Inhibitory effect of Ketotifen on rat isolated uterus contraction in compare with a β2-adrenoceptor agonist and an ATP-dependent K channel activator

Ketotifen is a Benzocycloheptathiophene with a range of pharmacological activities, including inhibitory effect on ileum and bladder smooth muscle contraction. However, effect of Ketotifen on uterus contraction has not been investigated. The present study was carried out to look for action of Ketotifen on rat isolated uterus contractions, induced by KCL and Acetylcholine, compared with effects of other drugs. Ketotifen inhibited the response to 80 mM KCL in a concentration-dependent manner (pD2=6.2±0.13) and shifted Acetylcholine concentration-response curve by 25 folds to the right at 5 µM bath concentration. Effect of Ketotifen on KCL concentration-response curve was similar to that of metaproterenol, inhibiting the response to all concentration of KCL and attenuating the maximum response. Diazoxide only at very high concentrations (50 and 500 µM) inhibited the induced contractions. This study showed that Ketotifen is a relaxant of rat isolated uterus. As the inhibition of contractile over-activity of the uterus is the base of the treatment of pre-term labor, provided that similar effect will be seen in vivo, then Ketotifen may have clinical benefits for treatment of this condition

Effects of some drugs on autonomic responses of Guinea pig seminal vesicle smooth muscle

Seminal vesicle smooth muscle contraction is mediated through sympathetic and parasympathetic activity. Although seminal vesicle plays an important role in male fertility, but little attention is given to mechanism involved in contraction of this organ. In this study effects of various drugs were examined on the contractile responses elicited by electrical field stimulation (EFS), Noradrenaline (NA), and Carbachol (CAR) in guinea-pig seminal vesicle. Atropine and Prazosin in concentrations, which totally blocked CAR and NA response respectively, reduced the response to EFS by 40% With Atropine and Prazosin together about 15% of the response remains. ATP seemed unlikely to be the additional spasmogen, since exogenous ATP had an inhibitory effect on EFS. Clonidine concentration-dependently blocked responses to NA, but potentiated the responses to EFS. Yohimbine produced a qualitatively similar effect, blocking the NA responses and reducing the EFS responses. These results are inconsistent with presynaptic α2-adrenoceptor exerting an inhibitory effect on NA release, but could be interpreted as post-synaptic α1-adrenoceptor blocked by both Clonidine and Yohimbine, but it is not clear how Yohimbine potentiate the EFS responses. Guanethidine progressively inhibited the EFS response while potentiated the NA responses. These findings allow the suggestion that NA, endogenous or exogenous, is removed from synapses by an uptake process, which is blocked, by Guanethidine and, that Guanethidine inhibits the release of neurotransmitter(s)

Inhibitory effects of Ketotifen in comparison with Terbutaline, Diazoxide and Diclofenac on spontaneous contractions of uterus in conscious rat

کتوتیفن یک بنزوسیکلوهپاتوفن با فعالیت های متعدد فارماکولوژیکی از جمله اثرات رفع انقباضی بر روی انقباضات ناشی از KCI، استیل کولین و اکسی توسین در بافت ایزوله شده رحم رات است. از آنجا که اساس درمان زایمان های زودرس بر مهار انقباضات زودرس رحم استوار است، در صورتی که کتوتیفن اثرات مشابهی بر روی رحم در In vivo هم داشته باشد، این دارو ممکن است برای درمان این عارضه مفید باشد. به همین دلیل اثرات این دارو بر روی انقباضات رحم در موش هوشیار بررسی شد و با آگونیست X2-آدرنوسپتور، تربوتالین و مهار کننده سنتز پروستاگلاندین ها، دیکلوفناک و فعال کننده کانال های پتاسیمی وابسته به ATP، دیازاکسید مقایسه گردید. علاوه براین، اثرات داروهای فوق بر روی فشار خون و ضربان قلب در شرایط مشابهی نیز بررسی شد. برای این منظور رات های ماده غیر حامله با کتامین بیهوش و اورکتومی گردیدند. سپس میکروبالون در رحم رات ها قرار داده شد و ورید ژاگولار نیز کانوله شد. یک روز بعد از عمل جراحی که رات ها آزادانه مشغول به تغذیه شدند، کانوله ژاگولار به سرنگ پمپ انفوزیون حاوی دارو و کانوله میکروبالون به Pressure transducer جهت ثبت انقباضات رحم با دستگاه فیزیوگراف متصل گردید. تجویز تربوتالین (400µg/kg) اثر مهاری سریعی بر روی انقباضات رحم داشت و پس از اتمام تجویز دارو (15 دقیقه) میزان انقباضات به 3±6 کنترل رسید. این اثرات مهاری تا 2 ساعت بعد هنوز ادامه داشت. دیازاکسید (45mg/kg) نیز اثر مهاری بر روی انقباضات رحم در موش هوشیار داشت و در زمان فوق انقباضات بترتیب به 5±13 میزان کنترل تقلیل یافت. ولی کتوتیفن در دز بالا هم نتوانست انقباضات خودبخودی رحم در Rat هوشیار را مهار کند و تفاوت معنی داری بین نرمال سالین و کتوتیفن (15mg/kg) مشاهده نشد. از طرف دیگر دیکلوفناک (75mg/kg) اثر مهاری خوبی بر روی انقباضات رحم Rat هوشیار داشت و در پایان آزمایش مقدار انقباضات هنوز 7±23 میزان کنترل قبل از دارو بود. دیازاکسید نیز اثر مهاری واضحی بر روی انقباضات رحم داشت. کتوتیفن و دیکلوفناک تغییر معنی داری در فشار خون بوجود نیاوردند ولی دیازاکسید و تربوتالین موجب کاهش فشار خون شدند. تربوتالین همچنین موجب افزایش ضربان قلب و دیازاکسید در دزهایی که اثرات مهاری بر روی انقباضات رحم داشت موجب کاهش ضربان قلب گردیدند. اثر مهاری دیکلوفناک بر روی انقباضات رحم In vivo مبین این است که سنتز و آزادسازی پروستاگلاندین ها در تولید انقباضات خودبخودی رحم Rat در روش بکار برده شده نقش مهمی دارد و ممکن است که کتوتیفن نتواند انقباضات ناشی از پروستاگلاندین ها را مهار کند. از این مطالعه می توان نتیجه گیری کرد که این روش راه مناسبی برای بررسی اثرات داروها بر روی انقباضات رحم ناشی از آزادسازی پروستاگلاندین ها در In vivo است و از آنجا که پروستاگلاندین ها نقش عمده ای در شروع زایمان های زودرس دارند کتوتیفن احتمالا داروی مناسبی برای کنترل انقباضات زودرس رحم در In vivo نیست

Driving simulator motion base right sizing

Driving simulator motion bases are available having various mechanisms and characteristics; among them, the synergistic 6DoF hexapod-type integrated with a sliding rail is the most commonly used. There is a large variety in workspaces (sizes) of both the hexapod and sliding rail used in research and training simulators, and there lacks consensus on what size of motion base is really needed in order to have high fidelity motion cueing. In this paper we introduce an approach that balances between having high fidelity motion cueing and at the same time addressing the minimum size requirement to reduce the purchase cost. A conventional classic motion cueing algorithm (MCA) is used together with an optimization method to establish the minimum workspace requirement, while meeting the fidelity criteria defined in literature. The right sizing requirements are driving task dependent, so in order to test this method, low and high motion-demanding driving tasks are tested using the experimental data collected from professional drivers. A standard (high) and a reduced (low) amount of tilt coordination is selected, showing how this defines a range of rail sizes to consider

An objective assessment of the utility of a driving simulator for low mu testing

Driving simulators can be used to test vehicle designs earlier, prior to building physical prototypes. One area of particular interest is winter testing since testing is limited to specific times of year and specific regions in the world. To ensure that the simulator is fit for purpose, an objective assessment is required. In this study a simulator and real world comparison was performed with three simulator configurations (standard, no steering torque, no motion) to assess the ability of a utility triplet of analyses to be able to quantify the differences between the real world and the different simulator configurations. The results suggest that the utility triplet is effective in measuring the differences in simulator configurations and that the developed “Virtual Sweden” environment achieved rather good behavioural fidelity in the sense of preserving absolute levels of many measures of behaviour. The main limitation in the simulated environment seemed to be the poor match of the dynamic lateral friction limit on snow and ice when compared to the real world

1549TiP DeLLphi-303: Phase Ib first-line combination study of tarlatamab, a DLL3-targeting half-life extended bispecific T-cell engager (HLE BiTE®), with carboplatin, etoposide, and PD-L1 inhibition in extensive stage small cell lung cancer (ES-SCLC)

Background: The inhibitory Notch ligand, delta-like ligand 3 (DLL3), is a compelling therapeutic target due to its aberrant expression on the cell surface in most small cell lung cancer (SCLC). Tarlatamab (AMG 757) is a half-life extended bispecific T-cell engager (HLE BiTE®) molecule designed to specifically bind DLL3 on target cancer cells and CD3 on T cells, resulting in T cell-dependent killing of tumor cells. Data from an ongoing first-in-human monotherapy study show acceptable safety with evidence of tarlatamab efficacy in patients with relapsed/refractory SCLC (NCT03319940). Adding programmed death ligand 1 (PD-L1) inhibitors to first-line platinum chemotherapy is the emerging standard-of-care (SOC) in ES-SCLC and preclinical data suggests increased antitumor activity of BiTE molecules when combined with PD-1/PD-L1 inhibition or chemotherapy.1 These data support a clinical trial of tarlatamab combined with frontline carboplatin, etoposide, and PD-L1 inhibition in ES-SCLC. Trial design: This is a phase 1b, multicenter, open-label study evaluating tarlatamab in combination with first-line SOC chemo-immunotherapy in subjects with ES-SCLC. Tarlatamab will be evaluated in two separate settings: A) In combination with carboplatin, etoposide, and a PD-L1 inhibitor followed by maintenance cycles of tarlatamab plus PD-L1 inhibitor, and B) In combination with PD-L1 inhibitor following SOC chemo-immunotherapy as a maintenance only approach. Key eligibility criteria include patients with histologically or cytologically confirmed ES-SCLC with no prior systemic treatment (except as specified in protocol) and ECOG performance status ≤1. The primary objective is to evaluate the safety, tolerability, and determine the recommended phase 2 dose and/or maximum tolerated dose of tarlatamab in combination with PD-L1 inhibition with or without chemotherapy. Secondary endpoints are objective response rate, duration of response, disease control, progression-free survival, overall survival, and pharmacokinetics

Citral Sensing by TRANSient Receptor Potential Channels in Dorsal Root Ganglion Neurons

Transient receptor potential (TRP) ion channels mediate key aspects of taste, smell, pain, temperature sensation, and pheromone detection. To deepen our understanding of TRP channel physiology, we require more diverse pharmacological tools. Citral, a bioactive component of lemongrass, is commonly used as a taste enhancer, as an odorant in perfumes, and as an insect repellent. Here we report that citral activates TRP channels found in sensory neurons (TRPV1 and TRPV3, TRPM8, and TRPA1), and produces long-lasting inhibition of TRPV1–3 and TRPM8, while transiently blocking TRPV4 and TRPA1. Sustained citral inhibition is independent of internal calcium concentration, but is state-dependent, developing only after TRP channel opening. Citral's actions as a partial agonist are not due to cysteine modification of the channels nor are they a consequence of citral's stereoisoforms. The isolated aldehyde and alcohol cis and trans enantiomers (neral, nerol, geranial, and geraniol) each reproduce citral's actions. In juvenile rat dorsal root ganglion neurons, prolonged citral inhibition of native TRPV1 channels enabled the separation of TRPV2 and TRPV3 currents. We find that TRPV2 and TRPV3 channels are present in a high proportion of these neurons (94% respond to 2-aminoethyldiphenyl borate), consistent with our immunolabeling experiments and previous in situ hybridization studies. The TRPV1 activation requires residues in transmembrane segments two through four of the voltage-sensor domain, a region previously implicated in capsaicin activation of TRPV1 and analogous menthol activation of TRPM8. Citral's broad spectrum and prolonged sensory inhibition may prove more useful than capsaicin for allodynia, itch, or other types of pain involving superficial sensory nerves and skin

SENSITIVE EFFECTS OF POTASSIUM AND CALCIUM CHANNEL BLOCKING AND ATP-SENSITIVE POTASSIUM CHANNEL ACTIVATORS ON SEMINAL VESICLE SMOOTH MUSCLE CONTRACTIONS

<font><font color="#555555"><span style="font-size: 10pt; font-family: Tahoma">Background. Seminal vesicle smooth muscle contraction is mediated through sympathetic and parasympathetic neurons activity. Although seminal vesicle plays an important role in male fertility, but little attention is given to mechanism involved in contraction of this organ.<br />Methods. In this study effects of drugs which activate ATP - sensitive K channels and blockers of K and Ca channels were examined on contraction of guinea - pig isolated seminal vesicle due to electrical filled stimulation (EFS), noradrenaline, carbachol and KCI.<br />Results. The K channel blocker tetraethyl ammonium potentate the EFS responses at all frequencies, while, the ATP - sensitive K channel inhibitor glibenclamide and the K channel opener levcromakalim, diazoxide, minoxidil and Ca channel blocker nifedipine all had relaxant effect on guinea - pig seminal vesicle.<br />Discussion. This study indicate that activities of K and Ca channels is important in regulation of seminal vesicle contraction due to nerve stimulation, noradrenaline or carbachol.</span></font></font&gt