Sex differences in cognitive function among people with HIV-1 clade C infection in Northern India.

Human immunodeficiency virus-1 (HIV-1) clade C is the most prevalent form of HIV-1 comprising nearly 46% of global infections and is the dominant subtype in India. Despite its predominance, the impact of HIV-1 clade C infection on cognitive function has been understudied in comparison with other subtypes, notably clade B, which is primarily found in Europe and North America. Few studies have assessed cognitive impairment in antiretroviral therapy (ART) naïve men and women with HIV-1 clade C infection. In this study conducted in Northern India, differences in neuropsychological functioning were compared between 109 participants (70 men, 39 women) with untreated HIV-1 clade C infection and 110 demographically matched healthy controls (74 men, 36 women). A comprehensive neuropsychological battery was used to examine depression, self-assessment of functioning, and cognitive performance in six domains of functioning. Group differences were assessed by HIV-1 status and sex, controlling for age and education. Results indicated that cognitive deficits were substantially greater among male participants with HIV-1 clade C compared to male controls in all domains of cognitive functioning; in contrast, women with HIV-1 clade C had only minor deficits compared to healthy female participants. In addition, a larger proportion of men with HIV-1 clade C exhibited high levels of depression than women with HIV-1 clade C. These findings suggest that untreated HIV-1 clade C infection in men can have debilitating effects on neuropsychological function and depression, and stress the importance of facilitating rapid access to treatment to reduce the impact of HIV-1 infection.

Prediction of in vivo drug performance using in vitro dissolution coupled with STELLA: a study with selected drug products.

Prediction of the in vivo performance of the drug product from the in vitro studies is the major challenging job for the pharmaceutical industries. From the current regulatory perspective, biorelevant dissolution media should now be considered as quality control media in order to avoid the risk associated. Physiological based pharmacokinetic models (PBPK) coupled with biorelevant dissolution medium is widely used in simulation and prediction of the plasma drug concentration and in vivo drug performance. The present investigation deals with the evaluation of biorelevant dissolution media as well as in vivo drug performance by PBPK modelling using STELLA® simulation software. The PBPK model was developed using STELLA® using dissolution kinetics, solubility, standard gastrointestinal parameters and post-absorptive disposition parameters. The drug product selected for the present study includes Linezolid film-coated immediate-release tablets (Zyvox), Tacrolimus prolonged-release capsules (Advagraf), Valganciclovir tablets (Valcyte) and Mesalamine controlled-release capsules (Pentasa) each belonging to different biopharmaceutics classification system (BCS). The simulated plasma drug concentration was analyzed and pharmacokinetic parameters were calculated and compared with the reported values. The result from the present investigation indicates that STELLA® when coupled with biorelevant dissolution media can predict the in vivo performance of the drug product with prediction error less than 20% irrespective of the dosage form (immediate release versus modified release) and BCS Classification. Thus, STELLA® can be used for in vivo drug prediction which will be helpful in generic drug development.

Critical attributes of transdermal drug delivery system (TDDS)--a generic product development review.

Bioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two products. These current regulatory procedures demand a complete characterization of the generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of products and also outlines their valuable applications in generic product success. Understanding these critical in vitro parameters can probably help to decode the complex bioequivalence outcomes, directing the generic companies to optimize the formulation design in reduced time intervals. It is difficult to summarize a common platform which covers all possible transdermal products; hence few case studies based on this approach has been presented in this review.

Establishment of in vitro-in vivo equivalence of highly variable drugs - a generic product development perspective.

In vivo equivalence of highly variable drugs (HVD) has always been a subject of great concern, in terms of both safety and efficacy, for regulatory agencies. Successful demonstration of their bioequivalence thus presents the most crucial component of a generic application, significantly contributing toward the cost and time of development. For poorly soluble drugs, such as telmisartan, dissolution represents the rate-limiting step in the gastric region and in many cases may not be complete, thereby contributing to low and highly variable bioavailability. Consequently, simulation of gastrointestinal conditions is essential to adequately predict the in vivo behavior of drug formulations. In this study, we evaluated usefulness of physiologically relevant dissolution method over commonly used acidic media to forecast comparable in vivo performance of telmisartan formulation to that of reference samples. In the present study, telmisartan was classified as a HVD and a partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability has been presented. The design has effectively decreased sample size, without increasing patient risk. Results from this project suggest that scaled average bioequivalence (SABE) provides a good approach for evaluating the bioequivalence of HVD, meeting the need for international guidelines for bioequivalence.

ChaQra: a cellular unit of the Indian quantum network.

Major research interests on quantum key distribution (QKD) are primarily focused on increasing 1. Point-to-point transmission distance (1000 km). 2. Secure key rate (Mbps). 3. Security of quantum layer (device-independence). It is great to push the boundaries in these fronts but these isolated approaches are neither scalable nor cost-effective due to requirements of specialised hardware and different infrastructure. Current and future QKD network requires addressing different set of challenges apart from distance, key rate and quantum security. In this regard, we present ChaQra-a sub quantum network with core features as 1. Crypto agility (integration in the already deployed telecommunication fibres). 2. Software defined networking (SDN paradigm for routing different nodes). 3. reliability (addressing denial-of-service with hybrid quantum safe cryptography). 4. upgradability (modules upgradation based on scientific and technological advancements). 5. Beyond QKD (using QKD network for distributed computing, multi-party computation etc). Our results demonstrate a clear path to create and accelerate quantum secure Indian subcontinent under national quantum mission.

Rare malignant adnexal tumour of the skin involving distal phalanx of right thumb with co-existing primary lung cancer in a 72-year-old patient: A case report.

INTRODUCTION AND IMPORTANCE: Malignant adnexal tumours of the skin are a group of rare malignancies. These tumours can further differentiate into eccrine, apocrine, sebaceous, sweat duct, or ceruminous glands within the skin or follicular cells. Sebaceous carcinoma, a malignant adnexal tumour of the skin, is a rare and malignant tumour of the sebaceous glands. They can occur anywhere in the body where sebaceous glands are present, the most common being the head and neck region. CASE REPORT: Here we report a case of a 72-year-old man who presented with a bleeding ulcer on the distal right thumb, which was progressively increasing in size. Biopsy and histology confirmed the diagnosis of MATS with sebaceous differentiation. He had been diagnosed with metastatic non-small cell lung carcinoma six months back. CLINICAL DISCUSSION AND CONCLUSION: SC is a rare and unusual tumour amounting to less than 1% of all cutaneous malignancies. Phalanges are an infrequent extra-ocular site of involvement, and initial presentation can be mistaken for a benign occurrence. Any patient presenting with extra-ocular SC is advised to undergo genetic and immunohistochemistry testing to rule out complex genetic syndromes like Muir Torre syndrome and Cowden syndrome.

The bispectral electroencephalogram during modified electroconvulsive therapy under propofol anesthesia: relation with seizure duration and awakening.

IMPLICATION STATEMENT: : Use of the bispectral electroencephalogram during modified electroconvulsive therapy (MECT) under propofol anesthesia was found to be an accurate predictor of seizure duration and awakening. This may have potential clinical implications on therapeutic success and elimination of the undesirable effects associated with this treatment modality. BACKGROUND AND OBJECTIVES: : Propofol anesthesia when compared with barbiturates may induce relatively shorter duration seizures during MECT. This study was designed with the intent to test the hypothesis that the bispectral index (BIS) electroencephalogram (EEG) could predict MECT-induced seizure duration and awakening under propofol anesthesia. METHODS: : Twenty-five patients, between 16 and 60 years of age (American Society of Anesthesiologists physical status I or II), underwent a total of 100 MECT sessions (4 sessions each) under propofol anesthesia (1.0 mg/kg) in a prospective, observational study. The BIS was monitored continuously, and average BIS values of each of the 4 sessions of MECT that each patient received were analyzed. Bispectral index values were recorded at T0 (baseline), T1 (before induction), T2 (after propofol), T3 (preictal), T4 (postictal), T5 (awakening), and T6 (1 minute after awakening). Motor seizure duration was measured by isolated forearm technique and electrical seizure duration by BIS EEG. RESULTS: : The mean preictal BIS was 50 (SD, 14), which was found to have a significant positive correlation (P < 0.01) with motor (r = 0.707) as well as electrical seizure duration (r = 0.736). A significant negative correlation was also found between the preictal BIS value and the time to eye opening (3.53 [SD, 1.8] minutes) (r = -0.397; P < 0.05). Awakening occurred at mean BIS value of 52 (SD, 17) (range, 20-97) during this procedure. CONCLUSIONS: : The mean pre-ECT BIS values correlate significantly with the durations of both the motor and electrical seizure activity and awakening time under propofol anesthesia. Before extrapolation to daily clinical practice, further large controlled clinical trials need to be done to establish the role of BIS monitoring in predicting seizure duration and awakening time during MECT.

Horseshoe kidney leading to ERCP failure; innovative use of guide wire during laparoscopic CBD exploration: A case report.

INTRODUCTION: Horseshoe kidneys are the most common fusion defect of the kidneys, which amounts to about 0.25% of the population. They are usually asymptomatic and are often identified incidentally. The horseshoe kidney can push the second and third part of the duodenum anteriorly, leading to an altered CBD course. Choledocholithiasis is seen in approximately 10-15% of patients with cholelithiasis. Presently, the most preferred approach for managing CBD stones is ERCP. However, in ERCP failure cases, Laparoscopic CBD exploration is the primary treatment modality, with or without T-tube use, with all the advantages of minimally invasive surgery. CASE PRESENTATION AND DISCUSSION: A 65-year-old female presented with complaints of pain in the right hypochondriac region for three months associated with nausea, jaundice, and loss of appetite and weight. Her USG abdomen showed cholelithiasis with dilated CBD with horseshoe kidney with severe hydronephrosis of the left kidney. They are usually asymptomatic and are often identified incidentally. In this patient, it was believed that the horseshoe kidney had pushed the second and third part of the duodenum anteriorly, leading to an altered CBD course leading to ERCP failure. MRCP confirmed cholelithiasis with choledocholithiasis with dilated CBD of 11.3 mm with horseshoe kidney. ERCP was attempted but was unsuccessful due to non-visualization of the papilla due to overcrowding of duodenal folds. For patients with ERCP failure, laparoscopic CBD exploration is mandatory. For this patient, the CBD was cannulated with a guidewire, if needed, for repeat ERCP and was closed with T-tube in situ. CONCLUSION: There are no particular preoperative indicators that can predict the failure of ERCP. However, in ERCP failure cases, laparoscopic CBD exploration (with or without T-tube use) is the primary treatment modality.

Improved ocular absorption kinetics of timolol maleate loaded into a bioadhesive niosomal delivery system.

BACKGROUND: Application of timolol maleate (TM) in a conventional dosage form (solution) into the eye results in almost 80% of the instilled dose being lost either through spillage or due to drainage into the nasolacrimal duct. Later results in systemic side-effects especially in patients suffering from heart diseases or bronchial asthma thus limiting the usefulness of TM for the control of glaucoma. Earlier we had reported on the development of a mucoadhesive coated niosomal system for TM (TM REV(bio)) containing 0.25% TM. Presently we establish and report the pharmacokinetic and pharmacodynamic superiority of the developed ocular formulation of TM. METHODS: Aqueous humor concentration of TM in male albino rabbits, after instillation of one drop of TM solution (TMS) or TMREV(bio) was measured using the microdialysis method. RESULTS: Peak concentration of drug in aqueous humor from TMREV(bio) (12.46 microg/ml achieved at 60 min) was almost 1.7 times that of the control drug solution (TMS, 0.25%; 7.2 microg/ml). An important observation was that the high drug concentrations achieved upon TMREV(bio) administration were maintained for up to 2 h. AUC for TMREV(bio) formulation was 2.34 times that of the TMS. CONCLUSIONS: This study confirms a sustained and controlled effect of the developed formulation.

Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q.

Doxorubicin (DOX) is used for treating various cancers. Its clinical use is, however, limited by its dose-limiting cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy still remains unknown. The goals were to investigate the molecular mechanism of DOX-induced cardiomyopathy and cardioprotection by mitoquinone (Mito-Q), a triphenylphosphonium-conjugated analog of coenzyme Q, using a rat model. Rats were treated with DOX, Mito-Q, and DOX plus Mito-Q for 12 weeks. The left ventricular function as measured by two-dimensional echocardiography decreased in DOX-treated rats but was preserved during Mito-Q plus DOX treatment. Using low-temperature ex vivo electron paramagnetic resonance (EPR), a time-dependent decrease in heme signal was detected in heart tissues isolated from rats administered with a cumulative dose of DOX. DOX attenuated the EPR signals characteristic of the exchange interaction between cytochrome c oxidase (CcO)-Fe(III) heme a3 and CuB. DOX and Mito-Q together restored these EPR signals and the CcO activity in heart tissues. DOX strongly downregulated the stable expression of the CcO subunits II and Va and had a slight inhibitory effect on CcO subunit I gene expression. Mito-Q restored CcO subunit II and Va expressions in DOX-treated rats. These results suggest a novel cardioprotection mechanism by Mito-Q during DOX-induced cardiomyopathy involving CcO.

Successful twin pregnancy in a unicornuate uterus with one fetus in the non-communicating rudimentary horn.

Rudimentary horn is a rare anomaly and results from arrested development of the mullerian ducts. We report a case of twin pregnancy in a unicornuate uterus with a non-communicating rudimentary horn, in which two siblings each in separate horn were delivered successfully by caesarean section.

Early detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography.

Doxorubicin is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiomyopathy that may lead to heart failure. Conventional measures of ventricular function, such as fractional shortening, are insensitive in detecting early doxorubicin cardiomyopathy. We tested whether novel two-dimensional radial strain echocardiography (2DSE) can detect early doxorubicin injury following chronic administration in a rat model. 14 male Sprague Dawley rats (240 to 260 g) received doxorubicin 2.5 mg/k i.v. per wk for 10 (n=4) or 12 wk (n=10); 17 controls received saline (10 wk, n=7 and 12 wk, n=10). Serial 2DSE from 0 to 12 wk was done at the mid left ventricle using Vivid 7 echo (General Electric, Waukesha, WI, USA). With Q analysis software, radial strain was obtained. From the two-dimensional (2D) image, anatomical M-mode through the anterior/inferior walls was used to measure fractional shortening. Fibrosis (Masson's trichrome) and caspase-3 activity were measured from excised hearts. Radial strain was lower in the doxorubicin group (12 wk: 26.7+/-3 versus 38.3+/-2.6%, p=0.006), with significant difference by 8 wk whereas fractional shortening was lower with doxorubicin only after 12 wk (30.2+/-1.7 versus 37.6+/-1.4%, p=0.02). Doxorubicin group had lower cardiac mass (0.85+/-0.09 versus 1.14+/-0.04 g, p=0.001), higher caspase-3 activity (1.95+/-0.2 fold increase over control, p<0.0001) and fibrosis (3.9 +/- 0.7 versus 0.7+/-0.1%, p=0.005). Radial strain was related directly to cardiac mass (r=0.61, p=0.0007) and inversely to caspase-3 activity (r= -0.5, p=0.005). 2-dimensional radial strain echocardiography is useful in the early detection of doxorubicin cardiac injury and the reduction in radial strain is associated with histologic markers of doxorubicin cardiomyopathy.

Study of the extent of ocular absorption of acetazolamide from a developed niosomal formulation, by microdialysis sampling of aqueous humor.

Acetazolamide, a carbonic anhydrase inhibitor is used orally (no topical formulation being available in the market) for the reduction of intraocular pressure (IOP) in patients suffering from glaucoma. Two major reasons responsible for the failure to develop a topically effective formulation of acetazolamide are its low solubility (0.7mg/ml) and its low permeability coefficient. It is generally recognized that topical acetazolamide formulation possessing efficacy similar to that achieved upon oral administration would be a significant advancement in the treatment of glaucoma. In order to enhance the bioavailability of acetazolamide by topical route and to improve the corneal permeability of the drug, the niosomes of acetazolamide were prepared (by reverse phase evaporation method) and coated with Carbopol for the latter's bioadhesive effect. The pharmacodynamic studies showed 33% fall in IOP with the developed formulation, and the effect was sustained for 6h after instillation. The effect compared well with a four times higher concentration of dorzolamide (Dorzox, a topical CAI available in the market. In the present study, the aqueous humor disposition of the drug from the developed bioadhesive coated niosomal formulation (ACZREVbio) is compared with the aqueous suspension of the drug (containing 1% (w/v) Tween 80 as a dispersing agent) at similar concentrations. The concentration of acetazolamide absorbed in the aqueous humor at various times from the control suspension and from ACZREVbio was determined by microdialysis in male albino rabbits. Microdialysis provides a complete concentration versus time profile and hence is an important advance to the regional sampling of tissues. The peak concentration of drug absorbed in the aqueous humor from the ACZREVbio formulation (14.94microg/ml) was almost two times of that obtained with the equivalent amount of acetazolamide control suspension (6.93microg). The results show a significant broadening of peak from 80 to 120min with the concentration of more than 13microg being maintained at these times, for the bioadhesive coated niosomal formulation (ACZREVbio). An important observation was the fact that a high drug concentration of 12.02microg reached immediately, i.e., 20min after instillation of ACZREVbio indicating a high penetration being achieved, while a meagre concentration of only 3.53microg is obtained at 60min after instillation of the control suspension. The aqueous humor disposition indicates peaks and troughs in drug concentration which may be related to the decrease in aqueous humor formation, such that the drug concentration/volume increased at these points.

Bergenin attenuates renal injury by reversing mitochondrial dysfunction in ethylene glycol induced hyperoxaluric rat model.

Bergenin, isolated from Bergenia ligulata is a potent antioxidant and antilithiatic agent. Present work was designed to establish the biochemical role of bergenin on mitochondrial dysfunction in the ethylene glycol induced hyperoxaluric rat model. Bergenin was administrated at a dose of 10mg/kg body wt i.p. from 14th day of establishing the 28 days hyperoxaluria rat model. α-Tocopherol was given as positive control at a dose of 100mg/kg body wt i.p. Mitochondrial dysfunction was studied by evaluating the activities of respiratory chain complexes, mitochondrial membrane potential and reactive oxygen species. Histopathological analysis of the kidney tissue was done after Pizzolato staining. Also, expression of monocyte chemoattractant protein -1(MCP-1) and kidney injury marker protein (KIM-1) were studied and the levels of IL-1ß were evaluated in kidney tissue homogenate. Mitochondrial dysfunction during stone crystallization was evident by decreased activities of electron transport chain complexes I, II and IV and augmented mitochondrial oxidative stress in hyperoxaluric rats. Bergenin treatment significantly (P<0.05) restored the activities of these complexes. Moreover, it curtailed the lipid peroxidation and up regulated antioxidant levels, ameliorating the state of mitochondrial dysfunction. The protective role of bergenin was also reinforced by reducing IL-1ß production and expression of KIM-1 and MCP-1 in the renal tissue. The findings of the present study provide evidence that bergenin exerted protective effects in hyperoxaluria through mitochondrial protection that involves attenuation of oxidative stress. Hence, it presented itself as an effective remedy in combating urolithiasis.

Improved pharmacodynamics of timolol maleate from a mucoadhesive niosomal ophthalmic drug delivery system.

In the present study chitosan (REVTMbio1) or Carbopol (REVTMbio2 and 3) coated niosomal timolol maleate (0.25%) formulations were prepared by reverse phase evaporation (REV) and compared to timolol solution (TMS; 0.25%) in terms of in vitro release and IOP lowering pharmacodynamic effect. The in vitro release phase of timolol (91% release in 2 h) was extended significantly by its incorporation into niosomes and further by the polymer coating (40-43% release upto 10 h). The developed formulations were evaluated for their pharmacodynamics in albino rabbits, by measuring intraocular pressure (IOP) using a non-contact pneumatonometer, and were compared to a marketed in situ gel forming solution of timolol (Timolet GFS, 0.5%; Sun Pharma). REVTMbio1 formulation showed a more sustained effect of upto 8h (vis a vis 6 h for carbopol-coated niosomes). TMS in comparison showed effect for only 2 h though the peak effect was slightly more (14%). Lowering of IOP in the contralateral eye (20-40% as compared to 100% in case of TMS), considerably reduces with REV and REVbio formulations indicating lesser systemic side effects. Moreover, the results of REVTMbio1formulation containing 0.25% of timolol maleate compared well with the 0.5% marketed gel formulation, indicating our formulation to be significantly better considering that similar effect is obtained at half the concentration. The later becomes especially important in context to the cardiovascular side effects associated with ocular timolol maleate therapy.

Paclitaxel and its formulations.

Paclitaxel (Taxol) is a promising anti-tumor agent with poor water solubility. It is effective for various cancers especially ovarian and breast cancer. Intravenous administration of a current formulation in a non-aqueous vehicle containing Cremophor EL may cause allergic reactions and precipitation on aqueous dilution. Moreover, the extensive clinical use of this drug is somewhat delayed due to the lack of appropriate delivery vehicles. Due to this there is a need for the development of alternate formulation of paclitaxel having good aqueous solubility and at the same time free of any side effects. Various approaches employed so far include cosolvents, emulsions, micelles, liposomes, microspheres nanoparticles, cyclodextrins, pastes, and implants etc. which are discussed in this paper.

Acetazolamide: future perspective in topical glaucoma therapeutics.

Through this review it is contemplated that acetazolamide (ACZ), an age-old treatment for glaucoma with a myriad of side effects and inadequate topical effectiveness, may be formulated into a topically effective agent by utilizing various newer formulation approaches of ocular drug delivery. Even though it has a poor solubility and penetration power, various studies mentioned in the review indicate that it is possible to successfully formulate topically effective ACZ by using: (i) high concentration of the drug, (ii) surfactant gel preparations of ACZ, (iii) ACZ loaded into liposomes, (iv) cyclodextrins to increase the solubility and hence bioavailability of ACZ, and (v) viscolyzers and other polymers either alone or in combination with cyclodextrins. With the advent of newer topical carbonic anhydrase inhibitors (CAIs) like dorzolamide and brinzolamide, a localized effect with fewer side effects is expected. But whenever absorbed systemically, a similar range of adverse effects (attributable to sulphonamides) may occur upon use. Furthermore, oral ACZ is reported to be more physiologically effective than 2% dorzolamide hydrochloride administered topically, even though in isolated tissues dorzolamide appears to be the most active as it shows the lowest IC(50) values for CA-II and CA-IV [M.F. Surgue, J. Ocular Pharmacol. Ther. 12 (1996) 363-376]. Hence, there exists considerable scope for the development of more/equally effective and inexpensive topically effective formulations of ACZ. The use of various formulation technologies discussed in this review can provide a fresh impetus to research in this area.

Vesicular systems in ocular drug delivery: an overview.

The main aim of pharmacotherapeutics is the attainment of effective drug concentration at the intended site of action for a sufficient period of time to elicit a response. Poor bioavailability of drugs from ocular dosage form is mainly due to the tear production, non-productive absorption, transient residence time, and impermeability of corneal epithelium. Though the topical and localized application are still an acceptable and preferred way to achieve therapeutic level of drugs used to treat ocular disorders but the primitive ophthalmic solution, suspension, and ointment dosage form are no longer sufficient to combat various ocular diseases. This article reviews the constraints with conventional ocular therapy and explores various novel approaches, in general, to improve ocular bioavailability of the drugs, advantages of vesicular approach over these and the future challenges to render the vesicular system more effective.

Development of a topical niosomal preparation of acetazolamide: preparation and evaluation.

Orally administered acetazolamide has a limited use in glaucoma due to the systemic side effects associated with its use. No topical formulation of acetazolamide is available, mainly because of it having a limited aqueous solubility and poor corneal permeation. To enhance the bioavailability of acetazolamide by the topical route and to improve the corneal permeability of the drug, niosomes of acetazolamide were prepared (employing span 60 and cholesterol) by different methods. Transmission electron microscopy (TEM) of the selected formulation was carried out to study the morphology. Niosomes were also prepared in the presence of dicetyl phosphate and stearylamine to obtain negatively and positively charged vesicles, respectively. It was found that the reverse-phase evaporation method (REV) gave the maximum drug entrapment efficiency (43.75%) as compared with ether injection (39.62%) and film hydration (31.43%) techniques. Drug entrapment efficiency varied with the charge and the percent entrapment efficiency for the REV method was 43.75, 51.23 and 36.26% for neutral, positively charged and negatively charged niosomes, respectively. Corneal permeability studies, however, showed that the percent permeation and the apparent permeability coefficient for the charged niosomes were less than for the neutral ones. A bioadhesive niosomal formulation of acetazolamide was also prepared and compared with the positively charged formulation, considering that both of them would have a prolonged stay in the cul-de-sac because of their expected interactions with mucin. The formulations were also compared based on their intraocular pressure (IOP)-lowering capacity. The positively charged niosomes (REV2), although showing good corneal permeability and pharmacodynamics, were however found to be inappropriate in terms of the corneal cell toxicity. The bioadhesive coated formulation (REV1bio) compared well with REV2 and also showed a much lesser toxicity. Further, the IOP-lowering effect of the developed formulations was compared with that of a marketed formulation of dorzolamide 2%, a topical carbonic anhydrase inhibitor. The developed niosomal formulations of acetazolamide showed a comparable physiological effect (33% reduction of IOP in REV1bio and 37% reduction in dorzolamide) with a duration of up to 6 h (the duration being 3 h for dorzolamide). Results of the study indicate that it is possible to develop a safe (as indicated by corneal toxicity studies) and physiologically active topical niosomal formulation of acetazolamide relative in efficiency to the newer local carbonic anhydrase inhibitor, dorzolamide. The developed formulations can form a cost effective treatment plan, which is especially important in the treatment of glaucoma, a chronic ailment affecting middle-aged to old patients.

Role of cyclodextrins in ophthalmics.

Cyclodextrins are oligosaccharides having outer hydrophilic surface and central hydrophobic cavity. These agents form inclusion complexes with poorly water-soluble drugs; hence they show an important implication for use in ophthalmics because of their applications in solubilising and stabilising the ocular drugs. Most of the drugs being used in ophthalmics were not tailor-made for the eye and considering the poor bioavailability of <1% from the corneal surface, presentation of the drug in a soluble form and at high concentration is important. Provision of a high drug concentration at the corneal surface increases the percent drug permeation indicating the usefulness of cyclodextrins as penetration enhancers. A decrease in irritation potential of some drugs upon incorporation of cyclodextrins is also reported. Polymer-cyclodextrin multicomponent systems further extend the role of cyclodextrins in improving the solubility and bioavilability of ocular drugs. Large hydrophilic cyclodextrins like hydroxypropyl-beta-cyclodextrin and sulphobutylether-beta-cyclodextrin are safe for the use in aqueous eye drop solutions especially since they do not cross the lipophilic cornea. Various aspects about the applications of cyclodextrins in ophthalmics, the formulation considerations and expected toxicity of cyclodextrins (especially if high concentration is used) is discussed in this review. Strategies like use of polymers to reduce the effective concentration of cyclodextrin required without compromising solubility are also included. Further the concept of incorporating the drug-cyclodextrin complexes into liposomes or niosomes for a better targeting of the drug at appropriate tissue destination is discussed as a possible future option.