Long Duration Of Action Research Articles

A versatile toxicity evaluation of ethyl carbamate (urethane) on zebrafish embryos: Morphological, physiological, histopathological, immunohistochemical, transcriptional and behavioral approaches

Ethyl carbamate (EC, urethane), which is used as an anesthetic especially by veterinarians due to its very long duration of action, is also a naturally occurring compound in all fermented foods and beverages. Although the health problem of EC is related to its carcinogenic potential, the scarcity of current studies that can be used in the evaluation of usage limits encouraged us to do this study. In this context, zebrafish embryos were exposed to serial doses of EC. According to the results, it was observed that EC exposure caused a significant decrease in survival and hatching rates as well as significant body malformations. Whole-mount staining results showed that EC caused dose-dependent increased apoptosis. Oxidative stress caused by EC exposure was demonstrated by whole-mount staining, transcriptional and immunohistochemically. Furthermore, it has been shown histochemically that EC exposure causes necrosis and degeneration in the brain. In behavioral tests, it was observed that EC caused hyperactivity associated with these neuronal degenerations. In addition, a dramatic decrease in blood flow was detected in association with pericardial edema. In the light of the current results, it should be carefully considered that EC can be found naturally in many human diets, especially fermented foods.

The use of diverted pharmaceutical opioids is associated with reduced risk of fentanyl exposure among people using unregulated drugs in Vancouver, Canada

BackgroundAlthough non-medical use of pharmaceutical opioids (POs) is associated with a number of risks, in the context of the opioid-overdose crisis, it may have the secondary benefit of decreasing the risk of exposure to more potent opioids from unregulated sources. The aim of this study was to assess the effects of using diverted POs on fentanyl exposure. MethodsUsing data from two prospective community-recruited cohorts of people who use drugs (PWUD) in Vancouver, Canada, we estimated the independent relationship between using diverted POs and fentanyl exposure (assessed through urine drug test [UDT]) between 2016 and 2018. We also explored if participant characteristics modified this relationship. ResultsOver the study period, among 1150 participants, 241 (21.0%) reported using diverted POs in 292 (12.8%) occasions. In adjusted analyses, PWUD using diverted POs had decreased odds of fentanyl exposure (Adjusted odds ratio [AOR] = 0.70, 95% CI: 0.52–0.94). The reduced odds of fentanyl exposure persisted among participants with morphine positive UDT (AOR = 0.57, 95% CI: 0.40–0.82), but not among those with negative morphine UDT (AOR = 0.91, 95% CI: 0.54–1.55). ConclusionPWUD using diverted POs in our sample were 30% less likely to be exposed to fentanyl. This reduced likelihood was primarily observed among PWUD with morphine positive UDT, which could partially be explained by longer duration of action and lower street cost of slow-release oral morphine relative to other POs and fentanyl. Findings suggest that access to a regulated supply of pharmaceutical-grade opioids may serve to reduce fentanyl-related harms.

Network robustness and structure depend on the phenological characteristics of plants and pollinators.

Many structural patterns have been found to be important for the stability and robustness of mutualistic plant–pollinator networks. These structural patterns are impacted by a suite of variables, including species traits, species abundances, their spatial configuration, and their phylogenetic history. Here, we consider a specific trait: phenology, or the timing of life history events. We expect that timing and duration of activity of pollinators, or of flowering in plants, could greatly affect the species' roles within networks in which they are embedded. Using plant–pollinator networks from 33 sites in southern British Columbia, Canada, we asked (a) how phenological species traits, specifically timing of first appearance in the network and duration of activity in a network, were related to species' roles within a network, and (b) how those traits affected network robustness to phenologically biased species loss. We found that long duration of activity increased connection within modules for both pollinators and plants and among modules for plants. We also found that date of first appearance was positively related to interaction strength asymmetry in plants but negatively related to pollinators. Networks were generally more robust to the loss of pollinators than plants, and robustness increased if the models allow new interactions to form when old ones are lost, constrained by overlapping phenology of plants and pollinators. Robustness declined with the loss of late‐flowering plants, which tended to have higher interaction strength asymmetry. In addition, robustness declined with loss of early‐flying or long‐duration pollinators. These pollinators tended to be among‐module connectors. Our results point to networks being limited by early‐flying pollinators. If plants flower earlier due to climate change, plant fitness may decline as they will depend on early emerging pollinators, unless pollinators also emerge earlier.

Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety

BackgroundMarzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia. ObjectivesTo investigate if daily SC administration of MarzAA in subjects with inhibitors can provide effective prophylaxis. MethodsThis multicenter, open‐label phase 2 trial (NCT03407651) enrolled men with severe congenital hemophilia with an inhibitor. All subjects had a baseline annualized bleeding rate (ABR) of ≥12 events/year. Subjects received a single 18 μg/kg intravenous dose of MarzAA to measure 24‐hour pharmacokinetics (PK) and pharmacodynamics (PD), single 30 μg/kg SC dose to measure 48‐hour PK/PD, then daily SC 30 μg/kg MarzAA for 50 days. If spontaneous bleeding occurred, the dose was sequentially escalated to 60, 90, or 120 μg/kg, with 50 days at the final effective dose without spontaneous bleeding to proceed to a 30‐day follow‐up. The primary end point was reduction in ABR. Secondary end points were safety, tolerability, and antidrug antibody (ADA) formation. ResultsIn the 11 subjects, the mean ABR significantly reduced from 19.8 to 1.6, and the mean proportion of days with bleeding significantly reduced from 12.3% to 0.8%. Of a total of 517 SC doses, six injection site reactions in two subjects were reported. No ADAs were detected. One fatal unrelated serious adverse event occurred: intracerebral hemorrhage due to untreated hypertension. ConclusionsThe data demonstrated that MarzAA was highly efficacious for prophylactic treatment in patients with inhibitors by significantly decreasing bleed frequency and duration of bleeding episodes.

Membrane-Facilitated Receptor Access and Binding Mechanisms of Long-Acting β2-Adrenergic Receptor Agonists.

The drugs salmeterol, formoterol, and salbutamol constitute the frontline treatment of asthma and other chronic pulmonary diseases. These drugs activate the β2-adrenergic receptors (β2-AR), a class A G protein-coupled receptor (GPCR), and differ significantly in their clinical onset and duration of actions. According to the microkinetic model, the long duration of action of salmeterol and formoterol compared with salbutamol were attributed, at least in part, to their high lipophilicity and increased local concentrations in the membrane near the receptor. However, the structural and molecular bases of how the lipophilic drugs reach the binding site of the receptor from the surrounding membrane remain unknown. Using a variety of classic and enhanced molecular dynamics simulation techniques, we investigated the membrane partitioning characteristics, binding, and unbinding mechanisms of the ligands. The obtained results offer remarkable insight into the functional role of membrane lipids in the ligand association process. Strikingly, salmeterol entered the binding site from the bilayer through transmembrane helices 1 and 7. The entry was preceded by membrane-facilitated rearrangement and presentation of its phenyl-alkoxy-alkyl tail as a passkey to an access route gated by F193, a residue known to be critical for salmeterol's affinity. Formoterol's access is through the aqueous path shared by other β2-AR agents. We observed a novel secondary path for salbutamol that is distinct from its primary route. Our study offers a mechanistic description for the membrane-facilitated access and binding of ligands to a membrane protein and establishes a groundwork for recognizing membrane lipids as an integral component in the molecular recognition process. SIGNIFICANCE STATEMENT: The cell membrane's functional role behind the duration of action of long-acting β2-adrenergic receptor (β2-AR) agonists such as salmeterol has been a subject of debate for a long time. This study investigated the binding and unbinding mechanisms of the three commonly used β2-AR agonists, salmeterol, formoterol, and salbutamol, using advanced simulation techniques. The obtained results offer unprecedented insights into the active role of membrane lipids in facilitating access and binding of the ligands, affecting the molecular recognition process and thus their pharmacology.

Reversible Covalent PROTACs: Novel and Efficient Targeted Degradation Strategy.

The proteolysis targeting chimeras (PROTACs), which are composed of a target protein binding moiety, a linker, and an E3 ubiquitin ligase binder, have been a promising strategy for drug design and discovery. Given the advantages of potency, selectivity, and drug resistance over inhibitors, several PROTACs have been reported in literature, which mostly focus on noncovalent or irreversible covalent binding to the target proteins. However, it must be noted that noncovalent or irreversible PROTACs have several drawbacks such as weak binding affinity and unpredictable off-target effects. Reversible covalent PROTACs, with properties of enhanced potency, selectivity, and long duration of action, have attracted an increasing amount of attention. Here, we propose a comparison between these three patterns and highlight that reversible covalent PROTACs could pave the way for a wide variety of challenging target degradations.

Supraclavicular Versus Infraclavicular Brachial Plexus Block Using Two Different Techniques: Comparative Study

Background: A perfectly conducted regional anesthetic guided by ultrasound offers much to anesthesiologists. Objective: This study was aimed to compare supraclavicular block with infraclavicular brachial plexus block for anesthesia in the forearm, hand surgery using two different methods: ultrasound alone or ultrasound together with a nerve stimulator. Patients and Methods: This prospective randomized study was performed on 80 adult patients, aged from 20 to 60 years, with ASA (American Society of Anesthesiology) physical status I and II. Patients were randomized in one of four groups: Supraclavicular block used Ultrasound (n =20), Supraclavicular block used ultrasound with nerve stimulator (n =20), Infraclavicular block used Ultrasound (n =20), Infraclavicular block used ultrasound with nerve stimulator (n =20). The local anesthetic solution used consisted of a 1:1 volume of 0.5 % bupivacaine and 2% lidocaine with 1:200.000 adrenaline. This solution was injected in a dose of 0.5 ml/kg to maximal 40 ml. The Measured parameters were: Demographic values, the scanning time, the block performance time, the onset time, the degree of pain during block performance, evaluation of sensory and motor block, and complications. Result: There were no significant differences between groups as regards all measured parameters. Conclusion: It could be concluded that the supraclavicular nerve block showed no significant difference from infraclavicular ultrasound-guided with or without nerve stimulator. It remains controversial whether the adding of the nerve stimulation to the ultrasound is more beneficial in ensuring rapid onset, longer duration of action, and avoiding complications.

Weekly Insulin Becoming a Reality

Insulin was first isolated in 1921 and developed as a therapeutic agent in the 1920s. The initial crude preparations were injected multiple times daily because of their short duration of action. Consequently, there were many attempts to develop insulin preparations with prolonged biological availability in the hope that less frequent once-daily administration would be feasible (1). A host of such preparations were introduced, including protamine insulin, protamine zinc insulin, surfen insulin, globin insulin, iso-insulin, isophane insulin (NPH), and insulin zinc suspensions (lente insulins) (1) (Fig. 1). The goal was mainly to reduce the number of injections and thus the patient burden. Yet, with the development of a radioimmunoassay for insulin (2), it became apparent that physiologic insulin secretion involved two components: meal-related insulin secretion with postprandial spikes and basal insulin secretion that remains relatively constant with some minor pulsatility (3). Subsequently, as modern insulin therapy evolved, facilitated by patient self-monitoring of blood glucose (4,5), it became apparent that the inherent peaks in basal insulin preparations, such as with the nonsoluble NPH or lente insulins, created risk of hypoglycemia, especially if the insulin vials were not correctly rolled to create a proper suspension. Moreover, these insulins did not have sufficiently long duration of action to be used once daily. Consequently, in addition to making them soluble, two of the goals in development of basal insulin analogs, such as insulin glargine and insulin detemir, were to eliminate insulin peaks and to prolong the action to approach 24 h (6,7). Second-generation basal insulin analogs, such as insulin degludec and insulin glargine U300, came with …

A comparative clinical study of methylprednisolone with ondansetron versus methylprednisolone with ramosetron in preventing postoperative nausea and vomiting in patients undergoing middle ear surgeries

Background: Postoperative nausea and vomiting (PONV) is one of the most unpleasant complications of anaesthesia and is more common following middle ear surgeries. Ondansetron, a 5-HT3 (5-hydroxytryptamine type 3) receptor antagonist provides significant reduction in early PONV. The other 5-HT3 antagonist ramosetron, with long duration of action, has been found to be more effective than ondansetron in reducing the early as well as delayed PONV. The antiemetic effects of glucocorticoids (dexamethasone and methylprednisolone) are well documented. So, the present study was designed to compare the efficacy of the combination of intravenous methylprednisolone and ondansetron with combination of intravenous methylprednisolone and ramosterone in preventing postoperative nausea and vomiting in patients undergoing middle ear surgeries. Methods: Sixty patients in the age group of 18-60 years, with American Society of Anaesthesiologists (ASA) physical status classification I or II, undergoing middle ear surgery were randomly allocated to receive a combination of methylprednisolone 40 mg (given at the beginning of surgery) and ondansetron 4 mg (given near the end of surgery) (group MO, n=30) or combination of intravenous methylprednisolone 40 mg and ramosetron 0.3 mg (near the end of surgery) (group R, n=30), by a computer-generated randomization table. Incidence of PONV in the both groups were studied and compared. Results: There was no significant difference in PONV between the groups in the first 2 h after the surgery. Between 2 and 24 h, the incidence of nausea was significantly lower in the methylprednisolone and ondansetron group compared to the methylprednisolone and ramosetron group (P=0.01). Between 24 and 48 h, there was no difference between the two groups with respect to incidence of nausea and vomiting. Conclusion: The combination of methylprednisolone and ondansetron is superior to combination of methylprednisolone and ramosetron for prevention of PONV after middle ear surgery especially in treatment of early PONV. Therefore, we recommend combination of methylprednisolone and ondansetron for prophylaxis for PONV in middle ear surgeries.

A 4 Year Experience with Copper T Intrauterine Contraceptive Device at Federal Medical Centre (Fmc), Katsina

Background: The prevalence of contraceptive use is still very low in Nigeria. Use of modern contraceptive methods has been shown to reduce unwanted pregnancy, high parity and maternal mortality. Objectives: The aim of this study is to determine the acceptance rate of intrauterine contraceptive method, the socio-demographic characteristics of its users, side-effects, discontinuation and the reason thereof, at Federal Medical Centre, Katsina. Method: A retrospective study that reviewed records of all clients who used intrauterine contraceptive method at the family planning clinic over a 4-year period (1st January 2011 to 31st December 2014). Results: Out of the 1892 family planning clients, 111 used IUCD, with IUCD acceptance rate of 5.87%. The modal age group was 20-24 years (30.0%). Most of them (n=54) were grandmultiparous (48.6%), and of Islamic faith (98%). Almost all the clients were married (97.8%), and majority had secondary education (71%). Thirty- ive (31.5%) of the users discontinued the method, with the commonest indication being desire for pregnancy (45.7%). No contraceptive failure was recorded during the study period. Conclusion: IUCD is the fourth commonly used method. Its use is influenced by maternal age, parity and literacy level. In spite of its long duration of action, most of the reversal was due to the desire for pregnancy. Acceptability of IUCD can be improved by health education, adequate counseling and careful client selection.

Modern H1- antihistamines in the treatment of allergic rhinitis: focus on bilastine

The second generation of H1-antihistamines is approved for the stepwise treatment of seasonal and perennial allergic rhinitis in adults and children by international and national guidelines. They reduce the severity of nasal and ocular symptoms of rhinitis and improve the quality of life of patients.
 Bilastine, a piperidine derivative, is a novel H1-antihistamine. It has a potent and selective effect on H1- receptors and a rapid onset and long duration of action and substantially reduces nasal and ocular symptoms of seasonal and perennial allergic rhinitis. Bilastine has no clinically substantial hepatic metabolism and has a high safety profile: it has no sedative effect, does not affect cognitive functions, has no cardiotoxic effects, and does not interact with alcohol and benzodiazepines in normal and high doses. Tachyphylaxis does not develop despite long-term (up to 1 year) use.
 Bilastine is registered for clinical use in adults and children aged 12 years. The results of clinical and experimental studies have demonstrated that bilastine has many of the features of modern H1-antihistamines recommended by international guidelines.

Solubility and Dissolution Enhancement of Ebastine by Surface Solid Dispersion Technique

Ebastine (EBS) is a non-sedating antihistamine with a long duration of action. This drug has predominantly hydrophobic property causing a low solubility and low bioavailability. Surface solid dispersions (SSD) is an effective technique for improving the solubility and dissolution rate of poorly soluble drugs by using hydrophilic water insoluble carriers.
 The present study aims to enhance the solubility and dissolution rate of EBS by using surface solid dispersion technique. Avicel® PH101, Avicel® PH 102, croscarmellose sodium(CCS) and sodium starch glycolate(SSG) were used as water insoluble hydrophilic carriers.
 The SSD formulations of EBS were prepared by the solvent evaporation method in different drug: carrier weight ratios and evaluated for their percentage yield, drug content , water solubility, dissolution study in 0.1 N HCl, crystal lattice using powder X-ray diffraction (PXRD) and Fourier Transform Infrared Spectroscopy (FTIR) for determination the drug-carrier interaction.
 Most of the prepared SSD formulas showed improvement of drug solubility. The best result was obtained with formula SSD16 (EBS:CCS 1:15) that showed high percentage yield (98.5%), high drug content (98.39%) and 8.2 fold increase in solubility compared to solubility of pure drug with improved dissolution rate. The drug was converted to amorphous form without chemical interaction with the carrier.

Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

Mortality Risk in Patients With Adrenal Insufficiency Using Prednisolone or Hydrocortisone: A Retrospective Cohort Study.

Prednisolone has been recommended rather than hydrocortisone for glucocorticoid replacement in adrenal insufficiency due its longer duration of action and lower cost. To determine mortality rates with prednisolone versus hydrocortisone. In this observational study, we used data extracted from a UK primary care database (Clinical Practice Research Datalink) to measure the relative mortality of patients with primary and secondary adrenal insufficiency, who were treated with either prednisolone or hydrocortisone, and control individuals who were individually matched for age, sex, period, and place of follow-up. As expected, mortality in adrenal insufficiency irrespective of cause was increased, based on 5478 patients (4228 on hydrocortisone; 1250 on prednisolone) and 54 314 controls (41 934 and 12 380, respectively). Overall, the adjusted hazard ratio (HR) was similar with the 2 treatments (prednisolone, 1.76 [95% CI, 1.54-2.01] vs hydrocortisone 1.69 [1.57-1.82]; P = 0.65). This was also the case for secondary adrenal insufficiency. In primary disease (1405 on hydrocortisone vs 137 on prednisolone; 13 965 and 1347 controls, respectively), prednisolone users were older, more likely to have another autoimmune disease and malignancy, and less likely to have mineralocorticoid replacement. Nevertheless, after adjustment, the HR for prednisolone-treated patients remained higher than for those taking hydrocortisone (2.92 [2.19-3.91] vs 1.90 [1.66-2.16]; P = 0.0020). In primary but not in secondary adrenal insufficiency, mortality was higher with prednisolone. The study was large, but the number of prednisolone-treated patients was small, and they had greater risk factors. Nonetheless, the increased mortality associated with prednisolone persisted despite statistical adjustment. Further evidence is needed regarding the long-term safety of prednisolone as routine replacement.

Rate of Onset as a Determinant of Abuse Potential Assessment Using Intracranial Self‐Stimulation in Rats

Background Intracranial self-stimulation (ICSS) is one procedure that has been used to evaluate abuse potential of drugs, and as with more commonly used drug self-administration procedures, ICSS is especially sensitive to drugs that activate the mesolimbic dopamine system. Drug self-administration studies have shown that abuse potential can also be influenced by temporal parameters, and especially rate of onset; however, the degree to which rate of onset influences abuse-potential metrics in ICSS procedures has not been systematically examined. To address this issue, this study evaluated three dopamine transporter (DAT) inhibitors that have different onset rates and were shown previously to maintain different peak break points in rhesus monkeys responding under a progressive-ratio schedule (cocaine > WIN35428 > RTI-31 for both rate of onset and break point). In ICSS, abuse potential is generally indicated when a drug increases low rates of responding maintained by low levels of brain stimulation, a phenomenon called “ICSS facilitation”. We hypothesized that these three DAT inhibitors would facilitate ICSS different time courses, but the degree to which rate of onset might influence peak facilitation was unknown. Methods Adult male and female Sprague-Dawley rats (n = 5-7 per drug) were surgically implanted with permanent stainless-steel electrodes targeting the medial forebrain bundle and trained to respond on a lever to receive electrical brain stimulation. Behavioral sessions were organized in components consisting of ten one-minute frequency trials over a range of brain-stimulation frequencies (56-158 Hz), such that a full curve relating brain-stimulation frequency to response rate could be determined every 10 min. On test days, three baseline ICSS components were followed first by intraperitoneal drug injection and then immediately by 12 consecutive test components (120 min). Additional pairs of test components were initiated at 300 and 1440 minutes post-injection. The drugs and dose ranges tested were as follows: cocaine HCl (1.0 - 10 mg/kg), WIN35428 (0.10 – 0.32 mg/kg), and RTI-31 (0.032 – 0.10 mg/kg). All drugs were tested up to doses that produced peak levels of ICSS facilitation; higher doses disrupted responding and produced stereotypies. Results Under baseline conditions, brain stimulation maintained a frequency-dependent increase in reinforcement rates. All three drugs dose-dependently and robustly facilitated ICSS, shifting ICSS frequency-rate curves to the left and increasing the total number of stimulations per component when data were collapsed across all frequencies. Consistent with previous studies, the rate of onset for ICSS facilitation was fastest for cocaine, slower for WIN35428, and slowest for RTI-31. Cocaine also had the shortest duration of action and the lowest potency, whereas RTI-31 had the longest duration of action and highest potency. However, despite these differences in time course and potency, peak ICSS facilitation was not statistically different across drugs. Conclusions These results suggest that ICSS studies should evaluate rate of onset as well as peak ICSS facilitation in reaching conclusions about overall abuse potential of a test drug.

Intra-cavernous injection of BOTOX® (50 and 100 Units) for treatment of vasculogenic erectile dysfunction: Randomized controlled trial.

Erectile dysfunction (ED) is a socioeconomic problem.There are several options for its management including intra-cavernosal injection (ICI). To compare the safety, efficacy, and durability of ICI of onabotulinum toxin-A (BTX) in different doses (50 and 100 U) against placebo (saline) in the management of vasculogenic ED non-responding to pharmacological therapy (phosphodiesterase type 5 inhibitors or/and ICI of trimix). A prospective randomized double-blind placebo-controlled trial was conducted between July 2016 and February 2019. A total of 176 patients were randomly assigned (1:1:1) to one of the treatment sequences: Botox 100 U group (BTX-100; 62 patients), Botox 50 U group (BTX-50; 59 patients), or placebo group (55 patients). All patients were followed up for 6 months. Significant improvement in all parameters, that is, SHIM score & Erection Hardness Score (EHS), Sexual Encounter Profile (SEP), Global Assessment Score (GAS), and Doppler parameters (p<0.001) was observed in patients of BTX-100 and BTX-50 groups with maximum improvement at 3rd month of treatment. Around 40% of patients were responders and were able to engage in sexual intercourse. Patients in placebo group did not experience significant improvement (p=0.264). It was noted that at the 2nd week and 3rd months after treatment, there was no statistically significant difference in the improvement of these parameters in BTX-100 and BTX-50 groups (p>0.05). In the 6th month, there was a statistically significant difference between the aforementioned groups in favor of BTX-100 (p<0.01). Only one-time ICI of BTX (50 U and 100 U) is effective and safe for the treatment of refractory ED. This agent has a considerable long duration of action, particularly BTX-100U seems to be more durable.

Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy.

We apply the magic methyl effect to improve the potency/efficacy of GAT211, the prototypic 2-phenylindole-based cannabinoid type-1 receptor (CB1R) agonist-positive allosteric modulator (ago-PAM). Introducing a methyl group at the α-position of nitro group generated two diastereomers, the greater potency and efficacy of erythro, (±)-9 vs threo, (±)-10 constitutes the first demonstration of diastereoselective CB1R-allosteric modulator interaction. Of the (±)-9 enantiomers, (-)-(S,R)-13 evidenced improved potency over GAT211 as a CB1R ago-PAM, whereas (+)-(R,S)-14 was a CB1R allosteric agonist biased toward G protein- vs β-arrestin1/2-dependent signaling. (-)-(S,R)-13 and (+)-(R,S)-14 were devoid of undesirable side effects (triad test), and (+)-(R,S)-14 reduced intraocular pressure with an unprecedentedly long duration of action in a murine glaucoma model. (-)-(S,R)-13 docked into both a CB1R extracellular PAM and intracellular allosteric-agonist site(s), whereas (+)-(R,S)-14 preferentially engaged only the latter. Exploiting G-protein biased CB1R-allosteric modulation can offer safer therapeutic candidates for glaucoma and, potentially, other diseases.

Revefenacin, a once-daily, long-acting muscarinic antagonist, for nebulized maintenance therapy in patients with chronic obstructive pulmonary disease.

PurposeThis article reviews the efficacy and safety of revefenacin, the first once-daily, long-acting muscarinic antagonist, when delivered via a standard jet nebulizer in patients with chronic obstructive pulmonary disease (COPD).SummaryRevefenacin 175 µg is indicated for the maintenance treatment of patients with moderate to very severe COPD. Preclinical studies showed that revefenacin is a potent and selective antagonist with similar affinity for the different subtypes of muscarinic receptors (M1-M5). Furthermore, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose dependent and lasted longer than 24 hours, demonstrating a long duration of action. In phase 2 and 3 trials, treatment with revefenacin was demonstrated to result in statistical improvements in pulmonary function (≥100 mL, P < 0.05) vs placebo, including among patients with markers of more severe disease and those who received concomitant long-acting β-agonists or long-acting β-agonists together with inhaled corticosteroids. Revefenacin was also demonstrated to have efficacy similar to that of tiotropium. The clinical trial findings indicated no significant difference between revefenacin and tiotropium with regard to rates of adverse events. Overall, revefenacin was well tolerated, with COPD worsening/exacerbation, dyspnea, headache, and cough among the most common adverse events noted in the clinical trials.ConclusionsRevefenacin treatment delivered via nebulization led to improvements in lung function in patients with COPD. It was also generally well tolerated, with no major safety concerns. Revefenacin provides a viable treatment option for patients with COPD and may be a suitable alternative for those with conditions that may impair proper use of traditional handheld inhalers.

Extreme dilutions of mercuric chloride produce longer binding interaction with ?-amylase as compared to blank solvents

Background&#x0D; High and ultra low doses of HgCl2 modulate ?-amylase starch interaction through two different binding sites of the enzyme. Mercurius corrosivus at ultra high dilution (UHD) is reported to have a long duration of action for 30-60 days.&#x0D; Objectives&#x0D; (i) To see whether the mother tincture and UHDs of mercuric chloride could directly act on ?-amylase without intervention of its substrate starch. (ii) To see whether the MT and UHDs produce longer binding interaction with ?-amylase than the control.&#x0D; Methods&#x0D; Mercuric chloride MT (0.15 M) or Merc cor ? and its three UHDs, 30, 200, 1000 cH called potencies were in 90% ethanol. Blank 90% ethanol and deionised and distilled (DD) water were used as controls. All ethanol based ligands were diluted with DD water to reduce EtOH content to 0.09%. Using an ITC instrument each ligand was injected once at 10 µl into15µM ?-amylase at 25 0C and the reaction was observed for 2000 s. &#x0D; Results&#x0D; While Merc cor ? produced endothermic reaction, all other ligands did exothermic reaction. Water control and blank ethanol maintained post injection heat change up to 1200 sec. All other ligands sustained heat change for the entire period of observation (2000 sec). &#x0D; Conclusions&#x0D; Merc cor ? and potencies produced exactly the opposite reaction at the protein binding sites. The reaction was short-lived with water control and blank ethanol, but prolonged with Merc cor ? and potencies. Merc cor 200 cH and 1000 cH produced highest heat change (6 µl/sec) during interaction with ?-amylase.

Cisatracurium Versus Atracurium for Abdominal Surgeries Regarding Condition of Intubation and Hemodynamic Effect

Abstract Background: Neuromuscular-blocking drugs block neuromuscular transmission, causing paralysis of the affected skeletal muscles. In clinical use, neuromuscular block is used adjunctively to anesthesia to produce paralysis, first to paralyze the vocal cords, and permit intubation of the trachea, and second to optimize the surgical field by inhibiting spontaneous ventilation, and causing relaxation of skeletal muscles. Patients and Methods: This was a prospective, randomized study registered in Clinical Trials Registry of India (CTRI/2019/04/018580). We included 100 patients divided into two groups of 50 each. Group A received atracurium (0.5 mg/kg), whereas Group B received cisatracurium (0.15 mg/kg). Efficacy of both the drugs was compared in terms of onset of action, duration of action, duration of recovery, hemodynamic conditions during and after intubation, and signs of histamine release in both the drugs. Results: Mean duration of 25% recovery from the reversal in the atracurium group was 32.4 ± 1.90 min which was significantly less as compared to 49.46 ± 1.86 min of cisatracurium group (P &lt; 0.001). The mean duration of recovery from the reversal in cisatracurium group was 2.18 ± 0.82 min which was significantly more as compared to 1.8 ± 0.75 min of atracurium group (P = 0.02). Conclusion: Cisatracurium in a dose of 0.15 mg/kg had a faster onset and duration of action than atracurium 0.5 mg/kg. At this dose, cisatracurium provides optimal intubating condition, rapid neuromuscular blocking with longer duration of action, stable hemodynamic status, no signs of histamine release clinically, and without any residual muscle paralysis compared to atracurium.