JOTROL, a Novel Formulation of Resveratrol, Shows Beneficial Effects in the 3xTg-AD Mouse Model

Background: Alzheimer’s disease (AD) has minimally effective treatments currently. High concentrations of resveratrol, a polyphenol antioxidant found in plants, have been reported to affect several AD-related and neuroprotective genes. To address the low bioavailability of resveratrol, we investigated a novel oral formulation of resveratrol, JOTROLTM, that has shown increased pharmacokinetic properties compared to non-formulated resveratrol in animals and in humans. Objective: We hypothesized that equivalent doses of JOTROL, compared to non-formulated resveratrol, would result in greater brain exposure to resveratrol, and more efficacious responses on AD biomarkers. Methods: For sub-chronic reversal studies, 15-month-old male triple transgenic (APPSW/PS1M146V/TauP301L; 3xTg-AD) AD mice were treated orally with vehicle or 50 mg/kg JOTROL for 36 days. For prophylactic studies, male and female 3xTg-AD mice were similarly administered vehicle, 50 mg/kg JOTROL, or 50 mg/kg resveratrol for 9 months starting at 4 months of age. A behavioral battery was run, and mRNA and protein from brain and blood were analyzed for changes in AD-related gene and protein expression. Results: JOTROL displays significantly increased bioavailability over non-formulated resveratrol. Treatment with JOTROL resulted in AD-related gene expression changes (Adam10, Bace1, Bdnf, Psen1) some of which were brain region-dependent and sex-specific, as well as changes in inflammatory gene and cytokine levels. Conclusion: JOTROL may be effective as a prophylaxis and/or treatment for AD through increased expression and/or activation of neuroprotective genes, suppression of pro-inflammatory genes, and regulation of central and peripheral cytokine levels.

Evaluation of The Food Effect On a Drospirenone Only Contraceptive Containing 4 mg Administered With and Without High-Fat Breakfast

Background:The objective of the present trial was to assess the difference in pharmacokinetics of an oral test preparation containing 4 mg drospirenone. under fasting conditions compared to food intake after single dose administration.Methods:Open label, single centre, two-treatment, two-sequence, crossover study in 24 healthy female volunteers, with duration of 1 day per sequence and with a real wash-out period of 14 days to investigate the relative bioavailability of DRSP with both forms of administration. The 90% confidence intervals were calculated for the intra-individual ratio (test with food vs. without food) of the pharmacokinetic endpoints AUC(0-72h) and Cmax of drospirenone. Results:The 90% CI calculated by means of ANOVA-log for the endpoint, intra-individual ratio (Test ‘A’ = with food intake) vs. Test ‘B’ = without food intake) of AUC(0-72h) of drospirenone was between 104.72% and 111.36%. The 90% CI calculated by means of ANOVA- log for the endpoint intra-individual ratio (Test ‘A’ vs. Test ‘B’) of Cmax of drospirenone was between 118.58% and 141.10%.The mean relative bioavailability of the Test with food ‘A’ compared to the Test without food ‘B’ after single dose administration based on the endpoints AUC(0-72h) was 107.99%; for the endpoint Cmax it was 129.35%.Conclusions:The rate of absorption, based on the endpoint Cmax of drospirenone was increased by about 30% under fed conditions which differs to a COC containing 0,02 mg EE and 3 mg drospirenone in a 24/4 regimen where the rate of absorption was reduced by about 40% for both components. Implications: Our results suggest that the food intake has no impact on the absorption of 4 mg drospirenone in the management for contraception.This raises up the contraceptive efficacy as no interference with food is expected in real life use when consuming the oral formulation

Crystal Structure, Solubility, and Pharmacokinetic Study on a Hesperetin Cocrystal with Piperine as Coformer

Hesperetin (HES) is a key biological active ingredient in citrus peels, and is one of the natural flavonoids that attract the attention of researchers due to its numerous therapeutic bioactivities that have been identified in vitro. As a bioenhancer, piperine (PIP) can effectively improve the absorption of insoluble drugs in vivo. In the present study, a cocrystal of HES and PIP was successfully obtained through solution crystallization. The single-crystal structure was illustrated and comprehensive characterization of the cocrystal was conducted. The cocrystal was formed by two drug molecules at a molar ratio of 1:1, which contained O–H–O hydrogen bonds between the carbonyl and ether oxygen of PIP and the phenolic hydroxyl group of HES. In addition, a solubility experiment was performed on powder cocrystal in simulated gastrointestinal fluid, and the result revealed that the cocrystal improves the dissolution behavior of HES compared with that of the pure substance. Furthermore, HES’s bioavailability in the cocrystal was six times higher than that of pristine drugs. These results may provide an efficient oral formulation for HES.

Human Metabolites of Hamaforton™ (Hamamelis virginiana L. Extract) Modulates Fibroblast Extracellular Matrix Components in Response to UV-A Irradiation

Hamamelis virginiana L. a rich source of both condensed and hydrolyzable tannins, utilized to treat dermatological disorders. Since no experimental and clinical data is available for its use as oral formulation in skin related disorders, the purpose of this study was to investigate the effects of Hamaforton™ (Hamamelis virginiana extract) metabolites on gene dysregulation induced by ultraviolet A radiation in cultured human dermal fibroblasts. A combination of in vivo and ex vivo experimental designs has been exploited in order to take into account the polyphenol metabolic transformation that occurs in humans. 12 healthy volunteers received either a capsule of Hamaforton™ or a placebo in a randomized, blinded crossover trial. After Hamaforton™ ingestion, the kinetic of appearance of galloyl derivatives was measured in plasma. Then, in the ex vivo experiment, the serum isolated after supplementation was used as a source of Hamaforton™ metabolites to enrich the culture medium of dermal fibroblasts exposed to ultraviolet A radiation. Three different gallic acid metabolites (4-O-methyl gallic acid, 4-O-methyl gallic acid sulphate and trimethyl gallic acid glucuronide) were identified in volunteer plasma. While, ultraviolet A irradiation of dermal fibroblasts affected the expression of extracellular matrix genes, the presence of Hamaforton™ metabolites in the culture media did not affect the expression of most of those genes. However, the activation of the expression of 10 different genes involved in repair processes for the maintenance of skin integrity, suggest that the metabolites can play a role in damage recovery. To our knowledge, this is the first study that demonstrates the bioavailability of Hamaforton™ phenolic compounds, and the effects of its metabolites on cultured dermal fibroblast response to ultraviolet A irradiation.

Probiotics Evaluation in Oncological Surgery: A Systematic Review of 36 Randomized Controlled Trials Assessing 21 Diverse Formulations

Background: Objectives were to evaluate probiotics safety and efficacy in oncological surgery. Methods: Systematic review methodology guided by Cochrane, PRISMA, SWiM, and CIOMS. Protocol registered on PROSPERO (CRD42018086168). Results: 36 RCTs (on 3305 participants) and 6 nonrandomized/observational studies were included, mainly on digestive system cancers. There was evidence of a beneficial effect on preventing infections, with 70% of RCTs’ (21/30) direction of effect favoring probiotics. However, five RCTs (17%) favored controls for infections, including one trial with RR 1.57 (95% CI: 0.79, 3.12). One RCT that changed (balanced) its antibiotics protocol after enrolling some participants had mortality risk RR 3.55 (95% CI: 0.77, 16.47; 7/64 vs. 2/65 deaths). The RCT identified with the most promising results overall administered an oral formulation of Lactobacillus acidophilus LA-5 + Lactobacillus plantarum + Bifidobacterium lactis BB-12 + Saccharomyces boulardii. Methodological quality appraisals revealed an overall substantial risk-of-bias, with only five RCTs judged as low risk-of-bias. Conclusions: This large evidence synthesis found encouraging results from most formulations, though this was contrasted by potential harms from a few others, thus validating the literature that “probiotics” are not homogeneous microorganisms. Given microbiome developments and infections morbidity, further high-quality research is warranted using those promising probiotics identified herein.

Nefecon (targeted-release formulation-budesonide) for the treatment of IgA nephropathy

Budesonide is a second-generation synthetic, nonhalogenated corticosteroid; it acts locally with minimal systemic absorption. The oral formulation Nefecon® is under clinical development from the treatment of IgA nephropathy. Thanks to its specific formulation, it could inhibit the pathogenetic process of IgA nephropathy at its source while avoiding the toxicity of systemic glucocorticoids. A Phase II clinical trial has shown a statistically significant antiproteinuric effect of budesonide on top of therapy with inhibitors of the renin–angiotensin system, with a good safety profile. More recently, preliminary results of a larger, Phase III clinical trial have confirmed the antiproteinuric efficacy of oral budesonide. These findings were submitted to the US FDA and the EMA to undergo fast revision and approval for clinical use.

A COMPARATIVE CLINICAL EVALUATION OF KATPHALADI CHURNA AND PIPPALYADI CHURNA IN MANAGEMENT OF TAMAKA SWASA

Since time immemorial man has been in a constant endeavor to find the solutions for the life-threatening and ago- nizing disorders, which afflicts the human race. One such condition is ‘Tamaka swasa’1 which is known by the name Bronchial Asthma in modern parlance, wherein remissions and exacerbations are the typical features, leav- ing the patient in a pathetic situation. The Objective of the study is to evaluate the comparative efficacy of Kat- phaladi Churna7 and Pippalyadi Churna8 in the management of Tamaka Swasa through subjective and objective parameters. The present study registers 40 out of 64 patients. Out of these 24 patients were discontinued. The re- maining 40 patients of Tamaka Swasa fulfilling the criteria of diagnosis and inclusive criteria were included in the study, fewer than two groups as distributed patients in Group–A are 20 patients and Group–B is 20 patients. While comparing between the group result shows that Pippalyadi Churna is statistically more effective in Swasa Krichrata (Dyspnoea), Pratishaya (Rhinorrhea), Kanthodavamsa (Hoarseness of voice) and AEC than the Kat- phaladi Churna. In the overall result, Pippalyadi Churna is more effective than the Katphaladi Churna in the management of Tamaka Swasa. Both of the trial drugs proved to be a safe and effective oral formulation, which helps in the management of Tamaka swasa, when the disease is not too advanced and not associated with compli- cations also when correctly used by the patient as per instructions. Keywords: Tamaka Swasa, Swasa Krichrata, Pratishaya, Kanthodavamsa, AEC, Katphaladi Churna and Pip- palyadi Churna.

Warfarin Sodium Stability in Oral Formulations

Warfarin sodium is a low-dose pharmaceutical blood thinner that exists in two forms: the clathrate form and the amorphous form. In commercially available warfarin sodium oral suspension, the active pharmaceutical ingredient (API) is added in the amorphous state. This study investigates the apparent instability of the commercially available warfarin liquid oral formulation using Raman and IR spectroscopy, X-ray diffraction, differential scanning calorimetry, UV spectroscopy, and optical microscopy. Warfarin, not its sodium salt, was identified as the undissolved solid existing in the suspension. This was found to be due to the dissociation of sodium salt and the protonation of the warfarin ion in the liquid phase, which triggered the crystallization of the sparingly soluble unsalted form. The coexistence of protonated and unprotonated warfarin ions in the supernatant, as detected by Raman and UV spectroscopy, confirmed this assumption. Study of the dissolution of warfarin sodium amorphous salt and crystalline sodium clathrate in the placebo and pure water verified the results. The effect of pH and temperature on warfarin precipitation was also explored.