A Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Effect of Topical Urea for Secondary Prophylaxis of Hand Foot Skin Reaction in Renal Cell Cancer Patients on Sunitinib Therapy.

INTRODUCTION: Hand foot skin reaction (HFSR) is a common dose-limiting adverse effect of multi kinase inhibitors (MKI) whose mechanism is not fully understood, and the prophylaxis is inadequate. OBJECTIVE: In this pilot study, a double-blind, randomized placebo-controlled trial was conducted to evaluate the effect of topical urea in secondary prevention of sunitinib-induced HFSR in renal cell cancer patients. METHODS: Out of 55 screened patients, 14 were randomized to receive topical urea or placebo for four weeks. The association of HFSR with drug levels of sunitinib and its metabolite (n-desethyl sunitinib), genetic polymorphism of VEGFR2 gene, quality of life (QOL) and biochemical markers was also assessed. RESULTS: The results showed that urea-based cream was not superior to placebo (P = .075). There was no change in the QOL in both the groups. Single nucleotide polymorphism was checked for two nucleotides rs1870377 and rs2305948 located in VEGFR2 gene on chromosome 4. SNP (variant T > A) at rs1870377 was associated with appearance of new HFSR as compared to the wild type, although the association was not statistically significant (OR 0.714). There was no statistically significant difference between mean plasma levels of sunitinib and N-desethyl sunitinib in urea arm as compared to placebo arm as compared to placebo. The best fit population pharmacokinetic model for sunitinib was one compartment model with first order absorption and linear elimination. The median (IQR) of population parameters calculated from the population pharmacokinetics model for Ka, V and Cl was 0.22 (0.21-0.24) h-1, 4.4 (4.09-4.47) L, 0.049 (0.042-0.12) L/hr, respectively. CONCLUSION: The study suggested that the urea-based cream was not superior to placebo in decreasing the appearance of new HFSR in renal cancer patients receiving 4:2 regimen of sunitinib.

Sinonasal mucormycosis and liposomal amphotericin B: A quest for dose optimization.

OBJECTIVES: Sinonasal mucormycosis is a serious fungal infection. Early diagnosis and prompt antifungal therapy along with surgical intervention is the key to its management. Liposomal amphotericin B (LAmB) given intravenously is the antifungal agent of choice. However, the current literature is not clear on its optimum dosage. We did a retrospective study to find the optimum dose of LAmB in cases with sinonasal mucormycosis. MATERIALS AND METHODS: Thirty patients diagnosed with mucormycosis involving sinonasal, rhino-orbital, or rhino-orbito-cerebral regions and receiving only LAmB as pharmacotherapy were included in our retrospective study from 2017 to 2020. A multiple logistic regression model was developed to correlate the total dose of LAmB and other parameters with the final outcome which was defined clinico-radiologically as improved, worsened, or death. The dose of LAmB which led to the first significant change in urea, creatinine, and potassium levels was also determined. RESULTS: The model showed a good fit in goodness-to-fit analysis (Pearson = 0.999, deviance = 0.995), while the likelihood ratio was statistically significant (0.001). The overall model prediction was 83.3%. However, the correlation of outcome with any of the variables, including mean LAmB dose per kilogram (82.2 ± 13.02 mg/kg), was statistically not significant. CONCLUSION: Many patient-related factors (such as age, comorbidities, extent of the disease, and side effects from LAmB therapy), which vary on a case-to-case basis, contribute to the outcome in a mucormycosis patient. The optimum dose of LAmB for improved outcome still requires individualization guided by experience, till well-designed studies address the question.

Effect of syringic acid and syringaldehyde on oxidative stress and inflammatory status in peripheral blood mononuclear cells from patients of myocardial infarction.

Oxidative stress and inflammation are considered as therapeutic targets in myocardial injury. The aim of the present study was to investigate the protective effect of syringic acid (SA) and syringaldehyde (SYD) on peripheral blood mononuclear cells (PBMCs) of myocardial infarction (MI) patients. PBMCs from MI patients were cultured in the presence and absence of SA and SYD. The level of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) was estimated. Reactive oxygen species (ROS) formation, oxidation of lipids, proteins, and activity of antioxidant enzymes were also quantified. To further determine biomolecular changes in treated PBMCs, Fourier transform infrared (FTIR) spectroscopic analysis was done. Molecular docking study was also conducted to evaluate the binding interaction of SA and SYD with various target proteins. SA and SYD treated PBMCs of MI patients showed decreased secretion of TNF-α, IL-6, and NO. Moreover, the content of ROS, level of lipid, and protein oxidation showed diminution by treatment with both the compounds. Enhanced antioxidant defense was also observed in treated PBMCs. The FTIR spectra of treated cells revealed safeguarding effect of SA and SYD on biomolecular structure. The molecular docking analysis displayed significant binding affinity of the two compounds towards TNF-α, IL-6, and antioxidant enzymes. Our findings demonstrated potent antioxidant and anti-inflammatory effects of SA and SYD on PBMCs of MI patients. Thus, SA and SYD supplementation might be beneficial in attenuating oxidative stress and inflammation in MI.

Anti-oxidant and anti-inflammatory effects of cinnamaldehyde and eugenol on mononuclear cells of rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is an autoimmune disorder affecting joints and frequently characterized by initial local and later systemic inflammation. The present study was conducted with the aim to determine the anti-inflammatory and antioxidant effects of cinnamaldehyde and eugenol in the peripheral blood mononuclear cells (PBMC) of RA patients. PBMCs obtained from RA patients were treated with varying concentrations of cinnamaldehyde and eugenol. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were monitored in the 24-h culture supernatant of PBMCs. Reactive oxygen species formation, biomolecular oxidation and the activities of antioxidant enzymes were also determined. FTIR analysis was done to determine structural alterations in the PBMCs. Molecular docking was performed to gain an insight into the binding mechanism of eugenol and cinnamaldehyde with pro-inflammatory cytokines. The levels of pro-inflammatory cytokines and markers of oxidative stress were found to be elevated in the PBMC culture of RA patients as compared to the healthy controls. Cinnamaldehyde and eugenol have significantly reduced the levels of cytokines. Reactive oxygen species formation, biomolecular oxidation and antioxidant defense response were also ameliorated by treating PBMCs with both the compounds. FTIR results further confirms cinnamaldehyde and eugenol mediated protection to biomolecules of PBMCs of RA patients. Molecular docking results indicates interaction of cinnamaldehyde and eugenol with key residues of TNF-α and IL-6. Cinnamaldehyde and eugenol were found to exert potent anti-inflammatory and anti-oxidant effects on the PBMC culture of RA patients. So, these compounds may be used as an adjunct in the management of RA.

Syringic acid protects from isoproterenol induced cardiotoxicity in rats.

Identification of pharmacologically potent antioxidant compounds for their use in preventive medicine is thrust area of current research. This study was undertaken with the aim of determining the protective role of syringic acid (SA) on isoproterenol (ISO) induced myocardial infarction (MI) in rats. SA was orally given to rats for 21 days at three different concentrations (12.5, 25 and 50 mg/kg). At 20th and 21st day, rats were subcutaneously injected with ISO and at the end of experimental period, rats were killed. ISO induced myocardial damage was averted by pre-co-treatment of SA, as decrease was found in serum level of marker enzymes (CKMB, LDH, AST, ALT), lipid peroxidation, protein carbonyl (PC) and proinflammatory cytokines (TNFα, IL 6). Furthermore, content of glutathione (GSH) and activities of antioxidant enzymes in heart tissue were significantly raised. Improvement in infarct size and erythrocyte (RBCs) morphology was also observed. The biochemical findings were supported by histopathological outcome and protective effect of SA was found to be dose dependent. The results of our study demonstrated that the cardioprotective potential of SA in rat model of ISO induced MI might be due to anti-lipid peroxidative and endogenous antioxidant system enhancement effects.

Cinnamaldehyde and eugenol attenuates collagen induced arthritis via reduction of free radicals and pro-inflammatory cytokines.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease which leads to bone and cartilage erosion. Oxidative stress and pro-inflammatory cytokines plays crucial role in the pathophysiology of RA. Cinnamaldehyde and eugenol have a long history of medical use in various inflammatory disorders. PURPOSE: The drugs available for the treatment of RA are associated with various side effects. The present study was conducted to evaluate the anti-arthritic effects of cinnamaldehyde and eugenol in rat model of arthritis. METHODS: Type II collagen was intradermally injected to rats for the induction of arthritis. Cinnamaldehyde (10 and 20 mg/kg/day) and eugenol (10 and 20 mg/kg/day) were given orally for 15 days, starting from day 21 to 35. Dexamethasone treated rats served as positive control. Histological, radiological and scanning electron microscopic analysis were done to monitor the effect of compounds on collagen induced arthritis (CIA). Reactive oxygen species (ROS) formation, nitric oxide and antioxidant status were also determined. The markers of biomolecular oxidation (protein, lipid and DNA) and activities of enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, catalase and glutathione reductase) were also evaluated in the joint homogenate and plasma of rats. For detecting inflammation, levels of TNF-α, IL-6 and IL-10 were monitored by ELISA. RESULTS: Our results showed anti-oxidant and anti-inflammatory effects of cinnamaldehyde and eugenol in arthritic rats. Scanning electron microscopy, histopathological and radiological findings also confirmed the anti-arthritic effects of cinnamaldehyde and eugenol. Both the compounds were effective in bringing significant decrease in the levels of ROS, nitric oxide, markers of biomolecular oxidation and increase in enzymatic and non-enzymatic antioxidants. The levels of TNF-α, IL-6 and IL-10 were also ameliorated by cinnamaldehyde and eugenol treatment. Between the two phytochemicals used, eugenol was found to be more effective than cinnamaldehyde in reducing the severity of arthritis. CONCLUSION: Cinnamaldehyde and eugenol were effective in ameliorating oxidative stress and inflammation in arthritic rats. These findings indicate that cinnamaldehdye and eugenol have a great potential to be used as an adjunct in the management of RA.

Protective effect of syringaldehyde on biomolecular oxidation, inflammation and histopathological alterations in isoproterenol induced cardiotoxicity in rats.

BACKGROUND: Ischemic injury during myocardial infarction (MI) is responsible for increased deaths among patients with cardiovascular disorders. Recently, research has been directed for finding treatment using natural compounds. This study was performed to investigate the effects of syrigaldehyde (SYD), a phytochemical against isoproterenol (ISO) induced cardiotoxicity model. METHODS: For induction of MI, rats were intoxicated with two doses of ISO and were treated with SYD at three different concentrations (12.5, 25 & 50 mg/kg) both prior and simultaneous to ISO administration. RESULTS: ISO group revealed amplified activity of marker enzymes (CKMB, LDH, AST, ALT), increased oxidation of proteins and lipid molecules. Moreover, augmentation in pro-inflammatory markers was also found. The same group also displayed marked changes in histopathology and erythrocyte (RBCs) morphology. SYD treated groups showed diminished levels of serum markers enzymes, lipid peroxidation and protein carbonyl (PC) with increment in antioxidant defense in cardiac tissues of ISO administered rats. Our findings also revealed the modulatory effect of SYD on membrane bound ATPases, showing that SYD significantly improved the ISO induced changes in membrane fluidity. Furthermore, decline in infarct size, alleviation of structural RBC damage and improved myocardial histopathological outcome were observed in treated groups. In addition, mitigation of biochemical and histopathological changes by SYD was found to be dependent on its concentration. CONCLUSION: SYD had cardioprotective efficacy owing to its antioxidative and anti-inflammatory properties. Our results support incorporation of SYD in regular diet for prevention of MI.

Cytokine Attenuation and Free Radical Scavenging Activity of a New Flavanone7,4'-Dihydroxy-3″,3″-Dimethyl -(5,6-Pyrano-2″-One)- 8- (3‴,3‴-Dimethyl Allyl)- Isolated from Mallotus philippensis: Possible Mechanism for Its Anti-Inflammatory Activity.

Mallotus philippensis L.(MP) commonly known as Kamala tree in Hindi,is a small to medium-sized monoecious tree.The objective of the study was to evaluate the anti-inflammatory activity of MPand a new flavanoneisolated from it by using in vivo models of inflammation.Albino wistar rats of either sex weighing 150-200g were used. Seven groups were made (n = 6), namely normal control group (normal saline, 1 ml/kg), standard control group (acetylsalicylic acid, 100 mg/kg), methanol crude extract (300 and 500 mg/kg), ethylacetate fraction (300 and 500 mg/kg) and active compound 4 (new flavanone, 50 mg/kg). The anti-inflammatory activity was studied using carrageenan induced paw edema method and cotton pellet granuloma method. Levels of cytokines (TNF-α, IL-1and IL-6) and activity of antioxidant enzymeslike catalase and glutathione peroxidase were estimated. It was found that the methanol extract, ethylacetate fraction and Flavanonedemonstrated significant reduction in paw edema in carrageenan induced paw edema method as compared to control. They also diminished the serum TNF-α, IL-6 and IL-1 levels. Significantly attenuated the malondialdehyde levels and increased the activities of catalase and glutathione peroxidase in paw tissue. Similarly there was asignificant decrease in granuloma formation in cotton pellet induced granuloma method. In conclusion, MP extracts and the newflavanonepossess anti-inflammatory activity and this might be due to the inhibition of various cytokines and increased free radical scavenging activity.

Alpha-1 antitrypsin, a diagnostic and prognostic marker of vernal keratoconjunctivitis.

INTRODUCTION: A major chunk of ocular allergies in humans involve the conjunctiva, of which Vernal Keratoconjunctivitis (VKC) appears to be more common. VKC, a chronic allergic conjunctivitis, frequently affects young males and is characterized by intense inflammation of the limbal and/or tarsal conjunctiva. The etiology and immuno-pathogenesis of VKC still remain unclear. Alpha-1 antitrypsin (AAT), a member of serine proteinase inhibitor (SERPIN) superfamily, is an acute phase protein whose concentration in blood increases in response to inflammation. AAT deficiency is one of the many factors that may be involved in several abnormalities such as liver disease, emphysema, inflammatory joint diseases and inflammatory eye diseases. In the present study, the role played by this protein in VKC was analyzed in a selective case/control study to assess its diagnostic and prognostic value. MATERIALS AND METHODS: The case control study included 50 patients of VKC reporting to Ophthalmology out patient department (OPD). Age and sex matched 40 healthy subjects served as control. Serum AAT level of both the cases and controls were evaluated and compared. Moreover the serum AAT levels of the patients at presentation were compared with their serum AAT level after three weeks post treatment. RESULT: Levels of AAT in the serum of VKC patients at presentation (2.80 ± 0.42 mg/ml) were significantly higher as compared to controls (2.31 ± 0.21 mg/ml) whereas no significant difference was observed between the serum level of post treatment VKC patients (2.48 ± 0.26 mg/ml) and controls. CONCLUSION: AAT is a potent acute phase protein whose concentration rises significantly in VKC, irrespective of the age and sex of the patient. Moreover, the serum level of AAT declined significantly post treatment; therefore it might be used as a prognostic marker.