Synthesis and activity of a novel series of 3-biarylquinuclidine squalene synthase inhibitors.

Quinuclidines with a 3-biaryl substituent are a new class of potent, orally active squalene synthase (SQS) inhibitors. Variants around these rigid structures indicate key structural requirements for cationic SQS inhibitors. Thus the lower in vitro potency found for quinuclidines bearing 3-substituents, which did not overlay the biphenyl group of 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (2) (IC50 = 16 nM, rat microsomal SQS), implied a directional requirement for the 3-substituent. Similarly, the lower potency of the 3-terphenyl analogue 6 (IC50 = 370 nM) indicated size constraints for this substituent. In compounds with a linking group between the quinuclidine and biphenyl ring, linking groups of lower lipophilicity were less well tolerated (e.g., 17, CH2CH2, IC50 = 5 nM vs 19, NHCO, IC50 = 1.2 microM). Replacement of the distal phenyl ring of 2 with a more polar pyridine heterocycle caused a reduction in in vitro potency. In general, good in vivo activity in the rat was restricted to 3-hydroxy analogues, with the 3-[4-(pyrid-4-yl)phenyl] derivative 39 (IC50 = 161 nM) showing the best inhibition (following oral dosing) of cholesterol biosynthesis from mevalonate (ED50 = 2.7 mg/kg).

Vasoactivity of cerebrospinal fluid from patients with brain swelling.

The triggering mechanisms of diffuse cerebral swelling are poorly understood. The findings in this study are in keeping with the hypothesis that chemicals released by brain trauma into the CSF promote vasodilatation. Other proposals have included brainstem stimulation with increased cerebral blood flow and defective autoregulation. A number of factors may be operative.

Hormonal influence on water permeability across the blood-brain barrier.

We have shown that steroid manipulations may influence the rate of flux of water across the blood-brain barrier. Such changes are regionally variable and are best seen in the cerebral cortex. Administration of dexamethasone produced decreased water permeability while withdrawal of dexamethasone and ethinyloestradiol resulted in increased permeability. Increased water content in cerebral cortex was demonstrated after steroid withdrawal and ethinyloestradiol administration. We believe that these experimental findings may have relevance in the clinical situation and may help in understanding the pathogenesis of some types of brain oedema. One such example is benign intracranial hypertension where brain swelling is seen typically in young obese females and is also associated with the contraceptive pill, pregnancy and corticosteroid withdrawal.

The effects of dexamethasone administration and withdrawal on water permeability across the blood-brain barrier.

We examined the effects of dexamethasone administration and withdrawal on regional cerebral blood flow (CBF) and the permeability surface area (PS) product for water in the central nervous system of conscious rats. There were no significant changes in CBF. Dexamethasone treatment produced a significant decrease in the PS product for water in the cerebral cortex, while withdrawal of dexamethasone resulted in a significant increase. Water content of the cerebral cortex was also increased in rats from which dexamethasone had been withdrawn. These findings may help in understanding the pathogenesis of brain swelling in some patients.

Arginine vasopressin levels in cerebrospinal fluid in neurological disease.

Levels of arginine vasopressin have been measured in the blood and cerebrospinal fluid of patients with benign intracranial hypertension and raised intracranial pressure, patients with other neurological diseases and in normal control subjects. There was no difference in blood levels in each of the 3 groups (mean +/- SEM, 2.8 +/- 0.5, 2.5 +/- 0.25, 2.53 +/- 0.4 pg/ml). However, levels of arginine vasopressin in the cerebrospinal fluid in patients with benign intracranial hypertension and other neurological diseases were higher (mean +/- SEM, 0.64 +/- 0.005, 0.61 +/- 0.04 pg/ml), than in the control group (0.49 +/- 0.06), but not different from each other. The origin of arginine vasopressin in cerebrospinal fluid is uncertain and a number of possibilities are discussed.

Spontaneous pneumocephalus following elective thoracotomy.

One month following a right upper lobectomy for bronchial carcinoma, a 50-year-old man developed headaches, confusion and a right hemiparesis. Radiographs revealed intraventricular air. This was thought to have originated from air being forced through a dural tear sustained at the time of operation. Both the intraventricular air and the accompanying symptoms and signs subsequently resolved.

Subacute Wernicke's encephalopathy due to gastric syphilis.

In a patient who presented with subacute Wernicke's encephalopathy the underlying gastric lesion was found to be due to syphilis.

Absence of significant endocrine deficiencies in benign intracranial hypertension.

Hypothalamic-pituitary function tests have been carried out in young, obese females with both recently diagnosed and longstanding benign intracranial hypertension. No abnormalities have been found which could be implicated in the pathogenesis of the condition, nor have we been able to demonstrate any convincing evidence of long-term hypothalamic pituitary damage. The results of these investigations can be difficult to interpret and invalid conclusions may be drawn if all factors involved are not carefully considered.

Serial ventricular volume measurements: further insights into the aetiology and pathogenesis of benign intracranial hypertension.

Ventricular volumes have been measured from CT scans of patients with benign intracranial hypertension both at initial presentation and at a later date. Volumes initially were smaller than normal, but at review five patients showed a significant increase in ventricular size. Persisting small ventricular volume correlated with persisting symptoms and signs and with persisting obesity. This supports the view that patients with benign intracranial hypertension have brain swelling and that obesity may be implicated in the pathogenesis, perhaps via a neuroendocrine disturbance. It is suggested that weight reduction may be an important component of treatment.

Volume of the ventricles in benign intracranial hypertension.

The volume of the lateral and third ventricles was measured by a non-invasive computerised axial tomographic method in 18 patients presenting with characteristic features of benign intracranial hypertension. Values obtained were significantly lower than in 18 controls matched for age and sex. The demonstration of smaller-than-normal ventricles in benign intracranial hypertension indicates that the syndrome is not primarily due to a disorder of cerebrospinal fluid absorption; rather, the increase in intracranial pressure may be caused by cerebral swelling, either due to oedema or engorgement.

Myelopathy during treatment for pulmonary tuberculosis.

A patient who developed a myelopathy during a course of treatment for pulmonary tuberculosis is described. The underlying mechanisms and problems in diagnosis are discussed.

Cerebral systemic lupus erythematosus: a case report and evaluation of diagnostic tests.

We describe a 34 year old woman who presented initially with a progressive pseudobulbar palsy. A delay of five months occurred before a diagnosis of cerebral systemic lupus erythematosus was made. Currently available investigations for cerebral systemic lupus erythematosus are evaluated and the need for an easily performed specific diagnostic test is discussed.

Flaccid quadriparesis due to Salmonella enteritis.

A case of profound myopathy due to electrolyte disturbances secondary to salmonella enteritis is reported. The relationship between hypomagnesaemia, hypocalcaemia and parathyroid hormone secretion is also demonstrated.