Precautions before starting tofacitinib in persons with rheumatoid arthritis

Tofacitinib is an immunosuppressive and disease-modifying therapy in rheumatoid arthritis. It may result in many infections flaring up. It is important to take precautions of all kinds (cardiovascular, malignancy, infections etc.) before starting tofacitinib. In this article, we have highlighted important steps where we need to take precautions before starting tofacitinib.     

Melatonin inhibits matrix metalloproteinase‐9 activity by binding to its active site

The zinc‐dependent matrix metalloproteinases (MMPs) are key enzymes associated with extracellular matrix (ECM) remodeling; they play critical roles under both physiological and pathological conditions. MMP‐9 activity is linked to many pathological processes, including rheumatoid arthritis, atherosclerosis, gastric ulcer, tumor growth, and cancer metastasis. Specific inhibition of MMP‐9 activity may be a promising target for therapy for diseases characterized by dysregulated ECM turnover. Potent MMP‐9 inhibitors including an indole scaffold were recently reported in an X‐ray crystallographic study. Herein, we addressed whether melatonin, a secretory product of pineal gland, has an inhibitory effect on MMP‐9 function. Gelatin zymographic analysis showed a significant reduction in pro‐ and active MMP‐9 activity in vitro in a dose‐ and time‐dependent manner. In addition, a human gastric adenocarcinoma cell line (AGS) exhibited a reduced (~50%) MMP‐9 expression when incubated with melatonin, supporting an inhibitory effect of melatonin on MMP‐9. Atomic‐level interaction between melatonin and MMP‐9 was probed with computational chemistry tools. Melatonin docked into the active site cleft of MMP‐9 and interacted with key catalytic site residues including the three histidines that form the coordination complex with the catalytic zinc as well as proline 421 and alanine 191. We hypothesize that under physiological conditions, tight binding of melatonin in the active site might be involved in reducing the catalytic activity of MMP‐9. This finding could provide a novel approach to physical docking of biomolecules to the catalytic site of MMPs, which inhibits this protease, to arrest MMP‐9‐mediated inflammatory signals.     

Paclitaxel loaded PEGylated gleceryl monooleate based nanoparticulate carriers in chemotherapy

A PEGylated drug delivery system of paclitaxel (PTX), based on glyceryl monooleate (GMO) was prepared by optimizing various parameters to explore its potential in anticancer therapy. The prepared system was characterized through polarized light microscopy, TEM, AFM and SAXS to reveal its liquid crystalline nature. As GMO based LCNPs exhibit high hemolytic toxicity and faster release of entrapped drug (66.2?±?2.5% in 24?h), PEGylation strategy was utilized to increase the hemocompatibility (reduction in hemolysis from 60.3?±?10.2 to 4.4?±?1.3%) and control the release of PTX (43.6?±?3.2% released in 24?h). The cytotoxic potential and cellular uptake was assessed in MCF-7 cell lines. Further, biodistribution studies were carried out in EAT (Ehrlich Ascites tumor) bearing mice using (99m)Tc-(Technetium radionuclide) labeled formulations and an enhanced circulation time and tumor accumulation (14 and 8 times, respectively) were observed with PEGylated carriers over plain ones, at 24?h. Finally, tumor growth inhibition experiment was performed and after 15 days, control group exhibited 15 times enhancement in tumor volume, while plain and PEGylated systems exhibited only 8 and 4 times enhancement, respectively, as compared to initial tumor volume. The results suggest that PEGylation enhances the hemocompatibility and efficacy of GMO based system that may serve as an efficient i.v. delivery vehicle for paclitaxel.     

Rehabilitation in long COVID-19: A mini-review

We have been experiencing multiple waves of the coronavirus disease 2019 (COVID-19) pandemic. With these unprecedented waves, we have entered into an era of ‘new normal’. This pandemic has enforced us to rethink the very basics of childhood learning: Habits, health etiquette, and hygiene. Rehabilitation has immense importance during this pandemic considering a few aspects. Multidisciplinary COVID-19 rehabilitation clinics are essential to address the demand. The equitable distribution of COVID-19 rehabilitation services for differently-abled individuals during the pandemic is an important aspect. Rehabilitation needs identification and further studies on various rehabilitation interventions are among the key unmet future research needs.     

Role of melatonin in regulating matrix metalloproteinase-9 via tissue inhibitors of metalloproteinase-1 during protection against endometriosis

Abstract:  Endometriosis is a gynecological disease of women and plausibly regulated by matrix metalloproteinases (MMPs). However, mechanisms of alterations in MMPs during endometriosis remain unclear. Human endometriotic tissues possessing varying degrees of severity were examined for expression of MMPs and tissue inhibitors of metalloproteinase (TIMP)-1. In addition, endometriosis was generated in mice and endometriotic tissues were tested for MMP-9 activity. Results show significant upregulation of secreted and synthesized proMMP-9 activity with duration and severity of endometriosis. Along with upregulation of activity, the expression of proMMP-9 was found increased while TIMP-1 expression followed an inverse trend. The effect of melatonin, a major secretory product of the pineal gland, on endometriosis was examined in preventive and therapeutic models in mice. The results show that melatonin arrested lipid peroxidation and protein oxidation and downregulated proMMP-9 activity and expression in a time and dose-dependent manner while protecting and regressing peritoneal endometriosis. Moreover, the attenuated activity and expression of proMMP-9 were associated with subsequent elevation in the expression of TIMP-1. Our study reveals for the first time the role of melatonin in arresting peritoneal endometriosis in mice and a novel marker, expression ratio of proMMP-9 versus TIMP-1, was identified for assessing severity and progression of endometriosis.     

Upregulation of collagenase-1 and -3 in indomethacin-induced gastric ulcer in diabetic rats: role of melatonin

Collagenases are key proteases involved in inflammation and injury. We addressed whether collagenases have an association with the susceptibility of gastric injury under diabetes as well as the effect of melatonin on collagenases in ulcerated gastric tissues. Diabetes was induced in rats by a single dose of streptozotocin (STZ) followed by gastric ulceration using indomethacin, and melatonin's action was studied by its application prior to indomethacin exposure. Ulcer indices and damage were elevated significantly in gastric tissues of diabetic compared with nondiabetic rats. Melatonin reversed the effect of indomethacin during protection of gastric ulcers in diabetic rats. Matrix metalloproteinase (MMP)-13 (i.e., collagenase-3) was upregulated in diabetic gastric mucosa and enhanced further upon ulceration while melatonin ameliorated their activity. In addition, gastric tissues showed enhanced expression of both MMP-1 (i.e., collagenases-1) and -13 significantly in diabetic rats compared with nondiabetic animals and more so during ulceration while tissue inhibitors of metalloproteinase-1 (TIMP-1) showed an opposite trend. MMP-2 activities exhibited a ～50% downregulation during gastric ulceration which were rescued by melatonin. Moreover, increased expression of both MMP-1 and -13 was mediated by activator protein-1 activation via extracellular signal-regulated kinase 1/2 which were parallel to upregulation of tumor necrosis factor-α, interleukin-1β, and heat shock protein-70 during ulceration. Melatonin arrested collagenase expression by downregulation of these signaling molecules thereby halting the progression of the disease. We conclude that diabetic gastric tissues are susceptible to ulceration and associated with MMP-1 and -13 upregulation in indomethacin-induced injury. Additionally, melatonin protects the gastric damage under diabetes via regulation of both MMP-1 and -13.     

“Helicobacter pylori treatment guideline: An Indian perspective”: Letter to the editor

Treatment guidelines in many countries for Helicobacter pylori (H. pylori) may differ. Owing to the various characteristics of bacteria, clinical manifestations, resistance to antibiotics and recurrence rate, treatment regimens may change. In this letter, we would like to give an Indian perspective on H. pylori treatment guidelines.     

Efficacy and safety of nintedanib in Asian patients with systemic sclerosis-associated interstitial lung disease: Subgroup analysis of the SENSCIS trial

Background and objectiveIn the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks by 44% in comparison with placebo, with manageable adverse events in most patients. We analyzed the efficacy and safety of nintedanib in patients of Asian race.MethodsPatients with SSc-ILD were randomized to receive nintedanib or placebo. The outcomes over 52 weeks were analyzed in Asian versus non-Asian patients.ResultsOf the 288 patients in each treatment group, 62 (21.5%) in the nintedanib group and 81 (28.1%) in the placebo group were Asian; 90.2% of the Asian patients were enrolled in Asian countries. In the placebo group, the rate of FVC decline over 52 weeks was consistent between Asian and non-Asian patients (?99.9 and ?90.6 mL/year, respectively). The effect of nintedanib on reducing the rate of FVC decline over 52 weeks was consistent between Asian (difference, 44.3 mL/year [95% CI: ?32.8, 121.4]) and non-Asian patients (difference, 39.0 mL/year [95% CI: ?5.1, 83.1]) (treatment-by-time-by-subgroup interaction, p = 0.91). Diarrhea was the most frequent adverse event and was reported in similar proportions of Asian and non-Asian patients in the nintedanib group (80.6% and 74.3%, respectively) and placebo group (28.4% and 32.9%, respectively).ConclusionsIn patients with SSc-ILD, nintedanib had a consistent benefit on slowing the progression of SSc-ILD in Asian and non-Asian patients, with a similar adverse event profile.Trial registrationClinicalTrials.gov NCT02597933.