Bromocriptine reduces cigarette smoking.

AIMS: Animal studies have shown that nicotine releases dopamine, a neurotransmitter implicated in drug reinforcement. We hypothesized that bromocriptine would decrease smoking behavior in humans. DESIGN: The study was conducted double blind and subjects' order of dose exposure was randomized. PARTICIPANTS: The smoking behavior of 20 heavy smokers was recorded for 5 hours after ingesting placebo or one of two doses of bromocriptine (2.50 mg, 3.75 mg) over three sessions (one dose per session). FINDINGS: There was a significant negative linear trend by dosage indicating shorter total puffing time with increasing bromocriptine dosages (p < 0.02). Other significant negative linear trends by increasing dosage include fewer number of puffs, fewer number of cigarettes smoked and mean latency to smoke after 3 hours (expected CMAX on the drug (all ps < 0.05). There was a negative significant linear trend showing decreased plasma nicotine (p < 0.02) and cotinine (p < 0.005) with increasing dosages of bromocriptine. Shiffman/Jarvik Withdrawal Scale (SJWS) cigarette craving subscale scores decreased significantly across increasing dosages (linear trend p < 0.02). There was a significant negative linear trend (p < 0.05) on the Profile of Mood States (POMS) Vigor and Depression subscales, with subjects reporting decreased vigor and depression with increasing bromocriptine doses. No other mood effects were observed. CONCLUSION: These results support the hypothesis that dopaminergic mechanisms mediate cigarette smoking reinforcement.

Nicotine blood levels and subjective craving for cigarettes.

This study examined cigarette craving and blood nicotine levels in 11 male heavy smokers who were observed during 16 h of tobacco abstinence. Subjects rated their urge to smoke on a new brief 10-item questionnaire, Urge to Smoke (UTS), Schuh and Stitzer's four-item Visual Analog Scale (SSI), and a Strength of Urge to Smoke (SUTS) item. Testing occurred: 1) after 16 h (1700 h the night before to 0900 h the next morning) of abstinence from smoking; 2) after an ad lib smoking period following the 16 h abstinence; 3) every hour during 6 hours of abstinence; 4) and finally, after the 6 h abstinence, another ad lib smoking period. Thus, subjects smoked twice in each session. Blood plasma nicotine levels were measured before, after, and every 2 h during the 6-h abstinence period for a total of six measures. Blood pressure and heart rate were measured prior to each blood draw. There was a significant negative correlation between blood nicotine levels and craving for cigarettes on all craving questionnaires (rs = -0.55 to -0.78; ps < 0.002). Carbon monoxide was shown to correlate highly with nicotine blood levels (rs = 0.83 to 0.98 across subjects; ps < 0.001). Results are consistent with the hypothesis that "urge to smoke" reflects nicotine seeking in continuing smokers.

L-2-oxothiazolidine-4-carboxylate, a cysteine precursor, stimulates growth and normalizes tissue glutathione concentrations in rats fed a sulfur amino acid-deficient diet.

The efficiency of L-2-oxothiazolidine-4-carboxylate, a cysteine precursor, in stimulating glutathione synthesis and growth was evaluated in growing rats. Animals were fed a sulfur amino acid-deficient diet (0.25% L-methionine and no cysteine) supplemented with L-2-oxothiazolidine-4-carboxylate (0.35%) for 3 wk and compared with age-matched animals receiving the sulfur amino acid-deficient diet alone. Rats fed the sulfur amino acid-deficient diet had lower glutathione concentrations in bronchoalveolar lining fluid, lung, lymphocytes, and liver than rats fed a sulfur amino acid-deficient diet supplemented with L-2-oxothiazolidine-4-carboxylate. Rats fed the supplemented diet had normal tissue and bronchoalveolar lining fluid glutathione levels. Central venous plasma glutathione concentrations, mostly reflecting liver excretion, were less affected by L-2-oxothiazolidine-4-carboxylate supplementation. Rats fed L-2-oxothiazolidine-4-carboxylate supplementation had normal weight gain compared with a much lower weight gain in animals fed the sulfur amino acid-deficient diet alone. Thus, L-2-oxothiazolidine-4-carboxylate increased tissue glutathione concentrations and stimulated growth in rats. The lung glutathione status of the rats was reflected by glutathione concentrations in lymphocytes and the bronchoalveolar lining fluid, but not by the central venous plasma glutathione concentrations.

The effect of dipeptide structure on dipeptide and amino acid clearance in rats.

The kinetics of disappearance from the blood of GlyTyr, TyrArg, AlaTyr, TyrAla, GlnGly, GlyGln, GlnAla, and AlaGln and their constituent amino acids was assessed in anesthetized (pentabarbitone) Sprague-Dawley rats (n = 5 for each peptide). Catheters were inserted into both internal jugular veins. A bolus injection of dipeptide was administered into one catheter, and rapid blood samples were taken from the other catheter for measurement of dipeptide and amino acid concentrations. Kinetic parameters for the disappearance of dipeptides and of the amino acids released from the dipeptides from the blood were calculated using standard equations. All dipeptides were cleared rapidly from the blood (clearances ranged from 42.9 +/- 3.28 mL/min/kg body weight for GlyGln to 278 +/- 70.7 for GlnAla, mean +/- SD). Glutaminyl dipeptides with alanine or glycine in the C-terminal position or dipeptides with alanine in the N-terminal position had the greatest clearance values and the shortest half-lives (t1/2). There were significant differences (P < .001) in the volume of distribution of the dipeptides. Many dipeptides had volumes of distribution greater than the blood volume of the animals. The amino acids released from the dipeptides had a longer t1/2 (P < .001) than their parent dipeptides. The t1/2 and the weight-corrected area under the blood concentration-versus-time curve (AUC) of the same amino acid released from different dipeptides differed (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Toxicity evaluations of L-cysteine and Procysteine, a cysteine prodrug, given once intravenously to neonatal rats.

Decreased enzymatic production of cysteine in premature and newborn infants may limit the synthesis of glutathione. Unfortunately, cysteine supplementation is limited by associated toxicity and product instability. Procysteine (L-2-oxothiazolidine-4-carboxylate) is a prodrug of cysteine that is inert until metabolized to cysteine intracellularly, thus stimulating glutathione synthesis. The potential toxicities of cysteine and Procysteine were compared in two studies with neonatal rats (10 per group; 3 +/- 1 days of age) after a single intravenous administration. In one study, acute high dosage survivorship was compared for approximately equimolar cysteine dosages of L-cysteine and Procysteine. Mortality at 7 days after single intravenous dosages of L-cysteine at 1.52 or 1.14 g/kg or Procysteine at 1.80 or 1.35 g/kg was 80, 50, 10 and 0%, respectively. Clinical pathology parameters and body and organ weights were compared in a second study, following a moderate dosage of Procysteine or equimolar or lower dosages of L-cysteine. No differences were observed in clinical pathology parameters nor body or organ weights at 14 days following single intravenous dosages of L-cysteine at 369, 185 or 37 mg/kg or Procysteine at 450 mg/kg. Also, Procysteine solutions were considerably more stable than L-cysteine solutions (months vs. hours, respectively). These studies indicated that cysteine supplementation in infants may be enhanced by Procysteine administration.

Competition for transport of amino acids into rat heart: effect of competitors on protein synthesis and degradation.

Transport of the neutral amino acids, 2-(methylamino)isobutyrate (MeAIB) and Phe, was examined in isolated rat hearts perfused by the Langendorff method. Hearts were perfused by recirculating for various time periods buffer containing [14C]-MeAIB or [14C]-Phe plus desired additions. Uptake of MeAIB was linear for approximately 30 minutes; Phe uptake was linear for a maximum of 5 minutes, and reached a steady state after 15 minutes. Km and Vmax for MeAIB were 1.1 +/- 0.03 mmol/L and 37.7 +/- 0.4 pmol/microL intracellular fluid (ICF)/min; values for Phe were 1.8 +/- 0.02 mmol/L and 364 +/- 5 pmol/microL ICF/minute. Uptake of MeAIB (0.2 mmol/L) was reduced 95% in the presence of Ser (10 mmol/L), and less severely by large neutral amino acids ([LNAA], 10 mmol/L) such as Phe and Leu (by 46% and 54%, respectively). Uptake of Phe (0.2 mmol/L) was reduced by LNAA such as Val, Leu, and Ile (by 51%, 78%, and 81%, respectively), or by commercial preparations used in parenteral nutrition, eg, Travasol or Travasol plus extra branched-chain amino acids (BCAA) (Branchamin); Ser had little effect (8% reduction). Insulin in the perfusion medium increased the fractional rate of protein synthesis. Individual BCAA at physiological concentrations (0.2 mmol/L) did not alter the rate of protein synthesis. Branchamin or Travasol plus Branchamin also had no effect on the rate of protein synthesis in heart, but did depress the rate of degradation. These studies suggest that amino acid transport into heart may be affected by normal levels of plasma amino acids, whereas protein synthesis is not.

Effects of Aureomycin on bile acids in rats.

Primary BA's secreted into the duodenum are extensively altered by bacteria in the large intestine. Such changes are not found in GF animals. As a result, GF rats reabsorb BA much more efficiently than do CV controls, and BA and cholesterol pools are higher in GF than CV rats. This indicates the importance of the intestinal flora in the homeostasis of cholesterol metabolism. Antibiotics can affect the extent to which BA's are altered by bacteria. In some cases, the antibiotic treatment also affects cholesterol levels in serum or liver. We have found that treatment of CV rats for only 5 days with low levels of Aureomycin (0.85 micron) led to a predominance of omega-MC over HDC in the feces at 10 days after withdrawal of the antibiotic. This reduced the usual HDC/omega-MC ratio from approximately 2.0 to 0.9 or less. These rats were also found to have liver cholesterol levels modestly elevated over those of controls. In other experiments the decrease in hyodeoxycholate/omega-muricholate ratio was found to persist for at least 90 days after discontinuation of treatment. Later experiments carried out with Aureomycin and with penicillin revealed the possible existence of a resistance factor to Aureomycin. A significant lowering of the hyodeoxycholate/omega-muricholate ratio was now found only with antibiotic concentrations 10 to 100 times greater than those used previously. Possible implications of the persistence of antibiotic effects, as measured by changes in fecal BA's, include effects on vitamin metabolism, colon cancer, and cholesterol metabolism.

Effects of cholestyramine on 1,2-dimethylhydrazine-induced enteric carcinoma in germfree rats.

Oral administration of 1,2-dimethylhydrazine (DMH) induced intestinal neoplasms in germfree rats. A supplement of 2% cholestyramine resin in the diet increased the frequency of DMH-induced intestinal tumors and accelerated malignant transformation. Bile acids in the cecal content were determined with and without cholestyramine in order to obtain a correlation between the bile acid metabolism and the enteric carcinogenesis.