Rehydration before Application Improves Functional Properties of Lyophilized Lactiplantibacillus plantarum HAC03

Preservation of probiotics by lyophilization is considered a method of choice for developing stable products. However, both direct consumption and reconstitution of dehydrated probiotic preparations before application “compromise” the survival and functional characteristics of the microorganisms under the stress of the upper gastro-intestinal tract. We evaluated the impact of different food additives on the viability, mucin adhesion, and zeta potential of a freeze-dried putative probiotic, Lactiplantibacillus (Lp.) plantarum HAC03. HAC03-compatible ingredients for the formulation of ten rehydration mixtures could be selected. Elevated efficacy was achieved by the B-active formulation, a mixture of non-protein nitrogen compounds, sugars, and salts. The survival of Lp. plantarum HAC03 increased by 36.36% compared rehydration with distilled water (4.92%) after passing simulated gastro-intestinal stress conditions. Cell viability determined by plate counting was confirmed by flow cytometry. B-active formulation also influenced Lp. plantarum HAC03 functionality by increasing its adherence to a Caco-2 cell-line and by changing the bacterial surface charge, measured as zeta potential.Hydrophobicity, mucin adhesion and immunomodulatory properties of Lp. plantarum HAC03 were not affected by the B-active formulation. The rehydration medium also effectively protected Lp. plantarum ATCC14917, Lp. plantarum 299v, Latilactobacillus sakei (Lt.) HAC11, Lacticaseibacillus (Lc.) paracasei 532, Enterococcus faecium 200, and Lc. rhamnosus BFE5263.

Trifluridine/tipiracil plus bevacizumab for third-line management of metastatic colorectal cancer: SUNLIGHT study design

Trifluridine/tipiracil (FTD/TPI) is an orally active formulation of trifluridine, a thymidine-based nucleoside analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor that increases the bioavailability of trifluridine. Preliminary studies of FTD/TPI plus bevacizumab have produced encouraging results in the treatment of refractory metastatic colorectal cancer. Here, we describe the design of the multinational Phase III SUNLIGHT, an open-label study of FTD/TPI plus bevacizumab as third-line treatment for patients with unresectable metastatic colorectal cancer. A total of 490 patients will be randomized 1:1 to receive either FTD/TPI plus bevacizumab, or FTD/TPI monotherapy. The primary objective is to significantly improve overall survival with FTD/TPI plus bevacizumab compared with FTD/TPI monotherapy. The first patient was enrolled in November 2020.

Facial Expression Wrinkles and Their Relaxation by a Synthetic Peptide

Expression wrinkles form over time due to repeated facial movements such as smiling and frowning. They have an imprint on facial skin in areas such as the corner of the eyes, where they take the form of crow’s feet, the forehead and the glabella, where they appear as frown lines, and around the mouth, as marionette lines. In the study presented here, we recruited two sets of volunteers. An older group of 57 volunteers aged 50 to 65 years, and a group of eight younger volunteers aged 21–35 who were the biological daughters of eight of the older volunteers. Using VISIA CR, we took images of the volunteers in relaxed, angry and smiling mode to assess similarities in expression wrinkle patterns. In addition, the older volunteers were split into a placebo group and an active group who applied a formulation of 4% of a cosmetic product containing the peptide diaminobutyroyl benzylamide diacetate (DABBA) for four weeks. Wrinkles were assessed by image analysis, expert grading and Primoslite measurements. Our study found striking similarities in the facial wrinkle patterns of mothers with relaxed faces and daughters with angry or smiling faces. We found a decrease in visible wrinkles in the group of older volunteers applying DABBA. We created a facial map for graded wrinkles showing these changes. Volunteers using the active formulation showed significantly less wrinkle area and length on the forehead when frowning compared to the placebo group (p < 0.05).

Efficacy of a Novel Integrated Active Herbal Formulation in Experimentally Induced Rat Model for Dry Eye Disease

Objectives Dry eye is common condition of eye with insufficient production of tears leading to inadequate lubrication of eyes. It is chronic in nature & may be associated with discomfort & eye redness, blurred vision & tear film instability leading to potentially damaged ocular surfaces. Inflammation & oxidative stress play significant role in pathogenesis of disease by causing ocular surface disruption. Traditional Rx for dry eyes such as artificial tears, punctual plugs, prescription eye drops, etc. doesn't adequately address underlying causes of dry eyes. Further many of treatments are in form of eye drops that require regular administration to eyes, which is inconvenient & contains preservatives that further irritate eyes. We evaluated integrated active formulation administered orally to alleviate symptoms of dry eyes in rat model. Methods We used proprietary formulation technology to blend multiple ingredients into an integrated oil suspension (OS) that can be conveniently used in an oral dosage form. Ingredients included bioavailable form of Curcumin, Lutein/Zeaxanthin (L/Z) and Vit D3 formulated as an integrated product. Dry eye condition was created by administration of BAK (benzalkonium chloride) to eyes of female Wistar rat twice daily for 14 days, followed by initiation of supplementation by administering integrated dry eye formulation by oral gavage for 4 weeks at dose of 100 & 200 mg/kg b.w. to evaluate effect of this novel formulation. 7 rats were included in each group. Results There was significant improvement in tear volume, tear breakup time, tear film integrity & reduced overall inflammation, histopathological examination with supplementation. Our formulation helped in lowering oxidative stress as evidenced by significant reduced serum & corneal MDA, increased corneal SOD & corneal GPx. Levels of inflammatory cytokines such as NF-κB, TNF-α, IL-1β, IL-6 & IL-8 were significantly reduced & protective proteins such as MUC1, MUC4, MUC5AC and MMP-9 were restored by supplementation with integrated dry eye formulation which were otherwise lowered in dry eye condition. Conclusions Our results strongly suggest that our novel integrated active formulation of Curcumin, L/Z, Vit D3 is effective in alleviating symptoms of dry eye condition with multi-modal mechanism of action in dose dependent manner. Funding Sources OmniActive Health Technologies Limited.

Dexlansoprazole is Effective in Relieving Heartburn during the Fasting Month of Ramadan

Background and Aims: Proton pump inhibitors are effective at reducing heartburn. No studies have evaluated their efficacy in Ramadan. Dexlansoprazole has a unique active formulation independent of time-of-day dosing or food. The aim is to investigate the efficacy of dexlansoprazole 60 mg during Ramadan in patients with symptomatic heartburn. Methods: Subjects recruited using poster, radio, and SMS advertisements completed a diary using a mobile-friendly application and received daily SMS reminders. Dexlansoprazole was started on day 8 for 3 weeks. No placebo arm was used in this trial. Primary endpoint was relief of heartburn expressed as mean 24-h free heartburn percentage (24FH%) per weekly period. Results: A total of 32 patients were enrolled. During week 1, only 1 person (3.1%) was heartburn-free and mean 24FH% was 41.1 ± 24.8%. On dexlansoprazole, mean 24FH% rose to 63.4 ± 23.8 and 81.6 ± 24.5% in weeks 2 and 4, respectively (p < 0.001 for both). Median 24FH% increased from 35.7% in week 1 to 71.4 and 85.7% in weeks 2 and 4, respectively. Mean Gastroesophageal Reflux Disease Questionnaire (GERDQ) scores decreased from 10.0 ± 3.2 in week 1 to 6.53 ± 2.2 in week 2 (p < 0.001) and 5.87 ± 2.1 in week 4 (p < 0.001). Mean heartburn severity score decreased from 2.5 ± 1.0 to 1.7 ± 0.8 (p = 0.001). Early response was higher in patients with GERDQ scores ≥8 (p = 0.012). Conclusion: Dexlansoprazole is effective in the treatment of heartburn during Ramadan. Clinicaltrials.gov number: NCT03079050.

Fludalanine: Nice Try But No Hallelujah

It is time that we experienced a tale of failure. As I have stated repeatedly, most drug discovery efforts fail. Choice of the wrong target dooms the effort from the start. Screening may fail to turn up actives, and molecular design may do no better. Given active molecules, medicinal chemistry efforts to improve properties may fail. Senior management’s heavy hand may terminate a promising effort. If one gets as far as development, a safety or efficacy issue may derail the project. Then, too, competitors may outrun you or financial support may dry up. There are many ways to fail, not so many to succeed. All five stories told so far have been successes: finasteride, ACE inhibitors, statins, imipenem/cilastatin, and the avermectins. Chapter 12 provides another example of a success: the gliptins. In this chapter, however, I pull together the threads of a failure: fludalanine. It is the most interesting failed drug discovery story that I know. There is much to learn from it, particularly about problem solving. It has a couple of surprises. By way of background, Merck had set its mind on finding an effective orally active antibiotic, driven in substantial part by the insistence of Max Tishler, Merck’s determined head of research. Orally active antibiotics are attractive. A patient with a bacterial infection may be treated in the hospital with an oral or a parenteral agent, one given by injection or inhalation. An injectable antibiotic may be given intravenously, intramuscularly, or subcutaneously. However, when the patient has been released from the hospital and sent home, it is convenient to have an antibiotic that can be taken by mouth, a tablet or capsule, for continued action against the infection. Ideally, an antibiotic should be available in both a parenteral (intravenous, intramuscular, or subcutaneous) formulation and an orally active formulation. In this way, the patient can be maintained on the same antibiotic when returning home from the hospital. Merck was having trouble meeting its objective.