Unique Pharmacological Profile Research Articles

Mirtazapine in Comorbid Major Depression and Alcohol Use Disorder: A Long-Term Follow-Up Study.

To date, pharmacotherapy trials of depressed alcoholics (MDD/AUD) have focused on SSRI medications, with disappointing results, so effective treatments for that comorbid population are lacking. Mirtazapine is an FDA-approved medication for treating MDD with a unique pharmacological profile whose efficacy may exceed that of SSRIs. Results from our recent open label study suggest robust acute phase efficacy for mirtazapine for decreasing both the depression and the drinking of that population. However, to date, no studies have evaluated the longer-term efficacy of mirtazapine in that population. We now report findings from a first long-term (two-year) naturalistic follow-up evaluation involving subjects from the acute phase trial. We hypothesized that the improvements would persist at follow-up. An eight-week open label study of mirtazapine and motivation therapy was conducted involving persons 18 to 55 years of age with DSM-IV diagnoses of comorbid MDD/AD. Two years after entry into the acute phase study, a long-term evaluation was conducted using the same instruments that had been used at baseline to assess whether the improvements seen during the acute phase trial had persisted. Ten of the twelve patients who entered the acute phase study participated in the follow-up study. The large magnitude improvements (p<.01) in depressive symptoms (BDI), drinking (TLFB), and sleep disturbance (HDRS) persisted at the follow-up evaluation. Two of the subjects demonstrated MDD on structured interview at follow-up, while all ten had demonstrated MDD at baseline. Six of the ten used antidepressants during the follow-up period. At baseline, three were employed, while at follow-up seven were employed. These findings suggest long-term efficacy for mirtazapine for decreasing the drinking and depression of depressed alcoholics. Double-blind, placebo-controlled studies are warranted to clarify the efficacy of mirtazapine in depressed alcoholics.

Two Cases of Hypersexuality Probably Associated with Aripiprazole

Sexual dysfunction is a common side effect in patients treated with antipsychotics but significant differences exist across different compounds. We report hypersexuality symptoms in two female patients with schizophrenia who were receiving treatment with aripiprazole. The patients experienced more frequent sexual desire and greater sexual preoccupation after taking aripiprazole. We discuss the potential neuro-chemical mechanisms for this and argue that aripiprazole's unique pharmacological profile, partial agonism with high affinity at dopamine D2-receptor, may have contributed to the development of these symptoms.

Modafinil as a Catecholaminergic Agent: Empirical Evidence and Unanswered Questions

Modafinil, in its two clinical formulations (Provigil® and Nuvigil®), is a widely prescribed wake-promoting therapeutic agent. It binds competitively to the cell-membrane dopamine (DA) transporter and is dependent on catecholaminergic (dopaminergic and adrenergic) signaling for its wake-promoting effects. The clinical spectrum of effects for modafinil is distinct from the effects seen with other catecholaminergic agents. Relative to other commonly used agents that act through catecholaminergic mechanisms, modafinil has a relatively low abuse potential, produces wakefulness with an attenuated compensatory sleep recovery thereafter, and does not ameliorate cataplexy in narcolepsy. These clinically relevant phenomenological differences between modafinil and agents such as amphetamines and cocaine do not eliminate catecholaminergic effects as a possible mediator of its wake-promoting action; they merely reflect its unique pharmacological profile. Modafinil is an exceptionally weak, but apparently very selective, DA transporter inhibitor. The pharmacodynamic response to modafinil, as measured by DA levels in brain microdialyzate, is protracted relative to other agents that act via catecholaminergic mechanisms. The conformational constraints on the interaction of modafinil with the DA transporter – and probably, as a consequence, its effects on trace amine receptor signaling in the catecholaminergic cell – are unique among catecholaminergic agents. These unique pharmacological properties of modafinil should be considered both in seeking to thoroughly understand its putatively elusive mechanism of action and in the design of novel therapeutic agents.

Linagliptin as add-on therapy to insulin for patients with type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a highly prevalent, progressive disease that often is poorly controlled. The combination of an incretin-based therapy and insulin is a promising approach to optimize the management of glycemic control without hypoglycemia and weight gain. Linagliptin, a recently approved oral dipeptidyl peptidase-4 inhibitor, has a unique pharmacological profile. The convenient, once-daily dosing does not need adjustment in patients with hepatic and/or renal impairment. In clinical studies linagliptin shows an important reduction of blood glucose with an overall safety profile similar to that of placebo. So far, the combination of linagliptin and insulin has been tested in three major clinical studies in different populations. It has been shown that linagliptin is an effective and safe add-on therapy to insulin in patients with T2DM. The efficacy and safety of this combination was also shown in vulnerable, elderly T2DM patients and in patients with T2DM and renal impairment. Favorable effects regarding the counteraction of hypoglycemia make linagliptin especially interesting as an add-on therapy to insulin. This review aims to present the existing clinical studies on the efficacy and safety of linagliptin as add-on therapy to insulin in patients with T2DM in the context of current literature. Additionally, the possible advantages of linagliptin as an add-on therapy to insulin in relation to cardiovascular safety, patient-centered therapy and the prevention of hypoglycemia, are discussed.

A-ring oxygenation modulates the chemistry and bioactivity of caged Garcinia xanthones

Natural products of the caged Garcinia xanthones (CGX) family are characterized by a unique chemical structure, potent bioactivities and promising pharmacological profiles. We have developed a Claisen/Diels-Alder reaction cascade that, in combination with a Pd(0)-catalyzed reverse prenylation, provides rapid and efficient access to the CGX pharmacophore, represented by the structure of cluvenone. To further explore this pharmacophore, we have synthesized various A-ring oxygenated analogues of cluvenone and have evaluated their bioactivities in terms of growth inhibition, mitochondrial fragmentation, induction of mitochondrial-dependent cell death and Hsp90 client inhibition. We found that installation of an oxygen functionality at various positions of the A-ring influences significantly both the site-selectivity of the Claisen/Diels-Alder reaction and the bioactivity of these compounds, due to remote electronic effects.

1053 – In vitro receptor-binding profile of lurasidone and other commonly-used antipsychotics

Introduction Atypical antipsychotics bind to multiple receptor types and subtypes. Improved outcomes in schizophrenia are linked to activity at D2 and serotonin receptors 5-HT7, 5-HT2A and 5-HT1A. Objectives To characterize the receptor-binding profile of lurasidone and other antipsychotics. Aims To compare receptor-binding profiles of antipsychotics. Methods Replicated, side-by-side receptor-binding assays used human recombinant receptors (for 5-HT7, α2A, and α2C) or membrane-fractions of animal CNS tissue. Affinities were determined via Hill plot analysis for IC50values; Ki values were determined using Ki=IC50/(1+ S/Kd) (S=concentration of competing radioligand, Kd=dissociation constant). Results Lurasidone displayed potent binding and full antagonism at dopamine D2(Ki, 1.68nM) and serotonin 5-HT2A(Ki, 2.03nM) receptors (the highest D2affinity of all tested agents). Lurasidone's dopamine binding was selective for D2receptors. Unlike other antipsychotics tested, lurasidone had very high affinity and full antagonism at serotonin 5-HT7(Ki, 0.49nM), and nanomolar affinity (Ki=6.75nM) with weak-moderate partial agonism at serotonin 5-HT1Areceptors., Lurasidone showed higher affinity for 5-HT7, 5-HT2A, and 5-HT1Areceptors relative to D2receptor-binding than other agents. Lurasidone displayed moderate affinity for α2C adrenoceptors (Ki, 10.8nM); moderate-weak affinity for α1adrenoceptors (Ki, 48nM); and minimal or unappreciable affinity for receptors associated with undesirable effects (5-HT2C [Ki, 415nM], histamine H1[IC50>1000nM] and muscarinic [cholinergic] M1[IC50>1000nM] receptors). Conclusions The unique pharmacological profile of lurasidone is consistent with observed antipsychotic efficacy, low-tomoderate likelihood of EPS, low weight-gain potential, and possible mood, anxiety, and cognitive benefits.

Discovery of INT131: A selective PPARγ modulator that enhances insulin sensitivity

PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure–activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.

Early versus conventional switching of antidepressant: a post-hoc analysis of clinical trial data for major depressive disorder with moderate to severe pain symptoms

A number of different antidepressants, each with unique pharmacological profiles, are used for treatment of major depressive disorder (MDD); however, these drugs have been found in placebo-controlled, large practical clinical trials to have limited efficacy for achieving full recovery in MDD patients. In particular, when depressed patients have pain symptoms, their chance of remission is significantly decreased. Pain also often leads to residual symptoms and incomplete functional recovery. Hence, while pain should be a principal target symptom in patients with MDD, there continues to be unmet need for pain treatment in depressed patients. Therefore, more diverse options for treatment approaches can be expected to enhance outcomes in clinical treatment of depressed patients with comorbid pain. In this context, Dr. Romera and colleagues have investigated an early antidepressant-switching strategy in patients with initial treatment failure. They found that early switching to a different antidepressant in MDD patients with moderate-to-severe symptoms of physical pain seems to lead to better pain and functional outcomes. This article discusses clinical significance, practical issues, potential limitations, and future research implications based on the findings from Dr. Romera and colleagues' study.

Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management.

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of one-two cases per 100,000 adults and accounts for ∼15% of newly diagnosed cases of leukemia in adults. CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL fusion oncogene, which in turn translates into a Bcr-Abl oncoprotein. Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib, have been approved by the US Food and Drug Administration for the first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with 2nd generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined. For patients who fail standard-dose imatinib therapy, imatinib dose escalation is a second-line option. Alternative second-line options include 2nd generation TKIs. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs and are candidate for clinical trials. Allogeneic transplantation remains an important therapeutic option for CML-CP harboring the T315I mutation, patients who fail 2nd generation TKIs, and for all patients in advanced phase disease.

Use of Buprenorphine in Children With Chronic Pseudoobstruction Syndrome

Abdominal pain is the most challenging symptom in chronic intestinal pseudoobstruction (CIPO) syndrome, because of its severity and the limited availability of suitable opioid formulations, especially in pediatric patients with digestive problems. Most of the children with CIPO cannot tolerate oral formulations. We present 4 cases of children with CIPO and severe intractable abdominal pain, and report on the use of a recently available form of opioid, transdermal buprenorphine in a dosage of 5 mcg/h. CIPO and the unique pharmacological profile of buprenorphine are reviewed briefly.

Characterization of a β-adrenergic-like octopamine receptor from the rice stem borer (Chilo suppressalis)

Octopamine, the invertebrate counterpart of adrenaline and noradrenaline, plays a key role in regulation of many physiological and behavioral processes in insects. It modulates these functions through binding to specific octopamine receptors, which are typical rhodopsin-like G-protein coupled receptors. A cDNA encoding a seven-transmembrane receptor was cloned from the nerve cord of the rice stem borer, Chilo suppressalis, viz. CsOA2B2, which shares high sequence similarity to CG6989, a Drosophila β-adrenergic-like octopamine receptor (DmOctβ2R). We generated an HEK-293 cell line that stably expresses CsOA2B2 in order to examine the functional and pharmacological properties of this receptor. Activation of CsOA2B2 by octopamine increased the production of cAMP in a dose-dependent manner (EC(50)=2.33 nmol l(-1)), with a maximum response at 100 nmol l(-1). Tyramine also activated the receptor but with much less potency than octopamine. Dopamine and serotonin had marginal effects on cAMP production. Using a series of known agonists and antagonists for octopamine receptors, we observed a rather unique pharmacological profile for CsOA2B2 through measurements of cAMP. The rank order of potency of the agonists was naphazoline > clonidine. The activated effect of octopamine is abolished by co-incubation with phentolamine, mianserin or chlorpromazine. Using in vivo pharmacology, CsOA2B2 antagonists mianserin and phentolamine impaired the motor ability of individual rice stem borers. The results of the present study are important for a better functional understanding of this receptor as well as for practical applications in the development of environmentally sustainable pesticides.

Discovery of γ-Secretase Modulators with a Novel Activity Profile by Text-Based Virtual Screening

We present an integrated approach to identify and optimize a novel class of γ-secretase modulators (GSMs) with a unique pharmacological profile. Our strategy included (i) virtual screening through application of a recently developed protocol (PhAST), (ii) synthetic chemistry to discover structure-activity relationships, and (iii) detailed in vitro pharmacological characterization. GSMs are promising agents for treatment or prevention of Alzheimer's disease. They modulate the γ-secretase product spectrum (i.e., amyloid-β (Aβ) peptides of different length) and induce a shift from toxic Aβ42 to shorter Aβ species such as Aβ38 with no or minimal effect on the overall rate of γ-secretase cleavage. We describe the identification of a series of 4-hydroxypyridin-2-one derivatives, which display a novel type of γ-secretase modulation with equipotent inhibition of Aβ42 and Aβ38 peptide species.

Total Synthesis and Biological Evaluation of Phidianidines A and B Uncovers Unique Pharmacological Profiles at CNS Targets

The synthesis of phidianidines A and B, the first 1,2,4-oxadiazole-containing alkaloid, from the marine opisthobranch mollusk Phidiana militaris is reported. The synthesis proceeds in six steps from known indole acetic acids in 39.9% (phidianidine A) and 21% (phidianidine B) overall yields from commercially available materials. Biological characterization found that phidianidines A and B are selective inhibitors of DAT (versus SERT and NET) and a selective, potent ligand and partial agonist of the μ opioid receptor (versus δ- and κ-opioid receptors). Moreover, neither phidianidines A and B are cytotoxic, and thus represent an attractive starting point for chemical optimization; therefore, we piloted a number of chemistries and prepared a diverse series of unnatural analogs.

Rivaroxaban for Stroke Prevention in Atrial Fibrillation and Secondary Prevention in Patients With a Recent Acute Coronary Syndrome

The occurrence of disabling stroke, the major fatal consequence of atrial fibrillation, can be reduced by almost two-thirds with warfarin oral anticoagulation. Recent estimates on the prevalence of atrial fibrillation in the USA suggest that approximately 3 million people suffer from this common cardiac arrhythmia, therefore, the socioeconomic impact of adequate oral anticoagulation is enormous. Rivaroxaban, a direct orally available factor Xa inhibitor, is the first of a new class of drugs that target a central factor of the coagulation cascade upstream of thrombin. In the ROCKET AF clinical trial, rivaroxaban demonstrated noninferiority compared with warfarin for stroke prevention in patients with atrial fibrillation, while intracranial and fatal bleeding occurred less frequently with rivaroxaban treatment. Rivaroxban has recently been approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation by the US FDA and EMA. Very recently, rivaroxaban in addition to dual antiplatelet therapy, was shown to reduce mortality in patients with a recent acute coronary syndrome in the ATLAS ACS 2-TIMI 51 clinical trial. The clinical evaluation of rivaroxaban in cardiovascular disease and the results of the ROCKET AF study, the landmark clinical trial of rivaroxaban for stroke prevention, are discussed along with the unique pharmacological profile of rivaroxaban.

Pitavastatin: a new option for the reduction of cardiovascular risk factors

pharmacological profile compared with other statins. In addition to pitavastatin being amongst the most potent LDL-C-lowering agents, the unique pharmacological profile also minimizes the potential for drug–drug interactions. Claudio Borghi reviews the characteristics of the ideal statin for polymedicated comorbid patients, presenting evidence obtained with pitavastatin in this diverse patient group. Pitavastatin not only impacts atherogenic lipoproteins, but also significantly increases HDL in a sustained manner and potentially to a greater degree than other statins. This added value of pitavastatin, in addition to recent findings relating to the role of HDL-C in CV medicine (the impact of low HDL-C levels as a risk factor for coronary heart disease events and, conversely, the potential beneficial effects of increased HDL levels) is reviewed by John Chapman. In the final chapter, John Kastelein reviews the ‘real life’ evidence gained with pitavastatin in the LIVALO Effectiveness and Safety (LIVES) study, a longterm postmarketing surveillance study in more than 20,000 patients in Japan.

Agomelatin ve etki mekanizması

Circadian system is an area of investigation related to etiology of depression and agomelatine is a new antidepressant related to circadian system. Suprachiasmatic nucleus is the center of circadian system regulates the rhytym and amplitidute of various physiological elements, influenced by peripherical stimuli mainly by light. Melatonin plays a role in regulation of the sleep-wake cycle through the circadian system Circadian system impairs in depression and impairment may be restored by antidepressant treatment. Agomelatine is an antidepressant, that affects melatonergic and 5-HT2C receptors and is shown that it regulates the circadian system in both preclinical and clinical studies. Agomelatine also has an efficacy on neurotrophic factors and neuroplasticity which contributes to its antidepressant effect. Agomelatine shows a better tolerability with a unique pharmacological profile which differs from other antidepressants

Ciclesonide - A Novel Corticosteroid for the Management of Asthma

Ciclesonide (CIC) is a novel inhaled corticosteroid (ICS) approved by US Food and Drug Administration for the treatment of persistent asthma, available as a pressurized metered-dose inhaler in two strengths, 80 mcg/activation and 160 mcg/activation. Ciclesonide is a corticosteroid with unique pharmacological profile including a high degree of serum protein binding, a low oral bioavailability and rapid systemic elimination. Ciclesonide is a prodrug metabolized by esterases to desisobutyryl ciclesonide (des-CIC), an active metabolite with a 100-fold greater affinity for the glucocorticoid receptor. It has shown to improve pulmonary functions, reduce the need for oral corticosteroids (OCSs) and cause lesser suppression of the hypothalamic-pituitary-adrenal axis in asthmatic patients. Clinical efficacy studies suggest that Ciclesonide is superior to placebo and is at least as effective as several active comparators with an improved therapeutic margin thereby improving the therapeutic outcome in patients of asthma.

The cognitive profile of aripiprazole differs from that of other atypical antipsychotics in schizophrenia patients

We investigated the effects of the atypical antipsychotics risperidone, olanzapine, and aripiprazole on the cognitive functions of Japanese patients with schizophrenia with respect to dosage amounts and dosing schedules. We performed a cross-sectional survey using the Brief Assessment of Cognition in Schizophrenia – Japanese Language Version (BACS-J) to evaluate the neurocognitive functions of 101 schizophrenic patients who took the same dose of one of the three aforementioned antipsychotics for at least 3 months. The BACS-J composite score correlated negatively with the prescribed dosages of risperidone and olanzapine. In contrast, we did not find a correlation between the BACS-J composite score and the prescribed dosage of aripiprazole. Moreover, the primary scores for verbal learning, motor function, and attention and processing speed were significantly lower among the patients who were taking the prescribed dosage of risperidone. The scores for verbal learning and motor function were also significantly lower when correlated with the prescribed dosage of olanzapine. We did not find a correlation between any of the primary scores on the BACS-J and the prescribed dosage of aripiprazole. In fact, the results suggest there is no linear relationship between the dose of aripiprazole and cognitive impairment, which may be due to its unique pharmacological profile.

The dopamine receptor antagonist levo-tetrahydropalmatine attenuates heroin self-administration and heroin-induced reinstatement in rats

Opiate addiction is a chronic recrudescent disorder characterized by a high rate of relapse. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance extracted from Corydalis and Stephania and is contained in a number of traditional Chinese herbal preparations. Compared to other dopamine receptor antagonists, l-THP has lower affinity for D2 receptors than for D1 receptors, and a recent study showed that l-THP also binds to D3 receptors, possibly functioning as an antagonist. The unique pharmacological profile of l-THP suggests that l-THP may be effective for the treatment of opiate addiction. In this study, we investigated the effects of l-THP on heroin self-administration and reinstatement triggered by a priming injection of heroin in abstinent rats trained to stably self-administer heroin under an extinction/reinstatement protocol, and found that l-THP (2.5 and 5mg/kg, i.p.) decreased heroin self-administration on the fixed-ratio 1 schedule and dose-dependently (1.25, 2.5 and 5mg/kg, i.p.) inhibited heroin-induced reinstatement of heroin-seeking behavior. Importantly, l-THP (1.25 and 2.5mg/kg, i.p.) did not affect locomotion, indicating that the observed effects of l-THP on reinstatement do not appear to be due to motor impairments. The present results demonstrated that dopamine receptor antagonist l-THP attenuates heroin self-administration and heroin-induced reinstatement.

Efficacy and safety of aripiprazole in child and adolescent patients

Aripiprazole (APZ) has a unique pharmacological profile, as a partial agonist at the dopamine D2 and serotonin 5HT1A receptors and an antagonist at the serotonin 5HT2A receptor; this drug has few side effects (such as extrapyramidal syndrome, hyperprolactinemia, weight gain, metabolic disorders, and sedation) which are typical problems with other antipsychotic drugs. Due to its high tolerability, it is possible to safely administer it to children and adolescents. Efficacy and tolerability of APZ in children and adolescents have been well demonstrated in many clinical studies, which supported approvals granted by the US Food and Drug Administration (FDA) for schizophrenia, bipolar diseases, and irritability associated with autistic disorder in children and adolescents. APZ is expected to exert sedative, anti-depressive, and anti-anxiety effects, and stabilize emotion. APZ is an antipsychotic drug which could be useful for a wider spectrum of psychiatric disorders in children and adolescents. There is little risk of deterioration (such as disinhibition and acting out) and rapid stabilization is easy to achieve in children and adolescents without definitive diagnoses or with a combination of more than one spectrum of disorders. The effectiveness of APZ in children and adolescents is reviewed and discussed, given its pharmacological profile and the outcomes of various clinical studies. However, randomized or blind studies are still limited, and the majority of reports referenced here are open-label studies and case reports. Conclusions drawn from such studies must be evaluated with caution, and a further accumulation of controlled studies is thus needed.