Characterization of oxytocin and vasopressin receptors in the Southern giant pouched rat and comparison to other rodents.

Vasopressin and oxytocin are well known and evolutionarily ancient modulators of social behavior. The distribution and relative densities of vasopressin and oxytocin receptors are known to modulate the sensitivity to these signaling molecules. Comparative work is needed to determine which neural networks have been conserved and modified over evolutionary time, and which social behaviors are commonly modulated by nonapeptide signaling. To this end, we used receptor autoradiography to determine the distribution of vasopressin 1a and oxytocin receptors in the Southern giant pouched rat (Cricetomys ansorgei) brain, and to assess the relative densities of these receptors in specific brain regions. We then compared the relative receptor pattern to 23 other species of rodents using a multivariate ANOVA. Pouched rat receptor patterns were strikingly similar to hamsters and voles overall, despite the variation in social organization among species. Uniquely, the pouched rat had dense vasopressin 1a receptor binding in the caudate-putamen (i.e., striatum), an area that might impact affiliative behavior in this species. In contrast, the pouched rat had relatively little oxytocin receptor binding in much of the anterior forebrain. Notably, however, oxytocin receptor binding demonstrated extremely dense binding in the bed nucleus of the stria terminalis, which is associated with the modulation of several social behaviors and a central hub of the social decision-making network. Examination of the nonapeptide system has the potential to reveal insights into species-specific behaviors and general themes in the modulation of social behavior.

Age-Related Orthostatic Hypotension: A Comprehensive Analysis of Prevalence, Mechanisms, and Management in the Geriatric Population.

Geriatric patients frequently encounter orthostatic hypotension (OH), a multifaceted condition characterized by a significant drop in blood pressure upon assuming an upright position. As the elderly population is particularly susceptible to OH, our review endeavors to comprehensively explore the complex nature of this condition and various factors contributing to its development. We investigate the impact of comorbidities, polypharmacy, age-related physiological changes, and autonomic dysfunction in the pathogenesis of OH. Geriatric patients with OH are faced with an elevated risk of falls, syncope, a decline in their overall quality of life, and hence increased mortality. These implications require careful consideration, necessitating a thorough examination of therapeutic strategies. We evaluate various pharmaceutical and nonpharmacological therapies, delving into the effectiveness and safety of each approach in managing OH within geriatric populations. We explore the role of pharmacotherapy in alleviating symptoms and mitigating OH-related complications, as well as the potential benefits of volume expansion techniques to augment blood volume and stabilize blood pressure. We place particular emphasis on the significance of lifestyle changes and nonpharmacological interventions in enhancing OH management among the elderly. These interventions encompass dietary modifications, regular physical activity, and postural training, all tailored to the unique needs of the individual patient. To optimize outcomes and ensure patient safety, we underscore the importance of individualized treatment plans that take into account the geriatric patient's overall health status, existing comorbidities, and potential interactions with other medications. This review aims to improve clinical practice and patient outcomes by advocating for early detection, properly tailored management, and targeted interventions to address OH in the elderly population. By raising awareness of OH's prevalence and complexities among healthcare professionals, we hope to foster a comprehensive understanding of OH and contribute to the overall wellness and quality of life of this vulnerable demographic.

Noninvasive assessment of pulmonary congestion in heart failure: Need of the hour.

Early pulmonary congestion detection and surveillance in acute heart failure patients can prevent decompensation, minimize hospitalizations, and improve prognosis. In India, the warm and wet types of HF are still the most common types and residual congestion at discharge is still a significant concern. Thus, there is an urgent need for a reliable and sensitive means of identifying residual and subclinical congestion. Two such monitoring systems are available and approved by US FDA. These include CardioMEMS HF System (Abbott, Sylmar, California) and ReDS System (Sensible Medical Innovations, Ltd., Nanya, Israel). CardioMEMS is a wireless pressure-sensitive implantable device, while ReDS is a wearable noninvasive device for measurement of the lung fluid and hence direct detection of PC. This review discusses the role of noninvasive assessment in PC monitoring in patients with heart failure and its implications from an Indian perspective.

Quality by design-steered development and validation of analytical and bioanalytical methods for raloxifene: Application of Monte Carlo simulations and variance inflation factor.

A sensitive, rapid, reproducible, and economical HPLC method is reported for the quantification of raloxifene hydrochloride employing Quality by Design (QbD) principles. Factor screening studies, employing Taguchi design, indicated buffer volume percentage and isocratic flow rate as the critical method parameters (CMPs), which significantly influence the chosen critical analytical attributes, that is, tailing factor and theoretical plate number. Method conditions were subsequently optimized using face-centered cubic design with magnitude of variance inflation factor for assessing multicollinearity among CMPs. Method operable design region (MODR) was earmarked and liquid chromatographic separation optimized using 0.05 M citrate buffer, acetonitrile, and methanol (57:40:3 v/v/v) as ggmobile phase at 0.9 mL min-1 flow rate, λmax of 280 nm, and column temperature of 40°C. Validation of the developed analytical method was accomplished as per International Council on Harmonization (ICH) guidelines confirming high levels of linearity, precision, accuracy, robustness, and sensitivity. Application of Monte Carlo simulations enabled the attainment of best plausible chromatographic resolution and corroboration of the demarcated MODR. Establishment and validation of the bioanalytical method using rat plasma samples, along with forced degradation and stability studies, corroborated the aptness of developed HPLC methods for drug quantification in the biological fluids, as well as in bulk and marketed dosage forms.

Ecological and human health risk assessment of metals in soils and wheat along Sutlej river (India).

Heavy metal (HMs) entry into soil affects the food chain, which is of great worry for human well-being hazards. In order to study the association of HMs in soil-plant system, surface (0-0.15 m) soil and wheat grain samples were collected within five km buffer zone of Sutlej river in Punjab (India). These samples were analysed for total arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), cobalt (Co), iron (Fe), manganese (Mn), nickle (Ni), lead (Pb), and zinc (Zn). Among all the HMs in soil and grain samples, the concentration of total Fe was maximum and As was minimum. The HM contamination of soils was assessed using contamination factor (CF), enrichment factor (EF), potential ecological risk (Er) and modified potential ecological risk (mEr). The CF, EF, Er and mEr were highest for Cd in soils. The bioaccumulation metal factor was highest for Zn and lowest for Ni in wheat grain. There was a significant (p < 0.05) positive relationship between HM concentration in soils and wheat grains indicating the health risk due to consumption of wheat cultivated around the five km buffer of the Sutlej river. The carcinogenic and non-carcinogenic risk due to ingestion of wheat grain were higher from Cd and Pb, respectively. These results are helpful for devising the remediation approaches to decrease the multi-metal contamination in soils and plants, and the epidemiological ways to preclude the human health risk from HM contamination.

Developing a Validated HPLC Method for Quantification of Ceftazidime Employing Analytical Quality by Design and Monte Carlo Simulations.

BACKGROUND: Ceftazidime, a third-generation cephalosporin, is widely used in the treatment of lung infections, often given as "off-label" nebulization. There is a need to develop a sensitive and robust analytical method to compute aerodynamic properties of ceftazidime following nebulization. OBJECTIVE: The current study entails development of a simple, accurate, and sensitive HPLC method for ceftazidime estimation, employing the principles of analytical quality-by-design (AQbD) and Monte Carlo simulations. METHOD: Selection of critical material attributes (CMAs) affecting method performance was accomplished by factor screening exercises. Subsequently, the influential CMAs, i.e., mobile phase ratio and flow rate, were systemically optimized using a face-centered cubic design for the chosen critical analytical attributes (CAAs). The factor relationship(s) between CMAs and CAAs was explored employing a 3 D-response surface and 2 D-contour plots, followed by numerical as well as graphical optimization, for establishing the optimal chromatographic conditions. The obtained method operable design region was validated by Monte Carlo simulations for defect rate analysis. RESULTS: The optimized HPLC conditions for estimating ceftazidime were acetonitrile to acetic acid solution (75:25) as mobile phase at a flow rate of 0.7 mL/min, leading to Rt of 4.5 min and peak tailing ≤2. Validation studies, as per International Conference on Harmonization Q2(R1) guidance, demonstrated high sensitivity, accuracy, and efficiency of the developed analytical method with an LOD of 0.075 and LOQ of 0.227 µg/mL. Application of this chromatographic method was extrapolated for determining aerodynamic performance by nebulizing ceftazidime at a flow rate of 15 L/min using a next-generation impactor. The study indicated superior performance, sensitivity, and specificity of the developed analytical system for quantifying ceftazidime. CONCLUSIONS: Application of an AQbD approach, coupled with Monte Carlo simulations, aided in developing a robust HPLC method for estimationof ceftazidime per se and on various stages of impactor. HIGHLIGHTS: (i) QbD-enabled development of robust RP-HPLC method for ceftazidime quantification, (ii) Analytical method optimization employing Risk Assessment and Design of Experiments, (iii) Design space verification and defect rate analysis using Monte Carlo simulations, (iv) Chromatographic method validation as per ICH Q2 R1 guidelines and (v) Quantitative estimation of ceftazidime on various stages of impactor.

QbD-steered development and validation of an RP-HPLC method for quantification of ferulic acid: Rational application of chemometric tools.

The present work describes the systematic development of a simple, rapid, sensitive, robust, effective and cost-effective reversed-phase high performance liquid chromatographic method for quantitative analysis of ferulic acid using analytical quality by design paradigms. Initially, apt wavelength for the analysis of ferulic acid was selected employing principal component analysis as the chemometric tool. An Ishikawa fishbone diagram was constructed to delineate various plausible variables influencing analytical target profile, viz. peak area, theoretical plate count, retention time and peak tailing as the critical analytical attributes. Risk assessment using risk estimation matrix and factor screening studies employing Taguchi design aided in demarcating two critical method parameters, viz. mobile phase ratio and flow rate affecting critical analytical attributes. Subsequently, the optimum operational conditions of the liquid chromatographic method were delineated using face-centred composite design. Multicollinearity among the chosen factors for optimization was analyzed by the magnitude of variance inflation factor optimized analytical design space, providing optimum method performance, was earmarked using numerical and graphical optimization and corroborated using Monte Carlo simulations. Validation, as per the ICH Q2(R1) guidelines, ratified the efficiency and sensitivity of the developed novel analytical method of ferulic acid in the mobile phase and the human plasma matrix. The optimal method used a mobile phase, comprising of acetonitrile: water (47:53% v/v, pH adjusted to 3.0 with glacial acetic acid), at a flow rate of 0.8 mL·min-1, at a λmax of 322 nm using a C18 column. Use of principal component analysis unearthed the suitable wavelength for analysis, while analytical quality by design approach, along with Monte Carlo simulations, facilitated the identification of influential variables in obtaining the "best plausible" validated chromatographic solution for efficient quantification of ferulic acid.

An Efficient and Cost-Effective Nose-Only Inhalational Chamber for Rodents: Design, Optimization and Validation.

The mainstay treatment of pulmonary disorders lies around the direct drug targeting to the lungs using a nebulizer, metered-dose inhaler, or dry powder inhaler. Only few inhalers are available in the market that could be used for inhalational drug delivery in rodents. However, the available rodent inhalers invariably require high cost and maintenance, which limits their use at laboratory scale. The present work, therefore, was undertaken to develop a simple, reliable, and cost-effective nose-only inhalation chamber with holding capacity of three mice at a time. The nebulized air passes directly and continuously from the central chamber to mouthpiece and maintains an aerosol cloud for rodents to inhale. Laser diffraction analysis indicated volume mean diameter of 4.02 ± 0.30 µm, and the next-generation impactor studies, however, revealed mean mass aerodynamic diameter of 3.40 ± 0.27 µm, respectively. An amount of 2.05 ± 0.20 mg of voriconazole (VRC) was available for inhalation at each delivery port of the inhaler. In vivo studies indicated the deposition of 76.12 ± 19.50 µg of VRC in the mice lungs when nebulized for a period of 20 min. Overall, the developed nose-only inhalation chamber offers a reliable means of generating aerosols and successfully exposing mice to nebulization.

Preclinical Explorative Assessment of Celecoxib-Based Biocompatible Lipidic Nanocarriers for the Management of CFA-Induced Rheumatoid Arthritis in Wistar Rats.

Celecoxib (CXB), a COX-2 inhibitor, is primarily indicated for long-term treatment of rheumatoid arthritis (RA). The effective therapeutic efficacy of CXB on RA via oral administration shows adverse systemic complications, and therefore, local application of CXB has been recommended. The aim of the present study was to develop and characterize solid lipid nanoparticles (SLNs) with enhanced skin permeation potential of CXB. The particle size, polydispersity index (PDI), and percentage drug entrapment (PDE) of the developed SLNs (CXB-SLNs) were found to be 240 nm, < 0.3, and ~ 86% respectively. The developed SLNs exhibited sustained release up to 70% at the end of 48 h. Drug permeation was found to be 45% for SLN gel and 31% for conventional gel. The dermatokinetic studies also confirmed enhanced permeation of CXB in the epidermis and dermis and revealed superiority of the developed SLN gel vis-à-vis the conventional gel. Further, in the CFA-induced arthritis rat model, % arthritis index (AI) of the CXB-SLN gel formulation was found to be very less (18.54%) as compared to untreated (187.34%) and conventional gel-treated (91.61%) animals. In conclusion, the current study can provide a suitable alternative for the development of an effective topical formulation of CXB in lipid nanocarriers.

Rational approach to prescription writing: A preview.

Prescription writing has to be properly addressed with regard to its correctness and appropriateness. Any errors in the procedure have to be eliminated. Electronic prescribing has abolished most of typographical prescription errors but the rationality involved in prescription of drugs is more of a thought process, which is still not optimum. Irrationality in prescriptions leads to medication errors causing increased morbidity or hospitalization and an economic loss. The rational use of medicines should be practiced which begins with defining the therapeutic objective, choosing the right medicine which is specific to the patient's needs, followed by monitoring of response to therapy. Compliance and outcome of therapy is totally dependent upon the doctor-patient relationship, a proper information and communication with the patient, and the physician's commitment and empathy towards the patient.

Assessment of knowledge about healthy heart habits in urban and rural population of Punjab after SMS campaign-A cross-sectional study.

OBJECTIVE: The prevalence of cardiovascular diseases (CVD) is increasing in developing countries but the awareness regarding prevention and treatment of these diseases is still low. Therefore the present study was conducted with the aim of imparting health education regarding certain changes in lifestyle and dietary habits among general population through the use of short message service (SMS) that may lead to improved knowledge about prevention of cardiovascular diseases. METHODS: This cross-sectional study was conducted over a period of seven months. In the first phase, health education messages were sent through SMS to about 40,000 individuals from urban and rural population in Punjab. Twenty eight messages were sent to each individual and hence more than eleven lakh messages were sent over a period of six months. A questionnaire containing 11 questions based on these health education SMS was generated. Every 40th individual enrolled in the study was contacted on phone, and their responses noted. The data so collected was analyzed for correct responses. RESULTS: Complete responses could be obtained from 800 participants (males: 561 and females: 239). The participants giving correct responses to different questions ranged from 43% to 94%. Majority of participants could retain knowledge about many aspects of healthy heart habits provided by SMS except for topics concerning foods to be avoided, target for normal BP and precautions to be taken before BP measurement. CONCLUSIONS: Health related information imparted through SMS can act as a very effective tool for disseminating knowledge about prevention of heart diseases in general population.

Systematic Development of Transethosomal Gel System of Piroxicam: Formulation Optimization, In Vitro Evaluation, and Ex Vivo Assessment.

Piroxicam is used in the treatment of rheumatoid arthritis, osteoarthritis, and other inflammatory diseases. Upon oral administration, it is reported to cause ulcerative colitis, gastrointestinal irritation, edema and peptic ulcer. Hence, an alternative delivery system has been designed in the form of transethosome. The present study describes the preparation, optimization, characterization, and ex vivo study of piroxicam-loaded transethosomal gel using the central composite design. On the basis of the prescreening study, the concentration of lipids and ethanol was kept in the range of 2-4% w/v and 0-40% v/v, respectively. Formulation was optimized by measuring drug retention in the skin, drug permeation, entrapment efficiency, and vesicle size. Optimized formulation was incorporated in hydrogel and compared with other analogous vesicular (liposomes, ethosomes, and transfersomes) gels for the aforementioned responses. Among the various lipids used, soya phosphatidylcholine (SPL 70) and ethanol in various percentages were found to affect drug retention in the skin, drug permeation, vesicle size, and entrapment efficiency. The optimized batch of transethosome has shown 392.730 µg cm-2 drug retention in the skin, 44.312 µg cm-2 h-1 drug permeation, 68.434% entrapment efficiency, and 655.369 nm vesicle size, respectively. It was observed that the developed transethosomes were found superior in all the responses as compared to other vesicular formulations with improved stability and highest elasticity. Similar observations were noted with its gel formulation.

Nanosized ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery against vitiligo: formulation optimization, in vitro evaluation and preclinical assessment.

The present investigation aimed for the development and characterization of ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery and effective treatment against vitiligo. The ethosomes were prepared by central composite design (CCD) and characterized for various quality attributes like vesicle shape, size, zeta potential, lamellarity, drug entrapment and drug leaching. The optimized ethosomes were subsequently incorporated int Carbopol® 934 gel and characterized for drug content, rheological behavior, texture profile, in vitro release, ex vivo skin permeation and retention, skin photosensitization and histopathological examination. Ethosomes were found to be spherical and multilamellar in structures having nanometric size range with narrow size distribution, and high encapsulation efficiency. Ethosomal formulations showed significant skin permeation and accumulation in the epidermal and dermal layers. The fluorescence microscopy study using 123 Rhodamine exhibited enhanced permeation of the drug-loaded ethosomes in the deeper layers of skin. Also, the developed formulation showed insignificant phototoxicity and erythema vis-à-vis the conventional cream. The results were cross-validated using histopathological examination of skin segments. In a nutshell, the ethosomes-based hydrogel formulation was found to be a promising drug delivery system demonstrating enhanced percutaneous penetration of methoxsalen with reduced phototoxicity and erythema, thus leading to improved patient compliance for the treatment against vitiligo.

Development and Validation of a Stability-Indicating Liquid Chromatographic Method for Estimating Olmesartan Medoxomil Using Quality by Design.

The current studies entail systematic quality by design (QbD)-based development of a simple, rapid, sensitive and cost-effective stability-indicating method for the estimation of olmesartan medoxomil. Quality target method profile was defined and critical analytical attributes (CAAs) for the reverse-phase liquid chromatography method earmarked. Chromatographic separation accomplished on a C18 column using acetonitrile and water (containing 0.1% orthophosphoric acid, pH 3.5) in 40 : 60 (v/v) as mobile phase at a flow rate of 1.0 mL/min with UV detection at 243 nm. Risk assessment studies and screening studies facilitated comprehensive understanding of the factors affecting CAAs. The mobile phase ratio and flow rate were identified as critical method parameters (CMPs) and were systematically optimized using face-centered cubic design, evaluating for CAAs, namely peak area, retention time, theoretical plates and peak tailing. Statistical modelization was accomplished followed by response surface analysis for comprehending plausible interaction(s) among CMPs. Search for optimum solution was conducted through numerical and graphical optimization for demarcating the design space. Analytical method validation and subsequent forced degradation studies corroborated the method to be highly efficient for routine analysis of drug and its degradation products. The studies successfully demonstrate the utility of QbD approach for developing the highly sensitive liquid chromatographic method with enhanced method performance.

Developing oral drug delivery systems using formulation by design: vital precepts, retrospect and prospects.

INTRODUCTION: Over the past few decades, the domain of drug formulations has metamorphosed from the conventional tablets and capsules to advanced and intricate drug delivery systems (DDS), both temporal and spatial. Formulation development of the oral DDS, accordingly, cannot be adequately accomplished using the traditional 'trial and error' approaches of one variable at a time. This calls for the adoption of rational, systematized, efficient and cost-efficient strategies using 'design of experiments (DoE)'. The recent regulatory guidelines issued by the key federal agencies to practice 'quality by design (QbD)' paradigms have coerced researchers in industrial milieu, in particular, to use experimental designs during drug product development. AREAS COVERED: This review article describes these principles of DoE and QbD as applicable to drug delivery development using a more apt expression, that is, 'formulation by design (FbD)'. The manuscript describes the overall FbD methodology along with a summary of various experimental designs and their application in formulating oral DDS. The article also acts as a ready reckoner for FbD terminologies and methodologies. Select literature and an extensive FbD case study have been included to provide the reader with a comprehensive portrayal of the FbD precept. EXPERT OPINION: FbD is a holistic concept of formulation development aiming to design more efficacious, safe, economical and patient-compliant DDS. With the recent regulatory quality initiatives, implementation of FbD has now become an integral part of drug industry and academic research.