Smokers deprived of cigarettes for 72 h: effect of nicotine patches on craving and withdrawal

Abstract Rationale. Research on the effects of nicotine abstinence and nicotine replacement has not provided consistent information about the impact of replacement therapies on tobacco withdrawal and craving. Objective. This study investigated craving and withdrawal symptoms over a 72-h period of abstinence from cigarettes. Methods. Twenty-four healthy volunteers, not intending to quit smoking, were housed in an experimental unit during three 72-h conditions, consisting of either free smoking, enforced smoking cessation with nicotine replacement therapy (NRT) patches, or enforced smoking cessation with placebo patches. The conditions were adhered to using a randomized crossover design, each separated by at least 10 days of washout. Patches, administered in a double-blind fashion, were given as nicotine (21 mg/24 h) and placebo every 24 h. Self-reported cigarette craving and withdrawal were assessed using multi-item scales at fixed intervals over each condition period. Urinary and plasma cortisol levels were also assayed at fixed intervals over each period. Results. Craving intensity was significantly lower with free smoke than with placebo and with NRT patches than with placebo. No difference in craving levels was found between those who smoked or those who had NRT patches. Withdrawal symptoms were significantly lower with free smoke than with either placebo or NRT patches, but there was no difference in levels of withdrawal between those on NRT patches and those on placebo. During the placebo and NRT patch periods, craving intensity displayed a circadian rhythm, with craving levels lowest in the morning and peaking in the evening. Nicotine delivered via the patch had no impact on these circadian variations in craving. There was no evidence of systematic temporal variations in craving levels during the free smoking period. Conclusions. The data suggested that craving and withdrawal symptoms may be sustained by different physiological pathways, and that only selected components of cigarette craving are influenced by NRT. Electronic Publication     

Genotype- and experience-dependent susceptibility to depressive-like responses in the forced-swimming test

Abstract Rationale. The forced-swimming test (FST) is utilized to reproduce passive coping responses to stress that may model a relevant aspect of human depression in rodent species. Animals showing high levels of passive responses to the FST are assumed to model pathologically depressed individuals. Objectives. We evaluated sensitivity of FST-induced behavioral responses to the interaction between genetic and environmental influences. Methods. Behavioral responses to FST were evaluated in naive mice of the C57BL/6 and DBA/2 strains, in mice of both strains pre-exposed to FST 14 days before test, and in FST-experienced animals subsequently exposed to 12 days of stress experience (food restriction). Results. C57BL/6 mice are characterized by high propensity to adopt passive coping responses in the FST. Moreover, stress enhances FST-induced immobility in mice of the C57BL/6 strain but reduces this response in DBA/2 mice. Finally, FST-induced immobility in C57BL/6 mice is reduced by chronic treatment with clinically effective antidepressants. Conclusions. These results support the view that behavioral and neural responses to FST exhibited by C57BL/6 mice can be usefully exploited by pre-clinical research on depression. Electronic Publication     

The unbound percentage of saquinavir and indinavir remains constant throughout the dosing interval in HIV positive subjects

AIMS: To measure the unbound plasma concentrations of saquinavir (SQV) and indinavir (IDV) and to relate them to the total plasma concentrations in order to establish the unbound percentage of protease inhibitors in vivo during a full dosage interval profile. METHODS: HIV-infected subjects (n = 35; median CD4 cell count = 340 x 10(6) cells l-1, range: 120-825; viral load < 50 copies ml-1 in 22/35) treated with SQV or IDV containing regimens were studied. Plasma drug samples were collected at 0, 2, 4, 8 and 12 h postdose for the twice daily regimens and 0, 1, 2, 4 and 8 h for the three times daily regimens. Ultra-filtration was used to separate unbound IDV and SQV in plasma and their respective concentrations were measured by a fully validated method using high performance liquid chromatography-mass spectometry (h.p.l.c.-MS/MS). RESULTS: Based on the ratio AUCunbound/AUCtotal, the median unbound percentage (95% CI for differences) of SQV and IDV from all the samples studied was 1.19% (0.99, 1.58%) and 36.3% (35.1, 44.2%), respectively. No significant difference was seen in the percentage binding of SQV between patients receiving SQV alone (median = 1.49%) or with ritonavir (median = 1.09%; P = 0.141; 95% CI for difference between medians = -0.145, 0.937) over the pharmacokinetic profile. Similarly, no significant difference was seen in the percentage binding of IDV in patients receiving IDV alone (median 35.2%) or with ritonavir (median = 41.3%; P = 0.069; 95% CI for difference between medians = -0.09, 15.4). The unbound concentrations of SQV (P < 0.0001; 95% CI for r(2) = 0.634, 0.815) and IDV (P < 0.0001; 95% CI for r(2) = 0.830, 0.925) remained constant as a proportion of total concentration over the full dosing profile. CONCLUSIONS: These in vivo data confirm previously published in vitro measurements of SQV and IDV protein binding. The unbound percentage of both protease inhibitors remained constant over the dosing interval.     

Occupational risk factors for renal cell cancer: a case--control study in northern Italy

Relatively little is known about occupational and other risk factors for renal-cell carcinoma (RCC). Associations between RCC and occupations, exposures and other factors were investigated in a hospital-based case-control study in Bologna (central-northern Italy). Between 1986 and 1994, 324 histologically confirmed RCC cases were diagnosed at Policlinico S. Orsola-Malpighi in patients from the Province of Bologna. Corresponding control subjects admitted to the same hospital with any diagnosis except RCC were matched for sex, age, and residency. We studied the 249 cases and 238 controls for whom detailed information on occupational history, diet, smoking habits, alcohol and drug intake was obtained. At conditional logistic regression, among males (167 matched pairs), significant matched odds ratios (OR) were found, after adjusting for cigarette smoking and alcohol intake, for high body-mass index BMI (third quartile: OR, 4.91; confidence interval [95% CI], 1.56-15.5; last quartile: OR, 4.42; 95% CI, 1.48-13.18), railway workers (OR, 10.14; 95% CI, 1.46-70.17) and asbestos exposure (OR, 7.11; 95% CI, 1.46-34.51); nearly significant OR were found for managers (OR, 3.59; 95% CI, 0.82-15.59) and metal workers (OR, 2.21; 95% CI, 0.99-5.37). Among females (52 pairs), significant OR were found for BMI > 25.4 (OR, 8.46; 95% CI, 1.02-68.0). Railway workers (on or near to trains) may have increased risk of developing RCC, possibly due to asbestos exposure. Studies are required on possible risks encountered by railway (and metal) workers and by managers.     

Will epidemiology succeed in saving the tumor registries?

The present paper focuses on the Italian registries: their actual achievements, future developments and the possible critical states. The present setting is analysed in perspective with the international and European framework of cancer registries. Given the recent development of new cancer registries in Italy, and their participation to traditional and new international publication of their data, there is an increasing delay in publication time, both in Italy and abroad International and national institutions played an important role in helping and supporting registries' development, but delays in publications and some uncertainty in coordinating incidence and survival analyses in a unique framework is posing an unavoidable challenge.     

Modeling and biological evaluation of 3,3'-(1,2-ethanediyl)bis[2-(4-methoxyphenyl)-thiazolidin-4-one], a new synthetic cyclooxygenase-2 inhibitor

Within the series of chiral 3,3'-(1,2-ethanediyl)bis[2-arylthiazolidin-4-ones], the 3,4-dimethoxyphenyl substituted derivative was found in the primary anti-inflammatory screening to be endowed with superior in vivo properties and good safety profile. Such a lead compound was modified by eliminating 3-methoxy group while retaining 4-methoxy group on the aryl rings at 2 and 2' stereogenic carbons. The 2R,2'S-meso isomer (VIG3b) of the resulting bisthiazolidinone has been widely investigated. The inhibitory effects on cyclo-oxygenase-1 and cyclo-oxygenase-2 isoenzymes were measured in a human whole blood assay. VIG3b was almost 50 times more selective on the inducible isoform. The cyclo-oxygenase-2 preferential selectivity has been confirmed by modeling VIG3b into the cyclo-oxygenase-1 and cyclo-oxygenase-2 active sites. Furthermore, VIG3b was assayed in the experimental model of carrageenan-induced lung injury by evaluating its ability to inhibit: (1) fluid accumulation in the pleural cavity, (2) neutrophil infiltration, (3) prostaglandin E(2) production and (4) lung injury. VIG3b exhibited interesting activity in all these tests.     

Adenosine A(1) receptor: analysis of the potential therapeutic effects obtained by its activation in the central nervous system

Adenosine modulates several physiological functions in the CNS and in peripheral tissues via membrane receptors which have been classified into four adenosine subtypes. A(1) activation produces neuronal depression: this inhibition allows A(1) agonists to produce ischemic tolerance and protection in neuronal tissue. In order to selectively reproduce these effects, several A(1) selective ligands have been synthesised and evaluated to understand how they interact with the adenosine A(1) receptor. The investigation methods include SAR studies using native and chemically modified A(1) receptors, molecular cloning of native and mutant adenosine A(1) receptors, molecular modeling and thermodynamic analysis of drug-receptor interaction. Despite the great quantity of information available on the adenosine A(1) receptor, no A(1) agonist has so far entered in clinical use against brain diseases in view of the side effects; moreover selective A(1) agonists appear to be poorly adsorbed into the brain and can be quickly degraded in vivo or in the whole blood. In an attempt to overcome these problems studies have been undertaken dealing with the use of partial agonists to inhibit side-effects and the employment of prodrugs to increase stability and diffusion through lipid barriers of A(1) ligands. Other attempts involve either the use of A(1) receptor enhancers as modulators able to locally enhance the action of endogenously produced adenosine, or the encapsulation of A(1)agonists in drug delivery systems targeted to the brain. In this review, these approaches will be described together with the effects of adenosine A(1) receptor ligands and their binding mechanisms on the central nervous system.     

A catalogue of polymorphisms related to xenobiotic metabolism and cancer susceptibility

High-throughput genotyping technology of multiple genes based on large samples of cases and controls are likely to be important in identifying common genes which have a moderate effect on the development of specific diseases. We present here a comprehensive list of 313 known experimentally confirmed polymorphisms in 54 genes which are particularly relevant for metabolism of drugs, alcohol, tobacco, and other potential carcinogens. We have compiled a catalog with a standardized format that summarizes the genetic and biochemical properties of the selected polymorphisms. We have also confirmed or redesigned experimental conditions for simplex or multiplex PCR amplification of a subset of 168 SNPs of particular interest, which will provide the basis for the design of assays compatible with high-throughput genotyping.