Many strokes are thought to develop as a consequence of platelet aggregation on areas of arterial endothelial damage, with subsequent embolism or thrombus formation. Aspirin prevents platelet adhesion and aggregation by inhibiting the formation of thromboxane A2 by platelets. This suggests that aspirin could be used to prevent stroke. However aspirin also inhibits endothelial formation of the anti-aggregatory substance prostacyclin, though probably only in a slightly higher dose than that just capable of inhibiting platelet aggregation. Consequently, too high an aspirin dose may defeat its purpose. The effect of aspirin on platelets lasts for as long as they survive, whereas the effects of aspirin on endothelium are shorter. Theoretical considerations suggest that aspirin, given in brief pulses just to reach platelet inhibitory concentrations in plasma, and administered at the maximum interval that will maintain inhibition of platelet aggregation, should offer the most favourable balance between altered platelet and altered endothelial function from the viewpoint of stroke prevention. Data are presented showing that rapid rather than slow or delayed release aspirin preparations are necessary to achieve suitable plasma aspirin concentration-time profiles in humans, and that a peak plasma aspirin concentration of around 1.2 mg/L is necessary in vivo to inhibit aggregability of previously untreated platelets.

Aspirin↗

PubMed1986

Peripheral venous plasma aspirin concentrations and platelet aggregation inhibition produced by enteric-coated aspirin formulations.

In a random cross-over design, six healthy consenting adult volunteers were given on separate occasions single doses of 300-650 mg of 3 different formulations of enteric-coated aspirin. Over various intervals for 48-54 h following dosage, plasma aspirin and salicylate concentrations were measured together with percentage inhibition of platelet aggregation activated by threshold concentrations of sodium arachidonate alone and combined with ADP and collagen. In all subjects each formulation delivered measurable quantities of aspirin to the peripheral circulation, the unchanged drug being detected at various times up to and including 28 h after dosage. Moreover, low aspirin concentrations were found to co-exist with unimpaired platelet aggregation. All 3 formulations yielded statistically significant (P less than 0.01) inhibition of platelet aggregation activated both by arachidonate and by the combination of aggregants when tested 24-29 and 48-54 h after dosage; there were no significant differences (P greater than 0.05) between the 3 formulations in this regard. Two different patterns of delivery of unchanged aspirin to the systemic circulation from these enteric-coated formulations were apparent. These patterns may be important when considering which aspirin formulation might be most appropriate in chronic use for an antiplatelet effect. None of the enteric-coated formulations used in this study may be optimal in this regard.

Adenosine Diphosphate↗

PubMed1986

A new formulation of aspirin: bioavailability and analgesic efficacy in migraine attacks.

Plasma aspirin and salicylate concentrations were followed after 600 mg of a new palatable glycinated preparation of aspirin was given to six healthy male volunteers in an attempt to investigate whether pre-gastric absorption of aspirin could occur. In each subject the drug was administered by three different routes, viz. (i) swallowed with water, (ii) dissolved sublingually and retained in the mouth, and (iii) allowed to disperse on the tongue, and then swallowed without water intake. Using the latter route of administration and the same aspirin formulation, plasma aspirin and salicylate concentrations were also followed in 10 patients during acute migraine attacks. These results were compared with those from another 10 migraineurs given 600 mg of soluble aspirin swallowed with water during attacks. Aspirin and salicylate pharmacokinetic parameters (Cmax, tmax, t1/2, Kabs and AUC) in the normal volunteers were not significantly different (p greater than 0.05) whether glycinated aspirin was swallowed with water or swallowed without water after dispersion in the mouth. However, negligible aspirin was absorbed when the glycinated preparation was retained in the mouth. In migraine patients, there was no significant difference (p greater than 0.05) between the bioavailabilities of soluble aspirin swallowed with water (AUC = 5.7 +/- 2.3 mg h/l) and glycinated aspirin swallowed without water (AUC = 4.4 +/- 1.6 mg h/l). There also was no significant difference (p greater than 0.05) when the time courses of pain relief were compared, both treatments being associated with a significant (p less than 0.01) analgesic effect. The glycinated aspirin was thus bioequivalent to swallowed aspirin but has no advantages for migraineurs over soluble aspirin if water is readily available for self-administration.

Administration, Oral↗

PubMed1985

A sensitive liquid chromatographic assay for plasma aspirin and salicylate concentrations after low doses of aspirin.

An original, highly sensitive and specific high performance liquid chromatographic method has been developed for the measurement of aspirin and salicylate in plasma. Minimum concentrations of 10 micrograms/L (aspirin) and 0.5 mg/L (salicylate) can be measured using 1 ml of plasma. After collection, plasma is first treated with physostigmine sulfate to inhibit enzymatic hydrolysis of aspirin to salicylate. Maximal recovery is achieved using an acid extraction into anhydrous diethyl ether with a subsequent drying-down step in an iced water bath. Aspirin and salicylate are separated by elution with a mixture of methanol, 1-butanol, orthophosphoric acid, and water on a reversed-phase octadecyl silane column at 47 degrees C and detected at 234 nm by ultraviolet absorption. Quantitation is achieved using the peak height ratio of aspirin and salicylate to internal standard (m-anisic acid). The assay has been used for the study of simultaneous aspirin and salicylate pharmacokinetics after a single oral dose of 100 mg soluble glycinated aspirin for platelet antiaggregatory therapy in six subjects, one of whom was also studied after receiving a 600 mg dose.

Adult↗

PubMed1985

Psychiatric complications associated with geriatric surgery.

Detection of pre-existing psychopathologic problems in the geriatric surgical patient can often preclude further psychiatric complications. When complications such as delirium arise, collaboration between the surgeon and the psychiatrist enhances a satisfactory outcome.

Aged↗

PubMed1984

Effect of premedication with acetylpromazine on the disposition kinetics of thiopental.

This study was performed to determine whether premedication with acetylpromazine alters the disposition kinetics of thiopental in normal dogs. Based on nonlinear least squares regression analysis of the plasma concentration-time data obtained in individual dogs, a three-compartment open model was selected to describe the pharmacokinetic behavior of thiopental. While clinically premedication appears to delay time of awakening from thiopental anesthesia, statistical comparison (Student's t-test for paired data) of pharmacokinetic terms showed no significant difference. This may be largely attributed to wide individual variation in each parameter. The rate of change in volume of distribution at zero time (mean +/- SD, n = 7), which is a parameter that might have been expected to vary significantly, was 97 +/- 106 ml/min X kg for thiopental alone and 77 +/- 60 ml/min X kg following acetylpromazine premedication. Body clearance of thiopental was 1.96 +/- 0.59 ml/min X kg in dogs without premedication and 1.55 +/- 0.49 ml/min X kg following acetylpromazine. By relating observed time of awakening to plasma concentrations of thiopental it was determined that awakening from anesthesia occurred at a concentration of 20 micrograms/ml whether or not the dogs were premedicated. It can only be concluded that while premedication with acetylpromazine appears to delay time of awakening from anesthesia, it does not change the disposition kinetics of thiopental or affect the plasma concentration at the observed time of awakening.

Acepromazine↗

PubMed1984

Drainage of lymph from the foreleg to the superficial cervical lymph node in sheep.

The superficial cervical (prescapular) node in sheep is large and readily accessible. It lies medial to the omotransverse muscle and 40 to 60 mm cranial to the ventral end of the scapular spine. Lymph vessels reaching this node from the foreleg all enter its ventral half. These lymphatics can be approached surgically opposite the elbow joint where they lie adjacent to the cephalic vein. Carbon particles infused into a single afferent lymphatic were restricted to a small segment of the ventrocranial quadrant of the node. When Evans' Blue dye, or a suspension of carbon particles, was injected subcutaneously just above the hoof they were carried to the node in two to five afferent lymphatics and were found mainly in the ventrocranial quadrant. A knowledge of the anatomy of the superficial cervical node and its afferent lymphatics may be of value in immunological studies, especially where it is desired to introduce antigen into a known part of a node and to leave the remainder for control observations.

Animals↗

PubMed1984

Dexamethasone and prednisolone in the horse: pharmacokinetics and action on the adrenal gland.

Pharmacokinetics of dexamethasone and prednisolone were studied in 6 horses given dexamethasone alcohol (IV or IM) or dexamethasone 21-isonicotinate as a solution IV or IM (50 micrograms/kg of body weight), prednisolone 21-sodium succinate IV or IM (0.6 mg/kg of body weight), or prednisolone acetate IM (0.6 mg/kg of body weight). Plasma concentrations were determined using a high-performance liquid chromatographic method. After dexamethasone alcohol (IV) or dexamethasone 21-isonicotinate (IV), the half-life of elimination was similar (53 minutes) for both formulations. After dexamethasone (alcohol and isonicotinate, IM), concentrations were low or nondetected. After prednisolone 21-sodium succinate (IV), the half-life of elimination (99.5 minutes) was significantly (P less than 0.01) longer than that for dexamethasone. After prednisolone 21-sodium succinate (IM), absorption was rapid and bioavailability was high. After prednisolone acetate (IM), absorption was slow and prednisolone was present in plasma for about 7 days. Due to the nonlinearity of prednisolone kinetics, a bioavailability higher than 100% was obtained. The basal plasma hydrocortisone concentration was approximately 70 ng/ml. After dexamethasone (IV or IM), plasma hydrocortisone values decreased after a 2-hour delay and returned to base line after a 3 to 4 day delay. After prednisolone 21-sodium succinate (IV or IM), plasma hydrocortisone decreased immediately (IV) or rapidly (IM) and returned to base line after a 24-hour delay. After prednisolone acetate (IM), plasma hydrocortisone decreased for up to 21 days.

Absorption↗

PubMed1983

Thiopentone pharmacokinetics and electrocorticogram pattern in sheep.

Thiopentone pharmacokinetics and electrocorticogram patterns were studied in a group of six sheep given thiopentone intravenously (20 mg/kg). Plasma concentrations were determined using a high-performance liquid chromatography method. A three-compartment open model was selected to describe the disposition kinetics of thiopentone. The drug had an apparent volume of distribution of 1005 +/- 196 ml/kg; body clearance was 3.5 +/- 0.8 ml/min-kg and the half-life, based on the slope of the terminal portion of the curve, was 196 +/- 64 min. From the electrocorticogram pattern, it seems likely that the highest concentrations in brain occurred between 47 and 217 sec after commencing administration and a brain penetration half-time of 26.5 +/- 2.87 sec was calculated. At the time of awakening (36.6 +/- 6.36 min) 24.1 +/- 6.3% of the dose was located in the central compartment, 12.6 +/- 8.2 was in the shallow peripheral compartment, 38.8 +/- 14.1 was in the deep peripheral compartment and 24.6 +/- 10.3 had been eliminated. Using simulated curves, it appeared that suppression of the shallow peripheral compartment (muscle) did not change the time of awakening; in contrast when elimination-rate constant was decreased, awakening was delayed. It was suggested that the relatively short duration of thiopentone anaesthesia in sheep should be attributed mainly to elimination of the drug by hepatic metabolism and uptake by body fat. This hypothesis, which differs from the widely accepted view that the duration of thiopentone anaesthesia is independent of the rate of hepatic metabolism, is discussed in terms of differences in regional blood flow between sheep and monogastric species.

Anesthesia, Intravenous↗

PubMed1982

Dexamethasone in cattle: pharmacokinetics and action on the adrenal gland.

The pharmacokinetics of Dexamethasone (DXM) was studied in four cows all of which received DXM alcohol and DXM 21 isonicotinate (as a solution) by the intravenous and intramuscular routes. Concentrations of DXM and cortisol were determined using high performance liquid chromatography. An additional study was made in a second group of four cows which received intramuscular DXM 21 isonicotinate suspension for the assessment of DXM suppression of adrenal gland function. This was determined by measurements of base-line and ACTH-stimulated cortisol concentrations, before and following DXM administration. Following intravenous administration, the disposition kinetics of both formulations were described by a two-compartment open model. The half-times of elimination were similar; 335 and 291 min, respectively, for DXM alcohol and DXM 21 isonicotinate. All other pharmacokinetic parameters were not statistically different indicating that DXM was almost totally available (from DXM 21 isonicotinate). Following intramuscular administration, no significant difference in parameters was observed between the two formulations. Peak plasma concentrations were reached at 3 to 4 h post injection and bioavailability was approximately 70%. DXM was not detected in the plasma after the intramuscular administration of the suspension. The mean control plasma cortisol concentration was 8.8 +/- 3.03 ng/ml. Following intravenous and intramuscular administrations of DXM alcohol and DXM 21 isonicotinate (solution), cortisol concentrations initially increased. However, at 120 min (intravenous) and 2-4 h (intramuscular), concentrations were negligible; 24-72 h and 48-96 h, respectively elapsed before concentrations returned control values. Following DXM 21 isonicotinate (suspension) there was no initial increase and concentrations had not returned to normal in all four cows until 52 days post administration. Similarly, ACTH-stimulated plasma cortisol concentrations decreased progressively and significantly post administration. At 52 days, response to ACTH was normal in all animals.

Adrenal Glands↗

PubMed1982

Dexamethasone concentrations in bovine blood plasma and milk after intravenous injection.

Passage of dexamethasone from plasma to milk in five lactating dairy cows after an intravenous injection was evaluated by a high performance liquid chromatographic technique for measurement of concentrations in blood plasma and milk. The dexamethasone ester was 21-isonicotinate as a solution and was administered at .1 mg/kg bodyweight. The drug was detected in milk postinjection from 15 min to 8 h with a peak concentration of 20.6 ng/ml at the second sample time (30 min). Half-times of dexamethasone in plasma and milk were 4.5 and 3.0 h. The ratio of mean concentration for milk/plasma was .39. It is anticipated that no residues of dexamethasone would be detected in milk if normal dairy practices are followed.

Animals↗

PubMed1981

Spermatophores of the salamander Ambystoma texanum.

Living spermatozoa were observed in freshly deposited spermatophores and in fluid from vasa deferentia. In the distal, but not proximal, vas deferens spermatozoa moved together in whorls with heads and tails in alignment. Around the entire periphery of the spermatophore cap, similar slowly undulating groups of spermatozoa had their heads aligned and directed outward. Over time, some individual spermatozoa left the cap of the spermatophore and moved into the surrounding water (cap deterioration). Microscopical observations were made on spermatophore squashes and paraffin sections of spermatophores and vasa deferentia. Spermatozoa around the periphery of the cap were underlain by a PAS-positive membrane-like material. Cytoplasmic droplets, which were attached to spermatozoan necks in the vas deferens, were accumulated in the center of the spermatophore cap deep to the PAS-positive membrane. Spermatophore stalks were strongly PAS and Alcian blue positive and showed positive reaction for RNA. Tests for lipids and proteins were negative in the whole spermatophore. Electron microscopic observations showed the stalk of the spermatophore to be composed of rounded 'balls' of fibrous material. At the juncture of the stalk and cap a less dense fibrous material impacted the stalk enclosing many sperm tails and some heads and, although no attachment devices were visualized, the sperm were closely apposed to this material as was the spermatophore stalk. This finely filamentous material encircled the cap and was more prominent in some regions than others. The PAS-positive material detected with the light microscope was also observed with the electron microscope. It was circumferentially oriented and was composed of 200 A packed filamentous densities. Sperm heads and tails were found lying external to the membrane, whereas only tails and cytoplasmic droplets occupied the core of the spermatophore. Cytoplasmic droplets were usually free of the sperm tail and contained membranous sacs and two types of nuage material.

Ambystoma↗

PubMed1981

Toxicity in the plethodontid salamanders Pseudotriton ruber and Pseudotriton montanus (Amphibia, Caudata).

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Animals↗