Development and verification of mechanistic vaginal absorption and metabolism model to predict systemic exposure after vaginal ring and gel application.

AIMS: The current work describes the development of mechanistic vaginal absorption and metabolism model within Simcyp Simulator to predict systemic concentrations following vaginal application of ring and gel formulations. METHODS: Vaginal and cervix physiology parameters were incorporated in the model development. The study highlights the model assumptions including simulation results comparing systemic concentrations of 5 different compounds, namely, dapivirine, tenofovir, lidocaine, ethinylestradiol and etonogestrel, administered as vaginal ring or gel. Due to lack of data, the vaginal absorption parameters were calculated based on assumptions or optimized. The model uses release rate/in vitro release profiles with formulation characteristics to predict drug mass transfer across vaginal tissue into the systemic circulation. RESULTS: For lidocaine and tenofovir vaginal gel, the predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits. The average fold error (AFE) and absolute AFE indicating bias and precision of predictions range from 0.62 to 1.61. For dapivirine, the pharmacokinetic parameters are under and overpredicted in some studies due to lack of formulation composition details and relevance of release rate used in ring model. The predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits for etonogestrel and ethinylestradiol vaginal ring (AFEs and absolute AFEs from 0.84 to 1.83). CONCLUSION: The current study provides first of its kind physiologically based pharmacokinetic framework integrating physiology, population and formulation data to carry out in silico mechanistic vaginal absorption studies, with the potential for virtual bioequivalence assessment in the future.

Unraveling pathogen deceptive disguise: from modules to mimicry.

Pathogens rely on their effector proteins to colonize host plants. These effectors have diverse functions. A recent study by Li et al. highlights the significance of protein modularity in generating functional diversity among Phytophthora effectors. It underscores the sophisticated tactics that phytopathogens adopt to alter host cellular processes.

Exploring the therapeutic potential of sodium deoxycholate tailored deformable-emulsomes of etodolac for effective management of arthritis.

The current piece of research intends to evaluate the potential of combining etodolac with deformable-emulsomes, a flexible vesicular system, as a promising strategy for the topical therapy of arthritis. The developed carrier system featured nanometric dimensions (102 nm), an improved zeta potential (- 5.05 mV), sustained drug release (31.33%), and enhanced drug deposition (33.13%) of DE-gel vis-à-vis conventional system (10.34% and 14.71%). The amount of permeation of the developed nano formulation across skin layers was demonstrated through CLSM and dermatokinetics studies. The safety profile of deformable-emulsomes has been investigated through in vitro HaCaT cell culture studies and skin compliance studies. The efficacy of the DE-gel formulation was sevenfold higher in case of Xylene induced ear edema model and 2.2-folds in CFA induced arthritis model than that of group treated with conventional gel (p < 0.01). The main technological rationale lies in the use of phospholipid and sodium deoxycholate-based nanoscale flexible lipoidal vesicles, which effectively encapsulate drug molecules within their interiors. This encapsulation enhances the molecular interactions and facilitates the transportation of the drug molecule effectively to the target-site. Hence, these findings offer robust scientific evidence to support additional investigation into the potential utility of flexible vesicular systems as a promising drug delivery alternative for molecules of this nature.

Effectiveness of neuromuscular taping on balance, proprioception, pain, and nerve conduction parameters in patients with diabetic peripheral neuropathy: a two-group pretest-posttest randomized sham-controlled trial study protocol.

Background: The management of diabetic peripheral neuropathy (DPN) comprises a multidimensional approach. Along with pharmacological treatment, physiotherapy has gained applaudable popularity in improving the symptoms of DPN. Neuromuscular taping (NMT) is effective in improving motor, sensory, and balance impairments in many neuromuscular and musculoskeletal conditions but no research has conducted to evaluate the effect of NMT on balance, proprioception, pain, and nerve conduction parameters in patients with DPN. Purpose: To evaluate the effectiveness of NMT on balance, proprioception, pain, and nerve conduction parameters in patients with DPN. Methods: 50 DPN patients aged 40-60 years, scored ≥ 2/13 on physical appearance and ≥ 1/10 on physical examination of Michigan Neuropathy Screening Instrument (MNSI), > 12 on Leeds Assessment of Neuropathic Symptom and Sign (LANSS) scale and < 45 on Berg Balance Scale (BBS) will be included. The experimental group (EG) will receive NMT at the tibialis anterior, tibialis posterior, and peroneus longus muscle and transverse arch of the foot and TENS at the tibial and peroneal nerves (80 Hz, 50 Amp, 0.2 ms square pulses, 2 to 3 times sensory threshold) and the control group (CG) will receive sham taping at the ankle joint and TENS with the same parameters as EG. Outcome measures will be taken at baseline, at 4 weeks, and at 8 weeks of intervention, respectively. Conclusion: The results obtained upon completion of this study may provide a cost-effective non-invasive treatment option to improve the outcomes that will be measured in the present study in patients with DPN. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01275-5.

Root system architecture for abiotic stress tolerance in potato: Lessons from plants.

The root is an important plant organ, which uptakes nutrients and water from the soil, and provides anchorage for the plant. Abiotic stresses like heat, drought, nutrients, salinity, and cold are the major problems of potato cultivation. Substantial research advances have been achieved in cereals and model plants on root system architecture (RSA), and so root ideotype (e.g., maize) have been developed for efficient nutrient capture to enhance nutrient use efficiency along with genes regulating root architecture in plants. However, limited work is available on potatoes, with a few illustrations on root morphology in drought and nitrogen stress. The role of root architecture in potatoes has been investigated to some extent under heat, drought, and nitrogen stresses. Hence, this mini-review aims to update knowledge and prospects of strengthening RSA research by applying multi-disciplinary physiological, biochemical, and molecular approaches to abiotic stress tolerance to potatoes with lessons learned from model plants, cereals, and other plants.

Pluronic F127-tailored lecithin organogel of acyclovir: preclinical evidence of antiviral activity using BALB/c murine model of cutaneous HSV-1 infection.

Herpes is a well-known contagious infection equally affecting both sexes. Among many antiviral drugs employed for its treatment, acyclovir (ACY) is the drug of choice. The currently available therapies of ACY suffer from limitations like poor oral bioavailability (10-15%) and high-dose requirement. The present scientific study aims to explore pluronic lecithin organogel (PLO) as a novel drug delivery platform for ACY to bring an improvement in its delivery through topical route. The properties of organogel like biocompatibility and amphiphilic nature which facilitates dissolution of various drugs of different solubility characteristics along with enhancing the permeation potential of active molecules make it a favorable drug delivery platform for the management of topical diseases. The developed PLO formulations were characterized for micromeritic characteristics, viz., zeta potential, percentage drug content, organogel morphology, skin permeation, retention, and stability studies. The selected topical formulation was further compared with the marketed one for its therapeutic efficacy by inducing cutaneous Herpes simplex virus type 1 infection followed by confirmation of viral load by immunofluorescence and PCR analyses. The developed formulation showed significant improvement over the marketed product as reflected in lesion scoring index and PCR analysis. Further, it proved better to the marketed formulation in t.i.d. treatment regimen in comparison to control. The improvement in overall performance leading to enhanced bioavailability and safety is attributed to the synergism between excipient properties and formulation characteristics. The drug ACY in this micro environment not only finds an improved delivery vehicle but it also offers enhanced drug-target interactions.

Co-delivery of isotretinoin and clindamycin by phospholipid-based mixed micellar system confers synergistic effect for treatment of acne vulgaris.

BACKGROUND: The combination therapy of Isotretinoin (ITR) and antibacterial formulations administered through topical route suffer from several limitations including reduced therapeutic efficacy and low patient-compliance. EXPERIMENT: The present study aimed to develop biocompatible lipid-based mixed micelles of ITR in combination with Clindamycin phosphate (CLIN) employing self-assembly method to improve its skin delivery, photostability, biocompatibility and pharmacodynamic efficacy. RESULTS: The MTT assay and cellular uptake studies showed non-cytotoxic effect to HaCat cell lines. The zone of inhibition studies conducted in Propionibacterium acnes provides the first literature evidence to support the antimicrobial property of Isotretinoin and Tretinioin. The nano-sized carriers offered (19.3 ± 1.03 nm particle size with -3.12 mV zeta potential) enhanced permeation, skin retention, pre-clinical efficacy and significant skin biocompatibility. The testosterone-induced acne model proved superior pharmacodynamic efficacy of lab developed formulation vis-à-vis marketed products of both the drugs. The results were further confirmed by the histopathological studies of respective skin samples treated with different formulations. CONCLUSION: The lab developed lipid-based micellar formulation of ITR and CLIN offers a better strategy for the combined delivery of unstable molecules like ITR and CLIN in acne management.

Implementation of Quality by Design (QbD) approach in development of silver sulphadiazine loaded egg oil organogel: An improved dermatokinetic profile and therapeutic efficacy in burn wounds.

Silver Sulphadiazine (SSD) is an effective antibacterial agent considered as the gold standard for burn wound treatment. The present study aimed to investigate EO-based organogel (SSD-EOOG) as an effective carrier system for SSD delivery in burn wound management employing Quality by Design (QbD) paradigm. The organogel-based formulations were prepared employing QbD-oriented approach and further evaluated for in vivo efficacy and stability. The developed formulations were characterized for particle size, drug content, morphology, in vitro drug release, skin safety studies, ex vivo permeation, skin retention, textural analysis and pharmacodynamic studies in murine burn wound model. I-optimal mixture design was employed for optimization and evaluating different critical quality attributes (CQAs). The optimized formulation exhibited particle size of 256.5 nm with enhanced permeation (72.33 ± 1.73%) and retention (541.20 ± 22.16 µg/cm2) across skin barrier as compared to SSD-MKT. The pharmacodynamic results proved superior therapeutic efficacy of SSD-EOOG in topical burn wounds inflicted with MRSA bacterium. The results indicated wound contraction rate (78.23 ± 5.65%) and faster re-epithelialization in SSD-EOOG treated group. The present study concluded that egg oil based organogel promoted therapeutic efficacy of SSD for burn wound treatment.

Stability kinetics of fusidic acid: Development and validation of stability indicating analytical method by employing Analytical Quality by Design approach in medicinal product(s).

A simple, rapid, accurate, reproducible and sensitive reverse phase HPLC method for the estimation of fusidic acid (FA) by means of Analytical Quality by Design (AQbD) was the aim of the present study. Initially, the vital pre-requisites for AQbD like analytical method target profile and critical analytical attributes (CAAs) like theoretical plates, tailing factor and percent assay were defined. An octadecyl silyl silica C18 column with a packing size of 5 µm was employed and the detection was performed at 235 nm using UV-detector. The separation was performed with isocratic elution employing mixture of methanol: acetonitrile (5: 95, v/v) and an aqueous phase with pH of 2.8 containing 0.1% orthophosphoric acid in the ratio of 60: 40 (v/v). Ishikawa fish-bone diagram provided the basis of the variation in CAAs with various inputs. Taguchi Design was selected as the initial screening design to select critical method parameters (CMPs) affecting method development and Central Composite Design (CCD) was further applied for systematic optimization of chromatographic method by evaluating CAAs. Crucial parameters viz. limit of detection, limit of quantification, specificity, linearity and sensitivity were employed to validate the method in accordance with the ICH guidelines. Stress degradation studies were performed and the developed method was able to successfully differentiate the degraded products from the parent drug, that too in a topical gel. In conclusion, the findings of the present study validated the utility of AQbD in the systematic design of a liquid chromatographic method with fine sensitivity for FA estimation in medicinal products.

Beta-carotene-Encapsulated Solid Lipid Nanoparticles (BC-SLNs) as Promising Vehicle for Cancer: an Investigative Assessment.

Beta-carotene (BC), a red-colored pigment found in plants and animals, is one of the most extensively investigated carotenoids due to its provitamin-A, antioxidant, and anticancer properties. The anticancer activity of BC through oral administration is severely affected due to its low bioavailability and oxidative degradation. The present study aimed to formulate and characterize solid lipid nanoparticles (SLNs) of BC for enhanced bioavailability and therapeutic efficacy. Beta-carotene-loaded solid lipid nanoparticles (BC-SLNs) were prepared employing different combinations of glyceryl monostearate and gelucire. The characterization studies were performed for particle size, morphology, release behavior, and stability. BC-SLNs were also studied for in vitro cytotoxicity in human breast cancer cell lines (MCF-7) and pharmacokinetic studies in Wistar rats. The cytotoxicity studies confirmed that encapsulation of BC within the lipid bilayers of nanoparticles did not affect its anticancer efficacy. An improved anticancer activity was observed in BC-SLNs as compared to the free BC. BC-SLNs enhanced the bioavailability of BC on oral administration by sustaining its release from the lipid core and prolongation of circulation time in the body. Similarly, area under the curve (AUCtotal) enhanced 1.92-times more when BC was incorporated into SLNs as compared to free BC. In conclusion, solid lipid nanoparticles could be an effective and promising strategy to improve the biopharmaceutical properties of carotenoids for anticancer effects.

Oral Delivery of Methylthioadenosine to the Brain Employing Solid Lipid Nanoparticles: Pharmacokinetic, Behavioral, and Histopathological Evidences.

The present study aimed to orally deliver methylthioadenosine (MTA) to the brain employing solid lipid nanoparticles (SLNs) for the management of neurological conditions like multiple sclerosis. The stearic acid-based SLNs were below 100 nm with almost neutral zeta potential and offered higher drug entrapment and drug loading. Cuprizone-induced demyelination model in mice was employed to mimic the multiple sclerosis-like conditions. It was observed that the MTA-loaded SLNs were able to maintain the normal metabolism, locomotor activity, motor coordination, balancing, and grip strength of the rodents in substantially superior ways vis-à-vis plain MTA. Histopathological studies of the corpus callosum and its subsequent staining with myelin staining dye luxol fast blue proved the potential of MTA-loaded SLNs in the remyelination of neurons. The pharmacokinetic studies provided the evidences for improved bioavailability and enhanced bioresidence supporting the pharmacodynamic findings. The studies proved that SLN-encapsulated MTA can be substantially delivered to the brain and can effectively remyelinate the neurons. It can reverse the multiple sclerosis-like symptoms in a safer and effective manner, that too by oral route.

Nano-engineered lipid-polymer hybrid nanoparticles of fusidic acid: an investigative study on dermatokinetics profile and MRSA-infected burn wound model.

Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA) have been a major cause of morbidity in thermally injured patients. The skin barrier gets disrupted and loss of immunity further makes burn sites an easy target for bacterial colonization. In the current study, combined potential of lipid-polymer hybrid nanoparticles (LPHNs) with fusidic acid was explored as a promising strategy toward combating resistant bacteria in burn wound infection sites. The developed systems exhibited particle size (310.56 ± 5.22 nm), zeta potential (24.3 ± 4.18 mV) and entrapment efficiency (78.56 ± 3.56%) with a spherical shape. The hybrid nanoparticles were further gelled into carbopol and demonstrated better permeation (76.53 ± 1.55%) and retention characteristics (56.41 ± 4.67%) as compared to the conventional formulation. The topical delivery of FA into the skin layers by FA-LPHN gel was found to be significantly higher (p < 0.05) compared to FA-CC. The in vivo potential was further assessed in murine burn wound model inflicted with MRSA 33591 bacterium with the determination of parameters like bacterial burden, wound contraction, morphological and histopathological examination of wounds. The bacterial count decreased drastically in FA-LPHN gel group (5.22 log CFU/mL) on day 3 with significant difference in comparison to FA-CC. The wound size reduction in FA-LPHN gel (68.70 ± 3.65%) was higher as compared to FA-CC (73.30 ± 4.23%) and control groups (83.30 ± 4.40%) on day 5. The current study presents a safe and effective formulation strategy for the treatment of MRSA-infected burn wounds by providing moist environment and prevention from bacterial infection.

Correction to: Plant stem cells: what we know and what is anticipated.

This correction stands to correct Fig. 2 of the original article as Fig. 2 provided in the manuscript has been modified. The corrected figure has been provided herewith. The original article has been corrected.

Plant stem cells: what we know and what is anticipated.

Plant stem cell research is of interest due to stem cells ability of unlimited division, therapeutic potential and steady supply to provide precursor cells. Their isolation and culture provides the important source for the production of homogenous lines of active constituents that allow large-scale production of various metabolites. The process of dedifferentiation and reversal to pluripotent cells involves the various pathways genes related to the stem cells and are associated to each other for maintaining a specific niche. Domains such as niche dynamics and maintenance signaling can be used for the identification of genes for stem cell niche. Significant findings have been achieved in the past on plant stem cells however our understanding towards mechanisms underlying some specific phenomenon like dedifferentiation, regulation, niche dynamics is still in infancy. The present review is based on the past research efforts and also pave a way forward for the future anticipation in the field of development of cell cultures for the production of active metabolites on large scale and undertanding transcriptional regulation of stem cell genes involved in niche signaling.

Current State of Nanomedicines in the Treatment of Topical Infectious Disorders.

BACKGROUND: Topical infections, involving a number of diseases such as impetigo, eczema, pustular acne, psoriasis and infected seborrheic dermatitis are one among the many challenges to health which stand out for their profound impact on human species. The treatment of topical infections has always been a difficult proposition because of the lack of efficacy of existing anti-infectives, longer period of treatment and yet incomplete recovery. The increasing emergence of antibiotic resistant bacterial strains like Staphylococcus aureus, Methicillin-Resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa undermines the need for the development of new delivery systems to enhance the therapeutic efficacy of existing topical anti-infectives. METHODS: The application of nanotechnology to medicine, or nanomedicine, is rapidly becoming a major driving force behind ongoing changes in the anti-infective field because of its interaction at the sub-atomic level with the skin tissue. The latter, in the current scenario, points towards vesicular carriers like liposomes, lipidic nanoparticles and silver nanoparticles. as the most promising drug delivery solutions for topical infection disorders. These have exhibited immense significance owing to their uniqueness to facilitate the interactions at interfaces with the barrier membranes. RESULTS: The present review summarizes the emerging efforts in combating topical infections particularly using nanomedicine based delivery systems as new tools to tackle the current challenges in treating infectious diseases. Besides, compiling various research reports, this article also includes formulation considerations, mechanisms of penetration and patents reported. CONCLUSION: Despite the new emerging technologies and delivery systems, efforts are still needed in the right direction to combat this global challenge.

Chitosan-tailored lipidic nanoconstructs of Fusidic acid as promising vehicle for wound infections: An explorative study.

The current research study intends to explore the combined potential of lipid nanoparticles and chitosan as an optimum therapy for the management of wound infections. Fusidic acid (FA), a steroidal antibiotic employed for treatment of primary and secondary topical infections was encapsulated within the nanoengineered lipid-polymer hybrid nanoparticles (FA-LPHNs). A number of variables like lipid/polymer ratio, lipid, surfactant and chitosan concentration, stirring speed were optimized to get the desired particle size and % entrapment efficiency. The developed carriers were further characterized for particle size, antibacterial activity, cytotoxicity studies in HaCat cell lines, ex vivo permeation studies and skin safety profile. The developed LPHNs offered nanometric size (284.67 ±â€¯5.67 nm), sustained drug release (79.31 ±â€¯0.45%) and enhanced drug permeation (72.09 ±â€¯1.26%). The changes in viability of HaCat cells were insignificant indicating the safety profile of LPHNs. The administration of FA-LPHNs resulted in 5-times and 4-times decrease in its inhibitory concentration against MRSA 33591 and MSSA 25921 respectively, along with antibacterial activity for a longer duration. Further, hydrogel incorporated nanoparticles were found to be topically applicable and compatible with mice skin. The studies indicated the superiority of FA-LPHNs for better management of wounds and associated infections over the conventional marketed product.

Cationic-bilayered nanoemulsion of fusidic acid: an investigation on eradication of methicillin-resistant Staphylococcus aureus 33591 infection in burn wound.

AIM: The aim of the current study was to investigate the therapeutic efficacy of cationic-charged bilayered nanoemulsion for topical delivery of fusidic acid in eradicating methicillin-resistant Staphylococcus aureus (MRSA) bacterial burn wound infection. MATERIALS & METHODS: The developed carriers were characterized for particle size, antibacterial activity, cell viability assay in HaCat cell lines, rheological profile, ex vivo and in vivo studies, namely, full thickness MRSA 33591 murine burn wound infection via topical route. RESULTS: The developed cationic bilayered nanogel offered enhanced drug permeation, reduction in bacterial load and enhanced wound contraction along with faster re-epithelialization in burn wounds. CONCLUSION: The results encourage the exploration of the potential of cationic nanogel in treating resistant microorganisms such as MRSA, especially for application in burn wound infection.

Preclinical Explorative Assessment of Dimethyl Fumarate-Based Biocompatible Nanolipoidal Carriers for the Management of Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease in which myelin sheath damage occurs due to internal and external factors. MS especially affects the young population. Dimethyl fumarate (DMF) is a promising agent for MS treatment, although it is associated with concerns such as poor brain permeation, multiple dosing, and gastrointestinal flushing. The present study attempts to evaluate the preclinical performance of specially designed DMF-based lipoidal nanoparticles in a cuprizone-induced demyelination model in rodents. The studies proved the efficacy of lipid-based nanoparticles containing DMF in a once-a-day dosage regimen over that of thrice-a-day plain DMF administration on crucial parameters like motor coordination, grip strength, mortality, body weight, and locomotor activity. However, neither blank lipid nor blank neuroprotective (vitamins A, D, and E) loaded nanoparticles were able to elicit any desirable behavioral response. Histopathological studies showed that the designed once-a-day DMF nanomedicines were well tolerated and rejuvenated the myelin sheath vis-à-vis the plain DMF thrice-a-day regimen. These findings provide proof of concept for a biocompatible nanomedicine for MS with tremendous promise for effective brain delivery and patient compliance on the grounds of a reduction in the dosage frequency.

Topical Drug Delivery of Anti-infectives Employing Lipid-Based Nanocarriers: Dermatokinetics as an Important Tool.

BACKGROUND: The therapeutic approaches for the management of topical infections have always been a difficult approach due to lack of efficacy of conventional topical formulations, high frequency of topical applications and non-patient compliance. The major challenge in the management of topical infections lies in antibiotic resistance which leads to severe complications and hospitalizations resulting in economic burden and high mortality rates. METHODS: Topical delivery employing lipid-based carriers has been a promising strategy to overcome the challenges of poor skin permeation and retention along with large doses which need to be administered systemically. The use of lipid-based delivery systems is a promising strategy for the effective topical delivery of antibiotics and overcoming drug-resistant strains in the skin. The major systems include transfersomes, niosomes, ethosomes, solid lipid nanoparticles, nanostructured lipid carriers, microemulsion and nanoemulsion as the most promising drug delivery approaches to treat infectious disorders. The main advantages of these systems include lipid bilayer structure which mimics the cell membrane and can fuse with infectious microbes. The numerous advantages associated with nanocarriers like enhanced efficacy, improvement in bioavailability, controlled drug release and ability to target the desired infectious pathogen have made these carriers successful. CONCLUSION: Despite the number of strides taken in the field of topical drug delivery in infectious diseases, it still requires extensive research efforts to have a better perspective of the factors that influence drug permeation along with the mechanism of action with regard to skin penetration and deposition. The final objective of the therapy is to provide a safe and effective therapeutic approach for the management of infectious diseases affecting topical sites leading to enhanced therapeutic efficacy and patient-compliance.

Lanolin-based organogel of salicylic acid: evidences of better dermatokinetic profile in imiquimod-induced keratolytic therapy in BALB/c mice model.

The primary aim of the present study was to develop lanolin-based organogel with enhanced delivery potential and reduced skin irritation for the treatment of hyperkeratotic lesions and scaling. The drug was encapsulated in the lipidic bilayers of organogel. The values of particle size, polydispersity index (PDI), and zeta potential of the developed carrier system was found to be 257.5 nm, 0.272, and -24.9 mV, respectively. The system was pseudoplastic in nature with the yield value of 2.3078 Pa. The skin permeation studies exhibited superiority of the prepared lanolin-based organogel formulation over the conventional gel formulation (CGF). Further, the dermatokinetic studies also confirmed better permeation and enhanced skin bioavailability of SA to epidermis as well as dermis vis-à-vis the CGF. In conclusion, the developed organogel system not only improved the delivery profile of SA but also reduced the skin irritant potential. The current findings can provide a suitable alternative for the development of an effective topical formulation of SA for the treatment of hyperkeratotic lesions.