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.

Pharmacokinetics-Based Optimization of Phototherapy in Neonates Undergoing Treatment for Hyperbilirubinemia.

Introduction: Neonatal jaundice results from combined effects of both increased production of bilirubin and decreased hepatic excretory capacity in neonates. Since its discovery, phototherapy is the most widespread treatment used in neonatal jaundice. In this work, we try to search for a relationship between exposure to phototherapy and decrease in serum bilirubin (linearity vs proportionality). Methods:The present research was non-randomized prospective study conducted in the Neonatal Intensive Care Unit (NICU), Department of Paediatrics, AIIMS, New Delhi, and the Department of Pharmacology, AIIMS, New Delhi, India. Subjects were recruited from neonates admitted in NICU AIIMS, which meets our selection criteria. Infants were given a low dose of either phototherapy continuously or phototherapy for the first six hours and a double dose of phototherapy for the next six hours. Samples were collected before the beginning of the study (0 hours) and then at six and 12 hours. Bilirubin concentration was measured using HPLC and (LC-MS/MS). Results and conclusion:The percentage of reduction during the 6-12-hour interval was compared with that during the 0-6-hour interval if all experimental conditions were kept unchanged. A relationship curve between percentage of reduction and irradiance was created based on the percentage of reduction in serum bilirubin during the 0-6-hour and 0-12-hour intervals. The present study suggests that the relationship between efficacy, as measured by percentage of reduction in serum bilirubin, and irradiance is unlikely to be linear. Collected data are insufficient to clearly distinguish between proportionality and saturation point, considering that the results may be possible with both of these hypotheses.

Ocular hazards of the colors used during the festival-of-colors (Holi) in India--malachite green toxicity.

The objective of this study was to evaluate the nature of the colors used and their toxicity to the eye upon exposure to them during celebration of Holi (our festival-of-colors). Color powders and formulations were procured at random in and around Delhi during the festival. The green/bluish-green colors reported with the higher incidence of ocular toxicity were subjected for further evaluation. Eyewash fluid collected from the patients exposed to the colors was also subjected for analysis. This study was further extended to evaluate the corneal penetration of malachite green using goat cornea in perfusion chamber. In 16/18 color samples collected, malachite green or 4-[(4-dimethylaminophenyl)-phenyl-methyl]-N,N-dimethyl-aniline was detected at different concentrations. In the eyewash fluid of four patients, HPLC estimation confirmed the presence of malachite green at concentrations of 1.3, 0.18, 3.5 and 5.4 microg in 250 ml which was responsible for its reported toxicity. The in vitrotrans-corneal penetration studies did not show any detectable amount of malachite green in effluent fluid-in vitro tissue retention studies revealed that increasing the contact time increases tissue concentration. After 2 min of exposure, the tissue concentration was significantly higher. To conclude, malachite green was extensively used in our festival of Holi and has caused severe ocular irritation with epithelial defect upon exposure, though it did not penetrate through the cornea-further in vitro and in vivo studies are required on colors used in Holi.

Comparative evaluation of possible ocular photochemical toxicity of fluoroquinolones meant for ocular use in experimental models.

Fluoroquinolones (FQs) are extensively used in bacterial keratitis and other intraocular infections. Since eye is constantly exposed to light, incidence of ocular phototoxicity due to commonly used FQs is of great interest for their safe use. Phototoxicity of commonly used FQs (ciprofloxacin, lomefloxacin, pefloxacin, ofloxacin, sparfloxacin and gatifloxacin), has been evaluated by using HET-CAM-UV model (Photo Hen Egg Test-C Chorioallantoic Membrane model). This study was further extended by adding lomefloxacin dissolved in bovine vitreous (0.5 ml) on the chorioallantoic membrane (CAM). Using a standard scale, the phototoxic damage was assessed at different time intervals. Respective controls were kept in dark to distinguish the toxicity of the drugs per se. The results showed that the phototoxicity induced by lomefloxacin was very high followed by gatifloxacin and sparfloxacin and least for other drugs studied. Interestingly, lomefloxacin along with vitreous showed significantly low phototoxicity. This could be due to the antioxidant property of ascorbic acid present in the vitreous.

Protection from ultraviolet radiation by spectacle lenses available in India: a comparative study.

BACKGROUND: Exposure to ultraviolet radiation (UVR) can result in several ocular ailments. We studied the UV absorption (UV-A and -B bands) in 20 lenses (11 hard resin and 9 glass) commonly available in India as uncut lenses for the purpose of prescription as well as non-prescription wear. METHODS: Using a UV-visible spectrophotometer (Thermo-Spectronic, UV-1 model, Thermo Electron Corporation, USA), the percentage transmittance was scanned between 190 and 400 nm, from which the results at 280, 320, 340, 360, 380 and 400 nm were analysed. RESULTS: At 360 nm (UV-A), 75% of the lenses studied failed to offer 95% protection as recommended by the United States Food and Drug Administration (US FDA). At 280 nm (UV-B), 35% of the lenses failed to offer 99% protection against UV-B. Hard resin lenses showed a higher degree of variation in protection from UV-A. CONCLUSIONS: Most of the lenses studied failed to meet the US FDA recommendations in terms of protection from UV-A. Glass lenses afforded better protection up to 320 nm compared with hard resin lenses. As the claims of lens manufacturers regarding UVR protection fall short of international standards, certification of UVR protection for different lenses should be introduced in India.

Ocular and cardiovascular autonomic function in diabetic patients with varying severity of retinopathy.

The study was conducted to assess the ocular and cardiovascular autonomic function in diabetic patients with varying severity of diabetic retinopathy. Ocular and cardiovascular autonomic function tests were performed in 30 patients with type 2 Diabetes Mellitus (10 in each group of proliferative retinopathy, non-proliferative retinopathy and no retinopathy) of more than 5 years duration and 10 normal controls. Ocular autonomic function tests were done by measuring pupil cycle time and denervation hypersensitivity with 0.125% pilocarpine and 0.5% phenylephrine. Cardiovascular autonomic function was measured by a battery of standard tests. Denervation hypersensitivity to 0.125% pilocarpine and to 0.5% phenylephrine and pupil cycle time showed statistically significant differences (P value < 0.001) between controls and patients with proliferative retinopathy (PDR) and also between no retinopathy and PDR (P < 0.001). Systemic autonomic function tests namely expiration--inspiration ratio, difference in heart rate, 30th beat and 15th beat ratio in head up tilt and difference in diastolic blood pressure in head up tilt test also showed significant difference (P < 0.01) between controls and all 3 groups of diabetics. There was statistically significant difference found in para-sympathetic ocular autonomic dysfunction between NPDR and controls. Ocular and systemic autonomic dysfunctions are related to the severity of diabetic retinopathy.

Evaluation of potentiating effect of a drop of lignocaine on tropicamide-induced mydriasis.

PURPOSE: To analyze whether preinstillation of lignocaine potentiates mydriasis by tropicamide in dark eyes and to determine possible mechanisms for this effect. METHODS: This investigation was conducted in two phases, the first being a double-masked, placebo-controlled, randomized clinical trial, enrolling 60 healthy dark brown eyes in 30 subjects aged 7 to 58 years. The control eye received a drop of (nonlignocaine) placebo before tropicamide 1%, and the contralateral study eye received a 4% lignocaine drop 3-minutes before the 1 drop of tropicamide was administered. A ruled pupillometer recorded pupil diameters every 10 minutes for 50 minutes. In phase II, to elucidate pathomechanisms after lignocaine, corneal and tear parameters were compared with baseline records in a further 60 such eyes. RESULTS: Pupillary diameters in the study eyes increased by 3.62 +/- 0.75 mm, significantly more than in the placebo (control) group (P = 0.000). Ninety percent of study eyes attained the clinically significant 6-mm size with preinstillation of lignocaine-many more than the 67% of control eyes (P = 0.016). The median time to achieve this critical 6-mm size was significantly faster in the study group (P = 0.005). In phase II, the 1 drop 4% lignocaine did not show corneal changes with slit lamp or fluorescein staining and did not reduce media clarity or induce a significant change in tear pH. It markedly decreased Schirmer values (P = 0.000), reduced tear break-up time (P = 0.003), and increased corneal thickness measured by optical pachymetry (P = 0.010). CONCLUSIONS: The phase II findings indicate corneal microepithelial damage and reduced tearing. Both may enhance intraocular penetration and hence potentiation of tropicamide. This remarkable phenomenon could find use with many other important topical medications.

Endogenous cortisol profile in patients with central serous chorioretinopathy.

AIM: To study the endogenous cortisol levels in patients with central serous chorioretinopathy (CSCR). METHODS: Endogenous cortisol levels in urine and plasma were determined in 30 patients with acute CSCR and compared with 30 age and sex matched controls. RESULTS: The mean values of the 8 am plasma cortisol (29.97 micrograms/dl v 18.76 micrograms/dl), 11 pm plasma cortisol (22.03 micrograms/dl v 13.06 micrograms/dl), and 24 hour urine cortisol (11.01 mg/24 h v 7.39 mg/24 h) revealed significantly higher values in the patient group (p < 0.001). CONCLUSIONS: Increased levels of endogenous cortisol are present in patients with CSCR.

Evaluation of umbilical cord serum therapy for persistent corneal epithelial defects.

AIMS: To evaluate umbilical cord serum therapy as a means of promoting the healing of persistent corneal epithelial defects. METHODS: Umbilical cord serum or autologous serum drops were used to promote the healing of persistent epithelial defects. The study design was a prospective randomised controlled clinical trial. 60 eyes of 59 patients were divided into two groups, 31 in the cord serum group and 29 in the autologous serum control group. Epithelial defects measuring at least 2 mm in linear dimension resistant to conventional medical management were included. Serial measurements of the size of the epithelial defects-namely, two maximum linear dimensions perpendicular to each other, and the area and perimeter was done at start of therapy and follow up days 3, 7, 14, 21. Rate of healing of the epithelial defects were measured as percentage decrease from the baseline parameter at each subsequent follow up. The data were analysed by the non-parametric Wilcoxon rank sum test using STATA 7.0. RESULTS: The median percentage decrease in the size of the epithelial defect was significantly greater in the cord serum group at days 7, 14 and 21 (p<0.05) when measured in terms of the area and perimeter. A greater number of patients showed complete re-epithelialisation with umbilical cord serum (n = 18) than with autologous serum (n = 11) (Pearson chi = 0.19). None of the patients reported any side effects or discomfort with either treatment. CONCLUSIONS: Umbilical cord serum leads to faster healing of the persistent corneal epithelial defects refractory to all medical management compared to autologous serum.

Anti-cataract activity of Pterocarpus marsupium bark and Trigonella foenum-graecum seeds extract in alloxan diabetic rats.

Long-term complications are frequently encountered in diabetes mellitus and are difficult to treat. This study was undertaken to assess the effect of three antidiabetic plants on the development of cataract in rats. An aqueous extract of Pterocarpus marsupium Linn bark (PM, Hindi name: Vijaysar) (1 g kg(-1) day(-1)), Ocimum sanctum Linn leaves (OS, Hindi name, Tulsi) (200 mg kg(-1) day(-1)) and alcoholic extract of Trigonella foenum-graecum Linn seeds (FG, Hindi name, Methi) (2 g kg(-1) day(-1)) were given to alloxan (120 mg kg(-1)) diabetic rats until the development of cataract. Serum glucose and body weight were monitored at regular intervals while cataract was examined through naked eye as well as slit lamp at 75, 100 and 115 days after alloxan administration. Administration of all the three plant extracts exerted a favorable effect on body weight and blood glucose, the effects were best with PM followed by FG and OS. On the course of cataract development, PM followed by FG exerted anti-cataract effect evident from decreased opacity index while OS failed to produce any anti-cataract effect in spite of significant antihyperglycemic activity.

Comparative studies on topical lomefloxacin and ciprofloxacin on ocular kinetic and experimental corneal ulcer.

Fluoroquinolones are antimicrobial agents that have a broad spectrum of activity and that are widely used against many of the ocular pathogens responsible for conjunctivitis, blepharitis, corneal ulcers, etc. The aim of our study was to compare the ocular pharmacokinetics of ciprofloxacin (0.3% w/v) and lomefloxacin (0.3% w/v) by HPLC after a single application of 50 microl topically. The study was also extended to compare their efficacy in experimentally-induced corneal ulcers. In ocular kinetic studies, lomefloxacin showed nearly 10 times more ocular bioavailability in aqueous humor as compared to ciprofloxacin. Lomefloxacin showed a Cmax of 1.62 microg/ml at the Tmax of 1 hr whereas ciprofloxacin showed a Cmax of 102.8 ngs/ml at the Tmax of 1 hr. Lomefloxacin was found to have significant efficacy in the healing of Staphylococcus aureus-induced corneal ulcers and associated lesions. Moreover, aqueous formulation oflomefloxacin showed a good compatibility at neutral pH. The results of our study indicate that a suitable treatment regimen with lomefloxacin (0.3%) therapy could be an excellent therapeutic alternative over ciprofloxacin in bacterial keratitis.

Therapy of acanthamoeba keratitis--an experimental study.

The study was conducted to determine the efficacy of various drugs/agents in the treatment of experimentally induced Acanthamoeba Keratitis (A. keratitis). Thirty rabbits were divided into 5 equal treatment groups and polyhexamethylene biguanide (PHMB) 0.02%, fluconazole 0.2%, povidone iodine 5%, aprotinin 40 IU/ml and normal saline were administered in a double blind manner, at a dose of one drop, 5 times/day. Neomycin 1700 U/ml was used as a common drug in all groups, with same frequency. Post therapy subsidence of lid oedema, mucopurulent discharge, conjunctival congestion, corneal epithelial defect and anterior chamber reactions were noted. Average healing time in days (Mean +/- S.D.) were 13.67 +/- 1.21, 22 +/- 1.41, 23.5 +/- 1.05, 17.0 +/- 1.41 and 28.0 +/- 1.90 for PHMB, fluconazole, povidone iodine, aprotinin and normal saline respectively. Lid oedema, mucopurulent discharge and conjunctival congestion improved faster in PHMB and aprotinin treated eyes. The results of this study suggest that PHMB is a better drug for A. keratitis, while aprotinin may be used as an adjuvant drug in the management of A. keratitis.

Effect of fatty diet on pharmacokinetics and pharmacodynamics of a liquid theophylline preparation in volunteers.

The effect of a standard breakfast and a fatty breakfast on the pharmacokinetics and pharmacodynamics of a theophylline liquid preparation (160 mg-single dose) was examined in 6 healthy, non-smoking male volunteers. The plasma theophylline concentrations after both standard and fatty diet were found to be comparable at each point of time and pharmacokinetic parameters like Cmax, Tmax, T1/2a, T1/2 beta and AUC0-alpha, were also comparable. However, the time taken to attain the therapeutic plasma concentration was earlier and sustained along with the standard breakfast in comparison to that with fatty breakfast. Peak change in PEFR and pulse rate was also observed earlier with the standard diet than with fatty diet. The plasma theophylline concentrations produced after both diets were insufficient to produce any detectable change in subjective symptoms like tremor palpitation, heart burn, nausea, restlessness and tenseness. However, theophylline after fatty breakfast was better tolerated than that after a standard breakfast.

Evaluation of antimuscarinic activity in human volunteers: a teaching aid in clinical pharmacology.

The antimuscarinic activity of oxyphenonium bromide, diphenhydramine hydrochloride and astemizole were evaluated in six volunteers. The parameters used were salivary secretion, heart rate and pupillary size. The results indicated that the changes in heart rate and pupillary size and measurements were not convenient parameters for class room demonstration. However, salivary secretion and dryness of mouth were found to be reliable parameters for measurement. It was concluded that simple procedures like evaluation of antimuscarinic activity could be introduced as teaching aids in clinical pharmacology for undergraduate students.

Patterns of prescriptions and drug use in two tertiary hospitals in Delhi.

The study was carried out to assess prescribing trends in outpatients at Dr. R.P. Centre for Ophthalmic Sciences (RPC) and other OPD's of All India Institute of Medical Sciences (AIIMS) and Safdarjung hospitals, two premier hospitals in Delhi. Prescriptions of 500 patients were audited and analysed under heads of average number of drugs per patient, percentages of drugs prescribed by generic name, antibiotics, injections, drugs from WHO recommended essential drug list, availability of drugs etc. using WHO basic drug indicators. Prescription analysis showed that 75 to 95% drugs were prescribed from essential drug list. The average number of drugs per prescription was 1.42 to 4.07. Percentage of antibiotics prescribed varied from 14.39% to 22.28%. The use of injections was from nil to 4.4%. Availability of drugs was however, not satisfactory. Though maximum drugs were prescribed from essential drug list, the results indicate that there is a considerable scope for improving prescribing habits according to rational drug use and to provide a feed back to hospital authority for making maximum number of drugs available to the patients.

Potential pharmacokinetic role of organic cation transporters in modulating the transcorneal penetration of its substrates administered topically.

PURPOSE: We hypothesize organic cation transporters (OCT) may have a potential role in determining the pharmacokinetics and toxicity of organic cation drugs applied topically. Hence, in the present in vivo study, we attempted to evaluate the role of OCT in modulating the transport of its substrates after topical application. METHODS: New Zealand albino rabbits of either sex were used. Transcorneal penetration of OCT substrates tetraethylammonium and metformin after single instillation was evaluated in the absence and presence of OCT blockers (quinidine and atropine). Aqueous humor (AH) samples were collected through paracentesis amounting to 70-100 µl under topical anesthesia at various time intervals. The samples were subjected for estimation of both substrate as well as blocker concentrations using liquid chromatography mass spectrometry. RESULTS: Topical pre-treatment (30 min before substrate) of OCT blockers significantly decreased the transcorneal penetration of OCT substrates after single topical administration. The levels of blockers reaching AH in the presence of substrates were also modulated at 60 min after its administration as compared with its control. CONCLUSION: OCT are functionally active in the uptake of their substrates from tear to AH. Therefore, OCT in the corneal epithelium may be positioned from apical to basolateral. When administering their substrates/blockers topically, both may be competing for OCT for their uptake across the cornea, thereby decreasing the corneal penetration. Hence OCT can have a potential pharmacokinetic role in modulating the ocular bioavailability of their substrates administered topically, which are used as ocular therapeutics.

Monoclonal antibodies in ophthalmology.

The monoclonal antibodies can selectively target specific molecules, proteins or receptors in the body responsible for pathogenesis of a particular disorder. Some cytokines play key role in the development of proliferative diabetic retinopathy, neovascular age related macular degeneration, glaucoma and many other inflammatory conditions of eye. Monoclonal antibodies against VEGF and TNF-alpha such as bevacizumab, ranibizumab, infliximab and adalimumab have been used to control neovascularization and inflammation in eye with significant positive results whereas others have been used to target CD20, CD52, CD11a, and IL-2. The growing interest in these drugs with current progress in biotechnology and genetic engineering has kindled active research and with more understanding of the molecular basis of many ocular disorders these antibodies are being explored in a variety of different pathological conditions of the eye. Various sight threatening serious eye disorders which are resistant to the conventional available therapy have responded favorably to these drugs. Despite the limitations of high cost and uncertainty around long term safety profile, rational use of the monoclonal antibodies holds immense promise in management of various ocular conditions.

Comparative double masked randomised placebo controlled clinical trial of a herbal eye drop preparation in trachoma and conjunctivitis.

A double blind controlled clinical trial has been done with a herbal eye drop preparation in case of trachoma stage III and chronic conjunctivitis of the eyes. In both trachoma and chronic conjunctivitis, the herbal eye drop formulation proved its superiority over placebo. Side-effects (burning sensations) were observed with normal saline which was used as placebo. But no side-effects were observed in the patients of trachoma and conjunctivitis who got the active drug. Both objective and subjective improvements were observed with the herbal eye drop preparation.

Controlled clinical trial of nifedipine alone and in combination with dilazep in patients with angina pectoris.

The present study was performed to see if the combined treatment with nifedipine and dilazep offers any advantage over monotherapy with nifedipine alone in angina of effort. Thirty-three patients out of 40 with classical stable angina of effort completed this double-blind, randomized, parallel design comparative clinical trial. Both nifedipine alone (15-60 mg) and in combination with dilazep (50 mg) three times a day produced a significant reduction in angina attacks, consumption of nitroglycerin tablets and increased exercise tolerance. There was, however, no difference in the reduction in these parameters between the two groups. There was no significant reduction in blood pressure both systolic as well as diastolic and rate pressure product both when nifedipine was given alone and when it was given in combination with dilazep. Laboratory data did not reveal any dysfunction of liver, kidney and hemopoietic system. The results obtained show that there was no beneficial effect of adding dilazep to nifedipine therapy in the treatment of angina pectoris.