Drug interactions with smoking.

PURPOSE: The mechanisms for drug interactions with smoking and clinically significant pharmacokinetic and pharmacodynamic drug interactions with smoking are reviewed. SUMMARY: Polycyclic aromatic hydrocarbons (PAHs) are some of the major lung carcinogens found in tobacco smoke. PAHs are potent inducers of the hepatic cytochrome P-450 (CYP) isoenzymes 1A1, 1A2, and, possibly, 2E1. After a person quits smoking, an important consideration is how quickly the induction of CYP1A2 dissipates. The primary pharmacokinetic interactions with smoking occur with drugs that are CYP1A2 substrates, such as caffeine, clozapine, fluvoxamine, olanzapine, tacrine, and theophylline. Inhaled insulin's pharmacokinetic profile is significantly affected, peaking faster and reaching higher concentrations in smokers compared with nonsmokers, achieving significantly faster onset and higher insulin levels. The primary pharmacodynamic drug interactions with smoking are hormonal contraceptives and inhaled corticosteroids. The most clinically significant interaction occurs with combined hormonal contraceptives. The use of hormonal contraceptives of any kind in women who are 35 years or older and smoke 15 or more cigarettes daily is considered contraindicated because of the increased risk of serious cardiovascular adverse effects. The efficacy of inhaled corticosteroids may be reduced in patients with asthma who smoke. CONCLUSION: Numerous drug interactions exist with smoking. Therefore, smokers taking a medication that interacts with smoking may require higher dosages than nonsmokers. Conversely, upon smoking cessation, smokers may require a reduction in the dosage of an interacting medication.     

Vasculin,a novel vascular protein differentially expressed in human atherogenesis

Recent suppressive subtractive hybridization analysis on human atherosclerotic plaque-derived RNA revealed genes upregulated in plaques with a thrombus versus stable plaques. Clone SSH6, containing part of a putative open reading frame of an unknown protein, was further investigated. Full-length cDNA, coding for a 473-amino acid (aa) protein, was identified in a vascular smooth muscle cell (SMC) cDNA library. Bioinformatics suggested the presence of multiple SSH6 variants due to alternative splicing of exon 3. Multiple-tissue Northern blot analysis demonstrated a differential expression pattern of these variants, as a ubiquitously expressed SSH6 mRNA missing exon 3, was detected apart from a putative vascular SMC-specific form containing exon 3. Western blot analysis indicated a ubiquitous 35-kDa protein (SSH6-beta), in addition to a 45-kDa protein (vasculin), detected in the vascular wall and in plasma. Analysis of arteries displaying various stages of atherosclerosis indicated that the vasculin/SSH6-beta ratio increases throughout atherogenesis. Immunohistochemical analysis demonstrated cytoplasmic expression of SSH6 gene products in macrophages, endothelial cells, and SMCs. In summary, we identified a novel mRNA/protein, vasculin, in the arterial wall and plasma. The regulated expression of vasculin in plaques suggests a role in atherogenesis. Moreover, its presence in plasma opens perspectives for vasculin as a marker for atherosclerosis.     

Expression of hNP22 is altered in the frontal cortex and hippocampus of the alcoholic human brain

BACKGROUND: Human neuronal protein (hNP22) is a gene with elevated messenger RNA expression in the prefrontal cortex of the human alcoholic brain. hNP22 has high homology with a rat protein (rNP22). These proteins also share homology with a number of cytoskeleton-interacting proteins. METHODS: A rabbit polyclonal antibody to an 18-amino acid epitope was produced for use in Western and immunohistochemical analysis. Samples from the human frontal and motor cortices were used for Western blots (n = 10), whereas a different group of frontal cortex and hippocampal samples were obtained for immunohistochemistry (n = 12). RESULTS: The hNP22 antibody detected a single protein in both rat and human brain. Western blots revealed a significant increase in hNP22 protein levels in the frontal cortex but not the motor cortex of alcoholic cases. Immunohistochemical studies confirmed the increased hNP22 protein expression in all cortical layers. This is consistent with results previously obtained using Northern analysis. Immunohistochemical analysis also revealed a significant increase of hNP22 immunoreactivity in the CA3 and CA4 but not other regions of the hippocampus. CONCLUSIONS: It is possible that this protein may play a role in the morphological or plastic changes observed after chronic alcohol exposure and withdrawal, either as a cytoskeleton-interacting protein or as a signaling molecule.     

Neurologic dysfunction in patients with rheumatoid arthritis of the cervical spine. Predictive value of clinical, radiographic and MR imaging parameters

The aim of this study was to evaluate if subjective symptoms, radiographic and especially MR parameters of cervical spine involvement, can predict neurologic dysfunction in patients with severe rheumatoid arthritis (RA). Sequential radiographs, MR imaging, and neurologic examination were performed yearly in 46 consecutive RA patients with symptoms indicative of cervical spine involvement. Radiographic parameters were erosions of the dens or intervertebral joints, disc-space narrowing, horizontal and vertical atlantoaxial subluxation, subluxations below C2, and the diameter of the spinal canal. The MR features evaluated were presence of dens and atlas erosion, brainstem compression, subarachnoid space encroachment, pannus around the dens, abnormal fat body caudal to the clivus, cervicomedullary angle, and distance of the dens to the line of McRae. Muscle weakness was associated with a tenfold increased risk of neurologic dysfunction. Radiographic parameters were not associated. On MR images atlas erosion and a decreased distance of the dens to the line of McRae showed a fivefold increased risk of neurologic dysfunction. Subarachnoid space encroachment was associated with a 12-fold increased risk. Rheumatoid arthritis patients with muscle weakness and subarachnoid space encroachment of the entire cervical spine have a highly increased risk of developing neurologic dysfunction. Received: 31 December 1999 Revised: 30 May 2000 Accepted: 5 June 2000     

Ketamine anesthesia with or without diazepam premedication for bone marrow punctures in children with acute lymphoblastic leukemia

Ketamine is a drug widely used for analgesia and sedation of children for diagnostic and therapeutic procedures. The authors investigated in a randomized controlled clinical trial if diazepam premedication would have a beneficial effect on side effects related to ketamine anesthesia for bone marrow punctures (BMPs) in children with acute lymphoblastic leukemia (ALL). Sixteen children 4 years or older at the time of BMP were eligible. The first 2 BMPs after complete remission was obtained were studied. BMPs were performed under ketamine anesthesia (1.0-1.5 mg/kg iv), as usual. Patients were randomized to receive 1 h before the first BMP blinded, either diazepam or placebo orally and before the second BMP the other way round. Blood pressure, heart rate, and oxygen saturation were monitored, and patients were observed for signs of anxiety, pain, and other side effects. The patients were interviewed after each BMP and asked for their preference 1 week after the second BMP. Ketamine anesthesia appeared as safe and effective after diazepam premedication as after placebo premedication. From the interviews and questionnaires, it was clear that half of the children preferred diazepam premedication because of less awful dreaming and more gradual falling asleep and waking up. Diazepam premedication may be useful for selected children with ALL receiving ketamine anesthesia for BMPs.     

The role of steroid hormones in protogynous sex change in the Blackeye goby, Coryphopterus nicholsii (Teleostei: Gobiidae)

To detect and describe correlations between steroid concentrations and sexual function in the protogynous Coryphopterus nicholsii, we examined whole-body concentrations of the gonadal steroids testosterone (T), 11-ketotestosterone (11-KT), and 17beta-estradiol (17beta-E2). Our results show that T, 11-KT, and 17beta-E2 are naturally occurring steroids in both female and male C. nicholsii. Further, mean whole-body concentrations of T and 11-KT in males were approximately twice those in females, whereas mean whole-body concentration of 17beta-E2 in females was almost twice that in males. Second, we tested hypotheses on the causation of sex change arising from these correlations between steroid concentrations and sexual function. We examined the effects of administration of 11-KT, 11-KA, 17alpha-methyltestosterone, and an aromatase inhibitor (Fadrozole) on gonadal structures of mature females. Complete sex change was induced by 11-KT, 11-KA, and Fadrozole. Our results strongly suggest that an increase in 11-KT concentration and perhaps also a decrease in 17beta-E2 concentration are involved in mediating natural sex change in C. nicholsii.     

Selective cognitive processing of drug cues in heroin dependence

Previous studies provide evidence for the selective processing of disorder related stimuli on anxiety, depression, and eating disorders. There exist some preliminary indications that selective processing of drug cues may be involved in drug craving and relapse that deserve further investigation. In order to investigate the role of processing bias in an abnormal motivational system, the attentional bias for drug related stimuli was studied in a heroin dependent population. Heroin dependent participants (n = 21) and control participants (n = 30) performed a supra- and subliminal heroin Stroop task and heroin craving was assessed. Heroin dependent participants showed a considerable attentional bias for supraliminally presented heroin cues. However, there was no evidence for a preattentive bias on the subliminal presented cues. Reaction time on heroin cues was significantly predicted by heroin craving-levels. Results indicate that selective processing may be related to motivational induced states in general. The finding are discussed in the context of selective information processing in general psychopathology and in motivational processes as addiction specifically.     

Influence of individual differences in craving and obsessive cocaine thoughts on attentional processes in cocaine abuse patients

In the present pilot-study, the relation between craving, obsessive thoughts about cocaine, experienced control, and attentional bias for cocaine related words is investigated. Sixteen cocaine abuse patients participated in a reaction time (RT) experiment which was employed to measure the ability of subjects to shift their attention away from cocaine related words. Postexperiment craving was found to be positively correlated with reaction times on drug related cues, in contrast to RT on neutral cues. Furthermore, obsessive thoughts about cocaine use and the experienced cocaine use control, in the week before the experiment, were correlated in a higher degree with RTs on drug cues than postexperiment craving. Attentional bias for drug cues was evidenced in patients with higher scores on obsessive cocaine thoughts and higher craving scores. This study shows that individual differences on information processing, within a cocaine abuse patient population, are present.