The association of alcoholism and anxiety

The relationship between alcoholism and anxiety disorders is complex and has been the subject of much investigation. While data from community samples as well as samples of treatment-seeking populations indicate that these disorders co-occur far more commonly than would be expected by chance, the nature of the relationship is unclear. It is clear from both prevalence as well as order of onset data that various anxiety disorders have differing associations with alcohol problems. There is much overlap in symptomatology of panic disorder, generalized anxiety disorder, and alcohol withdrawal. This observation has led to speculation about common neurochemical perturbations and a kindling phenomenon as a possible connection between these disorders. Cognitive theories have been used to connect alcohol abuse and phobic disorders. Treatment of patients with co-morbid anxiety and alcoholism is discussed.     

EFFECTS OF LOSARTAN ON THE CARDIOVASCULAR SYSTEM, RENAL HAEMODYNAMICS AND FUNCTION AND LUNG LIQUID FLOW IN FETAL SHEEP

1. The angiotensin type 1 (AT₁) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125–132 days gestation). Losartan reduced the fetal systolic (P < 0.01) and diastolic (P < 0.01) pressor response to 5 μg angiotensin II (AngII) i.v. from 27.4 ± 1.5 to 7.4 ± 0.9 and from 17.5 ± 1.3 to 5.4 ± 0.6 mmHg, respectively, after 1h and to 6.1 ± 0.5 and 4.4 ± 0.5 mmHg, respectively, after 2h. Maternal pressor responses to 5 μg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P < 0.05) after losartan administration, but fetal heart rate did not change. 2. Fetal haematocrit increased (P < 0.05), fetal PO₂ decreased (P < 0.01), PCO₂ did not change and pH decreased (P < 0.01), as did plasma bicarbonate levels (P < 0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis. 3. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P < 0.01) and an increase in blood flow (P < 0.05). Glomerular filtration rate decreased (P < 0.05); thus, filtration fraction decreased (P < 0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P < 0.01) and became negative. Urine flow decreased (P < 0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium:potassium ratio decreased (P < 0.05). There was a decrease in lung liquid flow (P < 0.05) following losartan. 4. It is concluded that the fetal renin-angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT₁ receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels.     

Inhibition of nitric oxide synthase attenuates blood-brain barrier disruption during experimental meningitis

Increased permeability of the blood-brain (B-B) barrier is observed during meningitis. Preventing B-B barrier alterations is important because adverse neurological outcomes are correlated with breeches in barrier integrity. It was hypothesized that pathological production of nitric oxide (NO) contributes to B-B barrier disruption during meningitis in the rat. Experimental meningitis was induced by intracisternal (i.c.) administration of lipopolysaccharides (LPS) or vehicle. Groups of rats were concomitantly infused intravenously (i.v.) with saline or the NO synthase inhibitor, aminoguanidine (AG). Eight h after i.c. dosing, B-B barrier alterations were quantitated pharmacokinetically using [¹⁴C]sucrose. Serum and regional brain tissues were obtained 0–30 min after tracer dosing and sucrose influx transfer coefficients ( K_{in (app)}) were calculated from the brain tissue data. Compared to the control groups (i.c. vehicle/i.v. saline), the K_{in (app)} of the i.c. LPS/i.v. saline group increased 1.6–2.1-fold in various brain regions, thus confirming previous observations of increased [¹⁴C]sucrose barrier penetration during meningeal inflammation. Remarkably, i.v. administration of AG to i.c. LPS-treated rats significantly inhibited meningeal NO synthesis and decreased K_{in (app)} permeability alterations in the B-B barrier, compared to i.c. LPS/i.v. saline-treated rats. Regional brain K_{in (app)} estimates in the i.c. LPS/i.v. AG group were similar to control groups (i.c. vehicle/i.v. AG and i.c. vehicle/i.v. saline). In conclusion, these data suggest the general concept that excessive NO production during neuroinflammatory diseases contributes to disruption of the blood-brain barrier.     

Substitution of the 5-HT1 agonist trifluoromethylphenylpiperazine (TFMPP) for the discriminative stimulus effects of ethanol: effect of training dose

The role of the ethanol training dose on the ability of the selective 5-HT¹ agonist TFMPP (m-trifluoromethylphenylpiperazine) to produce ethanol-like discriminative stimulus effects was evaluated in three groups of rats trained to discriminate 1.0 g/kg (n=5), 1.5 g/kg (n=6) or 2.0 g/kg (n=7) ethanol (IG) from water using a two-lever procedure with food reinforcement available under a fixed ratio 20 (FR 20) schedule. Ethanol generalization gradients were comparable in the three groups, indicating few potency differences in the ethanol stimulus across training dose. However, the ability of TFMPP (0.1–1.7 mg/kg; IP) to substitute for ethanol was dependent on the training dose. TFMPP resulted in partial substitution in the 1.0 g/kg group, complete substitution for 1.5 g/kg group and no substitution in the 2.0 g/kg ethanol training group. The results indicate a serotonergic component to the discriminative stimulus effects of an intermediate dose of ethanol that is not prominent as the dose of ethanol is raised. These data add further support for the hypothesis that ethanol produces a mixed discriminative cue, the components of which are not uniformly amplified when the dose of ethanol is increased.     

Human dolasetron pharmacokinetics: II Absorption and disposition following single-dose oral administration to normal male subjects

Dolasetron is a 5-hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapyinduced nausea and vomiting. A previous study demonstrated that following intravenous administration to healthy male subjects, dolasetron disappeared extremely rapidly from plasma, and less than 1 per cent of the dose appeared in the urine. A major plasma metabolite, reduced dolasetron, peaked rapidly in the plasma. In this study, dolasetron was administered orally to healthy male subjects at doses ranging from 50 to 400 mg (mesylate monohydrate). Plasma concentrations of dolasetron were low and sporadic, and there was little excreted in urine; this prevented dolasetron pharmacokinetic analysis. Reduced metabolite concentrations peaked rapidly, with a median value of 1.00 h. The median terminal disposition half-life was 7.80 h. Median values for fraction of dose excreted in urine and renal clearance were 22.2 per cent and 2.56 ml min^?1 kg^?1. Whereas areas under the plasma concentration—time curves were proportional to dose, renal clearance increased with dose (p < 0.05). However, given dose proportionality to AUC, this is probably of little therapeutic consequence. Since reduced dolasetron has significant anti-emetic activity in the ferret model, it appears that this metabolite may play a significant role in pharmacodynamic activity.     

Interaction of Nucleoside Analogues with the Sodium–Nucleoside Transport System in Brush Border Membrane Vesicles from Human Kidney

The therapeutic efficacy of nucleosides and nucleoside analogues as antitumor, antiviral, antiparasitic, and antiarrhythmic agents has been well documented. Pharmacokinetic studies suggest that many of these compounds are actively transported in the kidney. The goal of this study was to determine if therapeutically relevant nucleosides or analogues interact with the recently characterized Na⁺-driven nucleoside transport system of the brush border membrane of the human kidney. Brush border membrane vesicles (BBMV) were prepared from human kidney by divalent cation precipitation and differential centrifugation. The initial Na⁺-driven ³H-uridine uptake into vesicles was determined by rapid filtration. The effect of several naturally occurring nucleosides (cytidine, thymidine, adenosine), a pyrimidine base (uracil), a nucleotide (UMP), and several synthetic nucleoside analogues [zidovudine (AZT), cytarabine (Ara-C), and dideoxycytidine (ddC)] on Na⁺–uridine transport was determined. At a concentration of 100 µM the naturally occurring nucleosides, uracil, and UMP significantly inhibited Na+-uridine transport, whereas the three synthetic nucleoside analogues did not. Adenosine competitively inhibited Na+-uridine uptake with a K _i of 26.4 µM (determined by constructing a Dixon plot). These data suggest that naturally occurring nucleosides are substrates of the Na⁺–nucleoside transport system in the renal brush border membrane, whereas synthetic nucleoside analogues with modifications on the ribose ring are not. The K _i of adenosine is higher than clinically observed concentrations and suggests that the system may play a physiologic role in the disposition of this nucleoside.     

Proposed definition of a smokeless tobacco user based on “potential” nicotine consumption

This study examined and operationally defined "light," "moderate," and "heavy" users of smokeless tobacco according to the potential amounts of nicotine consumed per week from chewing tobacco and/or snuff products. Fifty adult male smokeless tobacco users ranging in ages from 18-85 were tested to determine nicotine content of smokeless tobacco products consumed. The smokeless tobacco products were blindly analyzed by gas chromatography to determine nicotine content. Mean nicotine yield per week was calculated by multiplying the number of cans and/or pouches used per week and placed on a normal probability distribution. The mean nicotine yielded 238 mg/wk and the categories emerged as "light" less than or equal to 87 mg/wk, "moderate" 88-388 mg/wk and "heavy" users greater than or equal to 389 mg/wk. Differences regarding type of user (light, moderate, heavy) were crossed tabbed with educational levels, years of smokeless tobacco use, age the habit was initiated, perception of harm and whether habit forming, and reason for using smokeless tobacco.     

Complexation of Nifedipine with Substituted Phenolic Ligands

The bioavailability of nifedipine in man is highly variable. This may be partly due to its poor aqueous solubility (5–6 µg/ml over pH 2.2–10.0, as determined in this laboratory). We initiated this study to examine the enhancement of aqueous nifedipine solubility via complexation. A series of substituted aromatic ligands was studied to identify those structural features important for complexation with nifedipine. The studies were performed at 25°C employing the solubility technique, using pH 2.2 or 7.0 buffers at an ionic strength of 0.25 M. The apparent equilibrium complexation constants for the 1:1 and/or 1:2 complexes were determined, where appropriate. A linear free-energy approach was used to relate K _1:1 with Hammett's sigma () and fractional partition coefficient () parameters. The following correlation was obtained: log (K _l:l/K _o = 0.31 + 0.l0 + 0.36 (r ² = 0.86, P < 0.003, N = 9), where K _o is the complexation constant for phenol. Statistical analyses showed that was more important than in affecting nifedipine complexation. The exact location of this interaction on the nifedipine molecule is undefined at present.     

Assessment of Skin Barrier Function Using Transepidermal Water Loss: Effect of Age

To probe age-related changes in skin barrier function, transepidermal water loss (TEWL) rates have been measured in young (19–42 years) and old (69–85 years) subjects. TEWL was determined at ventral forearm skin sites, which had been occluded for 24 hr with polypropylene chambers. Baseline TEWL rates (J , which showed no dependence on age, were measured for each subject before and after the experiment. Following removal of the occlusive chamber, TEWL was monitored continuously from t = 0.5 min until its return to the baseline (preocclusion) level, which was typically in the range of 2–7 g/m²/hr. Initial TEWL rates (mean ± SD) were found to differ significantly between young (28.6 ± 7.5 g/m²/hr; n = 26) and old (36.9 ± 10.5 g/m²/hr; n = 18) subjects (P < 0.01). Relaxation of TEWL to J was significantly slower in the aged cohort, such that the characteristic time for diffusion of water in the stratum corneum was estimated to be (mean ± SD) 176 ± 59 min for the young subjects, compared to 360 ± 76 min for the old (P < 0.001.). Thus, the initial TEWL value following removal of occlusion is significantly greater, and the excessive stratum corneum hydration produced by occlusion is dissipated more slowly, in old skin than in young. A hypothesis to explain the slower relaxation of perturbed TEWL in old skin is proposed.