Syndromes due to the abrupt withdrawal of drug treatment occur mainly with adrenal corticosteroids and agents with an action on either the cardiovascular system or central nervous system. The abrupt withdrawal of antihypertensive therapy typically results in symptoms of overactivity in the sympathetic nervous system. Clonidine and beta-adrenoceptor antagonists are clinically the most important of these agents, but numerous other drugs have been implicated. Overall, the problem is small when viewed in the context of the huge scale of prescribing of antihypertensive medicines. A more serious problem is the occurrence of crescendo angina following the abrupt withdrawal of beta-adrenoceptor antagonists. Although other factors may be involved, adaptive up-regulation of beta-adrenoceptor density is the most likely cause of crescendo angina, and renders the patient more susceptible to sympathetic nervous stimulation following withdrawal of treatment. Besides leading to a recrudescence of the disease being treated, the withdrawal of corticosteroids can cause a variety of syndromes. In particular, problems can arise as a result of treatment-induced suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Another steroid withdrawal syndrome of unknown aetiology, without significant abnormalities of the HPA axis occurring, has been described. Benign intracranial hypertension may rarely follow steroid withdrawal in children. The syndromes associated with withdrawal of drugs which have an action on the CNS are poorly understood. Withdrawal of neuroleptic drugs can be followed by symptoms that resemble those described following withdrawal of anticholinergic drugs, and those agents with the greatest muscarinic-receptor-blocking properties are those which are most frequently implicated. However, the less common withdrawal dyskinesias are thought to reflect up-regulation of dopaminergic receptors during long term treatment. Gastrointestinal symptoms predominate following the abrupt withdrawal of antidepressants but hypomania and an 'akathisia-like' syndrome have been reported. Barbiturates are no longer recommended as hypnotics because of severe effects of withdrawal and the existence of safer alternatives. Short acting barbiturates can be withdrawn by replacement with either phenobarbitone (phenobarbitol) or diazepam and subsequent gradual reduction in dose. The recognition of dependency on benzodiazepines has been slow because of the similarity of mild withdrawal symptoms to the original problem which led to treatment being offered.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex Hormones↗

PubMedDate not supplied

Comparison of lifibrol to other lipid-regulating agents in experimental animals.

In vitro data suggests that lifibrol lowers plasma cholesterol by inhibiting cholesterol synthesis. We report that lifibrol is far less potent in vitro and in vivo than lovastatin for inhibiting 14C-acetate incorporation into sterols. Moreover, several major differences between lifobrol and lovastatin were noted in various animal models. In contrast, lifibrol exhibited several activities in common with gemfibrozil, another phenoxy-acid-type drug. Specifically, in normal rats lifibrol, like gemfibrozil, lowered plasma non-HDL-cholesterol and triglycerides, and increased liver weight and hepatic peroxisomal marker enzyme activities. Lovastatin only lowered plasma triglycerides. In cholesterol-fed rats lifibrol and gemfibrozil lowered non-HDL-cholesterol and elevated HDL-cholesterol while lovastatin was inactive. Finally, lovastatin but not lifibrol exhibited hypocholesterolemic activity in normal guinea pigs and resin-primed dogs. Our interpretation is that these data do not support the notion that lifibrol lowers plasma cholesterol in vivo by inhibiting cholesterol synthesis.

Animals↗

PubMedDate not supplied

Counselling for vasectomy.

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Adult↗

PubMedDate not supplied

GABA immunoreactivity in the human cerebellar cortex: a light and electron microscopical study.

The distribution of gamma-aminobutyric acid (GABA) in surgical samples of human cerebellar cortex was studied by light and electron microscope immunocytochemistry using a polyclonal antibody generated in rabbit against GABA coupled to bovine serum albumin with glutaraldehyde. Observations by light microscopy revealed immunostained neuronal bodies and processes as well as axon terminals in all layers of the cerebellar cortex. Perikarya of stellate, basket and Golgi neurons showed evident GABA immunoreactivity. In contrast, perikarya of Purkinje neurons appeared to be negative or weakly positive. Immunoreactive tracts of longitudinally- or obliquely-sectioned neuronal processes and punctate elements, corresponding to axon terminals or cross-sectioned neuronal processes, showed a layer-specific pattern of distribution and were seen on the surface of neuronal bodies, in the neuropil and at microvessel walls. Electron microscope observations mainly focussed on the analysis of GABA-labelled axon terminals and of their relationships with neurons and microvessels. GABA-labelled terminals contained gold particles associated with pleomorphic vesicles and mitochondria and established symmetric synapses with neuronal bodies and dendrites in all cortex layers. GABA-labelled terminals associated with capillaries were seen to contact the perivascular glial processes, basal lamina and endothelial cells and to establish synapses with subendothelial unlabelled axons.

Aged↗

PubMedDate not supplied

A study of tea tree oil ototoxicity.

Tea tree oil shows promise as an effective treatment for a number of micro-organisms commonly associated with otitis externa and otitis media, but its possible ototoxicity has not been previously assessed. The ototoxicity of tea tree oil was examined in the guinea pig by measuring the thresholds of the compound auditory nerve action potential (CAP) to tone bursts before and after instillation of the oil into the middle ear. After 30 min of instillation, 100% tea tree oil caused a partial CAP threshold elevation at 20 kHz. A lower concentration of oil [2% tea tree oil dissolved in saline using 0.5% detergent (Tween-80)] did not cause any significant lasting threshold change after middle ear instillation for the same period of time. The latter concentration of oil is greater than the minimum inhibitory concentration reported for most micro-organisms in the effective spectrum of the oil and this suggests that this concentration may be safe and effective provided only short exposures (about 30 min) are used. The results suggest that high concentrations of tea tree oil applied to the round window for a relatively short time are to some extent ototoxic to the high-frequency region of the cochlea. Hence further study is needed to establish whether tea tree oil can be used with safety in the treatment of external and middle ear infections.

Animals↗

PubMedDate not supplied

Alterations in the responses of the sympathetic nervous system and renin in borderline hypertension.

We investigated the effect of stimuli activate the sympathetic nervous system on plasma catecholamines, renin activity, urinary metanephrine and normetanephrine, and various hemodynamic parameters in normal subjects (NIs) and borderline hypertensive (BH) subjects. No differences were observed in sympathetic nervous system activity or renin activity when the subjects were in the resting state on a 150 mEq sodium diet. However, the BH group exhibited greater responses in terms of plasma catecholamines and plasma renin activity in response to sodium deprivation and treadmill exercise. Although hemodynamic differences in the cold pressor test and handgrip exercise did not emerge, the radio of atrial size decrement to venous tone increment during the Valsalva maneuver was significantly reduced in the BH group. The investigations suggest that in the basal state, BH subjects have appropriate levels of activation of the sympathetic and renin systems for a normal level of pressure but that perturbations of pressure and volume factors lead to unmasking of abnormalities in regulation of both systems. The data are also consistent with the suggestion that venous compliance is reduced in these patients.

Adolescent↗

PubMedDate not supplied

Influence of yohimbine on blood pressure, autonomic reflexes, and plasma catecholamines in humans.

We studied the influence of the alpha 2-adrenoreceptor-blocking drug, yohimbine, on blood pressure, plasma norepinephrine, and other measures of autonomic function in normal male volunteers. These studies were designed to evaluate the role of alpha 2-receptors in the tonic regulation of sympathetic outflow in humans. In a dose-ranging study, we found that yohimbine HCl (0.016-0.125 mg/kg) elicited dose-related rises in mean, systolic, and diastolic pressures. At the maximal dose used (0.125 mg/kg), respective increments in mean, systolic, and diastolic pressures were 14 +/- 1 torr; 28 +/- 3 torr; and 8 +/- 1 torr (p less than 0.01) (mean +/- SE). No significant changes in heart rate occurred. Associated with the rise in blood pressure were enhanced pressor and heart rate responses to the cold pressor, isometric handgrip, and Valsalva maneuvers. In a double-blind study, yohimbine (0.125 mg/kg bolus, 0.001 mg/kg/min infusion) induced a two-to-threefold rise in plasma norepinephrine (p less than 0.01), without significantly altering plasma epinephrine or plasma renin activity. Ex vivo platelet aggregation in response to epinephrine was inhibited during yohimbine, showing that non-innervated alpha 2-adrenoreceptors were inhibited. Central effects of yohimbine were evaluated through use of linear analog mood rating scales which showed a shift from calm toward excited ends of these scales. If yohimbine is acting through blockade of alpha 2 receptors, then these receptors tonically suppress sympathetic outflow in humans.

Adult↗

PubMedDate not supplied

Evidence for the existence of vascular alpha 2-adrenergic receptors in humans.

Many studies have suggested that alpha-adrenergic receptors on vascular smooth muscle are heterogeneous and that both alpha 1- and alpha 2-adrenergic receptors can cause vasoconstriction when stimulated. We explored this hypothesis in normal humans by comparing the capacity of yohimbine, an alpha 2-adrenergic receptor antagonist, and prazosin, an alpha 1-adrenergic receptor agonist, with differentially blocked pressor responses to phenylephrine, an alpha 1-adrenergic receptor agonist, and epinephrine, a nonselective alpha-agonist. We studied these responses in normal male volunteers who had been pretreated with propranolol (80 mg orally every 8 hours for 5 days) to obviate stimulation of beta-receptors by either agonist. We found differential effects of the antagonists on responses to the two agonists. Yohimbine induced a 3.1-fold (+/- 0.5) shift in the dose of epinephrine, which raised blood pressure 25 mm Hg, and only a 1.9-fold (+/- 0.2) shift in the response to phenylephrine (p less than 0.01). Prazosin induced a 2.4-fold (+/- 0.5) shift in the responses to epinephrine and a 4.5-fold (+/- 1.2) shift in the response to phenylephrine (p less than 0.05). These data are consistent with the notion that alpha-adrenergic receptors in the human vasculature are not homogeneous, but rather may be subdivided into at least two subtypes, one resembling alpha 1-adrenergic receptors and the other resembling alpha 2-adrenergic receptors.

Adult↗

PubMedDate not supplied

Antihypertensive metabolites of alpha-methyldopa.

alpha-Methyldopa acts through a metabolite in the central nervous system. Of the three metabolites most prominently considered as potential mediators of alpha-methyldopa hypotension--alpha-methyldopamine, alpha-methylnorepinephrine (MNE), and alpha-methylepinephrine (ME)--ME is the most potent depressor agent following intravenous infusion into rats, following injection into the lateral ventricle, and following injection into the solitary tract nucleus (NTS). The depressor effect of ME in the NTS is attenuated as effectively by timolol as by yohimbine, while the combination of both timolol and yohimbine completely abolishes the pharmacological activity of ME in the NTS. ME is approximately eightfold more potent than MNE in the NTS and also has a greater susceptibility to timolol attenuation.

Animals↗

PubMedDate not supplied

Electrophysiological and morphological changes in the guinea pig cochlea following mechanical trauma to the organ of Corti.

Small discrete lesions were produced in the organ of Corti of the guinea pig cochlea using fine probes to produce direct mechanical insult. The electrophysiological state of the cochlea was assessed using N1 electrocochleography and loss of receptor cells determined by scanning electron microscopy. Principal findings were: 1) Excellent agreement between the location of hair cell losses and the frequency of maximum sensitivity change in the N1 audiogram; 2) The spatial extent of the mechanically induced lesion appears to be more important than the total number of hair cells lost, in determining the magnitude of N1 sensitivity loss; 3) Hair cell losses extending over only 72 micrometers could be detected as significant changes in N1 sensitivity. These results further emphasize the accuracy and usefulness of the N1 electrocochleogram for assessing the functional status of the cochlea; 4) Lesions involving only outer hair cell loss also produced marked elevations of N1 threshold.

Action Potentials↗

PubMedDate not supplied

Could it happen here?

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Abortion, Legal↗