Co-induction of cytochrome P4504A1 and peroxisome proliferation: A causal or casual relationship?

1. The hypothesis that xenobiotic induction of hepatic microsomal cytochrome P4504A1 and peroxisome proliferation are closely-related phenomena has been further investigated.

2. Five rat strains (Gunn, Fischer, Wistar, Long Evans and Sprague Dawley) were all susceptible to xenobiotic induction of both microsomal cytochrome P4504A1 and peroxi-some proliferation, and no strain exhibited a dissociation of these phenomena.

3. In comparison to rat, the marmoset was substantially less susceptible to the above hepatic changes.

4. Induction of both cytochrome P4504A1 and peroxisome proliferation by a structural analogue of clofibrate (2-(4-(4-chlorophenyl)benzyloxy)-2-phenyl acetic acid) demonstrated stereochemical selectivity, in that the R(-)-isomer was a more potent inducer of both phenomena than the S(+)-antipode, with the racemic mixture exhibiting an intermediate potency.

5. Cycloheximide inhibition of clofibrate-dependent induction of acyl CoA mRNA, but not cytochrome P4504A1 mRNA has inducated a protein dependency for peroxisome proliferation, not inconsistent with participation of cytochrome P4504A1 in the biogenesis of peroxisome proliferation.

6. Taken collectively, the data described herein provide further evidence for a close linkage between xenobiotic induction of cytochrome P4504A1 and peroxisome proliferation, and possible molecular mechanisms inter-relating these two phenomena are discussed.     

Euphoriant effects of nicotine in smokers: fact or artifact?

Rationale The claim that nicotine in cigarettes is euphoriant to smokers is largely based on two studies (Pomerleau and Pomerleau, Psychopharmacology, 108:460–465, 1992; Tobacco Control, 3:374, 1994) in which smokers were instructed to respond to sensations of rush, buzz, or high while smoking low-nicotine or regular cigarettes. However, the assumption that these sensations are pleasurable was not tested and may have biased the results. Objectives The aim of this study was to re-examine the claim that smoked nicotine is euphoriant to smokers. Methods Study 1 surveyed the frequency and pleasantness of the smoking-related sensations of rush, buzz, and high in a sample of smokers. Study 2 replicated Pomerleau and Pomerleau (Psychopharmacology, 108:460–465, 1992) with two sets of instruction. One set, as in the original study, defined these sensations as pleasurable, whereas the other defined them as unpleasant. Results Study 1 found that whereas rush and high were perceived as pleasant, buzz was unpleasant to most smokers. Study 2 found that under both sets of instructions, smokers reported more sensations when smoking the regular, as compared to the low-nicotine cigarette. Additionally, the sensations of rush, buzz, and high were rated as more pleasant under the pleasant instructions as compared to the unpleasant instructions. Finally, in the pleasant instructions condition, many participants reported having pressed the button to indicate a pleasurable sensation despite having actually experienced that sensation as unpleasant. Conclusions Our results suggest that the findings of Pomerleau and Pomerleau (Psychopharmacology, 108:460–465, 1992; Tobacco Control, 3:374, 1994) may have been biased by the experimental instructions and cannot be taken as evidence that smoked nicotine is euphoriant to smokers.     

Cigarette smoking and attention: processing speed or specific effects?

RATIONALE: It has been evidenced that nicotine acts on some dimensions of human attention. OBJECTIVE: This study was carried out to test whether the positive effects of nicotine usually observed on the posterior system are specific or should rather be explained in terms of an effect of nicotine on eye movement velocity. METHODS: Ten participants were submitted to four tasks assessing attention. The tasks were borrowed from Zimmermann and Fimm's Battery for the Assessment of Attention: alert, eye movements, visual search and incompatibility. The order of the different tasks was balanced among participants. A within-subjects repeated-measure design was used. Participants received a 0.9-mg or 0.1-mg nicotine cigarette. The 0.1-mg cigarette was used as control. The order of administration of doses over sessions was counterbalanced. During the testing day, volunteers smoked their own cigarette and then waited 3 h without smoking. At the end of this abstinence period, participants completed the baseline tests before smoking an experimental cigarette ad libitum. They were then tested again. RESULTS: Participants who received nicotine appeared to respond faster in an eye movement task--a task associated with a non-elaborated attentional process. Similarly, their alert state improved. On the contrary, no effect of nicotine was observed in the incompatibility task and in the visual search task depending on elaborated attentional process. CONCLUSIONS: Data support previous observations and suggest that, first, non-elaborated information processing appeared to be more sensitive to nicotine and, second, this effect is not due to a velocity factor.     

Behavioral effects of betacarbolines in pigs:. anxiety or aversion?

Betacarbolines are often considered to be anxiogenic and may, therefore, have similar behavioral effects to those of corticotrophin releasing hormone (CRH); however, their actions have been little studied in pigs. This investigation was concerned with the effects of ethyl-beta-carboline-3-carboxylate (BCCE) and noreleagnine (NOR) on operant feeding, cortisol release, and overt behavior in swine, all of which are known to be affected by CRH in this species. Three experiments are described in which BCCE or NOR were given intravenously to prepubertal boars (n = 7). In Experiment 1, 400 microg/kg, but not 100 or 200 microg/kg, BCCE produced a rapid inhibition of ingestive activity whereas NOR (100, 200, or 400 microg/kg) was without effect. In Experiment 2, both BCCE and NOR increased plasma cortisol, but not growth hormone, concentrations. In Experiment 3, a high dose of BCCE (2 mg/kg) produced transient arousal and a sustained increase in respiration rate and plasma cortisol. These results indicate that although the responses of pigs to BCCE and CRH are similar in some respects, there are also marked behavioral differences. The possibility that BCCE has aversive rather than anxiogenic actions in this species is discussed.     

Non‐specific effects of acupuncture: genuine or placebo?

Linde K, Niemann K, Schneider A, Meissner K. How large are the nonspecific effects of acupuncture? A meta‐analysis of randomized controlled trials. BMC Med 2010; 8: 75.     

Tumor intracellular redox status and drug resistance--serendipity or a causal relationship?

Reducing tumor load by therapeutic induction of cell death in the transformed phenotype is the desirable goal of most chemotherapeutic regimens. Despite the tremendous strides made in our understanding of mechanisms that endow tumor cells with the ability to evade execution signals, development of chemo-resistance is still a major obstacle in the successful management of the disease. A host of factors have been implicated in the acquisition of the resistant phenotype, such as activation of drug efflux pumps, overexpression of proteins that inhibit cell death, absence of critical members of the death circuitry, and selective loss of cell cycle checkpoints. Consequently, it is now well established that the process of carcinogenesis is not only a result of an increase in cells' proliferative capacity, but a product of increased proliferation and defective or diminished cell death signaling. To that end, one of the critical determinants of cellular response to exogenous stimuli is the cellular redox status. Intracellular generation of reactive oxygen species (ROS) is tightly regulated by the intrinsic anti-oxidant defense systems. Despite the conventional dogma that ROS are harmful to the cell, experimental evidence over the last decade or so bear witness to the fact that ROS also play an important role as signaling molecules in diverse physiological processes. Indeed, low levels of intracellular ROS have been linked to cellular proliferation and cell cycle progression, which provides an explanation for the pro-oxidant state invariably associated with the transformed phenotype. Coupled to that are recent observations implicating pro-oxidant intracellular milieu in tumor cells' resistance to cell death signals delivered through the cell surface receptor or upon exposure to chemotherapeutic drugs. These studies provide convincing evidence to support a direct or indirect role for intracellular superoxide anion in creating an intracellular milieu non-permissive for cell death execution. Thus a novel approach to enhancing tumor cell sensitivity to chemotherapy-induced cell death would be to favourably tailor the cytosolic milieu to allow efficient apoptotic execution. Here we present a brief discussion on the role of ROS in cell growth and differentiation, and more specifically address the issue of chemo-resistance from the standpoint of cellular redox status.     

Smoking and hypertension: independent or additive effects to determining vascular damage?

A causal relationship between exposure to smoking and increase in blood pressure (BP) is not yet clearly demonstrated. Some observations suggest a transient increase while smoking a cigarette or when exposed to passive smoking. Late stable hypertension may also occur as a consequence of smoking. This could be attributed to the progression of atherogenesis triggered by smoking (e.g. endothelial dysfunction). Endothelial dysfunction is strongly associated with hypertension. Impaired nitric oxide (NO) availability attributable to oxidative stress production, which causes NO breakdown, has also been considered as another mechanism. Smoking and hypertension seem to have an additive effect as risk factors for cardiovascular disease.     

Long-term effects of BRAF inhibitors in melanoma treatment: friend or foe?

The clinical development of selective BRAF inhibitors for metastatic BRAF V600 mutant melanoma patients has been a major breakthrough in targeted therapeutics. Objective response rates of approximately 50% have been observed in the Phase III studies of the BRAF inhibitors vemurafenib and dabrafenib. The side effects can be relatively common, including proliferative skin toxicities. The latter range from hyperkeratosis and keratoacanthomas (KAs) to squamous cell carcinomas (SCCs) and new primary melanomas. In addition, case reports on the emergence of gastric/colonic polyps and RAS mutant malignancies have been described during BRAF inhibitor therapy. These events have been attributed to paradoxical activation of the MAPK pathway in BRAF wild-type cells exposed to selective BRAF inhibitors in addition to increased RAS activity. Combined BRAF and MEK inhibition appears to improve clinical outcomes and reduce cutaneous proliferation events as fewer KAs and SCCs have been observed with combination therapy. Next-generation pan-RAF inhibitors (‘paradox breakers’) and ERK inhibitors may further enhance clinical activity in metastatic BRAF-mutant melanoma patients and mitigate this paradoxical oncogenesis. Further investigation into the potential long-term effects of selective BRAF inhibitors is warranted as expanded use of these agents is expected in patients with BRAF-mutant melanoma and other malignancies.     

A history of medical payments: continuity or crisis?

The form and amount of medical payments has been a contentious issue throughout the history of Western medicine. The prices charged by doctors, and the actual payments they receive, have reflected a complex interaction of the social, economic, and political forces impinging upon medical practice. Contemporary concerns about the medical payment system in the U.S. relate, in part, to the unprecedented scale and complexity of the modern system of medical payments. Historical analysis reminds us that medicine and money have always made odd bedfellows. Today's problems may seem intractable, but such problems have been consistent throughout medical history.     

Zeranol: doping offence or mycotoxin? A case-related study

Zeranol ((7R,11S)-7,15,17-trihydroxy-11-methyl-12-oxabicyclo[12.4.0]octadeca-1(14),15,17-trien-13-one, also referred to as 7α-zearalanol, Ralone?, Frideron?, Ralgro?, etc.) is a semi-synthetic estrogenic veterinary drug with growth-promoting properties. Its use regarding animal husbandry has been prohibited in the European Union since 1981 and, due to its anabolic effects, it is further recognized as a banned substance in sport. Numerous studies were conducted concerning the identification of the illicit application of zeranol to domestic livestock. These studies also considered the natural occurrence of zeranol as a metabolite of the mycotoxin zearalenone and the issue of differentiating both scenarios, i.e. illegal use or unintended contamination. Human sports drug testing authorities are facing comparable challenges since the deliberate misuse of the (for human application non-approved) drug should be discriminated from adverse analytical findings resulting from the biotransformation of the mycotoxin zearalenone possibly ingested with contaminated food. The active drug (zeranol), its major human metabolites (zearalanone, 7β-zearalanol) and the mycotoxin (zearalenone) plus its major and unique metabolic products (α-zearalenol, β-zearalenol) have been monitored in routine doping controls by means of validated gas chromatography-(tandem) mass spectrometry (GC-(MS/)MS) methods since 1996, and between 2005 and 2010 four samples providing suspicious signals were detected. In agreement with literature data, in vitro metabolism studies demonstrated the metabolic pathway from zearalenone towards zeranol (and common metabolites). In contrast, an administration study urine sample (collected after oral application of 20 mg of zeranol) yielded only ultra-trace amounts of zearalenone and its characteristic metabolites, which supported the assumption that a mycotoxin contamination caused the finding of zeranol in the doping control specimens rather than a misuse of the anabolic agent.     

A high affinity ligand for GABAA-receptor containing α5 subunit antagonizes ethanol’s neurobehavioral effects in Long-Evans rats

Rationale Previously, we reported that the GABA_A receptor containing ₅ subunit played a significant role in the reinforcing actions of EtOH in rats selectively bred to consume alcohol. However, the role of the ₅ receptor in regulating the neurobehavioral effects of EtOH in outbred rats is not known.Objective In the present study, RY024, a novel benzodiazepine (BDZ) inverse agonist with high affinity (K_d~ 0.40 nM) and selectivity (~67.3-fold) for the ₅ receptor, was investigated for its capacity to antagonize EtOHs reinforcing, motor impairing, and sedative effects in Long-Evans rats.Methods Rats were trained to lever press for EtOH under a fixed-ratio 1 schedule of reinforcement. Subsequent studies evaluated EtOHs motor-impairing effects in an oscillating bar task, while EtOHs sedative effects were measured in the open field.Results RY024 (0.125–3.5 mg/kg; IP) markedly reduced EtOH-maintained responding with no effects on water responding, except for the highest dose. RY024 (3.0–15 mg/kg; IP) also reversed the motor impairing effects of a moderate (0.75 g/kg), and intoxicating EtOH dose (1.25 g/kg) in the absence of intrinsic effects. Finally, RY024 (7.5 mg/kg) attenuated the sedation produced by the 1.25 g/kg EtOH dose; however, it failed to attenuate the sedation induced by the 0.75 g/kg EtOH dose. Given alone, RY024 exhibited intrinsic effects in the open field.Conclusion The results suggest the GABA_A receptor containing ₅ subtype plays an important role in regulating the reinforcing, motor-impairing, and sedative effects of alcohol in outbred rats.     

The effects of concurrent cannabis use among ecstasy users: neuroprotective or neurotoxic?

The research evidence regarding the potential effects of ecstasy suggests that it may be neurotoxic and that its use is associated with cognitive impairment. In recent years evidence has emerged suggesting that cannabinoids, the active ingredients in cannabis, can be neuroprotective under certain conditions. Given that many ecstasy users also consume cannabis at the same time, the possibility emerges that these individuals might be less susceptible to ecstasy-related impairment. The present paper reanalyses the data from a number of previous studies, contrasting the performance of those individuals who generally consume cannabis and ecstasy at the same time with those who generally consume ecstasy on its own. The two ecstasy-using groups are compared with non-ecstasy users on a range of measures including processing speed, random letter generation, verbal and visuo-spatial working memory span, reasoning and associative learning. The two ecstasy user groups did not differ significantly from each other on any of the measures. Both user groups were significantly worse than non-ecstasy users on measures of associative learning, verbal and visuo-spatial working memory and reasoning. The results suggest that consuming cannabis at the same time as ecstasy does not reduce the likelihood of cognitive impairment.     

Idiopathic intracranial hypertension and oxaliplatin: a causal association?

We report a case of a 54-year-old woman presented at the emergency service with complaints of transitory visual obscurations for four days, and headache, nausea and occasional vomiting in the last two months. She had been diagnosed of colorectal cancer one year ago and she was on treatment with oxaliplatin on a FOLFOX schedule. On ophthalmic examination, the vision was of 20/20 in both eyes and bilateral disc swelling was noted. The neurologic examination was normal. Magnetic resonance revealed no changes. A diagnostic lumbar puncture demonstrated an elevated opening pressure of 290?mm H₂O with normal compounds. Due to the suspicion of ocular toxicity, oxaliplatin treatment was stopped. Treatment with oral acetazolamide was started and maintained for one month. In three weeks ocular and systemic symptoms totally disappeared and disc swelling gradually improved in the following months. Ocular toxicity has been reported as an infrequent adverse effect of oxaliplatin, but intracranial idiopathic pressure has not yet been described. Findings in this case suggest that oxaliplatin could be the cause for these symptoms. As the use of oxaliplatin is increasing as first-line treatment in colorectal cancer, we have to be alert to its potential toxicity.