Unique Pharmacological Profile Research Articles

Development of Selective LH Receptor Agonists by Heterodimerization with a FSH Receptor Antagonist.

The structural resemblance of the luteinizing hormone receptor (LHR) and follicle-stimulating hormone receptor (FSHR) impedes selective agonistic targeting of one of those by low molecular weight (LMW) ligands. In the present study, we describe a series of dimeric ligands consisting of a LMW agonist with dual activity on the FSHR and the LHR linked to a selective FSHR antagonist. Biological evaluation shows these compounds to be potent and selective LHR agonists, since no agonistic activity on the FSHR was observed. Equimolar mixing of the monomeric counterparts did not yield the pharmacological profile observed for the heterodimeric ligands, and FSHR agonism of the monomeric LHR agonist was still observed. The here-described results show that ligands with unique pharmacological profiles can be obtained by dimerizing monomeric molecules with distinct apposite properties.

Long‐term outcomes in the second‐line treatment of chronic myeloid leukemia

AbstractChronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative neoplasm. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph), which results in the synthesis of the breakpoint cluster region‐Abelson murine leukemia (BCR‐ABL) fusion oncoprotein, a constitutively active tyrosine kinase. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) that is specific for BCR‐ABL, was a major breakthrough in CML therapy. Although most patients respond to first‐line imatinib therapy, some experience loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). For patients with CML, failure on standard‐dose imatinib therapy (400 mg daily), imatinib dose escalation (600‐800 mg daily) is a second‐line option. However, high‐dose imatinib is not an appropriate approach for patients who experience drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second‐line options include the TKIs dasatinib and nilotinib. A substantial amount of long‐term data for these agents is available. Although both are potent and specific BCR‐ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR‐ABL mutation status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historic response, adverse‐event tolerance, and risk factors. Cancer 2010. © 2010 American Cancer Society.

Where to Position Clozapine: Re-Examining the Evidence

To review clozapine's position in treatment algorithms for schizophrenia. Clozapine's status is reviewed in the context of its initial discovery and unique clinical and (or) pharmacological profile, withdrawal and link with hematologic concerns, reintroduction with monitoring guidelines, prototype for atypicality, positioning in treatment algorithms, and current evidence regarding efficacy, effectiveness, and side effects. The hematologic monitoring implemented with clozapine's reintroduction here in North America has proven successful in preventing clozapine-related deaths secondary to agranulocytosis. While its other side effects are not without concern, present evidence does not link clozapine to increased mortality rates; indeed, it appears better than other antipsychotics in this regard. Moreover, its clinical superiority compared with all other antipsychotics has been confirmed both in efficacy and in effectiveness trials. Schizophrenia continues to represent a treatment challenge, with many people demonstrating suboptimal response and poor functional outcome. Clozapine is routinely positioned as a third-line treatment in schizophrenia, but in light of existing evidence this warrants re-examination.

Chronic Myeloid Leukemia and Second-Generation Tyrosine Kinase Inhibitors: When, How, and Which One?

Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative disorder. The introduction of imatinib, a tyrosine kinase inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience a loss of response (resistance) or require treatment discontinuation due to toxicity (intolerance). For patients who fail with standard-dose imatinib therapy, imatinib dose escalation is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. 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. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse-event tolerance level, and risk factors.

L‐Stepholidine‐induced excitation of dopamine neurons in rat ventral tegmental area is associated with its 5‐HT1A receptor partial agonistic activity

l-Stepholidine (l-SPD), a tetrahydroprotoberberine alkaloid, possesses a pharmacological profile of a D₁/5-HT(1A) agonist and a D₂ antagonist. This unique pharmacological profile makes it a promising novel antipsychotic candidate. Preliminary clinical trials and animal experiments suggest that l-SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. To further explore the antipsychotic mechanisms of the drug, we studied the effects of l-SPD on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) using in vivo single-unit recording technique in rats. We found that l-SPD increased VTA DA neurons firing rate and induced slow oscillation in firing pattern. Moreover, l-SPD, not clozapine, reversed d-amphetamine-induced inhibition which induced an excitation of VTA DA neurons. Furthermore, our data indicated that the excitatory effect of l-SPD is associated with its partial agonistic action for the 5-HT(1A) receptor since the 5-HT(1A) receptor antagonist WAY100635 could block the l-SPD-induced excitatory effect. However, activation of 5-HT(1A) receptor alone by specific agonist (±)-8-Hydroxy-2-(dipropylamino) tetralin (8-OH-DPAT) was insufficient to elicit excitation of VTA DA neurons, but the excitation of 8-OH-DPAT on VTA DA neurons was elicited in the presence of D₂-like receptors antagonist raclopride. Collectively, these results indicate that l-SPD excited VTA DA neurons requiring its D₂-like receptors antagonistic activity and 5-HT(1A) receptor agonistic activity. The present data demonstrate that D₂ receptor antagonist/5-HT(1A) receptor agonistic dual properties modulate dopaminergic transmission in a unique pattern that may underlie the different therapeutic responses between l-SPD and other atypical antipsychotic drugs.

Levo-tetrahydropalmatine attenuates cocaine self-administration under a progressive-ratio schedule and cocaine discrimination in rats

Levo-tetrahydropalmatine ( l-THP) is an alkaloid found in many traditional Chinese herbal preparations and has a unique pharmacological profile that includes dopamine receptor antagonism. Previously we demonstrated that l-THP attenuates fixed-ratio (FR) cocaine self-administration (SA) and cocaine-induced reinstatement in rats at doses that do not alter food-reinforced responding. This study examined the effects of l-THP on cocaine and food SA under progressive-ratio (PR) schedules of reinforcement and the discriminative stimulus effects of cocaine. In adult male Sprague–Dawley rats self-administering cocaine (0.5 or 1.0 mg/kg/inf), l-THP significantly reduced breaking points at the 1.875, 3.75 and 7.5 mg/kg doses. l-THP also reduced the breaking point and response rate for PR SA of sucrose-sweetened food pellets, although the decrease was significant only at the 7.5 mg/kg l-THP dose. In rats trained to discriminate cocaine (10 mg/kg, ip) from saline, l-THP (1.875, 3.75 and 7.5 mg/kg) produced a rightward shift in the dose–response curve for cocaine generalization. During generalization testing, l-THP reduced response rate, but only at the 7.5 mg/kg dose . l-THP also prevented substitution of the dopamine D2/D3 receptor agonist, (±) 7-OH-DPAT, for cocaine suggesting a potential role for antagonism of D2 and/or D3 receptors in the effects of l-THP. These data further demonstrate that l-THP attenuates the reinforcing and subjective effects of cocaine at doses that do not produce marked motor effects and provide additional evidence that l-THP may have utility for the management of cocaine addiction.

Current Knowledge of Buprenorphine and Its Unique Pharmacological Profile

Despite the increasing clinical use of transdermal buprenorphine, questions have persisted about the possibility of a ceiling effect for analgesia, its combination with other μ-opioid agonists, and the reversibility of side effects. In October 2008, a consensus group of experts met to review recent research into the pharmacology and clinical use of buprenorphine. The objective was to achieve consensus on the conclusions to be drawn from this work. It was agreed that buprenorphine clearly behaves as a full μ-opioid agonist for analgesia in clinical practice, with no ceiling effect, but that there is a ceiling effect for respiratory depression, reducing the likelihood of this potentially fatal adverse event. This is entirely consistent with receptor theory. In addition, the effects of buprenorphine can be completely reversed by naloxone. No problems are encountered when switching to and from buprenorphine and other opioids, or in combining them. Buprenorphine exhibits a pronounced antihyperalgesic effect that might indicate potential advantages in the treatment of neuropathic pain. Other beneficial properties are the compound's favorable safety profile, particularly in elderly patients and those with renal impairment, and its lack of effect on sex hormones and the immune system. The expert group agreed that these properties, as well as proven efficacy in severe pain and favorable tolerability, mean that buprenorphine can be considered a safe and effective option for treating chronic cancer and noncancer pain.

Clinical algorithms for the treatment of patients with chronic myeloid leukemia: the 2010 perspective.

Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative disorder. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph) that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase (TK). The introduction of imatinib, a TK inhibitor (TKI) specific for BCR-ABL, was a major breakthrough in CML therapy. Although most patients respond to first-line imatinib therapy, some experience a loss of response (resistance) or require treatment discontinuation because of toxicity (intolerance). In patients for whom standard-dose imatinib therapy (400 mg/day) fails, imatinib dose escalation (600-800 mg/day) is a second-line option. However, high-dose imatinib is not an appropriate approach for patients experiencing drug toxicity, and there remain questions over the durability of responses achieved with this strategy. Alternative second-line options include the newer TKIs dasatinib and nilotinib. A substantial amount of long-term data for these agents is available. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacologic profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. To optimize therapeutic benefit, clinicians should select treatment based on each patient's historical response, adverse event tolerance level, and risk factors.

Ascent of the kappa-opioid receptor in psychopharmacology

Often overshadowed by other members of the endogenous opioid receptor family, kappa-opioid receptors (KORs) are rapidly emerging as an important target for the study and treatment of a variety of central nervous system disorders. This Special Issue is dedicated to 18 papers that describe some of the newest and most important developments. Since the seminal work of Pasternak (1980), there has been great interest in selective KOR agonists for the management of pain. Stimulation of KORs produces analgesia, while the lack of effects at mu-opioid receptors (MORs) minimizes abuse liability. Pain remains a likely indication for KOR agonists (this issue). However, early studies demonstrated that administration of selective KOR agonists to humans elicited unwanted effects including dysphoria, derealization, and depersonalization, some of which can be modeled in animals (this issue). The prominence of these effects has tempered enthusiasm for further development of these agents for clinical use. It is now better understood that MORs and KORs are often located in anatomical apposition within brain areas such as the nucleus accumbens (NAc). As a result of this arrangement, selective activation of these receptor subtypes tends to produce opposite effects on behavior: whereas stimulation of MORs is rewarding, stimulation of KORs causes dysphoria. The work by Negus et al. (this issue) shows that KOR agonists concurrently reduce pain while producing depressive-like behavior, and provides a novel methodology that could be used to screen for novel analgesics with less propensity to affect mood. Chartoff et al. (this issue) use an interesting new ligand, salvinorin A, to provide a potential mechanism by which KOR agonists cause depressive-like behavior: reduction of phasic dopamine release in the NAc. Salvinorin A is of special interest because it is a potent and highly selective KOR agonist that binds to few (if any) other receptors in the brain. Butelman et al. (this issue) and Nemeth et al. (this issue) show how the unique pharmacological profile of salvinorin A can enable new insights on the brain substrates of the types of altered perception that often accompany psychiatric conditions such as schizophrenia. Bruchas and Chavkin (this issue) provide evidence that in addition to their acute dysphoric effects, KOR agonists mimic the cellular effects of stress. The work of Sperling et al. (this issue) implicates the stress-like effects of KORs in increased vulnerability to drugs of abuse including ethanol. Wee and Koob (this issue) describe how KOR stimulation may play a key role in the addiction cycle by influencing processes of positive and negative reinforcement, tying together the ways in which stress, depression, and addiction can interact to control behavior. Until recently, the potential for clinical applications of KOR antagonists seemed limited. These agents were originally envisioned as tools for studies of interactions between agonists and KORs and the functional significance of KORs for behavior, or for understanding receptor– receptor interactions (e.g., dimers). Several papers in this issue suggest that KOR antagonists have potential for broad clinical applicability. As one example, Carr and Lucki (this issue) demonstrate that the KOR antagonist DIPPA has acute anxiolytic-like effects in addition to acute antidepressantW. A. Carlezon Jr. (*) Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, MRC 217, 115 Mill Street, Belmont, MA 02478, USA e-mail: bcarlezon@mclean.harvard.edu

Abstract 3566: Anti-tumor activity of CXR1002, a novel anti-cancer compound that induces ER stress: Human tumor xenograft efficacy and in vitro mode of action

Abstract Summary: CXR1002 is an ammonium salt of perfluorooctanoic acid. It has a unique pharmacokinetic, pharmacologic and toxicity profile and induces cell death in a wide range of human tumor cells in vitro and in vivo. CXR1002 causes an ER stress response, acts as a fatty acid mimetic, and binds to PPARs in both an agonistic and antagonistic manner. The aim of this study was to explore further its mechanism of action in vitro, and to determine its cytotoxicity both in vitro and in vivo. Methods: In vitro cytotoxicity of CXR1002 was determined using an ATP depletion assay, alone and and in combination with 12 other drugs in a panel of tumor cell lines. The mode of action was examined using microarray analysis (followed by analysis using the Ingenuity system), transactivation assays and western blots. Four CXR1002 xenograft studies (25 mg/kg p.o. 3x per week) were performed in nu/nu mice. Results: CXR1002 was cytotoxic to a wide range of human tumor cells, including pancreatic and ovarian carcinoma and sarcoma. The IC50 value was lower after 7 days vs 2 days exposure (range 229 - 625 μM vs 300 - >1000 μM), suggesting potency was linked to duration of exposure. IC50 values were comparable to the plasma concentrations achieved with a non-toxic dose in an on-going Phase I trial. Drug combination studies with 12 anti-cancer drugs in 11 human cancer cell lines indicated that CXR1002 was synergistic with other anti-tumor drugs, particularly doxorubicin, gemcitabine, geldanamycin, MAPK inhibitors and AKT/PI3K inhibitors, but it was antagonistic when combined with rapamycin. In transactivation assays CXR1002 was an agonist of PPARα, and to a lesser extent PPARγ, but it demonstrated antagonist activity against PPARδ, in the presence of bezafibrate. Microarray studies in the pancreatic cell line PANC-1 treated with an IC15 dose of CXR1002 showed 4996 gene changes. Representation analysis of the 4996 signature list identified a number of pathways that were over-represented, in particular, genes in the ER stress pathway, including the ATF family of transcription factors. Western blot analysis of PANC-1 cells using PCNA and cleaved PARP antibodies showed that PCNA was reduced and cleaved PARP increased 24 hr after treatment with 450 μM CXR1002, suggesting a pro-apoptotic/anti-proliferative outcome. CXR1002 was active in all 4 human xenograft (i.e. pancreatic, liver, prostate and colon) models examined with best absolute tumor volume as a % of control of 50.13%, 77.05%, 19.14% and 49.22% respectively. Conclusions: CXR1002 is a unique potential anti-cancer therapy that exhibits unique pharmacokinetics and a wide spectrum of biological activities. CXR1002 appears to act in part by its ability to induce ER stress. A Phase I human trial is on-going. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3566.

Ethinylestradiol/Dienogest in Oral Contraception

The low-dose combined oral contraceptive of ethinylestradiol 30 microg and dienogest 2 mg was launched in Germany in 1995, and is now the most commonly prescribed oral contraceptive in this country. Dienogest is a novel 19-nortestosterone-derived progestin with a unique pharmacokinetic and pharmacological profile, including antiandrogenic properties. Clinical studies have demonstrated that ethinylestradiol/dienogest is a reliable ovulation inhibitor with high contraceptive efficacy that is comparable with other combined oral contraceptives. It also provides effective cycle control, with reduced intensity and duration of menstrual bleeding, and improves dysmenorrhoea. The combination of ethinylestradiol and dienogest reduces serum androgen levels, and increases the levels of thyroid hormones; however, although thyroid hormone levels increase, there is no increased activity due to increases in transporter protein. Like other low-dose oral contraceptives, ethinylestradiol/dienogest has only minor influences on lipid and carbohydrate metabolism, adrenal hormones and blood pressure parameters, and appears to have a balanced effect on the haemostatic system. Ethinylestradiol/dienogest also has beneficial effects on hair and skin; a number of studies have reported decreased hair and skin greasiness, and improvements in acne vulgaris following treatment with ethinylestradiol/dienogest. After discontinuation of ethinylestradiol/dienogest, there may be a small delay in conception during the first three cycles, but there is no subsequent impairment of fertility. Furthermore, the duration of use of ethinylestradiol/dienogest does not seem to influence the rate of conception or time to conception. Ethinylestradiol/dienogest is well tolerated; adverse reactions associated with treatment include breast pain, headache and nausea/vomiting. These adverse reactions are rare and decrease in incidence over time.

Cognition and depression: the effects of fluvoxamine, a sigma‐1 receptor agonist, reconsidered

Cognitive impairment is a primary feature of patients with major depressive disorder (MDD) and is characterised by stress-induced neural atrophy. Via alpha-adrenergic, anti-cholinergic and anti-histaminic activities, several antidepressants can cause significant counter-therapeutic cognitive impairment. Evidence is emerging of the involvement of sigma-1 receptor agonism in the mechanism of action of some antidepressants, notably fluvoxamine. Sigma-1 receptors are abundant in areas affected by depression/stress-induced cerebral atrophy and their ligands have a unique pharmacological profile; they may promote neurogenesis and initiate adaptive neural plasticity as a protection/reaction to stress. Fluvoxamine, as a potent sigma-1 receptor agonist, has shown ameliorating effects in animal models of psychosis, depression, stress, anxiety, obsessive-compulsive disorder (OCD) and aggression and has been shown to improve cognitive impairments. In humans, fluvoxamine may repair central nervous system (CNS) atrophy and restore cognitive function. The current review explores the mechanisms through which sigma-1 receptors can modulate cognitive function and examines how antidepressant therapy with fluvoxamine may help improve cognitive outcomes in patients with depression.

Characterization of a novel octopamine receptor expressed in the surf clam Spisula solidissima

We have cloned and sequenced a cDNA from the surf clam ( Spisula solidissima, a pelecypod mollusc) that encodes an octopamine receptor which we have named Spi-OAR. The sequence of Spi-OAR shares many similarities with two Aplysia and three Drosophila octopamine receptors belonging to a sub-group of β-adrenergic-like octopamine receptors. Using an expression vector and transient transfections of Spi-OAR into HEK 293 cells, we observed an increase of cAMP upon addition of octopamine and, to a lesser extent, of tyramine, but not after addition of dopamine, serotonin, or histamine. Using a battery of known agonists and antagonists for octopamine receptors, we observed a rather unique pharmacological profile for Spi-OAR through measurements of cAMP. Spi-OAR exhibited some constitutive activity in HEK 293 cells and no Ca 2+ responses could be detected following addition of octopamine to Spi-OAR-transfected cells. RT-PCR analysis revealed ubiquitous expression of Spi-OAR mRNA in all adult tissues, oocytes and early embryos examined. While addition of serotonin to isolated clam oocytes resulted in meiotic activation, similar additions of octopamine had no effect, suggesting that its potential role in clam reproductive physiology differs significantly from that of serotonin. This work identifies Spi-OAR as a novel mollusc octopamine receptor closely related to other invertebrate β-adrenergic-like octopamine receptors, with possible reproductive and other physiological functions. This initial characterization of Spi-OAR makes possible further investigations and comparisons with more studied and familiar insect or gastropod mollusc octopamine receptors.

AZD8931, an Equipotent, Reversible Inhibitor of Signaling by Epidermal Growth Factor Receptor, ERBB2 (HER2), and ERBB3: A Unique Agent for Simultaneous ERBB Receptor Blockade in Cancer

To test the hypothesis that simultaneous, equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo. A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors. In vitro, AZD8931 showed equipotent, reversible inhibition of EGFR (IC(50), 4 nmol/L), erbB2 (IC(50), 3 nmol/L), and erbB3 (IC(50), 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. AZD8931 has a unique pharmacologic profile providing equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2.

ChemInform Abstract: The Discovery and Unique Pharmacological Profile of RO4938581 and RO4882224 as Potent and Selective GABAA α5 Inverse Agonists for the Treatment of Cognitive Dysfunction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Cariprazine (RGH-188), a Dopamine D3 Receptor-Preferring, D3/D2 Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Cariprazine {RGH-188; trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea hydrochloride}, a novel candidate antipsychotic, demonstrated approximately 10-fold higher affinity for human D(3) versus human D(2L) and human D(2S) receptors (pKi 10.07, 9.16, and 9.31, respectively). It displayed high affinity at human serotonin (5-HT) type 2B receptors (pK(i) 9.24) with pure antagonism. Cariprazine had lower affinity at human and rat hippocampal 5-HT(1A) receptors (pK(i) 8.59 and 8.34, respectively) and demonstrated low intrinsic efficacy. Cariprazine displayed low affinity at human 5-HT(2A) receptors (pK(i) 7.73). Moderate or low affinity for histamine H(1) and 5-HT(2C) receptors (pK(i) 7.63 and 6.87, respectively) suggest cariprazine's reduced propensity for adverse events related to these receptors. Cariprazine demonstrated different functional profiles at dopamine receptors depending on the assay system. It displayed D(2) and D(3) antagonism in [(35)S]GTPgammaS binding assays, but stimulated inositol phosphate (IP) production (pEC(50) 8.50, E(max) 30%) and antagonized (+/-)-quinpirole-induced IP accumulation (pK(b) 9.22) in murine cells expressing human D(2L) receptors. It had partial agonist activity (pEC(50) 8.58, E(max) 71%) by inhibiting cAMP accumulation in Chinese hamster ovary cells expressing human D(3) receptors and potently antagonized R(+)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pK(b) 9.57). In these functional assays, cariprazine showed similar (D(2)) or higher (D(3)) antagonist-partial agonist affinity and greater (3- to 10-fold) D(3) versus D(2) selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D(2)-related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist-partial agonist properties of cariprazine at D(3) and D(2) receptors, with very high and preferential affinity to D(3) receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics.

SS01-04 - Clinical experience with agomelatine in depressed patients

Agomelatine, the first melatonergic antidepressant, has been widely recognized as a true innovation since its launch in Europe one year ago. Agomelatine has a unique pharmacological profile: an agonist at MT1/MT2 melatonergic receptors and antagonist at 5-HT2C receptors, it resynchronizes altered circadian rhythms in depression.Agomelatine has already become a first-line treatment option for patients with a first depressive episode, as well as those with recurrent depression. In daily practice, agomelatine can be used in all depressed patients, and is particularly indicated in patients complaining of sleep difficulties. Agomelatine ensures unimpaired daytime vigilance, cognition, gastrointestinal transit, and sexual functioning. Feedback to date from both inpatients and outpatients with major depression is positive: beyond the antidepressant effect, patients frequently report improvement in sleep-wake rhythms and daily functioning, as early as by the first week (mostly within the first 3 days), which differentiates agomelatine from other antidepressants. Most patients report improvement in mood and other symptoms after 2/3 weeks and satisfactory tolerability. The most frequently noted side effects are dizziness, headache, and nausea; liver function tests at initiation of treatment are not considered to be an issue. Because agomelatine, unlike conventional antidepressants, does not affect serotonin levels, in case of switch the initial antidepressant should be progressively downtitrated to avoid discontinuation symptoms, which risk masking the benefits of agomelatine.In summary, the early effects of agomelatine shown in controlled studies are also experienced by the majority of patients in daily practice and reflect its ability to resynchronize circadian rhythms.

Propofol

Known by the proprietary name Diprivan or its generic name propofol, this anesthetic drug is among the most widely used sedatives in the United States. Propofol has a unique pharmacologic profile, making it an ideal drug for use in plastic surgery nursing. Propofol is utilized as an anesthetic induction agent and sedative during many plastic surgeries. This article explores indications, pharmacokinetics, adverse effects, and potential abuse of propofol.

Aripiprazole-induced behavioural disturbance related to impulse control in a clinical setting

Aripiprazole is a novel antipsychotic with a unique pharmacological profile as a dopamine partial agonist; it is approved by the FDA for treatment of schizophrenia and mood disorders. This new antipsychotic has a low risk of adverse events including extrapyramidal syndrome, prolactin elevation, weight gain, and metabolic changes and is recommended by clinical guidelines as a first-line drug for treatment of schizophrenia. However, previous case reports have shown that administration of aripiprazole could induce mood switching and worsening of psychosis, especially after long-term exposure to other antipsychotics (DeQuardo, 2004; Padala et al. 2007). We report two cases that exhibited unexpected adverse effects after administration of aripiprazole for treatment of bipolar disorder. A 57-yr-old male had his first depressive episode with insomnia, loss of concentration, and suicidal ideas at age 22 yr. He was diagnosed with bipolar I disorder when a manic episode occurred at age 38 yr. Because antidepressants induced rapid mood changes, he was hospitalized 14 times and lost his job at the age of 50. Since his last hospitalization when he was aged 51 yr, his symptoms were relatively stable under a medication regimen of 1000 mg/d lithium carbonate and 600 mg/d carbamazepine. From June 2007, he felt a loss of energy and poor concentration, and he withdrew from social activity. In July 2007, 3 mg/d aripiprazole was started. The following week he reported unusual sexual desire and a strong urge to masturbate, although he was still in a depressive state and showed no other manic symptom. One week after stopping aripiprazole, the hypersexuality disappeared. The depressive phase gradually improved to euthymia by October 2007 without any other change of medication. One year later, in September …

The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABA A α5 inverse agonists for the treatment of cognitive dysfunction

Lead optimisation of the imidazo[1,5- a][1,2,4]-triazolo[1,5- d][1,4]benzodiazepine class led to the identification of two clinical leads [RO4882224 ( 11) and RO4938581 ( 44)] functioning as novel potent and selective GABA A α5 inverse agonists. The unique pharmacological profiles and optimal pharmacokinetic profiles resulted in in vivo activity in selected cognition models.