Diazepam tolerance: effect of age,regular sedation,and alcohol.

The dose of intravenous diazepam required for sedation was estimated in a series of 78 patients aged 17-85 years given the drug for dental and endoscopic procedures. Multiple regression analysis showed a significant correlation (r = 0.71; p less than 0.001) between dose and age, body weight, the taking of regular sedation, and the taking of more than 40 g alcohol daily, but there were no differences in the doses required between men and women, smokers and non-smokers, inpatients and outpatients, or dental and endoscopy patients. Patients aged 80 required an average dose of 10 mg and patients aged 20 an average dose of 30 mg, and the dose required was much higher in those receiving regular sedation or having a high alcohol intake. Plasma total and free diazepam concentrations were measured in the second half of the series of patients (n = 37). Plasma concentrations required for sedation fell twofold to threefold between the ages of 20 and 80 and were significantly higher in those taking regular sedation or alcohol. Differences in the acute response to diazepam appeared to be due to differences in the sensitivity of the central nervous system (pharmacodynamic tolerance) rather than to differences in pharmacokinetic factors.     

Postprandial plasma lipoprotein changes in human subjects of different ages

Plasma lipoprotein changes were monitored for 12 hr after a fat-rich meal (1 g of fat/kg body weight) in 22 subjects (9 males, 13 females, 22-79 yr old). Plasma triglyceride, measured hourly, peaked once in some subjects, but twice or three times in others. The magnitude of postprandial triglyceridemia varied considerably between subjects (range: 650-4082 mg.hr/dl). Males tended to have greater postprandial triglyceridemia than females, and elderly subjects had significantly (P less than 0.05) greater postprandial triglyceridemia than younger subjects. Total plasma cholesterol, measured every three hr, increased significantly (6.0 +/- 2.1%) in 7 subjects, decreased significantly (7.1 +/- 1.2%) in 10 subjects, and remained unchanged in the remainder. Single spin ultracentrifugation and dextran sulfate precipitation procedures were used to quantitate triglyceride and cholesterol in triglyceride-rich lipoproteins (TRL, d less than 1.006 g/ml), low density lipoproteins (LDL), and high density lipoproteins (HDL). Plasma TRL and HDL triglyceride increased after the fat meal, while LDL triglyceride decreased at 3 hr but increased at 9 and 12 hr. TRL cholesterol increased postprandially, while LDL and HDL cholesterol decreased. Phospholipid (PL), free (FC) and esterified (EC) cholesterol measurements were carried out on the plasma and lipoprotein fractions of 8 subjects. Plasma PL increased significantly at 3, 6, and 9 hr after the fat-rich meal, due to increases in TRL and HDL PL. TRL CE increased postprandially, but a greater decrease in LDL and HDL CE caused plasma CE to be decreased. Plasma FC increased, predominantly due to an increase in TRL FC. Plasma concentrations of apolipoprotein A-I and apolipoprotein B both decreased after the fat-rich meal. The magnitude of postprandial triglyceridemia was inversely correlated with HDL cholesterol levels (r = -0.502, P less than 0.05) and positively correlated with age (r = -0.449, P less than 0.05), fasting levels of plasma triglyceride (r = 0.636, P less than 0.01), plasma apoB (r = 0.510, P less than 0.05), TRL triglyceride (r = 0.564, P less than 0.01), TRL cholesterol (r = 0.480, P less than 0.05) and LDL triglyceride (r = 0.566, P less than 0.01). Change in postprandial cholesterolemia was inversely correlated with fasting levels of HDL cholesterol (r = -0.451, P less than 0.05) and plasma apoA-I (r = -0.436, P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

Compensatory mechanisms governing the concentration of plasma low density lipoprotein

To evaluate factors regulating the concentrations of plasma low density lipoproteins (LDL), apolipoprotein B metabolism was studied in nine Pima Indians (25 +/- 2 yr, 191 +/- 20% ideal wt) with low LDL cholesterol (77 +/- 7 mg/dl) and apoB (60 +/- 4 mg/dl) and in eight age- and weight-matched Caucasians with similar very low density lipoprotein (VLDL) concentrations, but higher LDL (cholesterol = 104 +/- 18; apoB = 82 +/- 10; P less than 0.05). Subjects received autologous 131I-labeled VLDL and 125I-labeled LDL, and specific activities of VLDL-apoB, intermediate density lipoprotein (IDL)-apoB, and LDL-apoB were analyzed using a multicompartmental model. Synthesis of LDL-apoB was similar (1224 +/- 87 mg/d in Pimas vs 1218 +/- 118 mg/d in Caucasians) but in Pimas the fractional catabolic rate (FCR) for LDL-apoB was higher (0.48 +/- 0.02 vs 0.39 +/- 0.04 d-1, P less than 0.05). In the Pimas, a much higher proportion of VLDL-apoB was catabolized without conversion to LDL (47 +/- 3 vs 30 +/- 5%, P less than 0.01). When all subjects were considered together, LDL-apoB concentrations were negatively correlated with both FCR for LDL-apoB (r = -0.79, P less than 0.0001) and the non-LDL pathway (r = -0.43, P less than 0.05). Also, the direct removal (non-LDL) path was correlated with VLDL-apoB production (r = 0.49, P = 0.03), and the direct removal pathway and FCR for LDL-apoB were correlated (r = 0.49, P = 0.03). In conclusion, plasma LDL appear to be regulated by both the catabolism of LDL and the extent of metabolism of VLDL without conversion to LDL; both of these processes may be mediated by the apoB/E receptor, and appear to increase in response to increasing VLDL production.     

Insulin receptor changes in type 2 diabetes after short term insulin treatment

We have studied erythrocyte insulin receptor changes before and after 8 days of continuous subcutaneous insulin infusion by a pump in 11 uncontrolled obese non-insulin-dependent diabetics (type 2), diet and drug resistant for at least three months previously. All the patients were hospitalized. On day 1 of the study, their oral hypoglycemic agents were stopped and hypocaloric diet (1000 Kcal/day) was maintained (strictly reinforced). This period of reinforced treatment was not accompanied by correction of hyperglycemia. On day 9 patients were placed for 12 hours on artificial pancreas in order to bring their fasting blood glucose levels down to normal values. Then they were submitted to a continuous subcutaneous insulin infusion (CSII) for the following 8 days. There was a significant decrease in mean fasting plasma glucose (P less than 0.001) and a rise in insulin (P less than 0.05) levels after insulin treatment. Mean specific insulin binding was also significantly increased (P less than 0.01). The increase in binding (with insulin therapy) correlated with the fall in fasting hyperglycemia (r = 0.786, P less than 0.01). In addition, the increase in binding correlated negatively with changes in fasting plasma insulin levels (r = -0.867, P less than 0.01), under treatment, on one hand and with the dose of exogenous insulin administered (r = -0.681, P less than 0.05) on the other hand. There was no correlation between binding and fasting plasma insulin levels (before and after insulin therapy), or between diabetes duration and any of the previous parameters.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of granulocyte depletion on pulmonary responsiveness to aerosol histamine

The effects of granulocyte depletion with hydroxyurea on pulmonary responsiveness to aerosol histamine were studied in 10 chronically instrumented unanesthetized sheep. Sheep were studied when granulocyte counts were normal (B), after 3 days of hydroxyurea but before granulocyte counts had dropped below 700 cells/mm3 (H), and after granulocyte counts had fallen below 200 cells/mm3 (D). Hydroxyurea itself had no effect on aerosol histamine responsiveness and the results were unaffected by the order of experimentation. All 10 sheep were less responsive (P less than 0.05) to aerosol histamine when granulocyte depleted effective dose of histamine that caused a reduction to 65% of control dynamic compliance (ED65Cdyn = 23.98 +/- 4.70 mg/ml) compared with base line (ED65Cdyn = 7.06 +/- 1.86 mg/ml). Those sheep initially most responsive to aerosol histamine had the greatest attenuation in their airway responsiveness to aerosol histamine (P less than 0.05). There was a significant negative correlation between absolute granulocyte counts in peripheral blood and pulmonary responsiveness to aerosol histamine during base-line (B) condition (r = -0.74, P less than 0.05) and for the data as a whole [r = -0.69, P less than 0.05 (B + H + D)]. Circulating granulocytes and/or pulmonary inflammation may contribute to pulmonary responsiveness to bronchial challenge.     

Nighttime immunoreactive somatostatin content of the median eminence in hypo- and hyperthyroid rats

The median eminence content of immunoreactive somatostatin (IRS) was measured by radioimmunoassay in 107 male albino rats, who were either hypothyroid after surgical thyroidectomy (N = 38), hyperthyroid following a subcutaneous implant of 5 mg of L-thyroxine (N = 36), or otherwise untreated (N = 33). Thyroid function was assessed by determining plasma levels of T4 and TSH from trunk blood obtained at the time of decapitation. Subgroups of animals from the 3 groups were killed either before (1800 hr), during (2200, 0200, 0400 hr), or after the dark portion of their 14:10 LD photoperiod. Although no changes in median eminence IRS content were found throughout the period of study within any of the 3 groups, hypothyroid animals (297.23 +/- 13.47 ng per ME; 620.41 +/- 58 ng IRS/mg protein) had a significantly lower median eminence IRS concentration than untreated rats (355.86 +/- 16.55 ng of IRS per ME, P less than 0.01; 906.86 +/- 96.38 ng IRS/mg protein, P less than 0.05) and hyperthyroid animals (384.12 +/- 14.67 ng per ME, P less than 0.001; 874.1 +/- 104.5 ng IRS@mg protein, P less than 0.05). It is concluded, that the feedback of thyroid hormones on the hypothalamic-pituitary axis during thyroid hormone excess in vivo, contrary to what occurs in hypothyroidism, is probably independent of hypothalamic somatostatin.     

Effect of acetylsalicylic acid on urinary excretion of prostaglandin E in stroke patients

In 12 of 76 stroke patients complicated by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), a significant increase in urinary prostaglandin E (PGE) (p less than 0.005), and a significant positive relationship between the plasma arginine vasopressin (AVR) level and urinary PGE excretion were observed (r = 0.72, p less than 0.05). The experimental results are consistent with the view that renal PGE acts as a modulator of ADH. Nowadays acetylsalicylic acid (ASA), an inhibitor of prostaglandin biosynthesis, is widely used in ischemic stroke, it was felt necessary to study the effect of this drug on urinary PGE excretion. Therefore various daily doses of ASA were given orally for 3 days to patients with ischemic stroke. PGE values in 24-hour urine samples were measured every day for 3 days before administration of the drug and for 3 days during ASA administration. In 10 patients who took 75 mg of ASA, the decrease in urinary PGE excretion was not statistically significant. On the other hand when ASA was administered 300 mg once in 19 patients or 300 mg 4 times in 11 cases, urinary PGE excretion decreased significantly (p less than 0.05 and p less than 0.05 respectively). In another group of 8 patients who were observed before, during and after the ASA administration, a daily oral dose of 300 mg for 3 days caused a significant decrease in urinary PGE excretion during these 3 days (p less than 0.05). The urinary PGE excretion returned to the control level within 3 days after cessation of the ASA administration.     

Further evidence for the usefulness of the salivary testosterone radioimmunoassay in the assessment of androgenicity in man in basal and stimulated conditions

Since correct assessment of testicular function and androgenic status in humans requires multiple sampling, a sensitive and accurate radioimmunoassay (RIA) of testosterone (T) was established for male and female saliva samples. This easily collected biological fluid, which contains nonprotein-bound T, may represent an attractive alternative or a complement to total plasma T assays. In saliva samples from 5 normal males, a clear circadian rhythm was observed, and morning concentrations (135 +/- 31 pg/ml) were significantly higher (p less than 0.02) than evening samples (85 +/- 23 pg/ml). In 11 normal females, morning saliva levels were 12.8 +/- 1.8 pg/ml. The levels of T in male saliva, in response to both exogenous T administration (100 mg i.m.) and HCG stimulation (2 X 2,000 IU i.m.), accurately reflected the changes observed in plasma T, and the magnitude of increase in T levels was clearly greater in saliva than in plasma samples during the intramuscular administration of the long-acting T preparation. In males, significant correlations were observed between salivary and plasma T concentrations in morning samples (r = 0.61, p less than 0.01), following HCG stimulation (r = 0.89, p less than 0.05) and during T administration (r = 0.87, p less than 0.05). In women, the correlation at 8 a.m. was also significant (r = 0.82, p less than 0.05).     

Comparison of the effects of perfusion in determining brain penetration (brain-to-plasma ratios) of small molecules in rats

In the process of drug discovery, brain and plasma measurements of new chemical entities in rodents are of interest, particularly when the target receptors are in the brain. Brain-to-plasma ratios (B/P) obtained from a rodent pharmacokinetic assay are useful in helping determine which compounds are brain penetrant. The study reported here was performed to determine whether whole-body saline perfusion for complete blood removal was required to accurately measure brain tissue compound concentrations. Diazepam was used as a positive control since it is highly brain penetrant. Compound A was used as a negative control since it had known poor brain penetration. After intravenous dosing with either diazepam or compound A, rats were anesthetized and blood was collected, then the brain was removed following no perfusion or whole-body perfusion with saline. The analytes described (compound A, diazepam, and the internal standard) were recovered from plasma or brain homogenate by use of protein precipitation, and were subsequently analyzed by use of liquid chromatography/tandem mass spectrometry (LC/MS/MS). The B/P values determined by use of LC-MS were not significantly different in perfused vs. non-perfused rats (P > or = 0.05). This approach (whole brain collected from non-perfused male rats) is an attractive alternative over brain penetration studies of perfused rats, since it has markedly reduced the technical time and potential for pain and distress required for generating B/P data due to elimination of the requirement for anesthesia and surgical preparation of animals.     

New non-steroidal aromatase inhibitors: focus on R76713

R76713 is a novel triazole derivative which selectively blocks the cytochrome P450-dependent aromatase. In human placental microsomes, in FSH-stimulated rat and human granulosa cells and in human adipose stromal cells, 50% inhibition of estradiol biosynthesis was obtained at drug concentrations of 2-10 nM. In PMSG-injected female rats, R76713 lowered plasma estradiol levels by 50 and 90% 2 h after single oral doses of 0.005 and 0.05 mg/kg respectively. After 1 mg/kg, estradiol levels were suppressed by 90% for 16 h. In male cynomolgus monkeys, R76713 dose-dependently (0.03-10 micrograms/kg) inhibited peripheral aromatization with an ED50 of 0.13 microgram/kg without altering metabolic clearance rates and conversion ratios. In vitro R76713 had no effect on other P450-dependent steroidogenic enzymes up to 1000 nM at least. In rats, LHRH-, ACTH- and sodium-deprived diet stimulated plasma testosterone, corticosterone and aldosterone levels were not modified 2 h after single oral administrations of R76713 (up to 20 mg/kg). Furthermore, R76713 did not show any in vitro or in vivo estrogenic or antiestrogenic property. R76713 also induced regression of DMBA-induced mammary tumors after daily oral administration of 1 mg/kg b.i.d. In male volunteers (n = 4), a single oral dose of 5 and 10 mg lowered median plasma estradiol levels from 70 pM to the detection limit of the assay (40 pM) 4, 8 and 24 h after intake whereas no changes were detected after placebo administration. In premenopausal women (n = 15), receiving a single oral dose of 20 mg, median plasma estradiol levels decreased from 389 pM (before) to 168, 133 and 147 pM, 4, 8 and 24 h after intake whereas they remained above 420 pM after placebo (n = 7).     

Inhibition of plasma prolactin in the rat by amantadine

A single iv injection of 15 or 30 but not 7.5 mg/kg BW of an antiviral drug, amantadine, significantly (P less than 0.05) decreased plasma prolactin (PRL) concentrations in male rats. This effect was dose-dependent, with the highest dose producing a longer-lasting decrease in plasma PRL. The amantadine-induced decrease was unaffected by a simultaneous injection of 5-hydroxytryptophan (30 mg/kg BW) but was completely blocked by a simultaneous injection of haloperidol (0.05 mg/kg BW). It is concluded that this novel effect of amantadine on PRL is produced by an interaction with the dopaminergic system.     

Relationship between post-heparin plasma lipases, triglycerides and high density lipoproteins in normal subjects

The relationship between plasma lipids and lipoproteins and the lipolytic activities of post-heparin plasma lipoprotein lipase (LpL) and hepatic-triglyceride lipase (H-TGL) was examined in normal subjects. Seven males and six females were given a high fat diet [15% carbohydrate (CARB), 65% fat, 20% protein] for 2 weeks followed by 4 weeks of a high CARB diet (65% CARB, 15% fat, 20% protein). Changes in plasma triglyceride concentrations associated with diet were negatively correlated with changes in HDL-C (r = -0.533, P less than 0.001) and the HDL subfraction HDL2b (r = -0.308, P less than 0.001). The activity of LpL in post-heparin plasma was positively correlated with changes in plasma HDL-C (r = 0.668, P less than 0.001) and HDL2b (r = 0.457, P less than 0.001), and negatively with plasma triglycerides (r = -0.546, P less than 0.001). Changes in H-TGL activity were negatively correlated with changes in HDL2b (r = -231, P less than 0.05) and positively correlated with HDL-C (r = 0.326, P less than 0.01). These results in normal subjects provide further evidence that LpL and H-TGL are important enzymes in the metabolism of plasma lipoproteins and that changes in their activities contribute to plasma lipid and lipoprotein concentrations.     

High dose propranolol in the treatment of angina pectoris: relationship of dose to blood levels and hemodynamic consequences

Propranolol blood levels and the effect of these levels on hemodynamic parameters were evaluated in 25 patients with coronary artery disease undergoing cardiac catheterization and coronary angiography. Fifteen patients were receiving high doses of propranolol (320--1920 mg/day) while ten patients were receiving conventional doses (80--240 mg/day). The high dose propranolol group had significantly higher plasma propranolol levels than the conventional dose group (788 +/- 134 SD vs. 43 +/- 7.2 ng/ml SD), and there was a direct linear relationship between propranolol dose and plasma drug levels (r = 0.85, P < 0.001). There were no significant differences between high and conventional dose propranolol groups in terms of all hemodynamic parameters measured, namely ejection fraction, ventricular volume, cardiac index, or peripheral vascular resistance. Despite high drug dosage and blood levels, only mild side effects were seen.     

Reduced GLP-1 and insulin responses and glucose intolerance after gastric glucose in GRP receptor-deleted mice

By applying a newly developed ELISA technique for determining biologically active intact glucagon-like peptide [GLP-1, GLP-1-(7-36)amide] in mouse, plasma baseline GLP-1 in normal NMRI mice was found to be normally distributed (4.5 +/- 0.3 pmol/l; n = 72). In anesthetized mice, gastric glucose (50 or 150 mg) increased plasma GLP-1 levels two- to threefold (P < 0.01). The simultaneous increase in plasma insulin correlated to the 10-min GLP-1 levels (r = 0.36, P < 0.001; n = 12). C57BL/6J mice deleted of the gastrin-releasing peptide (GRP) receptor by genetic targeting had impaired glucose tolerance (P = 0.030) and reduced early (10 min) insulin response (P = 0.044) to gastric glucose compared with wild-type controls. Also, the GLP-1 response to gastric glucose was significantly lower in the GRP receptor-deleted mice than in the controls (P = 0.045). In conclusion, this study has shown that 1) plasma levels of intact GLP-1 increase dose dependently on gastric glucose challenge in correlation with increased insulin levels in mice, and 2) intact GRP receptors are required for normal GLP-1 and insulin responses and glucose tolerance after gastric glucose in mice.     

Changes in fetal and maternal plasma protein concentration and colloid osmotic pressure with gestation.

In pregnant ewes, plasma protein levels over the gestation age range of 58-141 days fell progressively (r = -0.332, P less than 0.05, n = 36) but colloid osmotic pressure (COP, mmHg) did not change significantly. In fetal sheep carried by these ewes, plasma protein levels increased with age (r = 0.85, P less than 0.00001, n = 32). COP also rose (r = 0.8, P less than 0.00001, n = 23). Since maternal COP did not change and fetal COP increased, the net transplacental COP gradient between mother and fetus decreased with increasing age (r = -0.589, P less than 0.004, n = 22). Fetal plasma protein levels can be used to calculate fetal COP while maternal plasma protein levels cannot be used to calculate maternal COP.     

Plasma LDH and CK activities after 400 m sprinting by well-trained sprint runners

Blood lactate concentration and the activities of plasma LDH and CK were determined in 13 well-trained middle distance runners after a 400-m sprint. It was found that there is a significant relationship between mean velocity in the 400-m sprint and plasma CK activity (r = -0.56, P less than 0.05), but the mean sprint velocity did not correlate with peak blood lactate concentration (r = -0.09) or plasma LDH activity (r = -0.40). There was a significant negative correlation between mean sprint velocity and H type LDH isozyme activity (r = -0.66, P less than 0.05), and a significant positive correlation with M type LDH isozyme activity (r = 0.66, P less than 0.05). These results suggest that the magnitude of enzyme efflux from tissue into blood may be depressed by training, and that in well-trained sprinters plasma CK and LDH isozyme activities may be better indicators of physical training and/or physical performance than peak blood lactate or plasma LDH activities.     

Effect of inhaled and systemic opiates on responses to inhaled capsaicin in humans

To determine the site of action of opiates in humans, we have studied the effect of systemic and inhaled opiates on cough and increase in respiratory resistance (Rrs) caused by inhaled capsaicin. In 13 subjects, a range of doses of capsaicin inhaled in single breaths given in random order produced a reproducible dose-cough response. Inhalation of a dose of capsaicin that caused fewer than two coughs increased Rrs by 28% (21-35, mean 95% confidence interval). Inhaled codeine (50 mg) and morphine (10 mg) did not alter the cough response. In contrast, both drugs increased base-line Rrs by 24% (16-44) and 13% (3-23), respectively, and significantly reduced the increase in Rrs after inhaled capsaicin (P less than 0.05). Oral codeine (60 mg) significantly (P less than 0.05) reduced the number of coughs at 1 and 2 h but did not alter base-line Rrs or its increase after capsaicin. Intravenous morphine (0.15 mg/kg) significantly reduced the sensitivity of the cough response (P less than 0.05), which was reversed by naloxone. However, there was no significant drug effect on either the base-line Rrs or its increase after capsaicin. Systemic dosing of opiates is therefore required to reduce the cough reflex, whereas inhaled opiates may reduce the increase in Rrs after inhaled capsaicin.     

Naloxone antagonism of diazepam-induced feeding in the Syrian hamster

Three experiments investigated the effects of the intragastric administration of the benzodiazepine diazepam on feeding in non-deprived Syrian hamsters ($\text{mesocricetus auratus}$). In the first experiment diazepam (0, 0.5, 1.0, 2.0, and 4.0 mg/kg) produced dose dependant increases in feeding. 4.0 mg/kg of diazepam produced significantly more feeding than the other doses tested and the lowest dose tested (0.5 mg/kg) produced a significant increase in feeding. In the second experiment naloxone (10 mg/kg) partially antagonized the effect of 4 mg/kg of diazepam on feeding. In the third experiment the ability of naloxone (0.1, 1.0, 5.0, 10.0 or 20 mg/kg) to reduce feeding produced by either 4 mg/kg or 2 mg/kg of diazepam was tested. Naloxone partially antagonized the effects of 4 mg/kg of diazepam on feeding in a dose dependant manner. While 2 mg/kg of diazepam produced significantly less feeding than 4 mg/kg, naloxone did not antagonize the effect of 2 mg/kg on feeding. The results suggest that two mechanisms are involved in diazepam-induced feeding in hamsters. The high dose of diazepam may produce increased feeding by activating the endorphin system while the low dose of diazepam produces increased feeding via a naloxone insensitive mechanism.     

Effect of atorvastatin on plasma apoE metabolism in patients with combined hyperlipidemia

Atorvastatin, a synthetic HMG-CoA reductase inhibitor used for the treatment of hyperlipidemia and the prevention of coronary artery disease, significantly lowers plasma cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. It also reduces total plasma triglyceride and apoE concentrations. In view of the direct involvement of apoE in the pathogenesis of atherosclerosis, we have investigated the effect of atorvastatin treatment (40 mg/day) on in vivo rates of plasma apoE production and catabolism in six patients with combined hyperlipidemia using a primed constant infusion of deuterated leucine. Atorvastatin treatment resulted in a significant decrease (i.e., 30-37%) in levels of total triglyceride, cholesterol, LDL-C, and apoB in all six patients. Total plasma apoE concentration was reduced from 7.4 +/- 0.9 to 4.3 +/- 0.2 mg/dl (-38 +/- 8%, P < 0.05), predominantly due to a decrease in VLDL apoE (3.4 +/- 0.8 vs. 1.7 +/- 0.2 mg/dl; -42 +/- 11%) and IDL/LDL apoE (1.9 +/- 0.3 vs. 0.8 +/- 0.1 mg/dl; -57 +/- 6%). Total plasma lipoprotein apoE transport (i.e., production) was significantly reduced from 4.67 +/- 0.39 to 3.04 +/- 0.51 mg/kg/day (-34 +/- 10%, P < 0.05) and VLDL apoE transport was reduced from 3.82 +/- 0.67 to 2.26 +/- 0.42 mg/kg/day (-36 +/- 10%, P = 0.057). Plasma and VLDL apoE residence times and HDL apoE kinetic parameters were not significantly affected by drug treatment. Percentage decreases in VLDL apoE concentration and VLDL apoE production were significantly correlated with drug-induced reductions in VLDL triglyceride concentration (r = 0.99, P < 0.001; r = 0.88, P < 0.05, respectively, n = 6). Our results demonstrate that atorvastatin causes a pronounced decrease in total plasma and VLDL apoE concentrations and a significant decrease in plasma and VLDL apoE rates of production in patients with combined hyperlipidemia.     

An isobolographic analysis of the hypnotic effects of combinations of dexmedetomidine with fentanyl or diazepam in rats.

The effects of the combinations of dexmedetomidine-fentanyl and dexmedetomidine-diazepam on the righting reflex were studied in rats. The doses that block the righting reflex for the agents given alone and for their combinations were determined with a probit procedure and compared with an isobolographic analysis. The interactions between dexmedetomidine and fentanyl or diazepam were found to be synergistic. In the dexmedetomidine-diazepam combination studies, less than one-fourth of the single drug dose (for each of two agents) was needed to produce the required effect. These data confirm synergistic interactions between dexmedetomidine and fentanyl or diazepam in producing hypnotic-anesthetic action.