Adrenosensitivity of injured afferent neurons does not require the presence of postganglionic sympathetic terminals.

Nerve injury sometimes triggers neuropathic pain states that are exacerbated by sympathetic efferent activity. A classic example is causalgia. The mechanism of coupling between sympathetic efferent activity and the afferent discharge responsible for pain sensation is a subject of controversy. Some authors hold to the 'direct coupling hypothesis' which proposes that noradrenaline (NA), released from sympathetic varicosities, acts directly on alpha-adrenoreceptors located in the membrane of injured primary afferents. Others believe that coupling is indirect; that the effects of NA are mediated by additional, non-adrenergic, chemical substances and their receptors (the 'indirect coupling hypothesis'). For example, it has been proposed that in inflamed skin NA acts back on the sympathetic endings which, secondarily, release a prostanoid mediator which sensitizes afferent endings. We report that the responsiveness of injured afferent axons to systemically applied NA persists, and in fact increases in prevalence, in rats that underwent prior chemical or surgical sympathectomy. The observation of adrenosensitivity in injured afferents in the absence of sympathetic postganglionic endings is consistent with the direct coupling hypothesis, which associates adrenosensitivity with the injured afferent axon. It is not consistent with the indirect coupling hypothesis which requires the presence of sympathetic endings as a source for NA-evoked prostanoid release.

A combined heat clearance method for tissue blood flow measurement.

Tissue Blood Flow is measured by applying a combined procedure of two independent approaches based on heat clearance: the Pulse Decay Method and the Continuous Method. The Pulse Method allows absolute assessment of tissue BF with no need for calibration, and can be applied only if the tissue BF is steady during the period of measurement. On the other hand, the Continuous Method enables the observation of rapid changes in tissue BF, and can be applied under non steady-state conditions. Using the combined method, a continuous quantitative measurement of transient changes in tissue BF can be obtained. For this purpose, we have developed two experimental systems consisting of independent electronic units: a Pulse Unit and a Continuous Unit. A micro-computer with dedicated software controls the operation of the electronic units and calculates tissue BF on-line. In vitro measurements are performed and demonstrate the reliability of the methods. In vivo measurements in rat brain tissue are also performed and include physiological and pharmacological changes of local tissue BF. The results of the two heat clearance methods correlate well with tissue BF values measured by a third independent method, the Hydrogen Clearance Method.

Cortical cerebral blood flow is enhanced by hornet venom.

This study examined the effect of Oriental hornet venom sac extract (VSE) on the rate of local blood flow in the cerebral cortex of rats. Sublethal doses of VSE in isotonic saline solution were injected into the femoral vein of anaesthetised rats and the rate of blood flow was assessed by the hydrogen clearance technique both before the envenomation as well as during the following 150 min. The injection of VSE was found to induce a prolonged elevation of blood flow in the cerebral cortex. The time of occurrence of this elevation varied in different rats and so also the intensity of the elevation, ranging between 47-212% of the basal values. No exceptional or toxic phenomena were recorded in the course of this investigation. It would seem that the factor(s) responsible for boosting the blood flow is probably one or more of the water soluble components of the hornet venom.

The ambivalent effects of early and late administration of mannitol in cold-induced brain oedema.

This study was undertaken in order to determine whether early administration of mannitol is different from late administration in its effect on brain oedema. Cold-induced brain oedema, which was confirmed by high resolution CT scan, was produced in 2 groups of cats. In group one mannitol was given early (90 minutes after injury); in group two 3-4 hours after the injury (late). Repeated CT scans following mannitol administration showed that the early group exhibited significantly greater dehydration (p less than 0.0001) while the late group showed significant hydration, in the lesioned hemisphere. The contralateral control hemisphere responded to mannitol with similar dehydration effect in both groups.

Transient effect on mannitol on cerebral blood flow following brain injury.

CBF and ICP were measured in cats following cerebral cold injury and mannitol infusion. Mannitol was found to reduce the intracranial hypertension caused by the injury. The restoration of CBF and ICP was of short duration and was followed by a reduction of CBF and elevation of ICP. A repeated restoration of CBF by a second dose of mannitol was followed by a more severe impairment of CBF. The prolonged beneficial effect of mannitol on CBF after brain injury has to be reassessed.

Use of hydrogen gas clearance for measurement of renal circulation. An experimental study.

Inhalation of hydrogen gas and its immediate diffusion into the blood permits an accurate and reproducible determination of its clearance through a fine platinum electrode inserted in the renal cortex. The oxidation of molecular hydrogen at the surface of the electrode generates a current which is then easily recorded. Such recordings accurately reflect regional arterial circulation. Experiments have been done in rats to determine regional renal cortical arterial circulation in (1) normal conditions, (2) immediately following unilateral, complete ureteral obstruction, and (3) following a twenty-four-hour ureteral obstruction. Hundreds of simple and reproducible recordings were obtained. Although acute obstruction does not immediately affect cortical blood supply, a twenty-four-hour obstruction was accompanied by a 31.3 per cent reduction in circulation.

Regional cerebral blood flow in the acute stage of experimentally induced subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) was induced in 13 adult mongrel cats by a slow injection of fresh autogenous blood into the cisterna magna. Serial determinations of regional cerebral blood flow (rCBF) in the cortex and deep-seated areas (internal capsule, thalamus, and caudate nucleus) were made during the following 2 hours, while intracranial pressure (ICP) was maintained at normal values. A decrease in rCBF was observed in all the areas examined. This reduction followed a characteristic triphasic pattern with an initial steep decline immediately after the SAH. The clinical implications of these findings are discussed.

Clinical pharmacological studies with LM 5008, a new antidepressant.

A spectrofluorometric assay has been developed for the measurement of LM 5008, a novel antidepressant, in biological fluids. A buccal absorption study in 12 healthy subjects showed increased uptake of LM 5008 under higher pH conditions. Single dose administration of 25 mg orally to 3 volunteers showed peak levels after 2 to 3 hours. Pharmacodynamic studies in 12 volunteers comparing 25 mg LM 5008, 1 mg atropine and placebo showed that pupil diameter increased significantly after LM 5008 compared with atropine and placebo, but no other significant anticholinergic effect was demonstrated. Atropine showed a significant decrease in saliva production and in eccrine sweating and a significant increase in dryness of the mouth and in pupil diameter compared with placebo. The distance of the near point tended to increase during atropine treatment but only significantly at 6 hours. LM 5008 produced no significant change in these measurements.

The different effects of sodium bicarbonate and aluminium hydroxide on the absorption of indomethacin in man.

The influence of oral sodium bicarbonate and aluminium hydroxide on the absorption of indomethacin has been studied in normal volunteers. While sodium bicarbonate appeared to increase indomethacin absorption, aluminium hydroxide markedly reduced both the rate and extent of absorption. The buccal absorption of indomethacin over the pH range 5-9 was also studied in normal volunteers, and showed that the percentage absorption increased markedly as the pH was reduced. The clinical importance both of pH-partition and of adsorption are discussed in the context of antacid interactions. It is concluded that caution must be exercised when prescribing an antacid with other orally-administered drugs.

The influence of thiethylperazine on the absorption of effervescent aspirin in migraine.

The absorption of effervescent aspirin was studied in three groups of patients during attacks of migraine. The first group received intramuscular thiethylperazine 10 min before effervescent aspirin; the second group received intramuscular metoclopramide 10 min before effervescent aspirin; and the third group received effervescent aspirin alone. Where possible each patient was retested when headache-free but under conditions which were otherwise as similar as possible to those during the acute attack. Intramuscular metoclopramide corrected the impairment of drug absorption that occurred during a migraine attack, whereas thiethylperazine did not. In the group of patients treated with thiethylperazine and aspirin, the impairment of absorption did not correlate with the duration of the symptoms, nor with the severity of the headache and nausea. Patients treated with thiethylperazine and aspirin tended to take longer to recover than those patients treated with metoclopramide and aspirin. However, in the thiethylperazine treated group, the time to recover did not correlate with the salicylate level achieved.

Procainamide absorption studies to test the feasibility of using a sustained-release preparation.

Using in vitro techniques it was confirmed that whilst the release of procainamide from the conventional formulation (Pronestyl) was rapid, that from the sustained-release preparation (Cardiorytmin Retard) occurred over a prolonged period. 2 The peak plasma procainamide concentrations after single doses of Cardiorytmin Retard were relatively lower and occurred later than those after single doses of Pronestyl. Furthermore, after reaching a peak, the fall in plasma procainamide concentration was less rapid after the sustained-release preparation. Early urinary recovery of procainamide in patients and in healthy volunteers was greater after Pronestyl than after Cardiorytmin Retard, though overall recovery in urine was similar. These findings indicate that the absorption of the sustained-release preparation is slower, though the overall bioavailabilities of the two preparations are almost the same. 3 These results confirm the feasibility of using a sustained-release procainamide preparation, such as Cardiorytmin Retard, since it would be possible to administer the same amount of drug in fewer daily doses without plasma concentrations becoming ineffective towards the end of each dosing interval.