Regional subacute cranial neuropathies following internal carotid cisplatin infusion.

The inferolateral trunk arises from the internal carotid artery at C-4 and provides vascular supply to cranial nerves III to VI. We report a patient who developed neuropathies of cranial nerves III, V1-3, and VI, 48 hours after infusion of cisplatin into the right internal carotid artery for an anaplastic oligoastrocytoma. The clinical and radiographic findings implicated direct toxicity to nerves in the distribution of the inferolateral trunk. We found additional cases by review of published brain tumor chemotherapy trials, thus identifying a novel, toxic neurovascular mechanism for injury to cranial nerves III to VI.

Human gliomas with wild-type p53 express bcl-2.

Human astrocytomas frequently overexpress wild-type p53, which suggests that gliomas have evolved a mechanism to subvert p53-mediated apoptosis. bcl-2 inhibits apoptosis mediated by p53, and it is expressed in several human cancers. We therefore examined a series of human gliomas to determine whether bcl-2 is expressed and whether this expression is associated with tumors which have wild-type p53. Twenty-eight paraffin-embedded gliomas (3 WHO grade II, 13 grade III, 12 grade IV) were immunohistochemically stained for bcl-2 and p53. p53 mutations were identified with single strand conformation polymorphism and DNA sequencing. Sixteen of 28 (57%) tumors expressed bcl-2, and bcl-2 expression was associated with wild-type p53 (P < 0.01). Among gliomas which overexpressed p53, bcl-2 was positive in 7 of 7 tumors with wild-type p53 but in only 1 of 7 with mutant p53 (P < 0.01). We conclude that bcl-2 is frequently expressed in human gliomas and that expression is more common in tumors with wild-type p53.

Peanut oil reduces diet-induced atherosclerosis in cynomolgus monkeys.

The atherogenicity of dietary peanut oil (PO) was examined in cynomolgus monkeys fed semipurified diets for 15 months. Four groups of six monkeys were fed diets containing 0.22 mg/kcal (0.1%) cholesterol and 0%, 5%, 10%, or 20% PO. An additional group was fed 2.0% cholesterol and 20% PO to serve as a literature control. Increasing the concentration of PO in the diet was associated with significant decreases in total plasma cholesterol (p less than 0.05) and the total/HDL cholesterol ratio (p less than 0.05) and an increase in the terminal HDL cholesterol concentration (p less than 0.05). Intimal thickness and composition were determined from cross sections of the thoracic aorta and the iliac and coronary arteries. Increasing dietary PO was associated with decreases in thickness (p less than 0.005), lipid (p less than 0.001), and smooth muscle cells (p less than 0.005) in the aortic intima. Aortic intimal lipid was positively correlated with the ratio of total to HDL cholesterol (r2 = 0.78, p less than 0.05). Monkeys fed 2.0% cholesterol and 20% PO revealed extensive atherosclerosis in all three arterial sites compared with those of any other group. Whereas the dietary fat effect was most demonstrable in the aorta, dietary cholesterol had a greater effect on the iliac and coronary arteries than it did on the aorta. Under these circumstances, dietary PO was not atherogenic in cynomolgus monkeys when fed with a concentration of cholesterol equivalent to that consumed by humans.

LDL enhances monocyte adhesion to endothelial cells in vitro.

Monocyte adhesion to the arterial endothelium is an early event in diet-induced atherogenesis. The possibility that low-density lipoprotein (LDL) may influence this adhesion was investigated by using an in vitro monolayer collection assay. Postprandial and fasting LDL was isolated from 12 normal adult human donors (8 male and 4 female) and incubated with primary cultures of bovine aortic endothelial cells (BAEC) for 6 hours. 51Cr-labeled mononuclear leukocytes (MNLs) were then added and incubated an additional 30 minutes. When results were expressed as the ratio of adherent counts per minute in LDL-treated BAEC cultures to that in PBS-treated controls, 10 of the 16 LDL samples isolated from male donors induced a significant increase (P less than 0.05) in MNL adhesion (1.06-1.27) attributable to esterase-positive cells. This increase was dose-dependent and maximal at 100 micrograms LDL protein/ml. The magnitude of the response was significantly correlated with LDL composition (r = 0.857, P less than 0.01) such that LDL rich in cholesterol and triglyceride relative to protein enhanced MNL adhesion, whereas lipid-poor LDL (typically isolated from the women) reduced adhesion.

Estimating steady state desipramine levels in noninstitutionalized elderly patients using single dose disposition parameters.

Clearances calculated from single oral dose data have been utilized to predict steady state levels of desipramine in 12 noninstitutionalized depressed elderly patients. Observed steady state plasma levels correlated very well (r = 0.967, p less than 0.0005) with those predicted from single dose clearances, but not with plasma levels obtained 20 hours after a single oral dose (r = 0.24, p greater than 0.2). The mean half-life of desipramine (20.9 hours) in this group of elderly (mean age, 72 years) was considerably less than values of "apparent disappearance" half-life previously reported for elderly patients receiving imipramine. The single dose clearance technique yielded a precise criterion for quantitating early compliance with and adjusting drug dosing regimens.

Imipramine disposition in alcoholics.

The disposition of orally administered imipramine (IMI) was studied in 11 depressed alcoholic and 12 depressed nonalcoholic male inpatients. Subjects received 50 mg three times daily for at least 10 days to ensure steady state. Following a temporary discontinuation of therapy, several blood samples were drawn over a 40-hour period. Imipramine, desipramine, and their 2-hydroxylated metabolites were measured in plasma using a high performance liquid chromatography assay. Eight hours following the last dose, alcoholics has significantly lower IMI (50 +/- 41 versus 106 +/- 46 ng/ml; p less than 0.005) and 2-hydroxyimipramine (12.8 +/- 7.5 versus 22.6 +/- 9.8 ng/ml; p less than 0.01) levels than controls. The mean terminal half-lives in the two groups were nearly identical (16.3 +/- 6.7 hours in alcoholics versus 17.1 +/- 5.4 hours in controls). Beck Depression Inventory scores were significantly reduced during IMI therapy (p less than 0.001) in the non-alcoholic controls, whereas no change was observed in the alcoholic group. These results are consistent with either a decrease in oral bioavailability of IMI in alcoholics or, assuming complete absorption, an increase in intrinsic clearance of 2.5 fold (2444 +/- 1151 versus 986 +/- 438 ml/min; p less than 0.005) over the clearance found in control subjects. The latter seems a more likely result of chronic ethanol intake. The fact that lower levels of IMI in the alcoholic group were accompanied by a lack of efficacy in relieving depressive symptomatology suggests that whether through an effect on bioavailability or intrinsic clearance, ethanol consumption is an important consideration when recommending tricyclic therapy.

Differential effects of gonadal steroids on dopamine metabolism in mesolimbic and nigro-striatal pathways of male rat brain.

Thirty days after castration the concentration of dopamine (DA) was significantly reduced in the septum and n. accumbens septi, but not in the caudate-putamen, of male rat brain. The concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the principle metabolites of DA, also tended to be lower in septum and n. accumbens septi after castration. Chronic s.c. administration of testosterone (T), estradiol (E2), 5 alpha-dihydrotestosterone (DHT), or E2 plus DHT in silastic capsules effectively reversed these effects of castration in septum and n. accumbens septi without affecting concentrations of DA, DOPAC, or HVA in caudate-putamen. The accumulation of DOPA after inhibition of aromatic amino acid decarboxylase activity, which was taken as an in vivo index of tyrosine hydroxylase activity, was not affected in these brain regions by long-term castration or by chronic administration of DHT to castrated males. Acute administration of haloperidol caused equivalent, significant increments in concentrations of DOPAC and HVA in all brain regions studied, regardless of whether castrated rats had been implanted with DHT capsules or no hormone. However, in the absence of haloperidol treatment the concentration of DOPAC in septum and n. accumbens septi, but not in caudate-putamen, was significantly higher in castrated rats implanted with DHT as opposed to no hormone. These results suggest that chronic exposure to T, or to its neural metabolites, E2 and DHT, selectively enhances metabolic activity in mesolimbic DA neurons.