and faeces were collected for 120 h. Concentrations of carprofen and its metabolites in body fluids were determined by TLC and mass spectral analysis. After a lag time of 0.3 +/- 0.1 h (mean +/- S.D.), carprofen was absorbed rapidly and peak concentrations in the plasma were reached in 2.7 +/- 1.3 h. The 14C plasma concentrations declined in a biphasic fashion. The mean half-lives of the initial (alpha) and terminal (beta) phases were 1.1 h and 20.6 +/- 6.1 h, respectively. Biotransformation to a glucuronide metabolite appeared to be the major mechanism of carprofen clearance. In 48 h 74.0 per cent of administered radioactivity was recovered in urine and 14.1 per cent was recovered in faeces. A glucuronide of carprofen comprised 85.0 per cent of the radiolabelled compounds in urine. The remaining radioactivity was comprised of parent drug (12.0 per cent) and un unidentified acid-labile conjugate of the parent drug (3.0 per cent). This pattern of metabolism and excretion is different from that in the dog and rat and may explain species differences in drug activity and toxicity.

Anti-Inflammatory Agents↗
PubMedDate not supplied

The pharmacokinetics of chlorbutol in man.

The pharmacokinetics of chlorbutol were studied after oral administration in 4 healthy subjects on two occasions. Following the rapid attainment of peak concentrations, plasma concentrations fell by approximately 50 per cent in 24 h. After the first dose of chlorbutol, the terminal elimination half-life was 10.3 +/-1.3 days (mean +/- S.E.M), the volume of distribution was 233 +/- 141 and the plasma clearance was 11.6 +/- 1.0 ml min-1. The binding to plasma proteins was 57 +/- 3 per cent. In 3 of the 4 subjects, there was a small but significant decrease in the terminal half-life of chlorbutol after the second dose. The mean urinary recovery over 17 days in two of the subjects accounted for only 9.6 per cent of the dose, 7.4 per cent of the total as the glucuronide and sulphate conjugates and 2.2 per cent as unchanged chlorbutol. A significant factor in the elimination of chlorbutol may be its instability under physiological conditions. Its half-life in vitro is 37 days at pH 7.4. The long terminal half-life of chlorbutol makes it unsuitable as a sedative drug because of the considerable accumulation which will occur when the drug is taken in multiple doses.

Adult↗
PubMedDate not supplied

Spectroscopic techniques in the study of protein binding. A fluorescence technique for the evaluation of the albumin binding and displacement of warfarin and warfarin-alcohol.

1. The binding of racemic mixtures of warfarin and warfarin-alcohol to human serum albumin (HSA) is accompanied by an increase in the fluorescence quantum yield of these compounds. This property has been used to measure the characteristics of the binding of warfarin and warfarin-alcohol to HSA at 22 degrees C and 37 degrees C. Within the limits of the technique, no significant differences between the number of binding sites and strength of binding at the tight site at either temperature were observed. 2. The fluorescence of warfarin and warfarin-alcohol was used to label their binding site on HSA and to study the effects of other drugs on their binding. The results indicate that these two molecules are bound to the same site on HSA. 3. The validity of using changes in the fluorescence of warfarin as a measure of its displacement from HSA was investigated. Good correlations were observed between drug-induced decreases in the fluorescence of bound warfarin and displacement as measured by equilibrium dialysis. The displacement of warfarfin, as detected by fluorescence, correlates well with the increase in free warfarin resulting from addition of therapeutic drug concentrations to undiluted human serum. 4. The most potent displacing agents, by all the methods used, were iophenoxic acid, phenylbutazone and oxyphenylbutazone. The first of these is no longer used clinically, but the latter two are and have been reported to cause hypoprothrominaemia by displacing warfarin from HSA. The present study indicates that changes in the fluorescence of warfarin bound to HSA can be used to measure displacement of bound warfarin and to screen drugs that may cause clinically significant interactions by this mechanism.

Alcohols↗
PubMedDate not supplied

The effect of various drugs on adenosine triphosphate content and histamine release from rat peritoneal cell suspensions rich in mast cells.

1. Iopanoic acid and iophenoxic acid were potent inhibitors of compound 48/80-induced histamine release from rat peritoneal cell suspensions rich in mast cells and caused a parallel dose-related reduction in ATP content of these cells. 2. Lignocaine was less potent and ouabain and probenecid were ineffective in inhibiting histamine release and reducing cellular ATP content. 3. Various drugs can inhibit 48/80-induced histamine release from rat peritoneal cells and this activity may result from depletion of cellular ATP. It is apparent that little structural specificity is required for activity in this cell system.

Adenosine Triphosphate↗
PubMedDate not supplied

Differential blockade of octopamine and dopamine receptors by analogues of clozapine and metoclopramide.

1. Sulpiride, but not procainamide, antagonizes the excitatory effects of (+/-)-octopamine receptors in the Tapes ventricle. Neither compound attenuates dopamine excitation. 2. Clozapine will attenuate the effects of (+/-)-octopamine and (-)-alpha-methyl octopamine at the octopamine receptor but not the excitatory effect of dopamine at dopamine receptors. 3. Clozapine is more potent than its 2-positional isomer HF 2046 in attenuating octopamine excitation. However, HF 2046, unlike clozapine, will attenuate the excitatory effects of dopamine. 4. These data indicate that replacement of the 8-chloro substituent in the clozapine nucleus with a 2-chloro substituent decreases the ability of the compound to blockaed octopamine receptors. However, the 2-chloro-substituted compound (HF 2046) now has the added ability to blockade excitatory dopamine receptors. 5. The greater potency of clozapine than HF 2046 as an octopamine antagonist suggests that it is the 8-chloro-substituted aromatic ring of clozapine which overlaps the aromatic site usually occupied by the octopamine aromatic ring.

Animals↗
PubMedDate not supplied

Effects of various drugs on the osmotic lysis of rat mast cells.

1. Rat mast cells were exposed to low osmotic pressures to produce a 'non-specific' disruption of the mast cell, with release of histamine along with other intracellular contents. 2. The effect of non-steroidal anti-inflammaotry drugs and various other drugs upon osmotically induced histamine release was examined. 3. Representative non-steroidal anti-inflammatory drugs indomethacin, phenylbutazone and flufenamic acid, the acidic compounds ethacrynic acid, iopanoic acid and probenecid, and the local anaesthetic lignocaine, all caused a dose-dependent facilitation of osmotically induced histamine release compared to controls. All drugs were active at 0.1 mmol/l. 4. The previously observed inhibition of compound 48/80 and the antigen-induced histamine release from rat mast cells by similar concentrations of the drugs used in the present study are unlikely to be due to mast cell plasma membrane stabilization.

Animals↗
PubMedDate not supplied

The pharmacokinetics of albumin conjugates of D-penicillamine in rats.

A protein conjugate that forms during the metabolism of D-penicillamine (D-PEN) in rats is electrophoretically indistinguishable from the (D-PEN-albumin) mixed disulfide that forms during the oxidation of D-PEN in plasma in vitro. Both the conjugate formed in vivo and the mixed disulfide synthesized in vitro are eliminated slowly in rats, with half-lives of 5.33 +/- 0.25 days and 3.48 +/- 0.42 days, respectively. These half-lives approximate or exceed the half-lives of radioiodinated plasma protein in the animals. The stability of the D-PEN-albumin conjugate contrasts with the rapid elimination of D-PEN itself and probably explains delayed elimination of D-PEN-containing disulfides in humans. Stable modification of tissue proteins by D-PEN may also be involved in the mode of action of D-PEN in rheumatoid arthritis.

Albumins↗