Water Activity and Its Significance in Topical Dosage Forms

Unique properties of thermodynamic activity of solvents in topical semisolids and its effects on in vitro product performance have not been fully understood. Mechanistic investigation was undertaken to demonstrate the significance of thermodynamic potential of solvents [water activity (a_w) or solvent activity (a_s)] on in vitro performance of model topical formulations. Drug transport across synthetic membranes was found to decrease with decreasing water activity of formulations. Similarly, in vitro permeation of model permeant (caffeine) across porcine epidermis was found to decrease with decreasing water activity of formulations. Notably, relatively low water activity formulations (a_w, 0.78) induced dehydration in porcine skin associated with significant structural changes like detachment of individual stratum corneum layers. Inclusion of hydrating agents (propylene glycol) in low water activity (a_w, 0.78) formulations restored hydration levels and structural integrity of porcine skin. Most importantly, incremental inclusion of propylene glycol in low water activity formulations (a_w, 0.78) enhanced in vitro permeation of model permeant (fluorescein sodium). Further investigation revealed that variability in processing conditions (high shear mixing during emulsification step) could modulate water activity in semisolid formulations despite their compositional sameness. In retrospect, water activity was found to be a critical quality attribute of topical semisolid products which impacts overall product performance and drug delivery.     

Repeated botulinum toxin type A (Dysport®) injections for women with intractable detrusor overactivity: a prospective outcome study

Introduction and hypothesis

We present the cohort of 33 women who underwent botulinum toxin type A (BTX-A) injections examining the efficacy and safety of BTX-A in idiopathic detrusor overactivity (IDO). The aim of this report is to describe the outcomes of those who underwent repeated injections of BTX-A.

Methods

All 33 women had 3 or more injections with an initial dose of 500 units of Dysport® with subsequent injections between 500 and 750 U, administered by the classic trigone-sparing flexible/rigid cystoscopic technique. An informed consent was obtained in all cases. Efficacy was measured using voiding diaries and quality of life (QOL) assessed with the International Consultation on Incontinence Questionnaire-Short Form (ICIQ -SF). This project was approved by the Clinical Effectiveness Department and the Drugs and Therapeutics Committee (DTC). Therefore, ethical approval was not required.

Results

This study included 33 women who have been successfully treated with repeated intradetrusor injections of BTX-A (Dysport®). Mean duration between the first and second injections was 15.2?±?7.2 months, whereas between the second and third was 19.2?±?10 months (P?=?0.025). Two women developed urinary tract infection and required clean intermittent self-catheterization. Three women required dose escalation to 750 units. Longer duration of subjective QOL improvement was noted between the second and third botulinum toxin injections compared to duration between the first and second injections.

Conclusions

BTX-A appears to be effective and safe after repeated administration in women with IDO. The duration of the injection tends to get prolonged after the second injection.     

Centella asiatica extract selectively decreases amyloid β levels in hippocampus of Alzheimer's disease animal model

PSAPP mice expressing the ‘Swedish’ amyloid precursor protein and the M146L presenilin 1 mutations are a well‐characterized model for spontaneous amyloid β plaque formation. Centella asiatica has a long history of use in India as a memory enhancing drug in Ayurvedic literature. The study investigated whether Centella asiatica extract (CaE) can alter the amyloid pathology in PSAPP mice by administering CaE (2.5 or 5.0 g/kg/day) starting at 2 months of age prior to the onset of detectable amyloid deposition and continued for either 2 months or 8 months. A significant decrease in amyloid β 1–40 and 1–42 was detectable by ELISA following an 8 month treatment with 2.5 mg/kg of CaE. A reduction in Congo Red stained fibrillar amyloid plaques was detected with the 5.0 mg/kg CaE dose and long‐term treatment regimen. It was also confirmed that CaE functions as an antioxidant in vitro, scavenging free radicals, reducing lipid peroxidation and protecting against DNA damage. The data indicate that CaE can impact the amyloid cascade altering amyloid β pathology in the brains of PSAPP mice and modulating components of the oxidative stress response that has been implicated in the neurodegenerative changes that occur with Alzheimer's disease. Copyright © 2008 John Wiley & Sons, Ltd.     

Antiparkinson drug--Mucuna pruriens shows antioxidant and metal chelating activity

Parkinson's disease is a neurodegenerative disorder for which no neurorestorative therapeutic treatment is currently available. Oxidative stress plays an important role in the pathophysiology of Parkinson's disease. The ancient Indian medical system, Ayurveda, traditionally uses Mucuna pruriens to treat Parkinson's disease. In our earlier studies, Mucuna pruriens has been shown to possess antiparkinson and neuroprotective effects in animal models of Parkinson's disease. The antioxidant activity of Mucuna pruriens was demonstrated by its ability to scavenge DPPH radicals, ABTS radicals and reactive oxygen species. Mucuna pruriens significantly inhibited the oxidation of lipids and deoxyribose sugar. Mucuna pruriens exhibited divalent iron chelating activity and did not show any genotoxic/mutagenic effect on the plasmid DNA. These results suggest that the neuroprotective and neurorestorative effect of Mucuna pruriens may be related to its antioxidant activity independent of the symptomatic effect. In addition, the drug appears to be therapeutically safe in the treatment of patients with Parkinson's disease.     

SKF-38393, a dopamine receptor agonist, attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity

Parkinson's disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic neurons. Several factors such as inhibition of the mitochondrial respiration, generation of hydroxyl radicals and reduced free radical defense mechanisms causing oxidative stress, have been postulated to contribute to the degeneration of dopaminergic neurons. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated animals is a useful experimental model of PD, exhibiting most of the clinical features, as well as the main biochemical and pathologic symptoms of the disease. In the present study, we have examined a dopaminergic (D1) receptor agonist, SKF-38393 HCl (SKF) for its possible neuroprotective action against MPTP-induced insults on dopaminergic neurons. MPTP is converted by monoamine oxidase-B (MAO-B) to its neurotoxic metabolite 1-methyl-4-phenyl-pyridinium (MPP+), which is then taken up into the dopaminergic neurons. SKF-38393 had no effects either on total or monoamine oxidase B in the striatum. SKF-38393 blocked the MPTP-induced depletion of glutathione and attenuated MPTP-induced depletion of dopamine. Furthermore, it enhanced the activity of superoxide dismutase and hence mimicked the action of selegiline. The results of these studies are interpreted to suggest that SKF-38393 may prove a valuable drug in the treatment of Parkinson's disease.     

Molecular evidence for absence of Y-linkage of the Hairy Ears trait

The human Hairy Ears phenotype has traditionally been regarded as the only Y-linked heritable trait. Here, we use Y-chromosomal DNA binary-marker haplotyping to show that a cohort of southern Indian Hairy-Eared males carries Y chromosomes from many haplogroups of the Y-phylogeny, which, under a hypothesis of Y linkage, would require multiple independent mutations within a single population. We further show that there is no significant difference between the Y-haplogroup spectrum in Hairy-Eared males and that in a geographically matched control sample of unaffected males. The trait cannot, therefore, be Y-linked in southern Indians, and by extension, is unlikely to be so in any population.     

Economic cost of cataract surgery procedures in an established eye care centre in Southern India

PURPOSE: To estimate the direct and indirect costs of three cataract surgery procedures: extracapsular cataract extraction with intra-ocular lens implantation (ECCE-IOL), phacoemulsification (PHACO) and manual small incision cataract surgery (MSICS) using economic costing principles in a well-established eye care programme (Aravind Eye Hospital) in Tamil Nadu, South India during 2000-01. Previous literature suggests that PHACO and MSICS have similar effectiveness. METHODS: The average unit cost for each surgical procedure was calculated from the societal perspective using economic costing methods. Total annual provider's direct costs for each input to surgery were calculated and apportioned appropriately to different cataract surgery techniques using a 'micro-costing approach'. The patient's direct and indirect costs for each procedure were calculated by interviewing staff and patients and by using assumptions about prices for relevant cost items such as transportation, food, medicine, spectacles and economic productivity loss. RESULTS: Average provider's direct costs were highest for PHACO procedures (25.55 US dollars) compared to MSICS (17.03 US dollars) and ECCE-IOL (16.25 US dollars). The difference can be attributed to the cost of equipment and materials. Average direct and indirect patient costs were highest for ECCE-IOL (19.85 US dollars), while the costs for PHACO and MSICS were identical (12.37 US dollars). ECCE-IOL had the highest total costs and MSICS had the lowest total costs from the societal perspective. CONCLUSIONS: Our results suggest that MSICS may have a lower societal cost than other options. Government and NGO hospitals providing cataract surgeries should invest in regular cost analyses, reviews of the literature on effectiveness, and formal cost-effectiveness analyses in order to plan economically efficient interventions. Considering the small incremental cost for providers (less than 1 US dollar), improved outcomes, and lower patient costs, we also believe that MSICS is an important technique to use in efforts to eliminate cataract blindness in India and this result may be generalised to other developing countries.