Impact of Social Restrictions During COVID-19 on the Aquatic Levels of Antimicrobials and Other Drugs in Delhi.

The relative contribution of factors responsible for the environmental exposure of active pharmaceutical ingredients (APIs) is of interest for appropriate remedial measures. This study was carried out to evaluate the post-lockdown levels of APIs in water resources, in comparison to our previously published study from 2016. The environmental levels of 28 drugs from different classes were analyzed in surface water (Yamuna River), aquifers, and leachate samples collected from 26 locations in Delhi-NCR using the previously validated liquid chromatography-mass spectrometry (LC-MS/MS) methods. In addition, the prevalence of antimicrobial resistance in coliforms isolated from targeted surface water samples was also studied. This study revealed that more than 90% of APIs, including antibiotics, decreased drastically in both surface water and aquifers compared to our previous data. Selected samples subjected to antimicrobial resistance (AMR) analysis revealed the presence of cephalosporin-resistant coliform bacteria. Tracing cephalosporins in the surface and drain water samples revealed the presence of ceftriaxone in the drain and water samples from Yamuna River. Higher levels of ceftriaxone in landfill leachate were also found, which were found to be associated with coliform resistance and indicate the un-segregated disposal of medical waste into landfills. Social restrictions enforced due to COVID-19 resulted in a drastic decrease in antimicrobials and other APIs in aquatic water resources. Increased ceftriaxone and cephalosporin resistance was seen in coliform from surface water and drain, indicating the possibility of hospital waste and treatment-related drugs entering Yamuna River. Enforcement of the regulations for the safe disposal of antibiotics at hospitals and preliminary disinfection of hospital sewage before its inflow into common drains might help minimize the spread of antibiotic resistance in the environment.

Evaluation of adjuvant role of topical cyclosporine 1% in acute Stevens-Johnson syndrome: a randomised control trial.

PURPOSE: To evaluate the role of topical cyclosporine A 1% (CsA) as an adjuvant therapy in patients with acute Stevens-Johnson syndrome (SJS). METHODS: This is a randomised controlled trial in which 44 patients (88 eyes) with acute SJS, presenting within 3 months from the onset of the disease, were enrolled and randomised. Group A (n=44 eyes) patients received treatment with topical CsA 1% along with standard therapy consisting of topical corticosteroids, antibiotics and lubricants. Group B (n=44 eyes) patients received topical saline drops in combination with standard therapy. Various ocular surface parameters were assessed at baseline and the 6-month follow-up. RESULTS: The mean age of patients (years) was 23.9±15.1 in the CsA group and 26.0±18.7 in the control group (p=0.6840). The mean time from disease onset to presentation (days) was 17.0±14.0 and 12.9±11.3 in CsA and control groups, respectively (p=0.1568). At presentation, the mean grades of severity scores of various parameters were comparable. At 6 months, both groups showed a significant improvement in the mean severity grades of conjunctival hyperaemia (A, p=0.001; B, p=0.0001), mucocutaneous junction involvement (A, p=0.001; B, p=0.0001) and meibomian gland involvement (A, p=0.0471; B, p=0.006). Compared with baseline, the grades of corneal keratinisation (baseline, 0.48±0.7; 6 months, 1.02±0.8; p=0.0015) and neovascularisation (baseline, 1.07±1.2; 6 months, 1.57±1.0; p=0.0412) worsened after 6 months of CsA therapy. Intergroup comparison of grades of various parameters however did not reveal any significant difference at 6 months. CONCLUSIONS: Adjuvant treatment with topical CsA is not superior to standard therapy, in cases of acute SJS.

Pharmacokinetic-Pharmacodynamic (PK-PD) Analysis of Second-Line Anti-Tubercular Drugs in Indian Children with Multi-Drug Resistance.

OBJECTIVES: To conduct a thorough pharmacokinetic (PK) - pharmacodynamic (PD) analysis of second-line anti-tubercular therapy (ATT) in children diagnosed with multi-drug resistant tuberculosis (MDR-TB). METHODS: Twenty-seven children undergoing second-line ATT, including kanamycin (KM, n = 13), fluoroquinolones (FQs, n = 26), ethionamide (ETH, n = 20), para amino salicylic acid (PASA, n = 4), and cycloserine (CS, n = 15), were sampled at 0 (pre-dose), 1, 2, 3, and 4 h post-drug administration. Plasma drug levels were determined using a mass spectrometer and the collected dataset underwent non-compartmental PK analysis using PK solver ver2.0. PK/PD assessments involved individual drug simulation studies on 1000 subjects using Modviz Pop ver 1.0 in R-software. RESULTS: A total of 22 and 5 children were considered as responders and non-responders, respectively. Non-compartmental PK analysis revealed mean plasma drug levels of this study cohort attained the targeted maximum drug plasma concentration (Cmax). The ratio of Cmax /minimum inhibitory concentration (MIC) or the area under the curve (AUC)/MIC of the studied drugs had not shown a significant difference between responders and non-responders. Non-responders of ETH and ofloxacin had shown deviation from the derived dose-response profile for the simulated population. CONCLUSIONS: The management of MDR-TB with second-line ATT following national guidelines had cured the majority of the children (> 80%) who participated in the study. Inter-individual variability in few children from the targeted Cmax range suggests the need for future investigations on pharmacogenomic aspects of drug metabolism.

Nanomicelles empower natamycin in treating fungal keratitis: An in vitro, ex vivo and in vivo study.

Fungal infections of cornea are important causes of blindness especially in developing nations with tropical climate. However, the challenges associated with current treatments are responsible for poor outcome. Natamycin is the only FDA-approved antifungal drug to treat fungal keratitis, but unfortunately due to its poor water solubility, it is available as suspension. The marketed suspension (5% Natamycin) has rapid precorneal clearance, poor corneal permeability, a higher frequency of administration, and corneal irritation due to undissolved suspended drug particles. In our study, we developed clear and stable natamycin-loaded nanomicelles (1% Natcel) to overcome the above challenges. We demonstrated that 1% Natcel could permeate the cornea better than 5% suspension. The developed 1% Natcel was able to provide sustained release for up to 24 h. Further, it was found to be biocompatible and also improved the mean residence time (MRT) than 5% suspension in tears. Therefore, the developed 1% Natcel could be a potential alternative treatment for fungal keratitis.

Endocannabinoids and cortisol in plasma, aqueous and tear samples of primary angle closure glaucoma versus controls.

PURPOSE: To compare the levels of endocannabinoids (EC) in plasma, aqueous humor and tears, cortisol in plasma and aqueous, in primary angle closure glaucoma (PACG) and controls, while comparing the quality of life in both groups. METHODS: A total of 60 patients, ≥40years of age, with a diagnosis of PACG or cataract, 30 in each group were recruited. They were subjected to a detailed ophthalmic evaluation, a WHO Quality of Life Brief Version (WHOQOL-BREF) questionnaire answering and collection of tear, aqueous and blood samples. The levels of endocannabinoids-anandamide (AEA), 2-arachidonoylglycerol (2AG) in plasma, aqueous humor and tears; cortisol in plasma and aqueous humor; and WHO-QOL score in each group were noted. RESULTS: Plasma AEA (p = 0.01) and plasma 2-AG, (p = 0.002) levels were significantly higher in the control group as compared to the PACG group. WHO-QOL score was better in controls (p < 0.001). The EC were in undetectable levels in aqueous. Plasma and aqueous cortisol were significantly higher in PACG and both had the highest Area under the receiver operating characteristics (AUROC) curve value for differentiating PACG from controls. Tear 2AG and tear AEA had a moderately strong positive correlation with plasma 2-AG. Females had insignificantly higher levels of plasma and tear endocannabinoids. CONCLUSIONS: Tear endocannabinoids were determined for the first time in PACG and normal with no difference between the two groups. Plasma and aqueous cortisol levels are a differentiating factor between normal and glaucoma patients with plasma endocannabinoids being remarkably higher in normals. Quality of life in glaucoma patients with high cortisol levels is poorer.

Effect of CYP2C19 polymorphism on response to bortezomib-based therapy in multiple myeloma patients.

BACKGROUND: Bortezomib, a commonly used anti-myeloma drug, is metabolized by liver microsomal enzymes which may be polymorphic and responsible for lack of response in 30% patients. Hence, the association of CYP2C19 polymorphism with treatment response was explored in this study. METHODS: Treatment naive multiple myeloma (MM) patients, eligible for bortezomib-based induction treatment, were recruited as per the inclusion - exclusion criteria. The genotyping of CYP2C19 was done using polymerase chain reaction-restriction fragment length polymorphism for *2, *3 and *17 alleles. The incidence and severity of peripheral neuropathy were noted at follow-up visits and graded as per CTCAE criteria ver 5.0. RESULTS: Total 220 patients were recruited from August 2016 till May 2021; with a mean age of 55.6 (9.5) years and 65.9% males. Bortezomib+cyclophosphamide+dexamethasone (41.8%) and bortezomib+lenalidomide+dexamethasone (38.2%) were the most prescribed regimens. The CYP2C19 was polymorphic in 38.6%, 2.3% and 23.7% patients for *2, *3 and *17 allele respectively. There were 195 treatment responders and 25 non-responders, and CYP2C19*2 allele was different between responders and non-responders (p = 0.02). All extensive metabolisers (n = 54) were noted to be treatment responders. Peripheral neuropathy was reported by 23.2% patients. The frequency of peripheral neuropathy was somewhat lower in patients having either *2/*2 or *3/*3 allele pattern for CYP2C19 (p = 0.44). CONCLUSIONS: Polymorphism in CYP2C19 enzyme is likely to have an impact on bortezomib treatment response and peripheral neuropathy. The study suggests the role of pharmacogenetics in personalised treatment of MM.

Analysis and remediation of phthalates in aquatic matrices: current perspectives.

Phthalic acid esters (PAEs) are high production volume chemicals used extensively as plasticizers, to increase the flexibility of the main polymer. They are reported to leach into their surroundings from plastic products and are now a ubiquitous environmental contaminant. Phthalate levels have been determined in several environmental matrices, especially in water. These levels serve as an indicator of plasticizer abuse and plastic pollution, and also serve as a route of exposure to different species including humans. Reports published on effects of different PAEs on experimental models demonstrate their carcinogenic, teratogenic, reproductive, and endocrine disruptive effects. Therefore, regular monitoring and remediation of environmental water samples is essential to ascertain their hazard quotient and daily exposure levels. This review summarises the extraction and detection techniques available for phthalate analysis in water samples such as chromatography, biosensors, immunoassays, and spectroscopy. Current remediation strategies for phthalate removal such as adsorption, advanced oxidation, and microbial degradation have also been highlighted.

Calotropis procera extract inhibits prostate cancer through regulation of autophagy.

Current treatment options available for prostate cancer (PCa) patients have many adverse side effects and hence, new alternative therapies need to be explored. Anticancer potential of various phytochemicals derived from Calotropis procera has been studied in many cancers but no study has investigated the effect of leaf extract of C. procera on PCa cells. Hence, we investigated the effect of C. procera leaf extract (CPE) on cellular properties of androgen-independent PC-3 and androgen-sensitive 22Rv1 cells. A hydroalcoholic extract of C. procera was prepared and MTT assay was performed to study the effect of CPE on viability of PCa cells. The effect of CPE on cell division ability, migration capability and reactive oxygen species (ROS) production was studied using colony formation assay, wound-healing assay and 2',7'-dichlorodihydrofluorescein diacetate assay, respectively. Caspase activity assay and LDH assay were performed to study the involvement of apoptosis and necrosis in CPE-mediated cell death. Protein levels of cell cycle, antioxidant, autophagy and apoptosis markers were measured by western blot. The composition of CPE was identified using untargeted LC-MS analysis. Results showed that CPE decreased the viability of both the PCa cells, PC-3 and 22Rv1, in a dose- and time-dependent manner. Also, CPE significantly inhibited the colony-forming ability, migration and endogenous ROS production in both the cell lines. Furthermore, CPE significantly decreased NF-κB protein levels and increased the protein levels of the cell cycle inhibitor p27. A significant increase in expression of autophagy markers was observed in CPE-treated PC-3 cells while autophagy markers were downregulated in 22Rv1 cells after CPE exposure. Hence, it can be concluded that CPE inhibits PCa cell viability possibly by regulating the autophagy pathway and/or altering the ROS levels. Thus, CPE can be explored as a possible alternative therapeutic agent for PCa.

Effect of "365 Breathing Technique" on Intraocular Pressure and Autonomic Functions in Patients With Glaucoma: A Randomized Controlled Trial.

PRCIS: Patients with primary open angle glaucoma were advised to follow the "365 breathing technique" for 6 weeks in addition to their pharmacological glaucoma treatment. It helped to reduce intraocular pressure (IOP), stress biomarker-cortisol, and improve autonomic dysfunction. OBJECTIVE: To study the effect of the "365 breathing technique" on IOP, autonomic functions, and stress biomarkers in patients with primary open angle glaucoma. METHODS: In this randomized, controlled, interventional trial, after randomization, 40 patients in the intervention group followed "365 breathing" (three times a day, breathing rate: 6 cycles/min for 5 min) in addition to their pharmacological glaucoma treatment and 40 patients in the control group continued only with their pharmacological glaucoma treatment. IOP, serum cortisol, heart rate variability (HRV), and heart rate response to deep breathing test (DBT) were recorded at preintervention and 6 weeks postintervention. RESULTS: The mean IOP, serum cortisol, parameters of the HRV test, and DBT were comparable between the two groups at baseline. At the 6-week follow-up, in the intervention group, mean IOP was significantly lower (16.09 ± 2.24 vs 18.38 ± 1.58 mm Hg, P = 0.03) and serum cortisol were significantly lower (13.20 ± 3.11 vs 14.95 ± 2.60 mcg/dL, P = 0.038) compared with the control group. In the HRV test, time domain analysis showed a significant difference in the root mean square of the successive difference between RR interval values between both groups at 6 weeks ( P = 0.015) pointing towards higher postintervention parasympathetic activation in the intervention group. In frequency domain analysis (HRV test), the ratio of the low-frequency component to the high-frequency component was significantly lower in the intervention group at 6 weeks (1.65 vs 1.79, P = 0.019) indicating a shift in sympathovagal balance towards greater vagal modulation.There was a significant increase in delta heart rate ( P = 0.019) and expiratory:inspiratory ratio ( P = 0.011) in the intervention group at 6 weeks when compared with baseline values, indicating improved parasympathetic reactivity to DBT. CONCLUSION: "365 breathing" technique can reduce IOP and serum cortisol, and improve autonomic dysfunction in patients with glaucoma.

Tear Tacrolimus Levels and Clinical Response After Adjunct Therapy With Cutaneous Application of Tacrolimus 0.1% Over Upper Eyelid Skin in Chronic Vernal Keratoconjunctivitis.

PURPOSE: The aim of this study was to evaluate the role of cutaneous application of 0.1% tacrolimus eye ointment over the skin of the upper eyelid in chronic vernal keratoconjunctivitis (VKC). METHODS: A prospective, longitudinal, noncomparative, open-label clinical study of moderate-to-severe grade steroid-dependent VKC was performed. Study participants were initiated on adjunct therapy of cutaneous application of 0.1% tacrolimus ointment twice daily on the upper eyelid skin. Ocular surface evaluation parameters, meibomian gland imaging, intraocular pressure, visual acuity, and clinical disease severity scoring were performed to assess clinical response at baseline and month 3 of therapy. Tear levels of tacrolimus were measured at month 3 using high-performance liquid chromatography tandem mass spectrometry and correlated with the clinical score. RESULTS: Palpebral form of VKC was observed in 85% of the cases, with positive family history in 5%, atopy in 7.5%, and keratoconus in 11.25%. Clinical assessment revealed improvement in 97.5% patients with discontinuation of concomitant topical steroids in 64% of patients. There were no changes in visual acuity, intraocular pressure, or ocular surface evaluation after therapy. Tacrolimus was detected in the tears of all our study patients after cutaneous application over the upper eyelid skin, proving its bioavailability with mean tear tacrolimus levels of 6.55 ± 21.43 ng/mL. Correlation analysis revealed a moderate negative correlation between the clinical score and tacrolimus concentration (Spearman correlation coefficient: -0.34, P = 0.002). CONCLUSIONS: Cutaneous tacrolimus 0.1% ointment over the upper eyelid skin is an efficacious alternative method of application in treatment of VKC, with no resultant ocular irritation.

Impact of Bundled Intervention on Outcomes of Patients Undergoing Clean Orthopedic Surgeries With Hardware Implants: Small Prospective Randomized Controlled Trial.

Background: Prosthesis-related infections (PRIs) and surgical site infections (SSIs) remain one of the most devastating complications among patients undergoing clean orthopedic surgeries. Prevention strategies are critical to reduce infection rates in orthopedic surgeries. The current study aimed to determine the effectiveness of a set of evidence-based practices (bundled intervention) in reducing the incidence of PRIs and SSIs among patients undergoing clean orthopedic surgeries with hardware implants. Patients and Methods: A prospective, interventional randomized controlled trial was conducted for a period of three years. A total of 597 patients were enrolled, and depending on their Staphylococcus aureus carrier status were categorized into carrier group (n = 98) and non-carrier group (n = 499). Only carrier group patients were analyzed for effectiveness of bundled interventions, after being randomly assigned to two subgroups: interventional carrier group (ICG; n = 50) and non-interventional carrier group (NICG; n = 48). Results: Of the 597 patients, 98 (16.4%) were colonized with Staphylococcus aureus, among whom 9 (19.4%) had methicillin resistance. During follow-up, overall infection rate of 1.1% was observed (PRI, 0.3%; SSI, 0.8%). There was no case of PRI/SSI in the ICG. However, in the NICG, one patient developed SSI because of methicillin-resistant Staphylococcus aureus. An endogenous source of infection was demonstrated by pulsed field gel electrophoresis (PFGE). The SSI rate was higher in the NICG (p = 0.002). In the non-carrier group (n = 499), SSIs/PRIs occurred among 1.2% of the patients, because of organisms other than Staphylococcus aureus. Conclusions: Benefit of bundle intervention approach could be demonstrated. Further studies assessing the effectiveness of the individual components of the bundle can inform clinical practice greatly.

Untargeted metabolomics in the aqueous humor reveals the involvement of TAAR pathway in glaucoma.

Understanding the metabolic dysfunctions and underlying complex pathological mechanisms of neurodegeneration in glaucoma could help discover disease pathways, identify novel biomarkers, and rationalize newer therapeutics. Therefore, we aimed to investigate the local metabolomic alterations in the aqueous humor and plasma of primary glaucomatous patients. This study cohort comprised primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), and cataract control groups. Aqueous humor and plasma samples were collected from patients undergoing trabeculectomy or cataract surgery and subjected to high-resolution mass spectrometry (HRMS) analysis. Spectral information was processed, and the acquired data were subjected to uni-variate as well as multi-variate statistical analyses using MetaboAnalyst ver5.0. To further understand the localized metabolic abnormalities in glaucoma, metabolites affected in aqueous humor were distinguished from metabolites altered in plasma in this study. Nine and twelve metabolites were found to be significantly altered (p < 0.05, variable importance of projection >1 and log2 fold change ≥0.58/≤ -0.58) in the aqueous humor of PACG and POAG patients, respectively. The galactose and amino acid metabolic pathways were locally affected in the PACG and POAG groups, respectively. Based on the observation of the previous findings, gene expression profiles of trace amine-associated receptor-1 (TAAR-1) were studied in rat ocular tissues. The pharmacodynamics of TAAR-1 were explored in rabbits using topical administration of its agonist, ß-phenyl-ethylamine (ß-PEA). TAAR-1 was expressed in the rat's iris-ciliary body, optic nerve, lens, and cornea. ß-PEA elicited a mydriatic response in rabbit eyes, without altering intraocular pressure. Targeted analysis of ß-PEA levels in the aqueous humor of POAG patients showed an insignificant elevation. This study provides new insights regarding alterations in both localized and systemic metabolites in primary glaucomatous patients. This study also demonstrated the propensity of ß-PEA to cause an adrenergic response through the TAAR-1 pathway.

Evaluation of the Levels of Low-dose Topical Atropine (0.01%) in Aqueous and Vitreous Humor in Human Eyes.

SIGNIFICANCE: This is the first human study that confirmed penetration of 0.01% topical atropine in aqueous and vitreous humor in live human eyes. This supports the possible mode of action of atropine via posterior ocular structures. This knowledge will help improve the outcomes in myopia management. PURPOSE: The purpose of this study was to evaluate penetration of low-dose atropine 0.01% in aqueous and vitreous humor. METHODS: In this cross-sectional interventional pilot study, 48 cataract cases were divided into four groups (12 each), and 30 epiretinal membrane/macular hole cases were divided into three groups (10 each). One drop of 0.01% atropine was put in the eye to be operated. Aqueous humor samples were taken from patients undergoing cataract surgery at 60 ± 15 minutes in group 1, 120 ± 15 minutes in group 2, 240 ± 15 minutes in group 3, and 360 ± 15 minutes in group 4. Vitreous humor samples were taken from patients undergoing vitreoretinal surgery for epiretinal membrane/macular hole at 120 ± 15 minutes in group 1, 240 ± 15 minutes in group 2, and 360 ± 15 minutes in group 3. The assay of atropine was performed using liquid chromatography-mass spectrometry. RESULTS: Median concentrations of atropine in aqueous samples were 1.33 ng/mL (min-max, 0.6 to 6.46 ng/mL; interquartile range [IQR], 3.05 ng/mL) at 60 minutes, 2.60 ng/mL (min-max, 0.63 to 4.62 ng/mL; IQR, 1.97 ng/mL) at 120 minutes, 1.615 ng/mL (min-max, 0.1 to 3.74 ng/mL; IQR, 1.62 ng/mL) at 240 minutes, and 1.46 ng/mL (min-max, 0.47 to 2.80 ng/mL; IQR, 1.73 ng/mL) at 360 minutes, and those in vitreous samples were 0.102 ng/mL (min-max, 0 to 0.369 ng/mL; IQR, 0.366 ng/mL) at 120 minutes, 0.1715 ng/mL (min-max, 0 to 0.795 ng/mL; IQR, 0.271 ng/mL) at 240 minutes, and 0.2495 ng/mL (min-max, 0 to 0.569 ng/mL; IQR, 0.402 ng/mL) at 360 minutes, respectively. CONCLUSIONS: Measurable concentration of low-dose topical atropine (0.01%) was noted in aqueous and vitreous humor after instillation of a single drop of low-dose atropine. Muscarinic receptors located in the posterior segment such as the choroid and retina could be the possible site of action of low-dose atropine in myopia.

Cationic Nano-Lipidic Carrier Mediated Ocular Delivery of Triamcinolone Acetonide: A Preclinical Investigation in the Management of Uveitis.

The current study was undertaken to evaluate the efficacy of a novel nano-lipoidal eye drop formulation of triamcinolone acetonide (TA) for the topical treatment of uveitis. The triamcinolone acetonide-loaded nanostructured lipid carriers (cTA-NLC) were developed by employing 'hot microemulsion method' using biocompatible lipids, which exhibited a sustained release nature and enhanced efficacy when evaluated in vitro. The in vivo efficacy of this developed formulation was tested on Wistar rats, and a single-dose pharmacokinetic study was conducted in rabbits. The eyes of animals were examined for any signs of inflammation using the 'Slit-lamp microscopic' method. The aqueous humor collected from the sacrificed rats was tested for total protein count and cell count. The total protein count was determined using BSA assay method, while the total cell count was determined by Neubaur's hemocytometer method. The results showed that the cTA-NLC formulation had negligible signs of inflammation, with a clinical score of uveitis 0.82 ± 0.166, which is much less than control/untreated (3.80 ± 0.3) and free drug suspension (2.66 ± 0.405). The total cell count was also found to be significantly low for cTA-NLC (8.73 ± 1.79 × 105) as compared to control (52.4 ± 7.71 × 105) and free drug suspension (30.13 ± 3.021 × 105). Conclusively, the animal studies conducted showed that our developed formulation holds the potential for effective management of uveitis.

Efficacy and safety of zinc in the prevention of oral mucositis in children with cancer receiving intensified chemotherapy: A randomized double-blind placebo-controlled trial.

BACKGROUND AND AIMS: A limited number of safe and effective preventive options for oral mucositis (OM) are available. This randomized, double-blind, placebo-controlled trial aimed to evaluate the efficacy and safety of zinc in preventing OM in children with cancer receiving intensified chemotherapy. METHODS: Children aged 3-18 years were randomized to receive oral zinc at 1 mg/kg/dose daily for 14 days or a placebo at the same doses and schedule. The primary outcome of this study was to determine the effect of oral zinc in the prevention of OM, and secondary outcomes included any adverse effect of oral zinc, the severity and duration of OM, and the need for hospitalizations. RESULTS: A total of 90 children were randomized to either the oral zinc (n = 44) or placebo group (n = 46). The incidence of OM in the zinc group was 20.5%, while that in the placebo group was 19.6% (p = .91; risk ratio: 1.04, 95% CI 0.45-2.30). There were no significant adverse events of the drug observed. There were no significant differences between the two groups in the severity (p = .79), the mean time of onset (p = .09), the mean duration of OM (p = .18), and the need for hospitalizations (p = 1.0). CONCLUSIONS: Among children on cancer chemotherapy, there was no decrease in the incidence of OM observed with oral zinc at a dose of 1 mg/kg/day. No significant adverse events were observed with administering oral zinc. Further research is warranted to test higher doses of oral zinc with longer duration for a clinically significant effect.

Analysis of the Systemic Exposure of Mitomycin C Used in Glaucoma Filtering Surgery Among Women in the Reproductive Age Group.

PURPOSE: Systemic absorbtion of topically applied mitomycin C (MMC) during trabeculectomy needs to be evaluated to look for any systemic toxicity, which might be a major concern in certain conditions like pregnancy. METHODS: After obtaining ethical committee clearance, female patients in the reproductive age group undergoing trabeculectomy with MMC were included. Pregnant/lactating patients, patients with any systemic illness were excluded. During trabeculectomy, 0.02% MMC was applied subconjunctivally for 2 min and then washed. Blood samples were withdrawn at 1, 2, 4, 8, 12, and 24 hrs after the surgery and analyzed of MMC levels using Liquid chromatography-tandem mass spectroscopy (LC-MS/MS). RESULTS: The mean age of the participants was 29 ± 12 years. MMC was not detected in any of the plasma samples analyzed as it was less than the detection limit (<1.56 ng/mL) of the employed LC-MS/MS assay. CONCLUSION: It can be deduced that the systemic absorption of MMC is negligible or the plasma concentration is less than 1.56 ng/ml (1000 times less than the concentration where systemic toxicity was not observed).

Ocular surface sphingolipids associate with the refractory nature of vernal keratoconjunctivitis: newer insights in VKC pathogenesis.

BACKGROUND: The etiopathogenesis of vernal keratoconjunctivitis (VKC) is incompletely understood. Bioactive lipids play a key role in allergic disorders. This study focused on the sphingolipid metabolism on the ocular surface of VKC and to explore if it has a contributory role in the refractoriness of the disease. METHODS: Active VKC cases, (n=87) (classified as mild/moderate and severe/very severe based on the disease symptoms) and age-matched healthy controls (n=60) were recruited as part of a 2-year prospective study at a tertiary eye care centre in South India. Conjunctival imprint cytology was used to assess gene expression of enzymes of sphingolipids metabolism. Sphingolipids were estimated in the tears by LC-MS/MS analysis. In vitro study was done to assess IgE-induced alterations in sphingosine-1-phosphate (S1P) receptor expression and histone modification in cultured mast cells. RESULTS: Significantly altered gene expression of the sphingolipids enzymes and S1P receptor (SIP3R) were observed in conjunctival imprint cells of VKC cases. Pooled tears analysis revealed significantly lowered levels of S1P(d17:0), S1P(d20:1) (p<0.001) and S1P(d17:1) (p<0.01) specifically in severe/very severe VKC compared with both mild/moderate VKC and control. Cer(d18:/17:0) (p<0.001), ceramide-1-phosphate (C1P)(d18:1/8:0) (p<0.01) and C1P(d18:1/2.0 (p<0.05) were lowered in severe/very severe VKC compared with mild/moderate VKC. Cultured mast cells treated with IgE revealed significantly increased gene expression of S1P1 and 3 receptors and the protein expression of histone deacetylases (1, 6). CONCLUSION: Altered sphingolipid metabolism in the ocular surface results in low tear ceramide and sphingosine levels in severe/very severe VKC compared with the mild/moderate cases. The novel finding opens up fresh targets for intervention in these refractory cases.

Comparison of two techniques (intermittent intravenous bolus morphine vs. morphine infusion) for analgesic titration in patients who had advanced cancer with severe pain: a prospective randomised study.

OBJECTIVE: To compare the analgesic efficacy of two techniques of morphine titration (intermittent intravenous bolus vs infusion) by calculating rescue dosage in a day at 1 week after analgesic titration. METHODS: One hundred and forty cancer patients were randomised into two groups. In group 1, intravenous morphine 1.5 mg bolus given every 10 min until Numerical Rating Scale (NRS) pain score <4 is achieved. Total intravenous dose converted to oral dose (1:1) and administered every 4 hours. In group 2, intravenous bolus morphine 0.05 mg/kg body weight administered followed by 0.025 mg/kg/hour intravenous infusion. The NRS pain score was recorded every 10 min but infusion rate was titrated every 30 min if required. The infusion rate of morphine was doubled if the pain score was unchanged and increased to 50% when NRS was between 4 and baseline. If NRS<4, then infusion at same rate was continued. Once the NRS<4 for two consecutive hours, total intravenous dose for 24 hours was calculated and converted to oral morphine in a ratio of 1:3 and divided into six doses given over 24 hours. For rescue (pain score ≥4) analgesia, one-sixth of the total daily oral dose was prescribed. The primary outcome of this study was to note the number of rescue doses of oral morphine in a day at 1 week. RESULTS: The rescue dosage in a day at 1-week post discharge from the palliative care unit was significantly higher in group 1 as compared with group 2. CONCLUSION: Intravenous infusion morphine may be a better analgesic titration technique for analgesia in patients with advanced cancer. TRIAL REGISTRATION NUMBER: CTRI/2018/04/013369.

Ocular manifestations of central insulin resistance.

Central insulin resistance, the diminished cellular sensitivity to insulin in the brain, has been implicated in diabetes mellitus, Alzheimer's disease and other neurological disorders. However, whether and how central insulin resistance plays a role in the eye remains unclear. Here, we performed intracerebroventricular injection of S961, a potent and specific blocker of insulin receptor in adult Wistar rats to test if central insulin resistance leads to pathological changes in ocular structures. 80 mg of S961 was stereotaxically injected into the lateral ventricle of the experimental group twice at 7 days apart, whereas buffer solution was injected to the sham control group. Blood samples, intraocular pressure, trabecular meshwork morphology, ciliary body markers, retinal and optic nerve integrity, and whole genome expression patterns were then evaluated. While neither blood glucose nor serum insulin level was significantly altered in the experimental or control group, we found that injection of S961 but not buffer solution significantly increased intraocular pressure at 14 and 24 days after first injection, along with reduced porosity and aquaporin 4 expression in the trabecular meshwork, and increased tumor necrosis factor α and aquaporin 4 expression in the ciliary body. In the retina, cell density and insulin receptor expression decreased in the retinal ganglion cell layer upon S961 injection. Fundus photography revealed peripapillary atrophy with vascular dysregulation in the experimental group. These retinal changes were accompanied by upregulation of pro-inflammatory and pro-apoptotic genes, downregulation of anti-inflammatory, anti-apoptotic, and neurotrophic genes, as well as dysregulation of genes involved in insulin signaling. Optic nerve histology indicated microglial activation and changes in the expression of glial fibrillary acidic protein, tumor necrosis factor α, and aquaporin 4. Molecular pathway architecture of the retina revealed the three most significant pathways involved being inflammation/cell stress, insulin signaling, and extracellular matrix regulation relevant to neurodegeneration. There was also a multimodal crosstalk between insulin signaling derangement and inflammation-related genes. Taken together, our results indicate that blocking insulin receptor signaling in the central nervous system can lead to trabecular meshwork and ciliary body dysfunction, intraocular pressure elevation, as well as inflammation, glial activation, and apoptosis in the retina and optic nerve. Given that central insulin resistance may lead to neurodegenerative phenotype in the visual system, targeting insulin signaling may hold promise for vision disorders involving the retina and optic nerve.

Guava Leaf Extract Suppresses Fructose Mediated Non-Alcoholic Fatty Liver Disease in Growing Rats.

Purpose: Fructose is highly lipogenic, and its unhindered ingestion by children and adolescents is understood to induce hypertriglyceridemia and non-alcoholic fatty liver disease (ped-NAFLD) that is till date managed symptomatically or surgically. The aim of the present study was to investigate the potential of hydroethanolic extract of leaves of Guava (PG-HM) to suppress the alterations in the hepatic molecular signals due to unrestricted fructose (15%) drinking by growing rats. Methods: Weaned rats (4 weeks old) in control groups had ad libitum access to fructose drinking solution (15%) for four (4FDR) or eight (8FDR) weeks, ie, till puberty or early adulthood, respectively, while treatment groups (4PGR, 8PGR) additionally received PG-HM (500 mg/kg, po). Results: The PG-HM suppressed ped-NAFLD through hepatic signalling pathways of 1) leptin-insulin (Akt/FOX-O1/SREBP-1c), 2) hypoxia-inflammation (HIF-1ɑ/VEGF, TNF-ɑ), 3) mitochondrial function (complexes I-V), 4) oxidative stress (MDA, GSH, SOD) and 5) glycolysis/gluconeogenesis/de novo lipogenesis (hexokinase, phosphofructokinase, ketohexokinase, aldehyde dehydrogenase). Parri passu, the insulin sensitizing effect of PG-HM and its ethyl acetate fraction (PG-EA) was elucidated using HepG2 cells grown in media enhanced with fructose. Further, in murine hepatocytes cultured in fructose-rich media, PG-HM (35 µg mL-1) outperformed Pioglitazone (15 µM) and Metformin (5 mM), to suppress hepatic insulin resistance. Conclusion: This study established that hydroethanolic extract of leaves of Guava (PG-HM) has potential to suppress hepatic metabolic alteration for the management of the pediatric NAFLD.