Semi-mechanistic Modeling of the Interaction Between the Central and Peripheral Effects in the Antinociceptive Response to Lumiracoxib in Rats

The model-based approach was undertaken to characterize the interaction between the peripheral and central antinociceptive effects exerted by lumiracoxib. The effects of intraplantar and intrathecal administrations and of fixed ratio combinations of lumiracoxib simultaneously administered by these two routes were evaluated using the formalin test in rats. Pain-related behavior data, quantified as the number of flinches of the injected paw, were analyzed using a population approach with NONMEM 7. The pain response during the first phase of the formalin test, which was insensitive to lumiracoxib, was modeled using a monoexponential decay. The second phase, which was sensitive to lumiracoxib, was described incorporating synthesis and degradation processes of pain mediators that were recruited locally after tissue injury. Upregulation at the local level and in the central nervous system (CNS) was set to be proportional to the predicted levels of pain mediators in the local (injured) compartment. Results suggest a greater role of upregulated COX-2_Local in generating the pain response compared to COX-2_CNS. Drug effects were described as inhibition of upregulated COX-2. The model adequately described the time course of nociception after formalin injection in the absence or presence of lumiracoxib administered locally and/or spinally. Data suggest that the overall response is the additive outcome of drug effects at the peripheral and central compartments, with predominance of peripheral mechanisms. Application of modeling opens new perspectives for understanding the overall mechanism of action of analgesic drugs.     

Characterization of the High Sensitivity of Rabbits to the Effects of TCV-116, an Angiotensin II Receptor Antagonist

A high incidence of maternal toxicity in rabbits characterizedby uremia and death was observed when TCV-116, a novel angiotensinII subtype-1 (AT1) receptor antagonist, was orally administeredto pregnant rabbits at dosage levels of 3 mg/kg/day or more.The effects of TCV-116 on blood pressure in nonpregnant or malerabbits and rats and on blood chemistry, renal circulation,and plasma renin activity in nonpregnant or male rabbits wereexamined to characterize the toxicity in rabbits. In a 2-weekrepeated dose study, most nonpregnant female rabbits receiving3 or 100 mg/kg/day died or were sacrificed in a moribund state,indicating that toxicity could be caused independently of pregnancy.When these rabbits became moribund, marked hypotension, accompaniedby increases in plasma concentrations of urea nitrogen, creatinine,and potassium, was observed, suggesting uremia. In a singledosestudy, blood pressure in rabbits was decreased after administrationof 10 or 100 mg/kg of TCV-116, and the hypotension was moremarked and sustained than that in rats, as was the case with30 mg/kg of enalapril. The sustained pharmacological effectin rabbits was also confirmed with regard to decreases in effectiverenal plasma flow and the glomerular filtration rate and increasedplasma renin activity. Species differences in the hypotensiveeffect and mortality could not be explained by toxicokineticdata for the active metabolite of TCV-116 in various species,which supported a possibility that the differences in toxicitymay be related to the species difference in sensitivity to thepharmacological effect of TCV-116. We conclude that the specificmaternal toxicity of TCV-116 in rabbits may be mainly due tothe higher sensitivity of rabbits to the pharmacological effectsand is caused by marked and sustained hypotension resultingin the decrease in glomerular filtration rate, uremia, and death.     

Azilsartan Medoxomil,an Angiotensin II Receptor Antagonist for the Treatment of Hypertension

Azilsartan (AZL) medoxomil was approved by the United States Food and Drug Administration in 2011 for the treatment of hypertension and has shown promising results both in blood pressure (BP) reduction and in tolerability, but has not yet been taken into practice to the same extent as other angiotensin II receptor blockers (ARBs) that have been on the market for a longer period. AZL antagonizes the AT₁ receptor for angiotensin II (ANG II), whereas angiotensin‐converting enzyme inhibitors block the conversion of angiotensin I to ANG II, but not alternative routes of formation of ANG II. The bioavailability of AZL is about 60% and it has a t_max of 1.5–3 hr and a half‐life of approximately 11 hr. With its IC₅₀ of 7.4 nM after 5 hr of drug washout in radioligand assays, AZL has a tighter and longer‐lasting binding to the AT₁ receptor by several orders of magnitude than other ARBs, which might lead to a more effective reduction in BP. Clinical studies have revealed that AZL doses of 40 and 80 mg/day reduce BP significantly better than maximal clinical doses of valsartan or olmesartan, while being well tolerated and exhibiting a spectrum of adverse effects comparable to those of other ARBs. These properties of AZL might lower the risk of cardiovascular disease and thereby reduce mortality rates. However, the existing mortality studies have not found this correlation, which should be further investigated.     

Effects of Interleukin-1 Receptor Antagonist in a Slow-Release Hylan Vehicle on Rat Type II Collagen Arthritis

Purpose. To determine the effect of hylan fluid (HA), a model slow release vehicle on the pharmacokinetic profile and efficacy of interleukin-1 receptor antagonist (IL-lra) in rats with established type II collagen arthritis. Methods. Female Lewis rats with type II collagen arthritis were treated daily, every other day or every third day with single subcutaneous (sc) injections of IL-lra formulated in HA and the effects on arthritis determined. Results were compared to those obtained with IL-lra in citrate buffered saline with EDTA and polysorbate (CSEP). Sequential blood levels were determined in rats injected sc with IL-lra in CSEP or HA. Results. Incorporation into HA led to slower release of IL-lra into the bloodstream and maintained therapeutic blood levels of IL-lra for a longer time compared to the IL-lra/CSEP formulation. Single daily sc doses of 100 mg/kg IL-lra in CSEP were ineffective in type II collagen arthritis. By contrast, once per day dosing of 100 mg/kg IL-lra in HA provided 78% inhibition of paw swelling. Every other day dosing with 100 mg/kg IL-lra in HA resulted in 62% inhibition. IL-lra (100 mg/ kg in HA) given every third day provided 19% inhibition of arthritis. Improved efficacy correlated with improved pharmacokinetics. Conclusions. Administration of IL-lra in the slow release vehicle HA improves pharmacokinetics and efficacy in rat type II collagen arthritis.     

Neurogenesis-Independent Antidepressant-Like Effects on Behavior and Stress Axis Response of a Dual Orexin Receptor Antagonist in a Rodent Model of Depression

Growing evidence indicates that an increase of orexin (or hypocretin) signaling is involved in the pathophysiology of major depression, but little is known regarding the causal link between the orexinergic system and depressive-like states. Here we blocked orexin receptors in mice subjected to unpredictable chronic mild stress (UCMS) to investigate putative antidepressant-like effects of this treatment, as well as the underlying mechanisms. BALB/c mice were exposed to 9 weeks of UCMS and from the third week onward treated daily with fluoxetine (20 mg/kg per day, per os) or with the dual orexin receptor antagonist almorexant (100 mg/kg per day, per os). The effects of UCMS regimen and pharmacological treatments were assessed by physical measures and behavioral testing. The dexamethasone suppression test was performed to examine the integrity of the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, and immunohistochemical markers were used to assess cell proliferation (Ki-67), immature newborn neurons (doublecortin), and mature newborn neurons (5-bromo-2′-deoxyuridine/NeuN) in the dorsal and ventral parts of the hippocampus. Our results show that 7 weeks of fluoxetine or almorexant treatments counteract the UCMS-induced physical and behavioral alterations. Both treatments prevented the HPA axis dysregulation caused by UCMS, but only fluoxetine reversed the UCMS-induced decrease of hippocampal cell proliferation and neurogenesis, while chronic almorexant treatment decreased cell proliferation and neurogenesis specifically in the ventral hippocampus. Taken together, this is the first evidence that pharmacological blockade of the orexinergic system induces a robust antidepressant-like effect and the restoration of stress-related HPA axis defect independently from a neurogenic action.     

Application of Lipid Microspheres to Prepare a Thromboxane A2 Receptor Antagonist Aerosol for Inhalation

Abstract

The methyl ester of a new thromboxane A₂ receptor antagonist, (+)S-145, i.e.(1R,2S,3S,4S)-(5Z)-7-(3-phenylsulfonyl-aminobicyclo[2,2,1]hept-2-yl)heptenoic acid, was incorporated into lipid microspheres (lipo S-145-Me) and its pharmacological effect and tissue distribution were examined in guinea pigs following aerosol delivery. Bronchoconstrictive responses induced by intravenous injection of U46619 or the inhalation of ovalbumin were suppressed in a dose-dependent manner by aerosol inhalation of lipo S-145-Me, which was 3-10 times more potent that the unencapsulated calcium dihydrate of the original drug (S-1452). There was no significant difference in the airway tissue distribution of labelled lipo S-145-Me versus S-1452 after 2 or 5 min of inhalation, but the encapsulated drug showed marked accumulation in the lungs after 30 min of inhalation. The in vitro uptake of lipo [¹⁴C] S-145-Me by fresh human neutrophils and an eosinophil cell line was respectively 7 times and 3.5 times higher than that of [¹⁴C] S-1452. These results suggest that lipo S-145-Me has the potential to be used as an inhalational antiasthma agent, and that its effect may be partly attributable to a for inflammatory cells which are responsible for allergic airway inflammation.     

Role of Prasugrel, a Novel P2Y12 Receptor Antagonist, in the Management of Acute Coronary Syndromes

Prasugrel is a new P2Y₁₂ receptor antagonist that has been investigated for the treatment of atherothrombosis in patients with cardiovascular disease undergoing percutaneous coronary intervention (PCI). Similar to other thienopyridines, prasugrel is a prodrug that requires biologic conversion to active metabolites. Studies have demonstrated the ability of prasugrel to selectively and irreversibly inhibit ADP-induced platelet aggregation to a greater degree than clopidogrel. In a large randomized, double-blind, double-dummy clinical trial, it was demonstrated that treatment with prasugrel (n=6813; 60mg loading dose followed by 10 mg/day) significantly reduced the incidence of a composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke during the median follow-up of 14.5 months, compared with clopidogrel (n=6795; 300mg loading dose followed by 75 mg/day) in patients with acute coronary syndromes scheduled to undergo PCI. The number of patients who would need to be treated with prasugrel instead of clopidogrel in order to prevent one primary efficacy outcome was 46. Landmark analyses found that prasugrel not only reduced the incidence of individual clinical endpoints and stent thrombosis during the loading dose phase (randomization to 3 days), but also that these benefits continued throughout the maintenance phase (from 3 days until the end of the trial). Nonsurgical-related Thrombolysis In Myocardial Infarction (TIMI)-major and life-threatening bleeds were significantly more frequent in patients receiving prasugrel compared with clopidogrel. Patients with a history of stroke or transient ischemic attack (TIA) seem to be at especially high risk for bleeding, as well as patients aged >75 years and those weighing <60kg. A prespecified analysis of net clinical benefit, which took into account the effects on both the primary efficacy and safety endpoints, was conducted. After taking into account the higher bleeding rates, the net clinical benefit still favored prasugrel use compared with clopidogrel. However, patients with prior stroke or TIA, patients older than 75 years, and patients weighing <60kg did not demonstrate a net clinical benefit with prasugrel use. Prasugrel was approved for use in Europe by the European Commission in February 2009, and is currently available in the UK. In July 2009, the US Food and Drug Administration (FDA) approved the use of prasugrel for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome who are to be managed with PCI.     

Effect of Solution Phase Composition on the Interaction Between Aqueous Model Solutes and Polymeric Container Materials

The interaction between several marker solutes and a polyolefin laminate polymer was studied in several solutions. Solutions studied included mixtures of sodium chloride and dextrose (at concentrations more less typical of iv administration solutions) and several actual iv products [lactated Ringer's injection, Dianeal, Travasol (amino acid) injection, and alcohol/dextrose injection]. The interaction properties of the candidate container material correlated well with the solute's octanol–water partition coefficient. For nonionic species, the magnitude of the container/solution interaction was independent of solution phase composition. For the ionic test solute, solution pH, which impacts the speciation of the solute, was the only solution composition variable that significantly influenced the interaction. Thus water (or a weak buffer solution) is suggested as an appropriate model solvent for use in container compatibility evaluations involving iv-related products.     

Pharmacodynamics, Pharmacokinetics, and Safety of AM211: A Novel and Potent Antagonist of the Prostaglandin D2 Receptor Type 2

The prostaglandin D(2) receptor type 2 (DP2) and its ligand, PGD(2), have been implicated in the development of asthma and other inflammatory diseases. The authors evaluated the pharmacodynamics, pharmacokinetics and safety of [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid sodium salt (AM211), a novel and potent DP2 antagonist, in healthy participants. Single and multiple doses of AM211 demonstrated dose-dependent inhibition of eosinophil shape change in blood with near-complete inhibition observed at trough after dosing 200 mg once daily for 7 days. Maximum plasma concentrations and exposures of AM211 increased in a greater-than-dose-proportional manner after single and multiple dosing. After multiple dosing, the exposures on day 7 were higher than on day 1 with accumulation ratio values ranging from 1.4 to 1.5. Mean terminal half-life values ranged from 14 to 25 hours across the dose range of 100 to 600 mg. AM211 was well tolerated at all doses in both the single- and multiple-dose cohorts. These data support additional clinical studies to evaluate AM211 in asthma and other inflammatory diseases.     

Receptor Occupancy in Myocardium,Adrenal Cortex,and Brain by TH-142177, a Novel AT1 Receptor Antagonist in Rats,in Relation to Its Plasma Concentration and Hypotensive Effect

Purpose. To study the relationship between angiotensin II (All) receptor occupancy ex vivo in tissues plasma concentration and hypotensive effect of a novel All receptor antagonist, TH-142177 and losartan in rats. Methods. At 2, 8 and 24 hr after oral administration of TH-142177 and losartan in rats, All receptors in myocardium, adrenal cortex and cerebral cortex were determined by radioligand binding assay using [¹²⁵I]Sar¹,Ile⁸-AII. Plasma concentrations of both drugs and metabolite in rats were also measured using validated HPLC assays. Further, systolic blood pressure (SBP) in conscious renal hypertensive rats treated orally with TH-142177 and losartan were measured by using a tail cuff plethysmographic method. Results. Oral administration of TH-142177 (1.8 and 5.5 mol/kg) and losartan (6.5 and 21.7 mol/kg) in rats brought about dose-dependent decreases in [¹²⁵I]Sar¹,Ile⁸-AII binding sites (Bmax) in myocardium and adrenal cortex. The extent of receptor occupancy by both drugs in adrenal cortex was maximal at 2 hr later but that in myocardium at 8 hr later. Further, the receptor occupancy was more sustained in myocardium than adrenal cortex. The ex vivo binding affinity of TH-142177 for All receptors in these tissues was roughly three times higher than that of losartan. Also, cerebral cortical [¹²⁵I]Sar¹,Ile⁸-AII binding was significantly reduced by oral administration of losartan but not by TH-142177. The time course of All receptor occupancy by both drugs in adrenal cortex appeared to be in parallel with that of their plasma concentrations, while the time course in myocardium correlated with that of their hypotensive effects rather than plasma concentrations. Conclusions. TH-142177 produced a relatively selective and sustained occupancy ex vivo of All receptors in myocardium and adrenal cortex of rats with approximately three times greater potency than losartan. Its time course of myocardial receptor occupancy was in parallel with that of hypotensive effect rather than plasma concentration.     

Absorption and Disposition of a Selective Aldosterone Receptor Antagonist,Eplerenone, in the Dog

Purpose. The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog. Methods. Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg). Results. After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses. Conclusions. EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile.     

New Topics in Vasopressin Receptors and Approach to Novel Drugs: Effects of Vasopressin Receptor on Regulations of Hormone Secretion and Metabolisms of Glucose,Fat, and Protein

The neurohypophyseal peptide [Arg⁸]-vasopressin (AVP) is involved in diverse functions such as the regulation of body fluid homeostasis, metabolism, and hormone secretion. In this study, we analyzed the functional roles of AVP in hormone release and metabolisms of glucose, fat, and protein in mutant mice lacking the V1a (V1aR-KO) or V1b receptor (V1bR-KO). Our study suggests that antagonists for the receptors could affect the hormone secretions and metabolisms.     

月桂氮卓酮促进胰岛素舌下粘膜吸收的研究

研究月桂氮卓酮作为胰岛素舌下粘膜吸收促进剂对正常家兔的降血糖作用,并探讨丙二醇及微晶纤维素的增强促进作用。方法：家兔麻醉后舌下给予 ７Ｕ／ｋｇ胰岛素舌下滴剂,测定给药后 ０、３０、６０、９０、１２０、１５０、１８０、２１０．２４０ｍｉｎ时血糖。结果：与空白对照组相比,含有促进剂的各舌下给药Ⅱ、Ⅲ、Ⅳ组动物血糖的降低率有显著性差异（Ｐ＜０／０５）,其最大降低率分别为３２．６±７．２％、４９．２±４．３％及６５．０±１５．２％,结论：月桂氮卓酮是一种有效的胰岛素舌下粘膜吸收促进剂,在丙二醇和微晶纤维浆的协助下,其促进吸收能力有所增强。     

Effect of Cyclosporine and Rifampin on the Pharmacokinetics of Macitentan, a Tissue-Targeting Dual Endothelin Receptor Antagonist

Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension. We investigated the effect of cyclosporine (Cs) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects. In addition, in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides (OATPs). The clinical study (AC-055-111) was conducted as a two-part, one-sequence, crossover study. Ten subjects in each part received multiple-dose macitentan followed by multiple-dose co-administration of Cs (part A) or rifampin (part B). In the presence of Cs, steady-state area under the plasma concentration-time profiles during a dose interval (AUC(τ)) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUC(τ) of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUC(τ) between the two treatments was observed. Macitentan co-administered with Cs or rifampin was well tolerated. The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested. Concomitant treatment with Cs did not have any clinically relevant effect on the exposure to macitentan or its metabolites, at steady-state. Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinically relevant extent.     

The Effect on Plasma Glucose,Insulin and Glucagon Levels of Treatment of Diabetic Rats with the Medicinal Plant Rhazya stricta and with Glibenclamide,Alone and in Combination

Because many diabetic patients in the United Arab Emirates use medicinal plants as a supplement to treatment with insulin or oral hypoglycaemic agents, the effect on plasma glucose, insulin and glucagon concentrations of simultaneous treatment of streptozotocin-diabetic rats with Rhazya stricta extract and glibenclamide has been examined. Treatment of control rats with the extract at oral doses of 0.5, 20 and 4.0 g kg^? did not significantly affect the concentration of glucose, insulin or glucagon for up to 4 h after administration of the extract. The same doses in diabetic rats reduced the glucose level 1 h (2 and 4 gkg^?) and 2h (4 gkg^?) after administration of the extract. This was accompanied by significant increases in insulin concentration 1, 2 and 4 h after administration of the extract at doses of 2 and 4 gkg^?. Glibenclamide (2.5, 5.0 and 10.0 mgkg^?) dose-dependently reduced glucose and glucagon levels, and increased that of insulin in normal and diabetic rats. Simultaneous treatment of normal and diabetic rats with the plant extract (0.5, 20 and 5.0 gkg^?) and glibenclamide (5.0 mg kg^?) significantly exacerbated the effects on glucose, insulin and glucagon induced by the extract or by glibenclamide when given separately. When the plant extract was given at doses of 0.5, 2 and 4 g kg^? per day for 6 consecutive days the glucose level was reduced by approximately 6, 8 and 30%, respectively. No significant effect was seen on the levels of cholesterol or protein. These results imply that co-administration of the extract with glibenclamide might adversely interfere with glycaemic control in diabetic patients.     

Prodrug and Analog Approaches to Improving the Intestinal Absorption of a Cyclic Peptide,GPIIb/IIIa Receptor Antagonist

Purpose. The purpose of this study was to test whether structural modifications improve the intestinal absorption of DMP 728 (cyclo(D-Abu-NMeArg-Gly-Asp-Amb)), a GPIIb/IIIa receptor antagonist. Methods. In vitro permeabilities of prodrugs and analogs of DMP 728 across excised rat intestinal segments were determined. Results. n-Butyl and n-octyl esters of DMP 728 were relatively stable during in vitro permeation of rat intestine. Intestinal permeation rates of these compounds were no greater than that of DMP 728, even though the octyl ester was much more lipophilic. A pivaloyloxymethyl ester, which was hydrolyzed to DMP 728 during intestinal permeation, also did not improve permeability. In another approach, analogs with an additional methyl substituent on various amide nitrogens were evaluated. Cyclo(D-Val-NMeArg-Gly-Asp-NMeAmb), cyclo(D-Abu-diN-MeLys-Gly-Asp-Amb), and cyclo(NMeGly-NMeArg-Gly-Asp-Amb) each had about 2-fold greater permeability than DMP 728. Two other analogs with improved permeability were linear Ac-D-Abu-NMeArg-Gly-Asp-Amb and a DMP 728 derivative in which the Asp was rearranged. An analog in which the charged amino acids were replaced by neutral amino acids had permeability similar to DMP 728. Conclusions. Within this series of peptides, hydrogen bonding tendency and structural constraint influenced intestinal permeation, but not always in ways consistent with the literature, whereas charge and lipophilicity were not shown to influence intestinal permeability. The failure of these approaches to improve permeation more significantly could be due to the influence of secretory transport.     

Differential Effects of a Dual Orexin Receptor Antagonist (SB-649868) and Zolpidem on Sleep Initiation and Consolidation,SWS, REM Sleep,and EEG Power Spectra in a Model of Situational Insomnia

Orexins have a role in sleep regulation, and orexin receptor antagonists are under development for the treatment of insomnia. We conducted a randomised, double-blind, placebo-controlled, four-period crossover study to investigate the effect of single doses of the dual orexin receptor antagonist SB-649868 (10 or 30 mg) and a positive control zolpidem (10 mg), an allosteric modulator of GABA_A receptors. Objective and subjective sleep parameters and next-day performance were assessed in 51 healthy male volunteers in a traffic noise model of situational insomnia. Compared with placebo, SB-649868 10 and 30 mg increased total sleep time (TST) by 17 and 31 min (p<0.001), whereas after zolpidem TST was increased by 11.0 min (p=0.012). Wake after sleep onset was reduced significantly by 14.7 min for the SB–6489698 30 mg dose (p<0.001). Latency to persistent sleep was significantly reduced after both doses of SB–6489698 (p=0.003), but not after zolpidem. Slow wave sleep (SWS) and electroencephalogram (EEG) power spectra in non-REM sleep were not affected by either dose of SB-640868, whereas SWS (p< 0.001) and low delta activity (<=1.0 Hz) were increased, and 2.25–11.0 Hz activity decreased after zolpidem. REM sleep duration was increased after SB-649868 30 mg (p=0.002) and reduced after zolpidem (p=0.049). Latency to REM sleep was reduced by 20.1 (p=0.034) and 34.0 min (p<0.001) after 10 and 30 mg of SB-649868. Sleep-onset REM episodes were observed. SB-649868 was well tolerated. This dual orexin receptor antagonist exerts hypnotic activity, with effects on sleep structure and the EEG that are different from those of zolpidem.     

A Novel Design of Artificial Membrane for Improving the PAMPA Model

PURPOSE: Since the first demonstration of PAMPA, the artificial membrane has been traditionally prepared by impregnating a porous filter with a solution of lipid mixture. While the lipid solution-based method is simple and seems to provide good predictability for many compounds, it is challenged by several shortcomings including reproducibility, stability, mass retention and the incorrect prediction of a group of highly permeable compounds including caffeine and antipyrine. Here we present the validation of a novel artificial membrane formed by constructing a lipid/oil/lipid tri-layer in the porous filter. METHODS: Permeability values obtained from traditional and new artificial membrane were compared for their correlation with Caco-2 and human absorption values. Mass retention, stability and organic solvent compatibility of the new artificial membrane were studied. RESULTS: The new artificial membrane correctly predicts the permeability of the traditionally under-predicted compounds and improves the correlation with Caco-2 and human absorption values. Furthermore, the new artificial membrane reduces the mass retention of compounds that are highly retained by the traditional artificial membrane. The new artificial membrane is also found to be robust enough to sustain long term storage and has good compatibility with organic solvents. CONCLUSIONS: The new artificial membrane provides an improved PAMPA model.