D-578, an orally active triple monoamine reuptake inhibitor, displays antidepressant and anti-PTSD like effects in rats.

Significant unmet needs exist for development of better pharmacotherapeutic agents for major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) as the current drugs are inadequate. Our goal in this study is to investigate behavioral pharmacological characterization of a novel triple reuptake inhibitor (TRI) D-578 which exhibits nanomolar potency at all three monoamine transporters (Ki; 16.2. 16.2, 3.23 nM, and 29.6, 20.6, 6.10 nM for the rat brain and cloned human dopamine, serotonin and norepinephrine transporters, respectively) and exhibited little to no affinity for other off-target CNS receptors. In a rat forced swim test, compound D-578 upon oral administration displayed high efficacy and not stimulating in locomotor behavior. The effects of D-578 and paroxetine were next evaluated in a rat model for traumatic stress exposure - the single prolonged stress (SPS) model - which has been shown to have construct, predictive, and behavioral validity in modeling aspects of PTSD. Our results show that SPS had no effect on the acquisition of conditioned fear, but impaired extinction learning and extinction retention of fear behavior compared to sham treatment. D-578, but not paroxetine, attenuated the extinction and extinction-retention deficit induced by SPS. These findings suggest that D-578 has greater efficacy in normalizing traumatic stress-induced extinction-retention learning in a model for PTSD compared to paroxetine. Overall these results suggest that D-578, in addition to producing a robust and efficacious antidepressant effect, may attenuate maladaptive retention of fearful memories and support further testing of this agent for the pharmacotherapy of depression and PTSD.

Mecanismos responsables de la relajación neuromuscular en el tracto gastrointestinal / Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

El sistema nervioso entérico (SNE) es responsable de la génesis de los patrones motores que aseguran un correcto tránsito intestinal. Las neuronas entéricas se clasifican en aferentes, interneuronas y motoneuronas, que pueden a su vez ser excitatorias, causando contracción, o inhibitorias, provocando la relajación de la musculatura lisa. Los mecanismos de relajación muscular son claves para entender procesos fisiológicos como la relajación de los esfínteres, la acomodación gástrica o la fase descendente del reflejo peristáltico. El óxido nítrico (NO) y el ATP o una purina relacionada son los principales neurotransmisores inhibitorios. Las neuronas nitrérgicas sintetizan NO a partir del enzima nNOS. El NO difunde a través de la membrana celular uniéndose a su receptor, la guanilil ciclasa, y activando posteriormente una serie de mecanismos intracelulares que provocan finalmente una relajación muscular. El ATP actúa como neurotransmisor inhibitorio junto con el NO y el receptor de membrana purinérgico P2Y1 ha sido identificado como elemento clave para entender cómo el ATP relaja la musculatura intestinal. Aunque probablemente ningún clínico duda de la importancia del NO en la fisiopatología motora digestiva, la relevancia de la neurotransmisión purinérgica es aparentemente mucho menor puesto que el ATP no ha sido todavía asociado a una disfunción motora concreta. El objetivo de esta revisión es mostrar el funcionamiento de ambos mecanismos de relajación para poder establecer las bases fisiológicas de posibles disfunciones motoras asociadas a la alteración de la relajación intestinal (AU)

The enteric nervous system (ENS) is responsible for the genesis of motor patterns ensuring an appropriate intestinal transit. Enteric neurons are classified into afferent, interneuron, and motoneuron types, with the latter two being further categorized as excitatory or inhibitory, which cause smooth muscle contraction or inhibition, respectively. Muscle relaxation mechanisms are key for the understanding of physiological processes such as sphincter relaxation, gastric accommodation, or descending peristaltic reflex. Nitric oxide (NO) and ATP or a related purine represent the primary inhibitory neurotransmitters. Nitrergic neurons synthesize NO through nNOS enzyme activity. NO diffuses across the cell membrane to bind its receptor, namely, guanylyl cyclase, and then activates a number of intracellular mechanisms that ultimately result in muscle relaxation. ATP acts as an inhibitory neurotransmitter together with NO, and the purinergic P2Y1 membrane receptor has been identified as a key item in order to understand how ATP may relax intestinal smooth muscle. Although, probably, no clinician doubts the significance of NO in the pathophysiology of digestive motility, the relevance of purinergic neurotransmission is apparently much lower, as ATP has not been associated with any specific motor dysfunction yet. The goal of this review is to discuss the function of both relaxation mechanisms in order to establish the physiological grounds of potential motor dysfunctions arising from impaired intestinal relaxation (AU)

Triple reuptake inhibitors as potential next-generation antidepressants: a new hope?

The current therapy for depression is less than ideal with remission rates of only 25-35% and a slow onset of action with other associated side effects. The persistence of anhedonia originating from depressed dopaminergic activity is one of the most treatment-resistant symptoms of depression. Therefore, it has been hypothesized that triple reuptake inhibitors (TRIs) with potency to block dopamine reuptake in addition to serotonin and norepinephrine transporters should produce higher efficacy. The current review comprehensively describes the development of TRIs and discusses the importance of evaluation of in vivo transporter occupancy of TRIs, which should correlate with efficacy in humans.

Involvement of opioid and monoaminergic pain pathways in Aegle marmelos induced analgesia in mice.

OBJECTIVE: To study analgesic activity and to evaluate the involvement of opioid and monoamines in the antinociceptive activity of methanol extract of leaves of Aegle marmelos. MATERIALS AND METHODS: Analgesic activity of methanol extract (ME) of A. marmelos alone (75,150 and 300 mg/kg orally) and in combination with morphine or venlafaxine (subanalgesic) were studied using tail flick test and acetic acid-induced writhing in mice. The effect of pre-treatment with opioid antagonist naltrexone 1mg/kg was also studied on antinociception induced due to ME. RESULT: ME produced a dose-dependent significant antinociceptive activity in the tail flick test and acetic acid-induced writhing in mice. (P<0.05) Administration of subanalgesic dose of ME with morphine or venlafaxine also resulted in significant (P<0.05) antinociceptive activity in both the pain models. Pre-treatment with naltrexone inhibited analgesic activity induced by ME alone and combination with morphine or venlafaxine. CONCLUSION: A.marmelos in induced antinociception is mediated through both opioid and monoaminergic pain pathways, suggest its possible use in chronic pain.

Effects of the triple monoamine uptake inhibitor DOV 102,677 on alcohol-motivated responding and antidepressant activity in alcohol-preferring (P) rats.

BACKGROUND: Concurrent inhibitors of dopamine, norepinephrine, and serotonin uptake have been proposed as novel antidepressants. Given the high comorbidity between alcoholism and depression, we evaluated the activity of DOV 102,677 (DOV) on alcohol-maintained responding and performance in the forced swim test (FST), a model of antidepressant (AD) activity, using alcohol-preferring (P) rats. METHODS: Following training to lever press for either alcohol (10% v/v) or sucrose (3, 2%, w/v) on a fixed-ratio 4 (FR4) schedule, DOV (1.56 to 50 mg/kg; PO) was given 25 minutes or 24 hours prior to evaluation. The effects of DOV (12.5 to 50 mg/kg; PO) in the FST were evaluated 25 minutes posttreatment. RESULTS: DOV (6.25 to 50 mg/kg) dose-dependently reduced alcohol-maintained responding by 59 to 88% at 25 minutes posttreatment, without significantly altering sucrose responding. The reduction in alcohol responding (44% at 50 mg/kg) was sustained for up to 120 hours after a single dose. Administration of a single dose of DOV (25, 50 mg/kg) 24 hours before testing suppressed alcohol responding for 48 hours by 59 to 62%. DOV (12.5 to 50 mg/kg) also dose-dependently reduced immobility of P rats in the FST. CONCLUSIONS: DOV produces both prolonged and selective reductions of alcohol-motivated behaviors in P rats. The elimination kinetics of DOV suggests that its long duration of action may be due to an active metabolite. DOV also produced robust AD-like effects in P rats. We propose that DOV may be useful in treating comorbid alcoholism and depression in humans.

Non-hormonal treatment strategies for vasomotor symptoms: a critical review.

Hot flashes (or flushes) are the most commonly reported symptoms during the menopause transition and early postmenopausal years, particularly in Western societies; they affect 60-90% of women and can lead to significant physical discomfort and functional impairment. The emergence of hot flashes and night sweats (also known as vasomotor symptoms [VMS]) coincide with a period in life that is also marked by dynamic changes in hormone and reproductive function that interconnect with the aging process, changes in metabolism, lifestyle behaviours and overall health. Estrogen-based therapies have long been the treatment of choice for women suffering from VMS. More recent concerns over long-term safety of menopausal hormone treatments, however, have led physicians and patients to pursue non-hormonal strategies to alleviate their symptoms. In this article, we review most of the efficacy and safety data on non-hormonal treatments for VMS published over the past 20 years. We discuss the evidence for treating symptomatic women in different clinical scenarios, e.g. VMS with and without concomitant depression or VMS following the use of anti-estrogen therapies. Overall, efficacy data support the use of some psychotropic medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors and gabapentin. Complementary and alternative methods for VMS also showed limited but promising results, although more definitive studies are warranted. Clinicians should therefore be able to tailor treatment strategies for those who are unable or unwilling to use hormones to alleviate VMS and improve overall functioning and quality of life.

Monoamine reuptake inhibition and mood-enhancing potential of a specified oregano extract.

A healthy, balanced diet is essential for both physical and mental well-being. Such a diet must include an adequate intake of micronutrients, essential fatty acids, amino acids and antioxidants. The monoamine neurotransmitters, serotonin, dopamine and noradrenaline, are derived from dietary amino acids and are involved in the modulation of mood, anxiety, cognition, sleep regulation and appetite. The capacity of nutritional interventions to elevate brain monoamine concentrations and, as a consequence, with the potential for mood enhancement, has not been extensively evaluated. The present study investigated an extract from oregano leaves, with a specified range of active constituents, identified via an unbiased, high-throughput screening programme. The oregano extract was demonstrated to inhibit the reuptake and degradation of the monoamine neurotransmitters in a dose-dependent manner, and microdialysis experiments in rats revealed an elevation of extracellular serotonin levels in the brain. Furthermore, following administration of oregano extract, behavioural responses were observed in mice that parallel the beneficial effects exhibited by monoamine-enhancing compounds when used in human subjects. In conclusion, these data show that an extract prepared from leaves of oregano, a major constituent of the Mediterranean diet, is brain-active, with moderate triple reuptake inhibitory activity, and exhibits positive behavioural effects in animal models. We postulate that such an extract may be effective in enhancing mental well-being in humans.

The novel triple reuptake inhibitor JZAD-IV-22 exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties.

Triple reuptake inhibitors (TRIs) that block the dopamine transporter (DAT), norepinephrine transporter, and serotonin transporter are being developed as a new class of antidepressant that may have better efficacy and fewer side effects compared with traditional antidepressants. We describe a novel TRI, 2-[4-(4-chlorophenyl)-1-methylpiperidin-3-ylmethylsulfanyl]-1-(3-methylpiperidin-1-yl)-ethanone (JZAD-IV-22), that inhibits all three monoamine transporters with approximately equal potency in vitro. (+/-)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride (DOV 216,303), a TRI shown to be an effective antidepressant in a clinical trial, shows reuptake inhibition similar to that of JZAD-IV-22 in vitro. Furthermore, both JZAD-IV-22 and DOV 216,303 increase levels of dopamine, norepinephrine, and serotonin in the mouse prefrontal cortex when administered by peripheral injection. JZAD-IV-22 and DOV 216,303 exhibited antidepressant-like efficacy in the mouse forced-swim and tail-suspension tests at doses that increased neurotransmitter levels. Because development of DAT inhibitors could be hindered by abuse liability, both JZAD-IV-22 and DOV 216,303 were compared in two assays that are markers of abuse potential. Both JZAD-IV-22 and DOV 216,303 partially substituted for cocaine in a drug discrimination assay in rats, and high doses of DOV 216,303 produced locomotor sensitization in mice. JZAD-IV-22 showed no evidence of sensitization at any dose tested. These results demonstrate that JZAD-IV-22 is a TRI with antidepressant-like activity similar to that of DOV 216,303. The striking feature that distinguishes the two TRIs is that locomotor sensitization, a common underlying feature of drugs of abuse, is seen with DOV 216,303 but is completely lacking in JZAD-IV-22. These findings may have implications for the potential for abuse liability in humans.

Tesofensine, a monoamine reuptake inhibitor for the treatment of obesity.

Tesofensine, a monoamine reuptake inhibitor, is under development by NeuroSearch A/S for the potential treatment of obesity. In vitro, the compound potently blocked dopamine, norepinephrine and serotonin reuptake. Initial development, which was conducted by NeuroSearch in collaboration with Boehringer Ingelheim Corp, demonstrated that although tesofensine was ineffective as a treatment for neurodegenerative conditions, a notable occurrence of unintended weight loss was observed in individuals treated with the drug. Preclinical data from diet-induced obese rats supported the hypothesis that tesofensine reduces body weight, and NeuroSearch has since pursued the development of the compound as an oral anti-obesity drug. In phase II clinical trials with tesofensine in obese individuals, dose-related reductions in body weight, body fat and waist circumference, as well as improvements in other obesity-related endocrine factors, were observed. Overall, tesofensine was associated with minor adverse events. Tesofensine caused dose-dependent elevations in heart rate, with significant increases in blood pressure at the highest dose tested. The initial positive findings suggest that tesofensine may be a well-tolerated long-term treatment for obesity, with minimal cardiovascular effects; this view appears to be shared by the FDA, which recently endorsed the phase III trial program for the agent.

Emerging targets for antidepressant therapies.

Despite adequate antidepressant monotherapy, the majority of depressed patients do not achieve remission. Even optimal and aggressive therapy leads to a substantial number of patients who show minimal and often only transient improvement. In order to address this substantial problem of treatment-resistant depression, a number of novel targets for antidepressant therapy have emerged as a consequence of major advances in the neurobiology of depression. Three major approaches to uncover novel therapeutic interventions are: first, optimizing the modulation of monoaminergic neurotransmission; second, developing medications that act upon neurotransmitter systems other than monoaminergic circuits; and third, using focal brain stimulation to directly modulate neuronal activity. We review the most recent data on novel therapeutic compounds and their antidepressant potential. These include triple monoamine reuptake inhibitors, atypical antipsychotic augmentation, and dopamine receptor agonists. Compounds affecting extra-monoamine neurotransmitter systems include CRF(1) receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, NMDA receptor antagonists, nemifitide, omega-3 fatty acids, and melatonin receptor agonists. Focal brain stimulation therapies include vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS).

Current investigational drugs for major depression.

BACKGROUND: The World Health Organization (WHO) report has predicted that major depression will become a key cause of illness-induced disability by the year 2020, second only to ischemic heart diseases. OBJECTIVES/METHODS: Although a large number of antidepressant drugs (from monoamine oxidase inhibitors and tricyclic antidepressants to dual reuptake inhibitors) are available for treatment of the disease, approximately 30% of patients failed to respond to this therapy. Therefore, the search for newer or novel drug targets for the treatment of major depression continues. Some of these targets include dopamine, triple reuptake inhibition, L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, sigma-1 receptors, neurosteroids, melatonin, glutamate, 5HT6, 5HT7 serotonin receptor antagonists, beta-3 adrenoceptor antagonist, vasopressin V(Ib) receptor antagonists, NK2 tachykinin receptor antagonists, glucocorticoid receptor antagonists and corticotropin-releasing factor-1 receptor antagonists, as well as herbal antidepressant drugs. The present review attempts to discuss the status of some of these novel approaches and the drugs that are under investigation for the treatment of major depression. An attempt is also made to review the status of three indigenous plant-derived drugs, berberine, curcumin and rutin, as novel and safe future herbal antidepressants. RESULTS/CONCLUSION: There is an exciting future in the discovery of novel targets and target-specific agents for the management of major depression.

Use of antidepressant drugs in transplant recipients.

Depression is the most prevalent psychiatric disorder in transplant recipients and may lead to noncompliance and negative outcomes without psychosocial and pharmacologic interventions. The pharmacologic treatment of depression in this patient population is complicated by complex immunosuppressant drug regimens and multiple potential drug interactions that can adversely affect the newly transplanted organs. This review provides a brief overview of the currently available antidepressant medications and highlights the clinically important features each class of agents in transplant recipients. Newer agents selective serotonin reuptake inhibitors, venlafaxine, bupropion, nefazodone, and mirtazapine are discussed as well as tricyclic antidepressants and monoamine oxidase inhibitors. A brief discussion of St. John's wort and its impact on posttransplant drug therapy is also included.

"Broad spectrum" antidepressants: is more better for the treatment of depression?

The majority of antidepressants in current use selectively inhibit the reuptake of serotonin and/or norepinephrine. "Broad spectrum" antidepressants are compounds that inhibit the reuptake of norepinephrine, serotonin and dopamine, the three biogenic amines most closely linked to depression. The pharmacological profile of one such compound has recently been described (European Journal of Pharmacology, 461 (2003) 99). DOV 21,947, an azabicyclo[3.1.0]hexane, potently inhibits norepinephrine, serotonin and dopamine reuptake by the corresponding human transporter proteins. DOV 21,947 is orally active in the forced swim and tail suspension tests, preclinical procedures that are highly predictive of antidepressant action in patients. A closely related compound, DOV 216,303 is safe and well-tolerated in Phase I studies. The plasma concentrations of DOV 216,303 following both single and multiple doses appear sufficient to inhibit norepinephrine, serotonin, and dopamine reuptake. Based on the pivotal role proposed for dopamine in depression, it has been hypothesized that a broad spectrum antidepressant will produce a more rapid onset and/or higher efficacy than agents inhibiting the reuptake of serotonin and/or norepinephrine.

[Pharmacological study on the effects of the adenosine uptake inhibitor KF24345 on inflammatory diseases].

Adenosine protects against cellular damage and dysfunction under several adverse conditions, including inflammation. We examined the effects of KF24345, a novel adenosine uptake inhibitor, on inflammatory diseases to investigate whether the adenosine uptake inhibition is useful for the treatment of inflammation. KF24345 inhibited adenosine uptake into washed erythrocytes (in vitro) and sampled blood cells from mice after its oral administration (in vivo). KF24345 significantly suppressed lipopolysaccharide-induced tumor necrosis factor-alpha production and leukopenia in mice, and the effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. In the experimental glomerulonephritis induced in mice by anti-glomerular basement membrane antiserum, KF24345 significantly inhibited proteinuria and glomerular damage without exhibiting the side effects observed following the treatment with prednisolone and cyclophosphamide. In addition, KF24345 ameliorated the severity of experimental acute pancreatitis induced by cerulein or choline-deficient and ethionine-supplemented diet in mice, and it decreased mortality accompanying severe acute pancreatitis. The anti-pancreatitis effects of KF24345 were abolished by the treatment with a non-selective or an A(2A)-selective adenosine receptor antagonist. These results suggest that KF24345 and adenosine uptake inhibitors can be a new therapeutic approach for various inflammatory diseases, including glomerulonephritis and acute pancreatitis.

Advances in the medical treatment of epilepsy.

Treatment options for epilepsy, especially using antiepileptic drugs, have increased substantially in the past five years. Since 1993, four novel antiepileptic drugs have been approved and marketed in the United States: felbamate, gabapentin, lamotrigine, and topiramate. Two others, tiagabine and vigabatrin, are likely to be approved in the near future. For many patients, these agents offer the realistic promise of improved seizure control, often with fewer adverse effects and less significant drug interactions compared with older agents. In addition, fosphenytoin, a water-soluble phenytoin prodrug with a number of advantages over intravenous phenytoin, has been released. There are new administration options for carbamazepine, diazepam, and valproic acid. For drug-resistant or -intolerant patients, there has been renewed interest in alternative therapies, especially the ketogenic diet. Taken together, these represent significant therapeutic advances that are benefiting patients with epilepsy. At the same time, improved understanding of the basic mechanisms of epileptogenesis, and of the cellular and molecular actions of available antiepileptic drugs, creates a framework for designing unique therapeutic strategies that are targeted at key sites of vulnerability involved in the development and maintenance of the epileptic state.

[Clinical observation and therapeutic mechanism of blocking agent of substance P nerves in the treatment of perennial allergic rhinitis].

This paper reported the clinical effects and therapeutic mechanism of blocking agent of substance P(SP) nerves on prerennial allergic rhinitis. We applied capsaicin (CAP) in the treatment of 50 cases of perennial allergic rhinitis once a week and 4 times as a therapeutic course. By using highly specific and highly sensitive SP radioimmunoassay, the SP contents in nasal secretions were determined before and after CAP therapy. The results showed that clinical symptoms of allergic rhinitis were obviously relieved and SP content in the nasal secretions was remarkably reduced from 29.444 +/- 14.280pmol/L before CAP therapy to 16.848 +/- 10.622 pmol/L after therapy (P < 0.001). Of the 50 cases, 35 cases (70.0%) showed the best effects, 12 cases (24.0%) better effects and 3 cases (6.0%) no effects. The total effective rate was 94.0%. The study indicated that therapeutic mechanism of CAP on perennial allergic rhinitis is related to the reducing of SP and the blocking of axonal reflex of the SP nerves.