In vitro methods to predict aerosol drug deposition in normal adults

This research was aimed at the development and validation of new in vitro methods capable of predicting in vivo drug deposition from dry powder inhalers, DPIs, in lung-normal human adults. Three physical models of the mouth, throat and upper airways, MT-TB, were designed and validated using the anatomical literature. Small, medium and large versions were constructed to cover approximately 95% of the variation seen in normal adult humans of both genders. The models were housed in an artificial thorax and used for in vitro testing of drug deposition from Budelin Novolizer DPIs using a breath simulator to mimic inhalation profiles reported in clinical trials of deposition from the same inhaler. Testing in the model triplet produced results for in vitro total lung deposition (TLD) consistent with the complete range of drug deposition results reported in vivo. The effect of variables such as in vitro flow rate were also predictive of in vivo deposition. To further assess the method’s robustness, in vitro drug deposition from 5 marketed DPIs was assessed in the “medium” MT-TB model. With the exception of Relenza Diskhaler, mean values for %TLD+SD differed by only \u3c 2% from their literature in vivo. The relationship between inhaler orientation and in vitro regional airway deposition was determined. Aerosol drug deposition was found to depend on the angle at which an inhaler is inserted into the mouth although the results for MT deposition were dependent on both the product and the formulation being delivered. In the clinic, inhalation profiles were collected from 20 healthy inhaler naïve volunteers (10M, 10F) before and after they received formal inhalation training in the use of a DPI. Statistically significant improvements in Peak Inhalation Flow Rate (PIFR) and Inhalation Volume (V) were observed following formalized training. The shapes of the average inhalation profiles recorded in the clinic were found to be comparable to the simulated profiles used in the in vitro deposition studies described above. In conclusion, novel in vitro test methods are described that accurately predict both the average and range of aerosol airway drug deposition seen from DPIs in the clinic

A NOVEL BIORELEVANT IN VITRO SYSTEM TO PREDICT THE IN VIVO PERFORMANCE OF ORAL TRANSMUCOSAL PRODUCTS

In vitro dissolution, release and permeation testing is a common practice during drug product research and development. These in vitro tests, if predictive, are referred to as biorelevant tests and can play diverse roles to facilitate and expedite product development in a cost effective manner. Oral transmucosal products (OTPs) are currently tested using compendial and modified in vitro tests which may or may not be good predictors of in vivo performance due to a lack of biorelevance. A critical need for a broadly applicable and biorelevant in vitro system for OTPs has been expressed in the literature and the goal of this research was the development and validation of a biorelevant in vitro method that can facilitate accurate prediction of the in vivo behavior of OTPs. A combined strategy of appropriate apparatus design and relevant physiological and in vitro variable adjustment was investigated to incorporate biorelevance into evaluation of OTPs. A novel in vitro device, the bidirectional transmucosal apparatus (BTA), was designed and fabricated which allowed simulation of the oral cavity and its physiological variables to evaluate OTPs in a more realistic fashion. The BTA was tested using snus (a type of smokeless tobacco) as the OTP product. A simple and selective high performance liquid chromatographic (HPLC) method with photodiode array (PDA) detection was developed and validated to assess in vitro nicotine release and permeation (Linearity: 0.5 – 32 μg/mL; calibration curve accuracy (%recovery, n=5 ): 97.98-103.20%; calibration curve precision (%RSD, n=5): 0.15-3.14%). The performance of BTA was compared with the modified USP IV flow through apparatus (USP IV) and a commercially available vertical diffusion cell (VDC). The observed in vitro in vivo relationship (IVIVR) slopes with the USP IV, VDC and BTA were 0.27, 2.01 and 2.11 respectively. The BTA was selected over the VDC and USP IV devices because of better simulation and adjustment of variables to incorporate biorelevance in the test of OTPs. Additionally, the BTA allows study of permeation and release simultaneously unlike VDC and USP IV apparatuses. Further, the different BTA parameters were sequentially screened for their impact on in vitro rate of nicotine permeation that can be employed for the optimization of IVIVR for snus. Based on the results, stimulated saliva swallowing rate (SSSR) and media temperature were considered as significant factors affecting in vitro permeation of nicotine and used to further optimize IVIVR for snus. A 32 multifactorial experimental design integrating SSSR (0.32, 1.66 and 3 mL/min) and media temperature (25, 37 and 45 °C) was employed. Based on the response surface analysis, 0.55 mL/min SSSR and 43 °C media temperature were identified as optimal BTA conditions that would give perfect IVIVR (i.e. IVIVR slope close to one) for snus. The experimental value of IVIVR slope (0.92) at these optimal conditions indicated that the BTA is a valid in vitro system for evaluation of OTPs in a biorelevant manner. The applicability of BTA for predicting nicotine permeation from ‘Stonewall’, a dissolvable compressed tobacco was also evaluated. However, comparable in vitro nicotine permeation and in vivo nicotine absorption profiles were not obtained (ratio of in vitro permeation to in vivo absorption rate ranged from 0.04 to 0.14 at different in vitro conditions) either due to the unavailability of reliable clinical data or due to inherently different in vivo behavior of Stonewall compared to snus that would require further modification in the BTA. In conclusion, this research demonstrated the potential of the novel in vitro device to be a valuable tool for the prediction of in vivo performance of snus. The application of the novel bidirectional transmucosal apparatus for other types of OTPs will be an interesting subject for further investigation

Effect of Different GA3 Concentration and Frequency on Growth, Flowering and Yield in Gaillardia (Gaillardia pulchella Foug.) Cv. Lorenziana

The present experiment was conducted at the Horticultural Instructional Farm, Department of Horticulture, J.A.U., Junagadh during the winter 2004-05. The experiment comprised of ten treatments, viz., three concentrations of GA3 (50, 150, 250 ppm) at three frequencies (single, double and triple spray at 30, 45 and 60 days from transplanting) and control. Each treatment was replicated thrice in randomized block design. Of the different treatments, GA3 250 ppm single spray recorded maximum plant height and plant spread. Number of branches per plant was highest under double spray of GA3 at 50 ppm. Longest flowering duration, maximum flower diameter and maximum shelf-life were observed with single spray of 250 ppm GA3. It also registered maximum number and weight of flowers per plant besides highest flower yield

Performance of Banana Cultivars in Gujarat

Field experiments were conducted for three years to assess the performance and select the cultivar ideally suited to Saurashtra region in Gujarat. The cultivars evaluated were Basrai, Harichal, Robusta, Gros Michel, Gandevi Selection and Lacatan. Of these, Gandevi Selection proved superior, with regard to growth parameters, yield characters and its attributes. It also yielded the highest benefit cost ratio

12-Month Outcomes of the US Patient Cohort in the SONATA Pivotal IDE Trial of Transcervical Ablation of Uterine Fibroids.

Objective: The prospective SONATA pivotal Investigational Device Exemption (IDE) trial was performed in the United States (US) and Mexico to examine the safety and effectiveness of transcervical fibroid ablation (TFA) in the treatment of symptomatic uterine fibroids. This is an analysis of 12-month clinical outcomes in the US cohort. Methods: TFA with the Sonata System was performed on women with symptomatic uterine fibroids. The 12-month co-primary endpoints were reduction in menstrual blood loss and freedom from surgical reintervention. Symptom severity, quality of life, patient satisfaction, safety, and reductions in uterine and fibroid volumes were also evaluated. Results: One hundred twenty-five patients were enrolled and treated in the US. Both co-primary endpoints were achieved in this US-based cohort, as 65.3% of patients reported ≥50% reduction in menstrual bleeding and 99.2% of patients were free from surgical reintervention. Symptom improvement was noted by 97.4% of patients and 98.3% were satisfied. Ninety-five percent of patients reported reduced menstrual bleeding at 12 months, and 86.8% noted \u3e20% reduction. Significant mean improvements at 12 months were realized in both symptom severity and health-related quality of life (33.8 points and 45.8 points, respectively; all P\u3c0.0001). Mean maximal fibroid volume reduction per patient was 63.8%. There was a 0% incidence of device related adverse events. Mean length of stay was 2.5 hrs and 50% of patients returned to normal activity within 1 day. Conclusion: This analysis of US patients in the SONATA pivotal IDE trial demonstrates results consistent with those in the full cohort. TFA with Sonata significantly reduced fibroid symptoms with a low surgical reintervention rate through 12 months. These results support the efficacy and safety of the Sonata system as a first-line treatment for women affected by symptomatic uterine fibroids

Characterisation of human saliva as a platform for oral dissolution medium development

Human saliva is a biological fluid of great importance in the field of dissolution testing. However, until now, no consensus has been reached on its key characteristics relevant to dissolution testing. As a result, it is difficult to select or develop an in vitro dissolution medium to best represent human saliva. In this study, the pH, buffer capacity, surface tension, viscosity and flow rate of both unstimulated (US) and stimulated (SS) human saliva were investigated in order to provide a platform of reference for future dissolution studies using simulated salivary fluids. Age and gender related differences in a sample size of 30 participants for each parameter were investigated. Significant differences were established between US and SS for all characteristics except surface tension. Therefore, the requirement for using two simulated salivary fluids should be considered when developing an oral dissolution model

Characterization of a Drosophila Alzheimer's Disease Model: Pharmacological Rescue of Cognitive Defects

Transgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of Aβ40 and Aβ42, the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a γ-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions

Improved Stand – Alone Solar Battery Charger with MPPT and TSC Algorithms for Quick Charging with Excess Power Extrication

As energy demand is increasing with ongoing development and population, the conventional energy resources are becoming curtailing and are eventually harmful to an environment. In recent times many forms of renewable and clean energy sources are being considered for development; out of which solar is easily harvestable and available on most of the part of the globe. Solar energy is accessible for the duration of the day albeit its irradiance shifts through day and with changing climatic conditions. As the efficiency of solar based PV panel is low it is obligatory to extract the maximum power from the PV board at any given timeframe. To boost the utilization of accessible power drawn from the solar panel and to enlarge the uses of solar energy, a few examinations have researched the outline and uses of DC-DC converters. Moreover,a broad examination and plan of battery charging with the use of SEPIC converter was proposed.Development of such a system faces several challenges to be resolved such as: 1) continuous tracking of Maximum power point for dynamic behaviour of overall load; 2) design of battery charger with quick charging algorithm; 3) extraction of residual power toward overall load side. As several objectives needed to be resolved, either the conventional approach for such a stand-alone system requires at least three converters resulting in reduced efficiency and reliability or doesn’t have quick charging. The proposed strategy over here will maintain the maximum power of panel as well as will follow quick charging algorithm utilizing only two converters. An appropriate hardware prototype and respectively a control strategy is verified by performing simulations and experiment