Pharmacological and non-pharmacological strategies for obese women with subfertility.

BACKGROUND: Clinicians primarily recommend weight loss for obese women seeking pregnancy. The effectiveness of interventions aimed at weight loss in obese women with subfertility is unclear. OBJECTIVES: To assess the effectiveness and safety of pharmacological and non-pharmacological strategies compared with each other, placebo, or no treatment for achieving weight loss in obese women with subfertility. SEARCH METHODS: We searched the CGF Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and AMED from inception to 18 August 2020. We also checked reference lists and contacted experts in the field for additional relevant papers. SELECTION CRITERIA: We included published and unpublished randomised controlled trials in which weight loss was the main goal of the intervention. Our primary effectiveness outcomes were live birth or ongoing pregnancy and primary safety outcomes were miscarriage and adverse events. Secondary outcomes included clinical pregnancy, weight change, quality of life, and mental health outcome. DATA COLLECTION AND ANALYSIS: Review authors followed standard Cochrane methodology. MAIN RESULTS: This review includes 10 trials. Evidence was of very low to low quality: the main limitations were due to lack of studies and poor reporting of study methods. The main reasons for downgrading evidence were lack of details by which to judge risk of bias (randomisation and allocation concealment), lack of blinding, and imprecision. Non-pharmacological intervention versus no intervention or placebo Evidence is insufficient to determine whether a diet or lifestyle intervention compared to no intervention affects live birth (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.65 to 1.11; 918 women, 3 studies; I² = 78%; low-quality evidence). This suggests that if the chance of live birth following no intervention is assumed to be 43%, the chance following diet or lifestyle changes would be 33% to 46%. We are uncertain if lifestyle change compared with no intervention affects miscarriage rate (OR 1.54, 95% CI 0.99 to 2.39; 917 women, 3 studies; I² = 0%; very low-quality evidence). Evidence is insufficient to determine whether lifestyle change compared with no intervention affects clinical pregnancy (OR 1.06, 95% CI 0.81 to 1.40; 917 women, 3 studies; I² = 73%; low-quality evidence). Lifestyle intervention resulted in a decrease in body mass index (BMI), but data were not pooled due to heterogeneity in effect (mean difference (MD) -3.70, 95% CI -4.10 to -3.30; 305 women, 1 study; low-quality evidence; and MD -1.80, 95% CI -2.67 to -0.93; 43 women, 1 study; very low-quality evidence). Non-pharmacological versus non-pharmacological intervention We are uncertain whether intensive weight loss interventions compared to standard care nutrition counselling affects live birth (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low-quality evidence), clinical pregnancy (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low-quality evidence), BMI (MD -3.00, 95% CI -5.37 to -0.63; 11 women, 1 study; very low-quality evidence), weight change (MD -9.00, 95% CI -15.50 to -2.50; 11 women, 1 study; very low-quality evidence), quality of life (MD 0.06, 95% CI -0.03 to 0.15; 11 women, 1 study; very low-quality evidence), or mental health (MD -7.00, 95% CI -13.92 to -0.08; 11 women, 1 study; very low-quality evidence). No study reported on adverse events . Pharmacological versus pharmacological intervention For metformin plus liraglutide compared to metformin we are uncertain of an effect on the adverse events nausea (OR 7.22, 95% CI 0.72 to 72.7; 28 women, 1 study; very low-quality evidence), diarrhoea (OR 0.31, 95% CI 0.01 to 8.3; 28 women, 1 study; very low-quality evidence), and headache (OR 5.80, 95% CI 0.25 to 133; 28 women, 1 study; very low-quality evidence). We are uncertain if a combination of metformin plus liraglutide vs metformin affects BMI (MD 2.1, 95% CI -0.42 to 2.62; 28 women, 1 study; very low-quality evidence) and total body fat (MD -0.50, 95% CI -4.65 to 3.65; 28 women, 1 study; very low-quality evidence). For metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo, we are uncertain of an effect on miscarriage (OR 3.58, 95% CI 0.73 to 17.55; 274 women, 1 study; very low-quality evidence), clinical pregnancy (OR 5.56, 95% CI 2.57 to 12.02; 274 women, 1 study; very low-quality evidence) or BMI (MD -0.3, 95% CI 1.17 to 0.57, 274 women, 1 study, very low-quality evidence). We are uncertain if dexfenfluramine versus placebo affects weight loss in kilograms (MD -0.10, 95% CI -2.77 to 2.57; 21 women, 1 study; very low-quality evidence). No study reported on live birth, quality of life, or mental health outcomes. Pharmacological intervention versus no intervention or placebo We are uncertain if metformin compared with placebo affects live birth (OR 1.57, 95% CI 0.44 to 5.57; 65 women, 1 study; very low-quality evidence). This suggests that if the chance of live birth following placebo is assumed to be 15%, the chance following metformin would be 7% to 50%. We are uncertain if metformin compared with placebo affects gastrointestinal adverse events (OR 0.91, 95% CI 0.32 to 2.57; 65 women, 1 study; very low-quality evidence) or miscarriage (OR 0.50, 95% CI 0.04 to 5.80; 65 women, 1 study; very low-quality evidence) or clinical pregnancy (OR 2.67, 95% CI 0.90 to 7.93; 96 women, 2 studies; I² = 48%; very low-quality evidence). We are also uncertain if diet combined with metformin versus diet and placebo affects BMI (MD -0.30, 95% CI -2.16 to 1.56; 143 women, 1 study; very low-quality evidence) or waist-to-hip ratio (WHR) (MD 2.00, 95% CI -2.21 to 6.21; 143 women, 1 study; very low-quality evidence). Pharmacological versus non-pharmacological intervention No study undertook this comparison. AUTHORS' CONCLUSIONS: Evidence is insufficient to support the use of pharmacological and non-pharmacological strategies for obese women with subfertility. No data are available for the comparison of pharmacological versus non-pharmacological strategies. We are uncertain whether pharmacological or non-pharmacological strategies effect live birth, ongoing pregnancy, adverse events, clinical pregnancy, quality of life, or mental heath outcomes. However, for obese women with subfertility, a lifestyle intervention may reduce BMI. Future studies should compare a combination of pharmacological and lifestyle interventions for obese women with subfertility.

Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling.

Several clinical reports indicate that the use of amphetaminic anorectic drugs or ergot derivatives could cause valvular heart disease (VHD). We sought to investigate whether valvular lesions develop in response to long-term oral administration of these drugs and to identify drug-targeted biological processes that may lead to VHD. Treatment of New Zealand White rabbits with pergolide, dexfenfluramine, or high-dose serotonin for 16 weeks induced valvular alterations characterized by extracellular matrix remodeling. Transcriptome profiling of tricuspid valves using RNA sequencing revealed distinct patterns of differentially expressed genes (DEGs) that clustered according to the different treatments. Genes that were affected by the three treatments were functionally enriched for reduced cell metabolism processes. The two drugs yielded more changes in gene expression than serotonin and shared most of the DEGs. These DEGs were mostly enriched for decreased biosynthetic processes, increased cell-matrix interaction, and cell response to growth factors, including TGF-ß, which was associated with p38 MAPK activation. Treatment with pergolide specifically affected genes involved in homeostasis, which was corroborated by the activation of the master regulator of cell energy homeostasis, AMPK-α, as well as decreased levels of metabolism-related miR-107. Thus, both pergolide and dexfenfluramine may cause VHD through valve metabolic reprogramming and matrix remodeling.

Hypothalamic neuropeptide Y (NPY) gene expression is not affected by central serotonin in the rainbow trout (Oncorhynchus mykiss).

Mammalian studies have shown a link between serotonin (5-HT) and neuropeptide Y (NPY) in the acute regulation of feeding and energy homeostasis. Taking into account that the actions of 5-HT and NPY on food intake in fish are similar to those observed in mammals, the objective of this study was to characterize a possible short-term interaction between hypothalamic 5-HT and NPY, by examining whether 5-HT regulates NPY gene expression, to help clarify the mechanism underlying the observed anorexigenic action of central 5-HT in the rainbow trout. We used qRT-PCR to determine the levels of NPY mRNA in the hypothalamus-preoptic area (HPA) of rainbow trout after intraperitoneal (i.p.) injection of a single dose of dexfenfluramine (dFF, 3mgkg(-1); 24h-fasted and fed fish) or intracerebroventricular (i.c.v.) administration of 5-HT (100µgkg(-1); 24h-fasted fish). Significant suppression of food intake was observed after administration of 5-HT and dFF. No significant changes in NPY gene expression were obtained 150min after administration of 5-HT or dFF. However, administration of the 5HT1B receptor agonist anpirtoline did not have any significant effect on food intake in rainbow trout. The results suggest that in fish, unlike in mammals, neither the NPY neurons of the HPA nor the 5-HT1B receptor subtype participate in the neural circuitry involved in the inhibition of food intake induced by central serotoninergic activation.

Assessment of serotonin release capacity in the human brain using dexfenfluramine challenge and [18F]altanserin positron emission tomography.

Although alterations of serotonin (5-HT) system functioning have been proposed for a variety of psychiatric disorders, a direct method quantitatively assessing 5-HT release capacity in the living human brain is still lacking. Therefore, we evaluated a novel method to assess 5-HT release capacity in vivo using dexfenfluramine challenge and [(18)F]altanserin positron emission tomography (PET). Thirteen healthy male subjects received placebo and single oral doses of 40 mg (n = 6) or 60 mg (n = 7) of the potent 5-HT releaser dexfenfluramine separated by an interval of 14 days. Three further subjects received placebo on both days. Two hours after placebo/drug administration, 250 MBq of the 5-HT(2A) receptor selective PET-radiotracer [(18)F]altanserin was administered intravenously as a 30s bolus. Dynamic PET data were subsequently acquired over 90 min. Moreover, arterial blood samples were drawn for measurement of total activity and metabolite correction of the input function. Dexfenfluramine as well as cortisol and prolactin plasma concentration-time profiles was quantitatively determined. Tracer distribution volumes for five volumes-of-interest (prefrontal and occipital cortex, insula, thalamus, caudatum) were calculated by the Logan plot and a 2-tissue compartment model. Dexfenfluramine dose-dependently decreased the total distribution volume of [(18)F]altanserin in cortical regions independent of the PET modeling approach. Cortisol and prolactin plasma concentrations were dose-dependently increased by dexfenfluramine. The decrease in cortical [(18)F]altanserin receptor binding under dexfenfluramine was correlated with the increase of plasma prolactin. These data suggest that the combination of a dexfenfluramine-induced 5-HT release and subsequent assessment of 5-HT(2A) receptor availability with [(18)F]altanserin PET is suitable to measure cortical 5-HT release capacity in the human brain.

O2 reduction by a functional heme/nonheme bis-iron NOR model complex.

O(2) reactivity of a functional NOR model is investigated by using electrochemistry and spectroscopy. The electrochemical measurements using interdigitated electrodes show very high selectivity for 4e O(2) reduction with minimal production of partially reduced oxygen species (PROS) under both fast and slow electron flux. Intermediates trapped at cryogenic temperatures and characterized by using resonance Raman spectroscopy under single-turnover conditions indicate that an initial bridging peroxide intermediate undergoes homolytic O--O bond cleavage generating a trans heme/nonheme bis-ferryl intermediate. This bis ferryl species can oxygenate 2 equivalents of a reactive substrate.

[The pharmacological treatment of obesity: past, present and future]. / Az elhízás gyógyszeres kezelése: múlt, jelen, jövo

Currently, obesity presents one of the biggest health problems. Management strategies for weight reduction in obese individuals include changes in life style such as exercise and diet, behavioral therapy, and pharmacological treatment, and in certain cases surgical intervention. Diet and exercise are best for both prevention and treatment, but both require much discipline and are difficult to maintain. Drug treatment of obesity offer a possible adjunct, but it may only have modest results, limited by side effects; furthermore, the weight lowering effects last only as long as the drug is being taken and, unfortunately, as soon as the administration is stopped, the weight is regained. These strategies should be used in a combination for higher efficacy. Drugs used to induce weight loss have various effects: they increase satiety, reduce the absorption of nutrients or make metabolism faster; but their effect is usually moderate. In the past, several drugs were used in the pharmacological therapy of weight reduction including thyroid hormone, dinitrophenol, amphetamines and their analogues, e.g. fenfluramine, At present, only orlistat is available in the long term treatment (≥ 24 weeks) of obesity as sibutramine and rimonabant were withdrawn form the market. Several new anti-obesity drugs are being tested at present, and liraglutide, a GLP-1 analogue (incretin mimetic), is the most promising one.

Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension.

Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT(2B)) receptor agonist. Thus, we investigated the contribution of the 5-HT(2B)receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT(2B)receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT(2B) receptor expression in pulmonary arteries. These data show that activation of 5-HT(2B) receptors is a limiting step in the development of pulmonary hypertension.

Drug-induced fibrotic valvular heart disease.

The initial association between the development of valvular heart disease and drugs stems from observations made during the use of methysergide and ergotamine for migraine prophylaxis in the 1960s. Since then, the appetite suppressants fenfluramine and dexfenfluramine, the dopamine agonists pergolide and cabergoline, and more recently, the recreational drug ecstasy (3,4 methylenedioxymethamphetamine; MDMA) have been implicated. Results from clinical trials show that drug dose and treatment duration affect both the risk of developing the disease and its severity. The natural history of the disease remains unclear, although regression of valvular lesions after the end of treatment has been reported. Interference with serotonin metabolism and its associated receptors and transporter gene seems a likely mechanism for development of the drug-induced valvular heart disease. Physicians need to balance the benefits of continued therapy with these drugs against possible risks. Further investigation is needed to assist with treatment decisions. Continued vigilance is necessary because several commonly prescribed treatments interact with serotonergic pathways.

The serotonin hypothesis of pulmonary hypertension revisited.

The serotonin hypothesis of pulmonary arterial hypertension (PAH) arose after an outbreak of PAH in patients taking the anorexigenic drugs aminorex and dexfenfluramine. Both of these drugs are serotonin transporter (SERT) substrates and indirect serotinergic agonists. There is now a wealth of evidence to support a role for serotonin in the pathobiology of PAH. Synthesis of serotonin can occur in pulmonary artery endothelial cells by the enzyme tryptophan hydroxylase 1 (TPH1). Serotonin then acts at the 5-HT(1B) receptor and the SERT to mediate constriction and proliferation of pulmonary artery smooth muscle cells. Downstream signalling molecules which play a role in serotonin-induced constriction and proliferation include reactive oxygen species (ROS), Rho-kinase (ROCK) p38 and extracellular signal-regulated kinase (ERK). There is also evidence to suggest that serotonin may interact with the bone morphogenetic receptor type II (BMPRII) to provide a 'second hit' risk factor for PAH.

Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice.

BACKGROUND: The incidence of pulmonary arterial hypertension secondary to the use of indirect serotinergic agonists such as aminorex and dexfenfluramine led to the "serotonin hypothesis" of pulmonary arterial hypertension; however, the role of serotonin in dexfenfluramine-induced pulmonary arterial hypertension remains controversial. Here, we used novel transgenic mice lacking peripheral serotonin (deficient in tryptophan hydroxylase-1; Tph1(-/-) mice) or overexpressing the gene for the human serotonin transporter (SERT; SERT(+) mice) to investigate this further. METHODS AND RESULTS: Dexfenfluramine administration (5 mg x kg(-1) x d(-1) PO for 28 days) increased systolic right ventricular pressure and pulmonary vascular remodeling in wild-type mice but not in Tph1(-/-) mice, which suggests that dexfenfluramine-induced pulmonary arterial hypertension is dependent on serotonin synthesis. Dexfenfluramine was also administered to normoxic SERT(+) mice and SERT(+) mice exposed to chronic hypoxia. Dexfenfluramine and SERT overexpression had additive effects in increasing pulmonary vascular remodeling; however, in hypoxic SERT(+) mice, dexfenfluramine reduced both systolic right ventricular pressure and pulmonary vascular remodeling. Pulmonary arterial fibroblasts from SERT(+) mice, but not wild-type mice, proliferated in response to hypoxia. Dexfenfluramine inhibited hypoxia-induced proliferation of pulmonary arterial fibroblasts derived from SERT(+) mice in a manner dependent on SERT activity. Dexfenfluramine also inhibited the hypoxia-mediated increase in phosphorylation of p38 mitogen-activated protein kinase in SERT(+) pulmonary arterial fibroblasts. CONCLUSIONS: The results suggest that peripheral serotonin is critical for the development of dexfenfluramine-induced pulmonary arterial hypertension and that dexfenfluramine and SERT overexpression have additive effects on pulmonary vascular remodeling. We propose that dexfenfluramine can also inhibit hypoxia-induced pulmonary vascular remodeling via SERT activity and inhibition of hypoxia-induced p38 mitogen-activated protein kinase.

A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine.

RATIONALE: Procedures for studying the effects of medications on satiation will assist the development of obesity medications. OBJECTIVES: Develop a procedure for measuring satiation during consumption of bland and highly palatable food and determine the effect of acute intramuscular administration of dexfenfluramine (DFEN), which increases serotonin levels, and memantine (MEM), which blocks N-methyl-D: -aspartate receptors. MATERIALS AND METHODS: A modified progressive ratio (PR) procedure was used to track changes in reinforcing strength when a food was consumed. The response requirement increased after each reinforcement, and reinforcing strength was estimated using the breakpoint (BP), which was the last completed response cost. There was one preferred food (sweet candy) and one chow pellet PR session per week. During each session, four male and four female adult baboons experienced three 1-h PR trials, separated by 30 min. Chow pellets were available at all other times. We examined the BP for one to 20 candies or chow pellets. Drug effects were examined when baboons had access to one and ten candies or chow pellets. RESULTS: BPs for candy were greater than for pellets. Varying the pellet/candy pieces per delivery produced an inverted U-shaped function on the first trial, i.e., maximal BP was observed for three items, and the BP for multiple items, but not a single item, decreased across trials, i.e., BP decreased with food intake and satiation. DFEN and MEM decreased responding with the greatest effects at ten deliveries, suggesting that DFEN and MEM enhanced satiation. CONCLUSION: Drugs that enhance satiation for several types of food may be particularly effective for decreasing food intake.

Characterization of a novel and selective cannabinoid CB1 receptor inverse agonist, Imidazole 24b, in rodents.

We document in vitro and in vivo effects of a novel, selective cannabinoid CB(1) receptor inverse agonist, Imidazole 24b (5-(4-chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)-1-methyl-imidazole-2-carboxamide). The in vitro binding affinity of Imidazole 24b for recombinant human and rat CB(1) receptor is 4 and 10 nM, respectively. Imidazole 24b binds to human cannabinoid CB(2) receptor with an affinity of 297 nM; in vitro, it is a receptor inverse agonist at both cannabinoid CB(1) and CB(2) receptors as it causes a further increase of forskolin-induced cAMP increase. Oral administration of Imidazole 24b blocked CP-55940-induced hypothermia, demonstrating cannabinoid CB(1) receptor antagonist efficacy in vivo. Using ex vivo autoradiography, Imidazole 24b resulted in dose-dependent increases in brain cannabinoid CB(1) receptor occupancy (RO) at 2h post-dosing in rats, indicating that approximately 50% receptor occupancy is sufficient for attenuation of receptor agonist-induced hypothermia. Imidazole 24b administered to C57Bl/6 mice and to dietary-induced obese (DIO) Sprague-Dawley rats attenuated overnight food intake with a minimal effective dose of 10 mg/kg, p.o. Administration had no effect in cannabinoid CB(1) receptor-deficient mice. DIO rats were dosed orally with vehicle, Imidazole 24b (1, 3 or 10 mg/kg), or dexfenfluramine (3 mg/kg) for 2 weeks. At 3 mg/kg, Imidazole 24b reduced cumulative food intake, leading to a non-significant decrease in weight gain. Imidazole 24b at 10 mg/kg and dexfenfluramine treatment inhibited food intake and attenuated weight gain. These findings suggest that selective cannabinoid CB(1) receptor inverse agonists such as Imidazole 24b have potential for the treatment of obesity.

Antagonism of glutamatergic NMDA and mGluR5 receptors decreases consumption of food in baboon model of binge-eating disorder.

Excessive consumption of highly palatable foods may contribute to the development of weight gain. Therefore medications that selectively suppress eating of such foods would be useful in clinical practice. We compared the effects of the glutamatergic antagonists memantine and MTEP to dexfenfluramine in baboons given periodic access to highly palatable food and ad libitum access to a standard chow diet. Three days a week baboons received a sugar-coated candy during the first meal and standard standard-diet chow pellets were available in subsequent meals. All baboons derived a greater amount of energy from the single single-candy meal than from the standard diet across an entire day. Pre-treatment with dexfenfluramine, memantine, and MTEP produced decreases in candy consumption without altering candy-seeking behaviour. At the same time, dexfenfluramine and memantine, but not MTEP, produced a decrease in seeking and consumption of standard chow pellets. Both memantine and MTEP are promising agents for the treatment of obesity.

Effects of acute administration of phentermine, alone or in combination with dexfenfluramine, on pain reactivity in the adult rat.

In the 1990s, phentermine was combined with either fenfluramine or its active enantiomer dexfenfluramine to promote weight loss. Appetite suppressants are known to alter pain reactivity. The current experiment examined the acute impact of phentermine (0, 2.5, 5, 10, or 20 mg/kg) on paw-lick/jump latencies recorded just before and at 10, 20, and 30 min after phentermine injection. In addition, separate groups of rats were treated with 1, 2, or 4 mg/kg dexfenfluramine or with selected combinations of phentermine with dexfenfluramine. Phentermine induced significant analgesia in rats at a dose of 2.5 mg/kg, whereas only the 4.0 mg/kg dose of dexfenfluramine induced significant analgesia. Combinations of 1 mg/kg dexfenfluramine or 2 mg/kg dexfenfluramine with phentermine were mostly additive in terms of changes in analgesia scores. The present results characterize the analgesic action of phentermine, further confirm the analgesic action of dexfenfluramine and suggest an additive analgesic effect for the combination of dexfenfluramine with phentermine.

[Hydrogen sulfide (H2S), an endogenous gas with odor of rotten eggs might be a cardiovascular function regulator]. / Le sulfure d'hydrogène (H2S), un gaz endogène à l'odeur d'oeuf pourri, pourrait être un régulateur des fonctions cardiovasculaires.

A novel concept of "gasotransmitter" arrived recently. They are small molecules of endogenous gases. Hydrogene sulfide (H2S) is qualified as the third gasotransmitter beside nitric oxide (NO) and carbon monoxide (CO). The physiological functions of endogenous H2S are not well-known. The location of the H2S synthetizing enzymes as well as the detector of endogenous levels of H2S in the tissues suggests that the cardiovascular system is a source of H2S generation. This gas relaxes vascular smooth muscle both in vitro and in vivo probably by opening smooth K+ATP channels. Being a reducing agent, H2S may alter cellular redox status. It is able to produce thiyls free radicals: SH degrees and S degrees . The advances in H2S researchs may revolutionize many conventional doctrines in the cardiovascular area.

Sex differences in the anorexigenic effects of dexfenfluramine and amphetamine in baboons.

The anorexigenic effects of intramuscular d-amphetamine HCl (0.06-0.50 mg/kg) and dexfenfluramine HCl (0.25-2.0 mg/kg) were determined in experimentally naïve baboons. A group of 8 adult male baboons was tested prior to a group of 7 adult female baboons. A 120-min session occurred at 9:00 a.m. during which baboons could respond for food pellets. Drug was given 30 min prior to the 9:00 a.m. morning session. Beginning at 11:00 a.m., baboons had a 6-hr multiple-meal session during which they could have up to 4 food pellet meals. Food was not available overnight, but food was available for 90 min upon awakening such that drug effects were evaluated in non-food-deprived animals. Under baseline conditions baboons earned between 30 and 70 pellets during the morning session and another 175-225 pellets during the remainder of the day. Amphetamine and dexfenfluramine produced dose-dependent decreases in food pellet intake during both the morning food session and the later multiple-meal session. Whereas there were minimal sex differences in the effects of dexfenfluramine, many of the amphetamine doses produced greater decreases in pellet intake in males than females. These results are discordant with much of the rodent literature on abuse-related drug effects that generally reports greater effects of amphetamine in females than males. Additional work is needed to replicate the current findings in nonhuman primates. (PsycINFO Database Record

Nitric oxide and nitroxidative stress in Alzheimer's disease.

Nitric oxide is a signaling molecule produced by neurons and endothelial cells in the brain. NO is synthesized from L-arginine and oxygen by nitric oxide synthase: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). The endothelial NO acts as a vasorelaxant in the vasculature and as a neurotransmitter when produced by neurons (under the pathological conditions of Alzheimer's disease). NO can be scavenged in a rapid reaction with superoxide (O2-) to generate peroxynitrite (ONOO-), with a half-life of < 1 s. ONOO- is a potent oxidant and the primary component of nitroxidative stress. At high concentrations (> 100 nM), ONOO- can undergo homolytic or heterolytic cleavage to produce NO2+, NO2, and OH., highly reactive oxidative species and secondary components of nitroxidative stress. The high nitroxidative stress can initiate a cascade of redox reactions which can trigger apoptosis and evoke cytotoxic effects on neurons and endothelial cells. This article reviews the functions of NO and the potential role of NO/O2-/ONOO- induced nitroxidative stress in neuronal and endothelial degeneration observed in Alzheimer's disease.

Functions of serotonin in hypoxic pulmonary vascular remodeling.

In lung vasculature, reversible constriction of smooth muscle cells exists in response to acute decrease in oxygen levels (hypoxia). Progressive and irreversible structural remodeling that reduces blood vessel lumen takes place in response to chronic hypoxia and results in pulmonary hypertension. Several studies have shown a role of serotonin in regulating acute and chronic hypoxic responses. In this review the contribution of serotonin, its receptors and transporter in lung hypoxic responses is discussed. Hypoxic conditions modify plasma levels of serotonin, serotonin transporter activity, and expression of 5-HT1B and 5-HT2B receptors. These appear to be required for pulmonary vascular cell proliferation, which depends on the ratio between reactive oxygen species and nitric oxide. A heterozygous mutation was identified in the 5-HT2B receptor gene of a patient who developed pulmonary hypertension after fenfluramines anorexigen treatment. This C-terminus truncated 5-HT2B mutant receptor presents lower nitric oxide coupling, and higher cell proliferation capacity than the wild-type receptor. Under low oxygen tension, cells increase the transcription of specific genes via stabilization of the transcription factor hypoxia-inducible factor (HIF)-1. Factors such as angiotensin II or thrombin that can also control HIF-1 pathway contribute to pulmonary vascular remodeling. The 5-HT2B receptor via phosphatidylinositol-3 kinase/Akt activates nuclear factor-kappaB, which is involved in the regulation of HIF-1 expression. Acontrol of HIF- 1 by 5-HT2B receptors explains why expression of pulmonary vascular remodeling factors, such as endothelin-1 or transforming growth factor-beta, which is HIF-1-alpha regulated, is not modified in hypoxic 5-HT2B receptor mutant mice. Understanding the detailed mechanisms involved in lung hypoxic responses may provide general insight into pulmonary hypertension pathogenesis.

Quantitative positron emission tomography studies of the serotonin transporter in humans previously treated with the appetite suppressants fenfluramine or dexfenfluramine.

PURPOSE: The appetite suppressants fenfluramine and dexfenfluramine were widely prescribed before being withdrawn from the market in 1997. Both drugs are known to have the potential to damage brain serotonin (5-HT) axons and axon terminals in animals, including nonhuman primates. This study used quantitative positron emission tomography (PET) with [(11)C] McN5652, a serotonin transporter (SERT) ligand to determine whether humans previously exposed to fenfluramines showed reductions in SERT binding parameters. PROCEDURES: Subjects previously treated with fenfluramines for weight loss (N = 15) and age-matched controls (N = 17) underwent PET studies with [(11)C] McN5652. Global and regional distribution volumes (DVs) of [(11)C] McN5652 were compared in the two subject groups using parametric statistical analyses. RESULTS: Compared to controls, subjects previously exposed to fenfluramines had significant reductions in [(11)C]McN5652 binding in 14 of 15 regions of interest, more than four years after drug discontinuation. CONCLUSIONS: These results are the first to provide direct evidence for fenfluramine-induced 5-HT neurotoxicity in humans.

Is it possible to predict the long-term response to venlafaxine with the use of biological markers and psychophysiological methods?

INTRODUCTION: The present study investigated whether it is possible to predict the medium term response to venlafaxine using biological markers and psychophysiological methods. MATERIAL: Fourteen (14) patients aged 21-60 years suffering from Major Depression according to DSM-IV were included in the study. METHODS: The SCAN v 2.0 and the IPDE were used to assist clinical diagnosis. Patients were investigated with electrooculogram (EOG), Pattern-Reversal Visual Evoked Potentials (PR-VEPs), Dexamethasone Suppression Test (DST), D-fenfluramine Challenge Test, and brain Single Photon Emission Tomography (SPECT). Venlafaxine 150-225 mg per os daily was administered. The follow-up period was 2 years. STATISTICAL ANALYSIS: Chi-square test and ANOVA were used for the analysis of data. RESULTS: There was a lower left globus pallidus regional cerebral blood flow in patients with better response. On the contrary, chronic patients were closer to normality. DISCUSSION: The results of the current study provide preliminary evidence concerning our ability to predict response to venlafaxine and to understand its way of action.