Partial Agonist Activity Research Articles

Kinetic characterization of selective peroxisome-proliferator-activated receptor gamma modulators in vitro

Background: The ligand-activated transcription factor, peroxisome-proliferator-activated receptor gamma (PPARγ), has been shown to play an essential role in immunosuppression during sepsis. PPARγ is upregulated in T cells of septic patients, sensitizing these cells to PPARγ-dependent apoptosis and thus contributing to T-cell depletion. In the polymicrobial cecum ligation and puncture (CLP) sepsis model in mice, both T-cell-specific gene knockout (Lck-Cre PPARγfl/fl) and systemic pharmacological PPARγ antagonism by GW9662 improved survival. Because GW9662 was only effective when applied 3 hours after CLP, we were interested to extend this time frame. For this reason we characterized the kinetics of SPPARγMs when administered before or in combination with the agonist thiazolidinedione, rosiglitazone. Methods: A PPARγ-dependent transactivation assay was used in HEK293T cells. It is based on the vector pFA-PPARγ-LBD-GAL4-DBD encoding the hybrid protein PPARγ-LBD-GAL4-DBD and the reporter vector pFR-Luc, carrying a GAL4-responsive element in front of the Firefly luciferase gene. These two vectors were co-transfected, in combination with a control vector encoding Renilla luciferase (pRL-CMV) to normalize Firefly luciferase activity for transfection efficiency. Following transfection, cells were incubated with the SPPARγMs F-MOC and MCC-555 and the PPARγ antagonist GW9662 for different times (2 to 48 hours) and at increasing doses (0.01 to 10 μM), with or without rosiglitazone (0.01 to 10 μM). Transactivation was analyzed using a 96-well plate format. Results: Rosiglitazone transactivated PPARγ in a time-dependent and dose-dependent manner, the response gradually increasing to a maximum at 48 hours with 10 μM. Low concentrations (0.01 to 0.1 μM) of SPPARγMs F-MOC and MCC-555 and the PPARγ antagonist GW9662 all exerted dose-independent antagonistic effects at an early incubation time point (2 hours). From 10 hours onwards, MCC-555 and GW9662, given alone, both exerted PPARγ agonistic effects, MCC-555 in parallel to responses to rosiglitazone, but GW9662 with characteristics of partial antagonism. F-MOC showed no dose-dependent effect at any concentration at later time points. Only GW9662 (1 to 10 μM) was able to inhibit rosiglitazone (0.1 to 1 μM)-induced PPARγ transactivation after 10 hours. Conclusion: Our kinetic analysis reveals clear differences in the modulatory characteristics of PPARγ inhibitors, with previously unreported early inhibitory effects and late agonistic or partial agonistic activity. New SPPARγMs with extended inhibitory activity may prove useful in the therapy of sepsis.

Coupled Control of Desensitization and Gating by the Ligand Binding Domain of Glutamate Receptors

The kinetics of ligand gated ion channels are tuned to permit diverse roles in cellular signaling. To follow high-frequency excitatory synaptic input, postsynaptic AMPA-type glutamate receptors must recover rapidly from desensitization. Chimeras between AMPA and the related kainate receptors demonstrate that the ligand binding domains alone control the lifetime of the desensitized state. Mutation of nonconserved amino acids in the lower lobe (domain 2) of the ligand binding domain conferred slow recovery from desensitization on AMPA receptors, and fast recovery on kainate receptors. Single-channel recordings and a correlation between the rate of deactivation and the rate of recovery across panels of mutant receptors revealed that domain 2 also controls ion channel gating. Our results demonstrate that the same mechanism that ensures fast recovery also sharpens the response of AMPA channels to synaptically released glutamate.

A phase II study of the androgen signaling inhibitor ARN-509 in patients with castration-resistant prostate cancer (CRPC).

TPS4697 Background: ARN-509 is a novel small molecule androgen signaling inhibitor that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. Preclinical data suggests that the maximal therapeutic index of ARN-509 can be achieved at low steady state plasma levels with minimal toxicity (Clegg et al, 2012). Enrollment in the Phase 1 dose escalation study of ARN-509 in patients with progressive CRPC with and without prior chemotherapy was completed in January 2012. The recommended Phase 2 dose of 240 mg was determined based on safety, PSA kinetics, and pharmacokinetic and pharmacodynamic analysis (Rathkopf et al, GU ASCO, 2012). Methods: The primary objective of this Phase 2 study is to determine the PSA response at 12 weeks according to Prostate Cancer Working Group 2 (PCWG2) Criteria (Scher et al, 2008). Three expansion cohorts will enroll a total of 80-90 patients for treatment with 240 mg continuous oral ARN-509 daily. These cohorts include: 1) non-metastatic treatment-naïve CRPC (50 patients); 2) chemotherapy-naïve metastatic (m) CRPC (20 patients); and 3) chemotherapy-naïve, post abiraterone mCRPC (10-20 patients). The effect of food on the PK of ARN-509 and the effect of ARN-509 on ventricular repolarization will also be evaluated. Phase 2 enrollment is ongoing. DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals. NCT01171898.

A phase I study of the androgen signaling inhibitor ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC).

4548 Background: ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. (Clegg et al., 2012) We conducted a phase I trial to assess safety, pharmacokinetics (PK), and determine the recommended phase II dose (RP2D). Methods: Eligible patients with mCRPC received ARN-509 orally on a continuous daily dosing schedule. Seven doses (30, 60, 90, 120, 180, 240, and 300 mg) were tested using standard 3x3 dose escalation criteria. Once drug concentrations were achieved that met or exceeded optimal levels predicted preclinically, an additional 2 dose levels were tested to further confirm the safety margin of ARN-509 (390 and 480 mg). Anti-tumor activity was assessed by PSA, radiographic responses, and FDHT-PET imaging. Results: Thirty patients were enrolled. The most common grades 1-2 treatment-related adverse events were fatigue (38%), nausea (29%), and pain (24%). There was only 1 treatment-related grade 3 adverse event (abdominal pain) at 300 mg, possibly related to a higher pill burden. PK was shown to be linear and dose-dependent. At 12 weeks, 42% of patients have had ≥ 50% PSA declines. Eleven (37%) patients have discontinued the study due to progression, with the longest patient still on study for more than 16 months. FDHT-PET imaging demonstrated AR blockade at 4 weeks across multiple dose levels. Conclusions: In this phase I study, ARN-509 was shown to be safe and well tolerated with linear PK. Based on promising activity across all dose levels and pharmacodynamic evidence of AR antagonism, an optimal biologic dose of 240 mg daily was selected for phase II investigation. DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals.

SM-368229, a Novel Promising Mineralocorticoid Receptor Antagonist, Shows Antihypertensive Efficacy With Minimal Effect on Serum Potassium Level in Rats

The purpose of this study was to evaluate the effects of SM-368229, a novel mineralocorticoid receptor (MR) antagonist with partial agonistic activity, and spironolactone (SPI) on systolic blood pressure (SBP) and serum potassium in spontaneously hypertensive rats. SM-368229 given for 2 weeks prevented the increase in SBP without serum potassium elevation, but the treatment with SPI prevented SBP increase with serum potassium elevation. To elucidate the contribution of partial agonistic activity of SM-368229 for MR in the mitigation of serum potassium elevation, we studied the relationships between sodium balance decrease, as an index of antimineralocorticoid action, and serum potassium elevation in adrenalectomized and/or potassium-loaded rats, using SM-368229 and its derivatives (DSR-11861 and DSR-14397) showing different partial agonist activities for MR (12%, 0%, and 36%, respectively). DSR-11861 and SPI reversed sodium balance and increased serum potassium. SM-368229 also reversed sodium balance but did not show apparent serum potassium increase. Although DSR-14397 did not show serum potassium increase, its antimineralocorticoid action was very weak. These findings indicate that serum potassium elevation is negatively related to partial agonistic activities for MR, and SM-368229 shows antihypertensive efficacy with minimal effect on serum potassium level, probably due to its partial agonistic property.

Positive Allosteric Modulators Differentially Affect Full versus Partial Agonist Activation of the Glycine Receptor

Taurine acts as a partial agonist at the glycine receptor (GlyR) in some brain regions such as the hippocampus, striatum, and nucleus accumbens. Ethanol, volatile anesthetics, and inhaled drugs of abuse are all known positive allosteric modulators of GlyRs, but their effects on taurine-activated GlyRs remain poorly understood, especially their effects on the high concentrations of taurine likely to be found after synaptic release. Two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes was used to compare the enhancing effects of ethanol, anesthetics, and inhalants on human homomeric α1-GlyR activated by saturating concentrations of glycine versus taurine. Allosteric modulators had negligible effects on glycine-activated GlyR while potentiating taurine-activated currents. In addition, inhaled anesthetics markedly enhanced desensitization rates of taurine- but not glycine-activated receptors. Our findings suggest that ethanol, volatile anesthetics, and inhalants differentially affect the time courses of synaptic events at GlyR, depending on whether the receptor is activated by a full or partial agonist.

Aromatase inhibitors and breast cancer.

Abstract Breast cancer is the most prevalent cancer and the second leading cause of death among women worldwide. The advent of hormonal therapy has revolutionized the treatment for breast cancer for a century. In the 1960s, an important advance was the development of the antiestrogen tamoxifen. While this drug has had a major impact on breast cancer treatment, its partial agonist activity is associated with increased risk of stroke and endometrial cancer as well as drug resistance. One of the breakthroughs in breast cancer treatment is the discovery of aromatase inhibitors (AIs) in the early 1970s. AIs have proven to be effective in treating hormone receptor-positive breast cancer and lack the estrogenic effects of tamoxifen. They are now considered to be the standard treatment for postmenopausal women with hormone receptor-positive breast cancer. While AIs are effective in treating hormone receptor-positive breast cancer, resistance to AIs inevitably occurs in metastatic setting after prolonged suppression of estrogen production. This chapter summarizes the evolution of AIs, clinical efficacy of AIs, mechanisms of AI resistance, and the strategies to overcome resistance.

Identification of a novel dopaminergic agonist that selectively activates the D2 dopamine receptor

In order to identify novel ligands with selectivity for the D2 dopamine (DA) receptor (DAR), we have interrogated small molecule chemical libraries using live cell functional assays and high throughput screening (HTS) techniques. Our primary HTS assay involves D2 DAR activation of a chimeric G protein, Gqi5, which links D2 DAR activation to Ca2+ mobilization. This process led to the identification of a ligand (compound A) that selectively activates the D2 DAR in comparison with other DAR subtypes. We found that compound A exhibits full agonist activity with EC50 values ranging from 100 nM – 1 μM using three different functional assays for the D2 DAR; Ca2+ mobilization, inhibition of cAMP accumulation, and β‐arrestin recruitment. Using β‐arrestin recruitment assays to compare with other DARs, we found that compound A has no activity at D1‐like DARs (D1 and D5), weak antagonist activity at D4 DARs (at concentrations > 10 μM), and either weak partial agonist (<20% of the DA response) or full antagonist activity at D3 DARs. Radioligand binding assays revealed that compound A exhibits Ki values of ~1 μM and ~100 nM for the D2 and D3 DARs, respectively. In summary, compound A is a full and selective agonist at the D2 DAR, although it is also functions as a D3 DAR antagonist. This is the first known compound that functionally discriminates between the D2 and D3 DARs and selectively activates the D2 DAR in the absence of D3 DAR activation.

The antipsychotic aripiprazole is a non‐competitive antagonist of dopamine‐stimulated D2 receptor interactions with β‐arrestin‐2

Aripiprazole is a recently approved drug for treating schizophrenia. It is often referred to as a 3rd generation antipsychotic with unique clinical and biological properties. Its mechanism(s) of action has been attributed to either functionally selective properties or low partial agonist activity for D2 receptor signaling. We have now evaluated the ability of aripiprazole, and 12 structurally related analogs (Vangveravong et al., 2011), to regulate D2 receptor‐β‐arrestin‐2 interactions, an important signaling arm of the D2 receptor. Two assays were employed to detect receptor‐arrestin interactions: 1) a bioluminescent resonance energy transfer (BRET) assay; and 2) a β‐galactosidsase complementation assay. In each assay, dopamine (DA) stimulates D2 receptor‐β‐arrestin interactions in a dose‐dependently. None of the aripiprazole derivatives exhibited agonist activity, although each fully antagonized the DA response. Interestingly, when the DA dose‐response curves were performed with increasing concentrations of test ligand (Schild experiments), aripiprazole and four derivatives were found to decrease the ECMAX without affecting the EC50 of DA (non‐competitive inhibition). In contrast, eight derivatives of aripiprazole decreased the EC50 of DA without affecting the ECMAX (competitive inhibition). The structure‐activity relationships for these effects are currently under investigation.

Properties of 7ND-CCL2 are modulated upon fusion to Fc

7ND, a truncated version of the chemokine MCP-1/CCL2 lacking amino acids 2-8, is a potent antagonist of CCR2. In contrast to CCL2, 7ND is an obligate monomer. Similar to other chemokines, the in vivo half-life of 7ND is very short and its use as an antagonist in disease models is thus limited. We therefore constructed a 7ND-Fc fusion protein to extend the half-life of 7ND and overcome its limitations as a potential therapeutic antagonist. When we tested the properties of the fusion molecule in vitro, we found to our surprise that 7ND-Fc, in contrast to 7ND, produced a distinct, albeit small, chemotactic response in THP-1 cells, and a robust chemotactic response in L1.2 cells stably transfected with CCR2. To test whether this unexpected observation might be due to the bivalency of 7ND-Fc stemming from the dimeric nature of Fc fusions, we produced a heterodimeric Fc fusion which displays only one 7ND moiety, using a technology called strand exchange of engineered CH3 domains (SEED). The monovalent construct had properties equivalent to the parent 7ND. Furthermore, partial agonist activity appears to depend on receptor density as well as the signaling pathway examined. However, we were able to show that 7ND-Fc, but not 7ND alone, has antagonistic activity in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis.

Separate regions of glucocorticoid receptor, coactivator TIF2, and comodulator STAMP modify different parameters of glucocorticoid-mediated gene induction

Increased specificity in steroid-regulated gene expression is a long-sought goal of endocrinologists. Considerable progress has resulted from the discovery of coactivators, corepressors, and comodulators that adjust the total activity (Amax) of gene induction. Two less frequently quantitated, but equally potent, means of improving specificity are the concentration of agonist steroid required for half-maximal activity (EC50) and the residual or partial agonist activity displayed by most antisteroids (PAA). It is usually assumed that the modulatory activity of transcriptional cofactors coordinately regulates Amax, EC50, and PAA. Here we examine the hypothesis that these three parameters can be independently modified by separate protein domains. The test system involves three differently sized fragments of each of three factors (glucocorticoid receptor [GR], coactivator TIF2, and comodulator STAMP), which are shown to form a ternary complex and similarly affect the induction properties of transfected and endogenous genes. Twenty-five different fragment combinations of the ternary complex are examined for their ability to modulate the Amax, EC50, and PAA of a transiently transfected synthetic reporter gene. Different combinations selectively alter one, two, or all three parameters. These results clearly demonstrate that Amax, EC50, and PAA can be independently regulated under some conditions by different pathways or molecular interactions. This new mechanistic insight suggests that selected activities of individual transcription factors are attractive targets for small molecules, which would have obvious clinical applications for increasing the specificity of steroids during endocrine therapies.

Phase I/II safety and pharmacokinetic (PK) study of ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase I results of a Prostate Cancer Clinical Trials Consortium study.

43 Background: In CRPC, androgen receptor (AR) overexpression is associated with resistance to first-generation anti-androgen therapy such as bicalutamide. ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. Preclinical data shows that ARN-509 binds AR with 5-fold greater affinity than bicalutamide, and induces tumor regression in hormone-sensitive and CRPC xenograft models. Methods: In this open-label, Phase 1/2 study, mCRPC patients received ARN-509 orally on a continuous daily dosing schedule. In Phase 1 , 7 doses (30, 60, 90, 120, 180, 240, 300 mg) were tested using standard 3x3 dose escalation criteria to assess safety, PK, and determine the recommended Phase 2 dose (RP2D). Preliminary anti-tumor activity was assessed by PSA kinetics, radiographic responses, circulating tumor cells (CTCs), and FDHT-PET imaging. Results: Twenty-four patients (median age 68 yrs, Gleason Score 8; prior docetaxel 13%) were enrolled. The most common Grade 1-2 treatment-related adverse events were fatigue (38%), nausea (29%), and pain (24%). There was only 1 treatment-related Grade 3 adverse event (abdominal pain) at 300 mg, possibly related to a higher pill burden, which led to an additional 3 patients being enrolled at the highest dose with no further dose limiting toxicities. PK was shown to be linear and dose-dependent. Twelve patients (55%) had ≥ 50% PSA declines. To date, 7 patients have discontinued the study due to progression, with the longest patient still on study for more than 1 year. FDHT-PET imaging demonstrated AR blockade at 4 weeks across multiple dose levels. Based on preclinical assessment of maximum efficacious dose, PK, and promising activity across all doses, 240 mg was selected as the RP2D. Conclusions: In this Phase 1 study, ARN-509 was shown to be safe and well tolerated, with promising preliminary activity based on PSA and pharmacodynamic evidence of AR antagonism. The Phase 2 portion of the study will enroll up to 90 patients with treatment-naïve non-metastatic and mCRPC.

Aripiprazole

Oral aripiprazole (Abilify®) is an atypical antipsychotic agent that is approved worldwide for use in adult patients with schizophrenia. It is a quinolinone derivative that has a unique receptor binding profile as it exhibits both partial agonist activity at dopamine D(2) receptors and serotonin 5-HT(1A) receptors and antagonist activity at 5-HT(2A) receptors. In several well designed, randomized, clinical trials of 4-6 weeks duration, aripiprazole provided symptomatic control for patients with acute, relapsing schizophrenia or schizoaffective disorder. Furthermore, following 26 weeks' treatment, the time to relapse was significantly longer for patients with chronic, stabilized schizophrenia receiving aripiprazole compared with those receiving placebo. Using a variety of efficacy outcomes, aripiprazole showed a mixed response when evaluated against other antipsychotic agents in randomized clinical trials. Longer-term data showed that improvements in remission rates and response rates favoured aripiprazole over haloperidol, although, the time to failure to maintain a response was not significantly different between the treatment arms. On the other hand, improvements in positive and negative symptom scores mostly favoured olanzapine over aripiprazole, although, the time to all-cause treatment discontinuation was not significantly different between the two treatments. Several open-label, switching trials showed that aripiprazole provided continued control of symptoms in patients with schizophrenia or schizoaffective disorder. Using a variety of efficacy outcomes or quality-of-life scores, longer-term treatment generally favoured patients switched to receive aripiprazole compared with standard-of-care oral antipsychotics. Aripiprazole was generally well tolerated in patients with schizophrenia. In particular, its use seems to be associated with a lower incidence of extrapyramidal symptoms than haloperidol and fewer weight-gain issues than olanzapine. Aripiprazole also showed a favourable cardiovascular tolerability profile and its use was associated with a reduced risk of metabolic syndrome than placebo or olanzapine. As a consequence, aripiprazole may provide a more cost-effective treatment option compared with other atypical antipsychotics. In conclusion, oral aripiprazole provides an effective and well tolerated treatment alternative for the acute and long-term management of patients with schizophrenia.

Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity

K2 and several similar purported “incense products” spiked with synthetic cannabinoids are abused as cannabis substitutes. We hypothesized that metabolism of JWH-073, a prevalent cannabinoid found in K2, contributes to toxicity associated with K2 use. Competition receptor binding studies and G-protein activation assays, both performed by employing mouse brain homogenates, were used to determine the affinity and intrinsic activity, respectively, of potential monohydroxylated (M1, M3–M5) and monocarboxylated (M6) metabolites at cannabinoid 1 receptors (CB1Rs). Surprisingly, M1, M4 and M5 retain nanomolar affinity for CB1Rs, while M3 displays micromolar affinity and M6 does not bind to CB1Rs. JWH-073 displays equivalent efficacy to that of the CB1R full agonist CP-55,940, while M1, M3, and M5 act as CB1R partial agonists, and M4 shows little or no intrinsic activity. Further in vitro investigation by Schild analysis revealed that M4 acts as a competitive neutral CB1R antagonist (Kb∼40nM). In agreement with in vitro studies, M4 also demonstrates CB1R antagonism in vivo by blunting cannabinoid-induced hypothermia in mice. Interestingly, M4 does not block agonist-mediated responses of other measures in the cannabinoid tetrad (e.g., locomotor suppression, catalepsy or analgesia). Finally, also as predicted by in vitro results, M1 exhibits agonist activity in vivo by inducing significant hypothermia and suppression of locomotor activity in mice.In conclusion, the present study indicates that further work examining the physiological effects of synthetic cannabinoid metabolism is warranted. Such a complex mix of metabolically produced CB1R ligands may contribute to the adverse effect profile of JWH-073-containing products.

Clonidine as an Adjuvant in Axillary Brachial Plexus Block for Below Elbow Orthopedic Surgeries: A Comparison Between Local and Systemic Administration

Background: Axillary brachial plexus block for below elbow orthopedic surgery provides a safe and low-cost technique with the advantage of prolonged postoperative analgesia. Clonidine, with selective partial agonist activity on adrenergic receptors, has significantly demonstrated its role in this regard as an adjuvant to local anesthetics.The current study compares the locally administered clonidine with systemically administered control group in terms of onset and duration of sensory block, motor block, and analgesia; hemodynamic variability; sedation; and other side effect profile. Materials and Methods: Seventy patients (ASA I or II) scheduled for below elbow orthopedic surgeries were randomly allocated in equal numbers to receive either 30 ml of 0.5% plain bupivacaine with 150 g (1 ml) of inj. clonidine locally in the axillary sheath and 1 ml of normal saline (NS) subcutaneously (Group L) or 30 ml of 0.5% plain bupivacaine with 1 ml of NS locally and 150 g (1 ml) of inj. clonidine subcutaneously (Group S). Standard monitoring of vital parameters was done. Duration of sensory and motor block, analgesia, hemodynamic changes, and any adverse effects were observed and recorded for different duration up to 24 h. Results: Duration of sensory block (625 ± 35 min), motor block (690 ± 38 min), and analgesia (930 ± 45 min) was significantly longer in Group L than in Group S [sensory block (480 ± 30 min), motor block (535 ± 25 min), and analgesia (720 ± 30 min)] (P < 0.05). Significant alteration of heart rate, systolic blood pressure and diastolic blood pressure, and mean arterial pressure in Group S was observed compared to Group L (P < 0.05). Side effects like nausea and vomiting were comparable,but highly significant sedation score (² = 47.75 and 49.51 at 120 and 240 min, respectively;P < 0.01) was observed between the two groups. Conclusion:Compared to systemic administration,local clonidine as an adjuvant in axillary block resulted in significant prolongation of duration of sensory and motor blockade, and analgesia without any hemodynamic alteration, probably by locally mediated mechanism of action.

Development of androgen receptor ligands by application of ten-vertex para-carborane as a novel hydrophobic core structure

We report here the design, synthesis, androgenic activity and anti-androgenic activity of novel derivatives of hexadecahedral 1,10-dicarba-closo-decaborane, which is generally called ten-vertex para-carborane. The synthesized compounds exhibited very high binding affinity for the androgen receptor and showed anti-androgenic activity toward the androgen-dependent SC-3 cell line. Two compounds also exhibited partial agonistic activity in SC-3 assay. The docking studies of carborane derivatives to AR demonstrate that ten-vertex carborane is useful for development of novel bioactive compounds as well as twelve-vertex carboranes that are well known to be versatile pharmacophores. Ten-vertex carborane, which has not previously been applied in the field of medicinal chemistry, appears to have potential as a hydrophobic pharmacophore with characteristic properties.

Clonidine as an adjuvant in axillary brachial plexus block for below elbow orthopedic surgeries: A comparison between local and systemic administration.

Background:Axillary brachial plexus block for below elbow orthopedic surgery provides a safe and low-cost technique with the advantage of prolonged postoperative analgesia. Clonidine, with selective partial agonist activity on α2 adrenergic receptors, has significantly demonstrated its role in this regard as an adjuvant to local anesthetics. The current study compares the locally administered clonidine with systemically administered control group in terms of onset and duration of sensory block, motor block, and analgesia; hemodynamic variability; sedation; and other side effect profile.Materials and Methods:Seventy patients (ASA I or II) scheduled for below elbow orthopedic surgeries were randomly allocated in equal numbers to receive either 30 ml of 0.5% plain bupivacaine with 150 μg (1 ml) of inj. clonidine locally in the axillary sheath and 1 ml of normal saline (NS) subcutaneously (Group L) or 30 ml of 0.5% plain bupivacaine with 1 ml of NS locally and 150 μg (1 ml) of inj. clonidine subcutaneously (Group S). Standard monitoring of vital parameters was done. Duration of sensory and motor block, analgesia, hemodynamic changes, and any adverse effects were observed and recorded for different duration up to 24 h.Results:Duration of sensory block (625 ± 35 min), motor block (690 ± 38 min), and analgesia (930 ± 45 min) was significantly longer in Group L than in Group S [sensory block (480 ± 30 min), motor block (535 ± 25 min), and analgesia (720 ± 30 min)] (P < 0.05). Significant alteration of heart rate, systolic blood pressure and diastolic blood pressure, and mean arterial pressure in Group S was observed compared to Group L (P < 0.05). Side effects like nausea and vomiting were comparable, but highly significant sedation score (χ2 = 47.75 and 49.51 at 120 and 240 min, respectively; P < 0.01) was observed between the two groups.Conclusion:Compared to systemic administration, local clonidine as an adjuvant in axillary block resulted in significant prolongation of duration of sensory and motor blockade, and analgesia without any hemodynamic alteration, probably by locally mediated mechanism of action.

Stargazing from a new vantage – TARP modulation of AMPA receptor pharmacology

Stargazing from a new vantage – TARP modulation of AMPA receptor pharmacology

Δ 9-Tetrahydrocannabinol attenuates MDMA-induced hyperthermia in rhesus monkeys

Background: Cannabis is commonly consumed by Ecstasy (3,4-methylenedioxymethamphetamine; MDMA) users, including as an intentional strategy to manipulate the drug experience. The most active psychoactive constituent in cannabis, Δ 9-tetrahydrocannabinol (THC), and other drugs with partial or full agonist activity at the CB 1 receptor, produces a reduction of body temperature in rodents. Reports show that administration of THC can attenuate temperature increases caused by MDMA in mice or rats; however, a recent study in humans shows that THC potentiates MDMA-induced temperature elevations. Relatively little scientific evidence on the thermoregulatory effects of THC in monkeys is available. Methods: The body temperature of male rhesus macaques was recorded after challenge with THC (0.1–0.3 mg/kg, i.m.) or combined challenge of THC with the CB 1 receptor antagonist SR141716 (Rimonabant; 0.3 mg/kg, i.m.) or combined challenge of THC (0.1, 0.3 mg/kg, i.m.) with MDMA (1.78 mg/kg p.o.) using minimally-invasive, implanted radiotelemetry techniques. Results: THC reduced the body temperature of monkeys in a dose-dependent manner with the nadir observed 3–5 h post-injection; however, an attenuation of normal circadian cooling was also produced overnight following dosing. Hypothermia induced by THC (0.3 mg/kg, i.m.) was prevented by Rimonabant (0.3 mg/kg, i.m.). Finally, 0.3 mg/kg THC (i.m.) attenuated the elevation of body temperature produced by MDMA for about 4 h after oral dosing. Conclusions: As with rodents THC produces a robust and lasting decrement in the body temperature of rhesus monkeys; this effect is mediated by the CB 1 receptor. THC also protects against the immediate hyperthermic effects of MDMA in monkeys in a dose-dependent manner. Nevertheless, a paradoxical attenuation of circadian cooling overnight after the THC/MDMA combination cautions that longer-term effects may be critical in assessing risks for the recreational user of cannabis in combination with MDMA.

NUCLEAR RECEPTORS

NUCLEAR RECEPTORS