RESUMEN

A growing body of evidence points to the existence of a crosstalk between the endovanilloid (EV)- and the endocannabinoid (EC) systems, leading to the concept of a single system based on a shared set of endogenous ligands and regulation mechanisms. The EV/EC system encompasses the ion channel TRPV1, the G protein coupled receptors CB1 and CB2, their endogenous ligands and the enzymes for biosynthesis and inactivation. Disorders in which the EV/EC interaction is involved are inflammation, pain, neurodegenerative diseases and disorders of bones and skin. In the present paper, with the aim of targeting the EV/EC system, the Passerini reaction is used in a diversity-oriented approach to generate a series of α-acyloxycarboxamides bearing different substructures that resemble endogenous ligands. Compounds have been screened for activity on TRPV1, CB1 and CB2 and metabolic stability in skin cells, liver subcellular fractions and plasma. This protocol allowed to generate agents characterized by a diverse activity on TRPV1, CB1 and CB2, as well as heterogeneous metabolic stability that could allow different routes of administration, from soft drugs for topical treatment of skin diseases to hard drugs for systemic use in inflammation and pain. Compared to natural mediators, these compounds have a better drug-likeness. Among them, 41 stands out as an agonist endowed with a well-balanced activity on both TRPV1 and CB2, high selectivity over TRPM8, TRPA1 and CB1, metabolic stability and synthetic accessibility.

RESUMEN

Epigenetic modulators such as lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) are drug targets for cancer, neuropsychiatric disease, or inflammation, but inhibitors of these enzymes exhibit considerable side effects. For a potential local treatment with reduced systemic toxicity, we present here soft drug candidates as new LSD1 and HDAC inhibitors. A soft drug is a compound that is degraded in vivo to less active metabolites after having achieved its therapeutic function. This has been successfully applied for corticosteroids in the clinic, but soft drugs targeting epigenetic enzymes are scarce, with the HDAC inhibitor remetinostat being the only example. We have developed new methyl ester-containing inhibitors targeting LSD1 or HDACs and compared the biological activities of these to their respective carboxylic acid cleavage products. In vitro activity assays, cellular experiments, and a stability assay identified potent HDAC and LSD1 soft drug candidates that are superior to their corresponding carboxylic acids in cellular models.

RESUMEN

Purpose: We report on a novel ultra-short-acting etomidate analogue, E161111, which has the same primary metabolite as etomidate. Methods: The metabolic rate of E161111 was determined in rat plasma and liver homogenate. Rats were infused for 30 or 60 min to maintain light sedation at Richmond Agitation-Sedation Scale (RASS) for -2 to 0 score. Mean arterial pressure (MAP) was monitored during 30 min infusion. The serum corticosterone was determined during and 3 h after infusion as a measure of adrenocortical function. Results: E161111 was not detected in rat plasma at 1 min (t1/2 = 6.69 ± 0.07 s) and in rat liver homogenates at 5 min (t1/2 = 10.20 ± 3.76 s); its main metabolic product was etomidate acid. The recovery time from loss of righting reflex (LORR) was 4.3 ± 1.5 min after 1-h infusion of E161111. During 30 min infusion, E161111 did not cause MAP changes. The stimulated serum corticosterone levels after 1-h infusion of E161111 were significantly higher than that after 1-h infusion of etomidate at all time points tested for the 3 h study. Conclusions: E161111 was metabolised rapidly, the metabolites were same as etomidate, and the recovery time after 1-h infusion was short. It elicited haemodynamic stability and milder suppression of corticosterone than that elicited by etomidate.

Asunto(s)

RESUMEN

PURPOSE: To evaluate ocular hypotensive efficacy and the safety of sovesudil (formally known as PHP-201), a novel Rho-associated protein kinase (ROCK) inhibitor, in patients with normal-tension glaucoma (NTG). DESIGN: Multicentre, prospective, double-masked, randomized, placebo-controlled, parallel clinical study. METHODS: Patients with NTG (unmedicated baseline IOP ≤ 21 mmHg) were randomized in 3 groups and treated with sovesudil in concentrations of 0.25% and 0.5%, or with a placebo three times daily (TID) for 4 weeks. The primary end-point was the mean diurnal IOP change from the baseline at week 4. Safety was recorded over a 4-week treatment period and the following 2-week observation period. RESULTS: A total of 119 patients were included in the primary efficacy analysis. The mean diurnal IOP change from the baseline at week 4 was -1.56 mmHg for the high-dose group, -1.10 mmHg for the low-dose group and -0.65 mmHg for the placebo group. The difference between the high-dose and the placebo groups was -0.91 mmHg (95% confidence intervals: -1.73, -0.09). 0.5% sovesudil TID met the criteria for superiority to the placebo. The most frequent ocular adverse event among sovesudil-treated patients was conjunctival hyperaemia (24.4% for the high-dose and 17.5% for the low-dose group) and predominately classified as mild. CONCLUSIONS: Sovesudil 0.25% and 0.5% TID showed statistically significant IOP-lowering effects and 0.5% concentration's IOP-lowering effects met the superiority criteria in comparison with the placebo at week 4. Sovesudil was well tolerated with mild adverse events including relatively low incidence of conjunctival hyperaemia in patients with NTG.

Asunto(s)

RESUMEN

INTRODUCTION: The lungs possess many xenobiotic metabolizing enzymes which influence the pharmacokinetics and safety of inhaled medicines. Anticipating metabolism in the lungs provides an opportunity to optimize new inhaled medicines and overcome challenges in their development. AREAS COVERED: This article summarizes current knowledge on xenobiotic metabolizing enzymes in the lungs. The impact of metabolism on inhaled medicines is considered with examples of how this impacts small molecules, biologics and macromolecular formulation excipients. Methods for measuring and predicting xenobiotic lung metabolism are critically reviewed and the potential for metabolism to influence inhalation toxicology is acknowledged. EXPERT OPINION: Drugs can be optimized by molecular modification to (i) reduce systemic exposure using a 'soft drug' approach, (ii) improve bioavailability by resisting metabolism, or (iii) use a prodrug approach to overcome pharmacokinetic limitations. Drugs that are very labile in the lungs may require a protective formulation. Some drug carriers being investigated for PK-modification rely on lung enzymes to trigger drug release or biodegrade. Lung enzyme activity varies with age, race, smoking status, diet, drug exposure and preexisting lung disease. New experimental technologies to study lung metabolism include tissue engineered models, improved analytical capability and in silico models.

Asunto(s)

RESUMEN

Introduction: Procedural sedation (PS) is a humane way to help patients get through painful medical procedures by the administration of sedative drugs combined with analgesics. However, each of the currently used medications has certain shortcomings, urging the search for a new drug. Remimazolam, a novel benzodiazepine, is an ultra-short-acting hypnotic agent invented out of the 'soft drug' development.Areas covered: This presented review provides an overview of the drugs used in clinical practice for the induction and maintenance of procedural sedation in adults, focusing on the newly investigated benzodiazepine remimazolam. Literature search was conducted using the MEDLINE and ClinicalTrial.gov databases from January 2007 to December 2020.Expert opinion: Based on the reported clinical trials so far, remimazolam has demonstrated its effectiveness and safety with promising properties including rapid onset, short duration of action, predictable and consistent recovery profile, metabolism almost unaffected by liver or renal function, with non or minimal cardiorespiratory depression, and availability with a reversal drug. With marketing approval received recently, remimazolam is expected to have a place in the practice for procedural sedation in the near future if its efficacy and safety are further confirmed by more clinical trials and post-market analyses.

Asunto(s)

RESUMEN

Steroidal glucocorticoids (GR agonists) have been widely used for the topical treatment of skin disorders, including atopic dermatitis. They are a very effective therapy, but they are associated with both unwanted local effects in the skin (skin thinning/atrophy) and systemic side effects. These effects can limit the long-term utility of potent steroids. Here we report on a topically delivered non-steroidal GR agonist, that has the potential to deliver high efficacy in the skin, but due to rapid metabolism in the blood & liver ("dual-soft") it should have greater systemic safety than existing treatments. In addition, compared to less selective steroidal GR agonists, the new non-steroidal Selective Glucocorticoid Agonists (SEGRAs) have the potential to avoid the skin atrophy observed with existing topical steroids. Due to its potential for reduced skin atrophy and low systemic exposure, LEO 134310 (17) may be suitable for long term topical treatment of skin diseases such as atopic dermatitis and psoriasis.

Asunto(s)

RESUMEN

The G-protein-coupled bile acid receptor TGR5 agonists were widely developed in type 2 diabetes and gastrointestinal disorders, but were also full of challenges, due to the systemic on-targeted side effects, especially the gallbladder-filling effects. Here, to circumvent these risks, several TGR5 agonists with soft-drug designation had been designed and synthesized with the properties of rapid metabolized after drug effect. Among them, compound 19 showed negligible systemic exposure and favorable gallbladder safety on a 3-day continuous administration, providing a novel strategy for developing TGR5 agonists.

Asunto(s)

RESUMEN

Introduction: Glaucoma is a group of progressive optic neuropathies in which elevated intraocular pressure (IOP) as a consequence of an increased aqueous humor (AH) outflow resistance, is the main and only clinically modifiable risk factor for its development and progression. Relaxing Trabecular meshwork (TM) tissue, Rho-Kinase (ROCK) inhibitors directly decrease resistance in the conventional AH outflow, thus resulting in a significant IOP-lowering effect. Areas covered: The progress made in the field of ROCK inhibitors for glaucoma treatment will be discussed, referring to the recent patent literature published mainly in the last 3 years. Development and last studies conducted on the recently approved ripasudil and netarsudil will be described, along with newly reported combinations with other antiglaucoma agents. New molecular entities as ROCK inhibitors will be reported as well as new biological approaches to affect the Rho/ROCK pathway. Expert opinion: With three drugs currently available on the market belonging to this class, ROCK inhibitors have been definitely validated as therapeutic agents for glaucoma treatment. The literature of the last 3 years confirmed the success of the soft-drug and bis-functional approaches in the design of ROCK inhibitors. However, few completely new molecular scaffolds have been reported.

Asunto(s)

RESUMEN

BACKGROUND: Prior research has documented a strong association between cigarette and marijuana use among young adults; it is critical to study patterns and risk factors for co-use. METHODS: Appended, cross-sectional National Health and Nutrition Examination Survey (NHANES) data were used to assess prevalence and correlates of cigarette and marijuana co-use among young adults (ages 21-30) over a 10-year period (2005-2014). Respondents (unweighted sample = 4,948) were classified into four categories regarding past-month behavior: neither use, cigarette-only use, marijuana-only use, and co-use of both. Regression models were computed to predict these categories using three waves of NHANES (unweighted sample = 3,073). RESULTS: Prevalence of past-month cigarette use decreased from 30.9% in 2005-2006 to 23.7% in 2013-2014 (p = 0.024) while past-month marijuana use (average 18.0%) and past-month co-use (average 9.8%) remained stable during this time. Co-use differed significantly by gender (p < 0.001; average 12.9% men, 6.8% women). Co-users were less likely to be married, more likely to endorse non-Hispanic black racial identity, more likely to have engaged in non-marijuana drug use in their lifetime and more likely to drink alcohol monthly than cigarette-only users. Co-users were more likely to have depressive symptoms, ever use non-marijuana drugs, live with a smoker, and initiate marijuana at a younger age than marijuana-only users. CONCLUSIONS: Co-use of cigarettes and marijuana remained stable but high over a ten-year period; understanding the unique characteristics, living situations, experiences, and substance use behaviors of co-users can contribute to more effective, tailored prevention and education strategies to reduce the burden of comorbid cigarette and marijuana use.

Asunto(s)

RESUMEN

The oral S1PR1 agonist ponesimod demonstrated substantial efficacy in a phase II clinical trial of psoriasis. Unfortunately, systemic side effects were observed, which included lymphopenia and transient bradycardia. We sought to develop a topical soft-drug S1PR1 agonist with an improved therapeutic index. By modifying ponesimod, we discovered an ester series of S1PR agonists. To increase metabolic instability in plasma we synthesised esters described as specific substrates for paraoxonase and butyrylcholinesterases, esterases present in human plasma.

Asunto(s)

RESUMEN

The enzymatic hydrolysis of chemicals, which is important for in vitro drug metabolism assays, is an important indicator of drug stability profiles during drug discovery and development. Herein, we employed a stepwise feature elimination (SFE) method with nonlinear support vector machine regression (SVR) models to predict the in vitro half-lives in human plasma/blood of various esters. The SVR model was developed using public databases and literature-reported data on the half-lives of esters in human plasma/blood. In particular, the SFE method was developed to prevent over fitting and under fitting in the nonlinear model, and it provided a novel and efficient method of realizing feature combinations and selections to enhance the prediction accuracy. Our final developed model with 24 features effectively predicted an external validation set using the time-split method and presented reasonably good R2 values (0.6) and also predicted two completely independent validation datasets with R2 values of 0.62 and 0.54; thus, this model performed much better than other prediction models.

Asunto(s)

RESUMEN

Inhaled corticosteroids are used as one of the first-line drug therapy in patients with asthma. However, their long-term use is associated with various oropharyngeal and systemic side and adverse effects. Design of pro-soft drug is one of the strategies, which was adopted in the design of ciclesonide for mitigation of side effects usually observed with the use of inhaled corticosteroids. Ciclesonide, a pro-soft drug, is converted to an active metabolite desisobutyryl-ciclesonide in the lungs. The anti-inflammatory effect of desisobutyryl-ciclesonide is much higher than ciclesonide, and therefore, the local effect of the metabolite is higher with lower systemic side effects. Ciclesonide has favorable pharmacokinetic and pharmacodynamic properties as inhaled corticosteroid including low oral bioavailability, high plasma protein binding and rapid systemic clearance, high pulmonary deposition and distribution and long pulmonary residence duration. These advantageous properties make ciclesonide a very effective treatment option with low side effects. Various clinical studies support safety and efficacy of ciclesonide use in mild, moderate, and severe asthma patients.

Asunto(s)

RESUMEN

Abstract:Currently, Mongolian 33 domestic pharmaceutical industries produce totaly of 364 different of drugs into pharm market, that includes 82% of the hard drug form of tablets, capsules, 14% of the liquid formulated drug form and 4% of the soft drug form. On the International pharmacopoeia articles such as Brithish pharmacopoeia have reported 11 types soft drug forms clearly. But, now in our national pharmacopoeia articles involved 3 types of soft drug form of cream, suppositorium, eye soft drug forms. So there are need to increase a number of soft drugs into national pharmacopoeia articles. Thus, we put our main goal is to make comperative study of national and international pharmacopoeia article of soft drug forms. This study will help to enter soft drugs in to National pharmacopoeia in the future.Keywords: Soft drug form, crem, supposi torium, eyes soft drug forms, Pharmacopoeia soft drug form articles.

RESUMEN

Inclusion of metabolic considerations in the drug design process leads to significant development in the field of chemical drug targeting and the design of safer drugs during past few years which is a part of an approach now designated as Retro metabolic drug design (RMDD). This approach represents systematic methodologies that integrate structure-activity and structure-metabolism relationships and are aimed to design safe, locally active compounds with an improved therapeutic index. It embraces two distinct methods, chemical delivery systems and a soft drug approach. Present review recapitulates an impression of RMDD giving reflections on the chemical delivery system and the soft drug approach and provides a variety of examples to embody its concepts. Successful application of such design principles has already been applied to a number of marketed drugs like esmolol; loteprednol etc., and many other candidates like beta blockers, ACE inhibitors, alkylating agents, antimicrobials etc., are also under investigation.

RESUMEN

PDE4 inhibitors are of high interest for treatment of a wide range of inflammatory or autoimmune diseases. Their potential however has not yet been realized due to target-associated side effects, resulting in a low therapeutic window. We herein report the design, synthesis and evaluation of novel PDE4 inhibitors containing a γ-lactone structure. Such molecules are designed to undergo metabolic inactivation when entering circulation, thereby limiting systemic exposure and reducing the risk for side effects. The resulting inhibitors were highly active on both PDE4B1 and PDE4D2 and underwent rapid degradation in human plasma by paraoxonase 1. In contrast, their metabolites displayed markedly reduced permeability and/or on-target activity.

Asunto(s)

RESUMEN

Ya son varios los países que han aceptado la marihuana como una droga "blanda", diferente a otras más peligrosas. Incluso se le ha atribuido diversas propiedades terapéuticas. Otros sin embargo piensan que su uso debería prohibirse, dadas las interferencias mentales y las alteraciones del comportamiento que produce, ya sea por su consumo esporádico, como también por los daños permanentes a que lleva su consumo crónico. Con el objeto de aclarar estas divergentes apreciaciones, se revisa la literatura científica existente. De ello se deduce el grave riesgo de su consumo crónico, especialmente para el adolescente por el significativo incremento de cuadros psicóticos y esquizofrénicos, los cuales pueden llegar a ser permanentes, mientras que su consumo durante el embarazo daña el desarrollo cerebral del feto en forma similar a lo que hace el alcohol en el síndrome fetal alcohólico. Investigaciones científicas también señalan que al fumar sus hojas, se va produciendo un daño bronquial, aún más grave que con el tabaco, incluyendo el cáncer pulmonar. En conclusión, el concepto de que la marihuana es una droga "blanda", libre de riesgos para la salud, constituye un grave error, dado la concluyente investigación científica disponible que señala lo contrario.

There are already several countries that have accepted marijuana as a soft drug, separating it from more dangerous ones. Yarious therapeutic properties have even been attributed to its use. Others, however, think that its use should be prohibited due to the mental interference and behavioral changes produced either by its occasional use as well as the permanent mental damage linked to chronic marijuana use. In order to clarify this divergence of opinions, the scientific literature is reviewed. It is concluded that there is a serious risk, especially for teenagers, associated to chronic marijuana use due to the presence of more frequent psychotic and schizophrenic episodes, which can be permanent, while consumption during pregnancy results in brain damage to the fetus, similar to fetal alcohol syndrome. Scientific research also indicated that smoking marijuana produces an even more severe bronchial damage than tobacco, with risk of lung cancer. In conclusion, the notion that marijuana is a risk-free soft drug is a serious mistake, based on the available conclusive scientific research that shows the opposite.

Asunto(s)

RESUMEN

Clinical development of ROCK inhibitors has so far been limited by systemic or local ROCK-associated side effects. A soft drug approach, which involves predictable metabolic inactivation of an active compound to a nontoxic metabolite, could represent an attractive way to obtain ROCK inhibitors with improved tolerability. We herein report the design and synthesis of a new series of soft ROCK inhibitors structurally related to the ROCK inhibitor Y-27632. These inhibitors contain carboxylic ester moieties which allow inactivation by esterases. While the parent esters display strong activity in enzymatic (ROCK2) and cellular (MLC phosphorylation) assays, their corresponding carboxylic acid metabolites have negligible functional activity. Compound 32 combined strong efficacy (ROCK2 IC50=2.5 nM) with rapid inactivation in plasma (t1/2 <5'). Compound 32 also demonstrated in vivo efficacy when evaluated as an IOP-lowering agent in ocular normotensive New-Zealand White rabbits, without ocular side effects.

Asunto(s)