Alternative methods to evaluate the protective ability of sunscreen against photo-genotoxicity

Numerous epidemiological investigations show that sunlight is carcinogenic to humans and that the use of sunscreen may be effective in decreasing the risk of skin cancer. The biological activity of a sunscreen is evaluated by its ability to protect human skin from erythema as represented by a Sun Protection Factor (SPF). We propose that the sunscreen's protective effect against sunlight-induced genotoxicity, including mutation, should also be taken into account. In this study we examined the protective ability of sunscreens against natural sunlight and UV-induced genotoxicity in Drosophila somatic cells. We prepared three kinds of sunscreen samples, each with an SPF value of 20, 40 or 60 and compared their protective activities with commercial sunscreens. When a sunscreen of SPF 20, 40 or 60 was pasted on the plastic cover of a petri dish in which Drosophila larvae were exposed to the sun or UV lamps, genotoxicity decreased as the SPF of the sunscreen increased, relative to levels of genotoxicity observed in samples without sunscreen. However, the protective abilities of sunscreens were unexpectedly not so different from each other. To reveal the relationship between the protective activity of sunscreen and the wavelength of light with which larvae were irradiated through the sunscreen, we measured the transmittance of light through the petri dish cover on which the sunscreen was pasted. Effective protection was demonstrated by removing components of light whose wavelengths were below 315 nm. We suggest, that the measurement of anti-genotoxic activity and the determination of the wavelengths of light transmitted through the sunscreen should be an alternative method for evaluating the effectiveness of a sunscreen.</p

Pharmacological characterization of a novel 5-hydroxybenzothiazolone-derived b2-adrenoceptor agonist with functional selectivity for anabolic effects on skeletal muscle resulting in a wider cardiovascular safety window in preclinical studies

Copyright ª 2019 by The Author(s) The anabolic effects of b2-adrenoceptor (b2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of b2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived b2-AR agonist in comparison with formoterol as a representative b2-AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human b2-AR and selectivity over the b1-AR and b3-AR. 5-HOB also shows potent agonistic activity at the b2-AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissue–derived membranes. In contrast, a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional b2-AR agonist formoterol in preclinical studies and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle-wasting conditions without cardiovascular limiting effects

Pharmacodynamic and pharmacokinetic characterization of the aldosterone synthase inhibitor FAD286 in two rodent models of hyperaldosteronism: comparison with the 11{beta}-hydroxylase inhibitor metyrapone

Aldosterone synthase (CYP11B2) inhibitors (ASI) represent an attractive therapeutic approach for mitigating the untoward effects of aldosterone. We characterized the pharmacokinetic/pharmacodynamic relationships of a prototypical ASI FAD286 (FAD) and compared these profiles to the "11beta-hydroxylase inhibitor" metyrapone (MET) in two rodent models of secondary hyperaldosteronism and corticosteronism. In chronically cannulated Sprague-Dawley rats, angiotensin II (ANG II, 300 ng/kg bolus + 100 ng/kg/min infusion) or adrenocorticotropic hormone (ACTH, 100 ng/kg + 30 ng/kg/min) acutely elevated plasma aldosterone concentration (PAC) from ~0.26 nM to a sustained level of ~2.5 nM for 9 h. ACTH but not ANG II elicited a sustained increase in plasma corticosterone concentration (PCC) from ~300 nM to ~1340 nM. After 1 h of Ang II or ACTH infusion, FAD (0.01-100 mg/kg p.o.) or MET (0.1-300 mg/kg p.o.) dose- and drug-plasma-concentration-dependently reduced the elevated PACs over the ensuing 8 h. FAD was ~12 times more dose-potent than MET in reducing PAC but of similar or slightly greater potency on a plasma drug concentration basis. Both agents also decreased PCC in the ACTH model at relatively higher doses and with similar dose potencies whereas FAD was 6-fold weaker based on drug exposures. FAD was ~50-fold selective for reducing PAC vs. PCC whereas MET was only ~3-fold selective. We conclude that FAD is a potent, orally active, and relatively selective ASI in two rat models of hyperaldosteronism. MET is an order of magnitude less selective than FAD but is, nevertheless, more potent as an ASI than as an 11beta-hydroxylase inhibitor

Sacubitril/valsartan (LCZ696) significantly reduces aldosterone and increases cGMP circulating levels in a canine model of RAAS activation

Simultaneous blockade of angiotensin receptors and enhancement of natriuretic peptides (NP) by the first-in-class angiotensin receptor neprilysin (NEP) inhibitor sacubitril/valsartan constitutes an effective approach to treating heart failure. This study examined the effects of sacubitril/valsartan (225 and 675 mg/day) vs. placebo, sacubitril (360 mg/day), valsartan (900 mg/day), and benazepril (5 mg/day) on the dynamics of the renin-angiotensin-aldosterone system (RAAS) and the NP system in dogs. Beagle dogs (n = 18) were fed a low-salt diet (0.05% Na) for 15 days to model RAAS activation observed in clinical heart failure. Drugs were administered once daily during the last 10 days, while the effects on the RAAS and NPs were assessed on Day 1, 5, and 10. Steady-state pharmacokinetics of the test agents were evaluated on Day 5. Compared with placebo, sacubitril/valsartan (675 mg) substantially increased cGMP circulating levels, while benazepril and valsartan showed no effect. Additionally, sacubitril/valsartan (675 mg) and valsartan significantly increased plasma renin activity, angiotensin I and angiotensin II concentrations. Finally, sacubitril/valsartan (both doses), and valsartan significantly decreased plasma aldosterone vs. placebo. Systemic exposure to valsartan following sacubitril/valsartan 675 mg administration was similar to that observed with valsartan 900 mg administration alone. Sacubitril/valsartan favorably modulates the dynamics of the renin and NP cascades through complementary NEP and RAAS inhibition.This is a manuscript of an article published as Mochel, Jonathan P., Chi Hse Teng, Mathieu Peyrou, Jerome Giraudel, Meindert Danhof, and Dean F. Rigel. "Sacubitril/valsartan (LCZ696) significantly reduces aldosterone and increases cGMP circulating levels in a canine model of RAAS activation." European Journal of Pharmaceutical Sciences 128 (2019): 103-111. DOI: 10.1016/j.ejps.2018.11.037. Copyright 2018 Elsevier. Posted with permission

Retrieving H2O/HDO columns over cloudy and clear-sky scenes from the Tropospheric Monitoring Instrument (TROPOMI)

This paper presents an extended scientific HDO/H2O total column data product from short-wave infrared (SWIR) measurements by the Tropospheric Monitoring Instrument (TROPOMI) including clear-sky and cloudy scenes. The retrieval employs a forward model which accounts for scattering, and the algorithm infers the trace gas column information, surface properties, and effective cloud parameters from the observations. Compared to the previous clear-sky-only data product, coverage is greatly enhanced by including scenes over low clouds, particularly enabling data over oceans as the albedo of water in the SWIR spectral range is too low to retrieve under cloud-free conditions. The new dataset is validated against co-located ground-based Fourier transform infrared (FTIR) observations by the Total Carbon Column Observing Network (TCCON). The median bias for clear-sky scenes is 1.4 x 10(21) molec cm(-2) (2.9 %) in H2O columns and 1.1 x 10(17) molec cm(-2) (-0.3 %) in HDO columns, which corresponds to -17 parts per thousand (9.9 %) in a posteriori delta D. The bias for cloudy scenes is 4.9 x 10(21) molec cm(-2) (11 %) in H2O, 1.1 x 10(18) molec cm(-2) (7.9 %) in HDO, and -20 parts per thousand (9.7 %) in a posteriori delta D. At low-altitude stations, the bias is small at low and middle latitudes and has a larger value at high latitudes. At high-altitude stations, an altitude correction is required to compensate for different partial columns seen by the station and the satellite. The bias in a posteriori delta D after altitude correction depends on sensitivity due to shielding by clouds and on realistic a priori profile shapes for both isotopologues. Cloudy scenes generally involve low sensitivity below the clouds, and since the information is filled up by the prior, a realistic shape of the prior is important for realistic total column estimation in these cases. Over oceans, aircraft measurements with the Water Isotope System for Precipitation and Entrainment Research (WISPER) instrument from a field campaign in 2018 are used for validation, yielding biases of -3.9 % in H2O and -3 parts per thousand in delta D over clouds. To demonstrate the added value of the new dataset, a short case study of a cold air outbreak over the Atlantic Ocean in January 2020 is presented, showing the daily evolution of the event with single-overpass results.ISSN:1867-1381ISSN:1867-854

Trans-3,4-Disubstituted Pyrrolidines as Inhibitors of the Human Aspartyl Protease Renin. Part II: Ether and Carbamate Prime Site Derivatives

Inhibition of the aspartyl protease renin is considered as an efficient approach for treating hypertension. Lately, we described the discovery of a novel class of direct renin inhibitors which comprised a pyrrolidine scaffold (e.g. 2). Based on the X-ray structure of the lead compound 2 bound to renin we reckoned that optimization of binding interactions to the prime site could offer an opportunity to further expand the scope of this chemotype. Pyrrolidine-based inhibitors were synthesized in which the prime site moieties are linked to the pyrrolidine core through an oxygen atom, resulting in an ether or a carbamate linker subseries, respectively. Especially the carbamate derivatives showed a pronounced increase in in vitro potency compared to 2. Here we report the structure-activity relationship of both subclasses and demonstrate blood pressure lowering effects for an advanced prototype in a hypertensive double-transgenic rat model after oral dosing

Structure-Activity Relationships, Pharmacokinetics and In Vivo Activity of CYP11B2 and CYP11B1 Inhibitors

CYP11B2, the aldosterone synthase, and CYP11B1, the cortisol synthase, are two highly homologous enzymes implicated in a range of cardiovascular and metabolic diseases. We have previously reported the discovery of LCI699, a dual CYP11B2 and CYP11B1 inhibitor which has provided clinical validation for the lowering of plasma aldosterone as a viable approach to modulate blood pressure in humans, as well normalization of urinary cortisol in Cushing’s disease patients. We now report novel series of aldosterone synthase inhibitors with single-digit nanomolar cellular potency and excellent physico-chemical properties. Structure-activity relationships and optimization of their oral bioavailability are presented. An illustration of the impact of the age of pre-clinical models on pharmacokinetic properties is also highlighted. Similar biochemical potency was generally observed against for CYP11B2 and CYP11B1, although emerging structure-selectivity relationships were noted leading to more CYP11B1-selective analogs