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Neuroinflammation, a key early pathomechanistic alteration of Alzheimer’s disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a longitudinal study in a monocentric cohort of cognitively healthy individuals at risk for Alzheimer’s disease exploring whether age, sex, and the apolipoprotein E e4 allele affect plasma YKL-40 concentrations. We investigated whether YKL-40 is associated with brain amyloid-β (Aβ) deposition, neuronal activity, and neurodegeneration as assessed via neuroimaging biomarkers. Finally, we investigated whether YKL-40 may predict cognitive performance. We found an age-associated increase of YKL-40 and observed that men display higher concentrations than women, indicating a potential sexual dimorphism. Moreover, YKL-40 was positively associated with memory performance and negatively associated with brain Aβ deposition (but not with metabolic signal). Consistent with translational studies, our results suggest a potentially protective effect of glia on incipient brain Aβ accumulation and neuronal homeostasis.

Neurodegenerative diseases (ND) are among the leading causes of disability and mortality. Considerable sex differences exist in the occurrence of the various manifestations leading to cognitive decline. Alzheimer’s disease (AD) exhibits substantial sexual dimorphisms and disproportionately affects women. Women have a higher life expectancy compared to men and, consequently, have more lifespan to develop AD. The emerging precision medicine and pharmacology concepts – taking into account the individual genetic and biological variability relevant for disease risk, prevention, detection, diagnosis, and treatment – are expected to substantially enhance our knowledge and management of AD. Stratifying the affected individuals by sex and gender is an important basic step towards personalization of scientific research, drug development, and care. We hypothesize that sex and gender differences, extending from genetic to psychosocial domains, are highly relevant for the understanding of AD pathophysiology, and for the conceptualization of basic/translational research and for clinical therapy trial design.

Introduction Blood-based biomarkers of pathophysiological brain amyloid β (Aβ) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods We investigated whether plasma concentrations of the Aβ 1–40 /Aβ 1–42 ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain Aβ positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-a-priori hypothesis study using machine learning. Results The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma Aβ 1–40 /Aβ 1–42 ratio. The accuracy is not affected by the apolipoprotein E ( APOE ) e4 allele, sex, or age. Discussion Our results encourage an independent validation cohort study to confirm the indication that the plasma Aβ 1–40 /Aβ 1–42 ratio, assessed via Simoa, may improve future standard of care and clinical trial design.

Cocaine abuse has long been known to cause morbidity and mortality due to its cardiovascular toxic effects. The pathogenesis of the cardiovascular toxicity of cocaine use has been largely reviewed, and the most recent data indicate a fundamental role of oxidative stress in cocaine-induced cardiovascular toxicity, indicating that mitochondrial dysfunction is involved in the mechanisms of oxidative stress. The comprehension of the mechanisms involving mitochondrial dysfunction could help in selecting the most appropriate mitochondria injury biological marker, such as superoxide dismutase-2 activity and glutathionylated hemoglobin. The potential use of modulators of oxidative stress (mitoubiquinone, the short-chain quinone idebenone, and allopurinol) in the treatment of cocaine cardiotoxic effects is also suggested to promote further investigations on these potential mitochondria-targeted antioxidant strategies.

Several data gathered in the last decade indicate an increase of abuse of prescription opioid drugs oxycodone (OXY) and hydrocodone (HYDRO) in women. However, to date there are no conclusive evidences investigating the gender-dependent abuse liability of prescription opioids. This study aims to supply a specific focus on women's data through a selective summary of the literature analyzing gender differences in the pharmacokinetic and pharmacodynamic dimension of OXY and HYDRO. Findings from this study suggest that the majority of OXY and HYDRO pharmacokinetic and pharmacodynamic effects do not differ according to gender, though confirming a significant difference in the incidence of adverse effects as demonstrated by the increased gastrointestinal adverse reactions in female subjects. Although the majority of recent clinical studies include an equal number of female and male subjects, the main outcome parameters do not relate specifically to gender differences. Due to the gender influence in activity of CYP3A4 and its crucial role in metabolism of both OXY than HYDRO, we suggest that assessing pharmacokinetic and pharmacodynamic interactions in clinical studies may be useful to clarify the effect of the higher CYP3A4 activity in female in relation to CYP2D6 genotype. Overall, considering the paucity of data regarding gender differences in European Union, this work highlights that impact of new abuse deterrent formulations should be assessed with a special focus on data concerning female subjects.

Khat chewing is deeply rooted in the every day life of people living in the Horn of Africa and in South Arabia, where Catha edulis is endemic. Considered little more than an exotic habit producing just mild pharmacological effects, systematic investigations on its active principles have instead lead to the isolation and chemical characterization of cathinone, a compound structurally related to amphetamine. Three decades of intense experimental and clinical research on khat have depicted a consistently clear picture of its pharmacological and toxicological effects.

Gender-related differences in the pharmacological effects of drug are an emerging topic. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of methadone, a long-acting opioid agonist that is prescribed as a treatment for opioid dependence and the management of chronic pain. Method: We performed a search in the Medline database from 1990 to 2014 in order to find published literature related to gender differences in pharmacokinetics (PK) and pharmacodynamics (PD) of methadone. Results: None of the studies were carried out with the primary or secondary aim to identify any gender differences in the pharmacokinetic profile of methadone. Importantly; high inter-subjects variability in PK parameters was found also intra female population. The reported differences in volume of distribution could be ascribed to the physiological differences between men and women in body weight and composition, taking into account that the dose of methadone was established irrespective of body weight of patients (Peles and Adelson, 2006). On the other hand, the few studies present in literature found no gender difference in some direct pharmacodynamic parameters. Some reports have suggested that female gender is associated with an increased risk for long-QT-related cardiac arrhythmias in methadone maintenance subjects. Conclusion: Even though it may be too simplistic to expect variability only in one parameter to explain inter-individual variation in methadone response, we believe that a better knowledge of gender-related differences might have significant implications for better outcomes in opioid dependence substitution therapy in women.

Over the last few years, several studies have described an increase in the use of anabolic-androgenic steroids (AAS). More important, frequency of AAS use was significantly associated with frequency of psychotropic drug use, such as cocaine. Since information is not available on the effects of their concomitant abuse, and taking into account that cocaine and testosterone, when singly abused, are known to induce severe adverse effects on vascular system, our purpose was to evaluate in vitro the combined effect of these drugs on platelet and endothelial functions. Results show that testosterone, at concentrations not exerting any appreciably acute effects on their own, is capable of potentiating the cocaine effect on endothelial and platelet functions, indicating that concomitant use of testosterone and cocaine could result in enhancement of the thrombotic risk ascribed to these drugs.

CHF5074 is a non-steroidal anti-inflammatory derivative holding disease-modifying potential for the treatment of Alzheimer's disease. The aim of the present study was to characterize the electrophysiological and metabolic profile of CHF5074 in the hippocampus. Electrophysiological recordings show that CHF5074 inhibits in a dose-dependent manner the current-evoked repetitive firing discharge in CA1 pyramidal neurons. This result is paralleled by a dose-dependent reduction of field excitatory post-synaptic potentials with no effect on the paired-pulse ratio. The effects of CHF5074 were not mediated by AMPA or NMDA receptors, since the inward currents induced by local applications of AMPA and NMDA remained constant in the presence of this compound. We also suggest a possible activity of CHF5074 on ASIC1a receptor since ASIC1a-mediated current, evoked by application of a pH 5.5 solution, is reduced by pretreatment with this compound. Moreover, we demonstrate that CHF5074 treatment is able to counteract in hippocampal slices the OGD-induced increase in alanine, lactate and acetate levels. Finally, CHF5074 significantly reduced the apoptosis in hippocampal neurons exposed to OGD, as revealed by cleaved-caspase-3 immunoreactivity and TUNEL staining. Overall, the present work identifies novel mechanisms for CHF5074 in reducing metabolic acidosis, rendering this compound potentially useful also in conditions of brain ischemia.

Aims Gender-related differences in the pharmacological effects of addictive drug are an emerging issue. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of alcohol and cocaine intake since they cause complex pharmacological interactions, not least the formation of the active metabolite cocaethylene. Methods The MEDLINE database was searched from 1990 to 2014 in order to find articles related to gender differences in alcohol, cocaine and cocaethylene pharmacokinetics and pharmacodynamics. Results Besides the well known gender differences in alcohol pharmacokinetics, women appear more susceptible to alcohol-mediated brain damage and seem to suffer more than men the acute effects of alcohol on hepatic and gonadal hormones. No significant gender differences have been found in the pharmacokinetics of cocaine taken alone; yet, in women pharmacological sensitivity to the drug seems to vary in relation to menstrual cycle; moreover, progesterone attenuates subjective effects of cocaine in women. Higher ratings at a subjective measure of mental/physical well-being have been observed in women when given cocaine and alcohol, alone or in combination. Finally, among subjects dependent on both alcohol and cocaine, men only benefit from naltrexone, whereas women used more cocaine during the trial and were less compliant to therapy than men. Conclusions The observed subtle gender differences in the pharmacokinetics and pharmacodynamics of both alcohol and cocaine may have no subtle influence on the natural history of the co-abuse of the two drugs by women.

Effects of cocaine on vascular endothelium relaxing properties and the related mechanism were investigated in vitro in rabbit aorta. Several vasorelaxing agents with different mechanisms, i.e. acetylcholine, substance P, calcium ionophore A23187, 2,5-di-tert-butylhydroquinone, or sodium nitroprusside, were employed. Cocaine effects on the vascular response to relaxing agents in cumulative (acetylcholine, substance P, or A23187) or single dose (2,5-di-tert-butyl-hydroquinone) were performed in endothelium-intact aortic rings precontracted with phenylephrine. Relaxing activity of cumulative doses of sodium nitroprusside was evaluated in endothelium-denuded aortic rings, in the presence of cocaine. Cocaine significantly reduced endothelium-dependent relaxations induced by acetylcholine, or substance P. By contrast A23187 endothelium-mediated relaxation as well as endothelium-independent relaxation by sodium nitroprusside were unaffected by cocaine. Furthermore, cocaine significantly increased endothelium-dependent relaxation response to 2,5-di-tert-butylhydroquinone, a sarcoplasmic Ca2+-ATPase pump inhibitor, in the aortic rings. These findings indicate that cocaine reduces nitric oxide release from vascular endothelium apparently through the inhibiting action of Ca2+-ATPase pump.

In a previous study, we found that the kappa opioid agonist U50,488H (U50) suppresses both appetitive and consummatory components of drinking behavior in rats trained to negotiate water in a straight runway. U50 also activates diuresis. Kappa opioid mechanisms could therefore play a dissipative role in the body's water balance. Since naloxone inhibits diuresis, but not hypodipsia produced by U50, these effects are probably mediated also by nonopioid mechanisms. In rats trained to negotiate water in a straight runway, we have studied the influence on the hypodipsic effects of U50 of the selective alpha-1 adrenoceptor antagonist dapiprazol (DAP), which we found to inhibit U50-mediated diuresis. When given alone, DAP (3 and 6 mg/kg IP) influenced neither running for water nor water intake; neither did it prevent the suppression of water intake produced by U50 (8 mg/kg IP) across the test. However, it did antagonize the U50-mediated slowing of running for water. Alpha-1 adrenoceptors thus appear to play a role in U50's effects on diuresis and the appetitive, but not consummatory, aspects of drinking.

Background Liver metabolism of morphine leads to the formation of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), the latter possessing strong opioid activity that however differs from that of the parent compound. In previous studies conducted in rats we have shown that repeated in vivo exposure to phenanthrene class of mu opioid receptor (MOR) agonists or antagonists (heroin, morphine, and naltrexone), but not to non-phenanthrene class of MOR agonist methadone, affects morphine glucuronidation by liver microsomes. Methods In the present study, we measured the in vitro formation of M3G and M6G by rat hepatocytes incubated for 120 min with morphine (0.1–1.0 mM) after 72 h pre-incubation with one of the following MOR agonists: heroin (3.3 or 6.6 μM), morphine (7.8 μM), or methadone (12 μM). The MOR antagonist naltrexone (10 or 25 μM) was also tested, alone or in combination with heroin. The amount of M3G and M6G synthesized was then measured by HPLC method. Results Heroin inhibited M3G synthesis and induced the formation of M6G, which under basal conditions is not synthesized in rats. Heroin effects were not blocked by naltrexone. Morphine, but not methadone, produced effects similar to those of heroin but more modest in intensity. Pre-incubation with naltrexone alone slightly increased M3G synthesis, but had no effect on M6G formation. Conclusions These results are in agreement with those of previous ex vivo studies and indicate that exposure to heroin or, to a lesser extent, morphine, can affect morphine glucuronidation via direct non-opioid actions on the hepatocytes.

We present data here indicating that stimulation of kappa but not mu opiate receptors influences motivational and consummatory aspects of feeding and drinking. To differentiate mu and kappa mechanisms controlling preparatory (appetitive) and consummatory components of ingestive behavior, the effects of morphine (MORPH), compound U50488H (U50) and naloxone (NAL) were studied in rats trained to negotiate a straight runway using food or water as reinforcer. At doses that increase feeding and drinking in conditions of free access to food and water (i.e., 1–2 mg/kg IP), MORPH affected neither food- nor water-maintained runway performance. Since 1 mg/kg of NAL is also devoid of effects, mu-opiate mechanisms are probably not involved in food- or water-maintained behavior. Pharmacological manipulation of kappa-opiate mechanisms had complex effects. At 5 mg/kg, NAL accelerated satiation, depressing food intake, without affecting running. U50 did not increase food intake, but accelerated running for food, an effect that was antagonized by a high dose of NAL (5 mg/kg). These findings suggest that motivational and consummatory components of food-maintained runway performance are both activated by kappa-opiate mechanisms. NAL also reduced water intake but had minimal influences on running. In contrast, U50 depressed both water intake and runway performance; rather than being antagonized, these effects were slightly enhanced by NAL. The combined antidipsic and diuretic effects of U50 suggest that kappa-opiate mechanisms play a dissipatory role in water balance. However, the similar antidipsic effects of U50 and NAL, and the fact that NAL did not antagonize the antidipsic effects of U50, suggest that U50 may reduce drinking by mechanisms other than kappa-opiate agonism.

The aim of the present study was to evaluate the ability of the calcium channel blocker (CCE), nimodipine (NIM), to interact with (±)-amphetamine (AMPH) in modifying ingestive behavior. Rats performed in a water-reinforced runway paradigm with multiple trials. Water was available in sufficient quantity to produce satiety under control conditions as measured by a decline in response rate over the session. NIM and AMPH, given alone, did not produce significant effects on performance but produced behavioral changes when administered in combination. In particular, the combination of the highest doses (13 mg/kg i.p. NIM plus 0.56 mg/kg i.p. AMPH) initially depressed both running and drinking, whereas in later trials it increased running rate, without producing a parallel increase in water intake. These results suggest that NIM enhances AMPH-produced inhibition of drinking, whereas it first depresses and then enhances the AMPH-mediated runway performance, suggesting the rate dependency of this latter effect.