Nose-to-brain Drug Delivery System: An Emerging Approach to Chemotherapy-induced Cognitive Impairment.

The rise in global cancer burden, notably breast cancer, emphasizes the need to address chemotherapy-induced cognitive impairment, also known as chemobrain. Although chemotherapy drugs are effective against cancer, they can trigger cognitive deficits. This has triggered the exploration of preventive strategies and novel therapeutic approaches. Nanomedicine is evolving as a promising tool to be used for the mitigation of chemobrain by overcoming the blood-brain barrier (BBB) with innovative drug delivery systems. Polymer and lipid-based nanoparticles enable targeted drug release, enhancing therapeutic effectiveness. Utilizing the intranasal route of administration may facilitate drug delivery to the central nervous system (CNS) by circumventing first-pass metabolism. Therefore, knowledge of nasal anatomy is critical for optimizing drug delivery via various pathways. Despite challenges, nanoformulations exhibit the potential in enhancing brain drug delivery. Continuous research into formulation techniques and chemobrain mechanisms is vital for developing effective treatments. The intranasal administration of nanoformulations holds promise for improving therapeutic outcomes in chemobrain management. This review offers insights into potential future research directions, such as exploring novel drug combinations, investigating alternative delivery routes, or integrating emerging technologies to enhance the efficacy and safety of nanoformulations for chemobrain management.

Kinetic View of Enzyme Catalysis from Enhanced Sampling QM/MM Simulations.

The rate constants of enzyme-catalyzed reactions (kcat) are often approximated from the barrier height of the reactive step. We introduce an enhanced sampling QM/MM approach that directly calculates the kinetics of enzymatic reactions, without introducing the transition-state theory assumptions, and takes into account the dynamical equilibrium between the reactive and non-reactive conformations of the enzyme/substrate complex. Our computed kcat values are in order-of-magnitude agreement with the experimental data for two representative enzymatic reactions.

A Clinico-Epidemiological Study of Cutaneous Adverse Drug Reactions in a Tertiary Care Centre of Eastern India.

Background: Adverse drug reactions (ADRs) are major problems in the drug therapy. Cutaneous adverse drug reactions (CADRs) are the most common ADRs. The pattern of CADRs differs among various drugs. Aims: To record various morphological patterns of CADRs and their causal relationships among patients attending in a tertiary care centre. Materials and Methods: An observational, cross-sectional, clinical study was conducted for a duration of one and a half years in a tertiary care centre in eastern India. Patients presenting with suspected CADRs were included if drug identity could be ascertained. Clinical profiling and drug history were recorded, and causality assessment was carried out as per the Naranjo scale. Result: The commonest CADR in our study was fixed drug eruption (FDE) 48.61%, followed by SJS-TEN spectrum 16.66%, maculopapular rash 11.11% and so on. Severe cutaneous adverse drug reactions (SCARs) such as SJS, TEN, SJS-TEN Overlap, AGEP and DRESS accounted for 18 cases (25%). The most common culprit drugs were antimicrobials (54.16%), followed by nonsteroidal anti-inflammatory drugs (15.27%) and anticonvulsants (12.5%). Most of the CADRs were in probable category. Conclusion: The pattern of CADRs and the drugs causing them in our study population are similar to some previous studies but somewhat different from most of the previous Indian studies. The incidence of SCARs was significantly higher than in previous other studies in India and abroad.

A Clinico-Epidemiological Study of Fixed Drug Eruption with a Special Focus on the Causative Agent and the Clinical Patterns.

Background: Fixed drug reaction (FDE) is characterized by the development of well-circumscribed, round, erythematous macules and plaques on cutaneous or mucosal surface following ingestion of the offending drug. Aim and Objectives: To study the etiological agents responsible for FDE and to study the clinical patterns of FDE due to different drugs. Materials and Methods: It was a hospital-based observational cross-sectional clinical study. The study period was 24 months. Fifty patients were included. The study was done after a literature search, hypothesis generation, protocol write-up, ethical submission, ethical clearance, patient enrollment, data collection, data analysis, and research. The patients were selected on the basis of the Naranjo scoring system. The patients with a history of combination drug intake were not included in the study. Results: A total of 0.11% patients presented with FDE in the study period. Out of them, 52% of the patients belonged to 20-39 years age group, having sex ratio of 1.6:1. About 64% of the patients presented with multiple lesions, whereas 36% had a single lesion. A total of 46% patients presented with first episode and 54% had recurrent episodes. The mean time intervals of first and subsequent episodes were 6.5 days and 4.3 hours, respectively. Also, 16% patients had a history of herpes infection. Extremities were more affected followed by trunk and mucosa. Fluoroquinolones were the most common etiological agent found in 56% patients having cutaneous (48%) and mucosal lesions (14%). The most common drug was norfloxacin (36%) followed by both paracetamol (12%) and metronidazole (12%). Fluoroquinolones were the most common drugs implicated in bullous lesions and generalized bullous FDE. Limitations: The study population was small and the study was for a limited period of time. Conclusion: The patient should be aware of the offending drug and opt for any alternative agent after visiting the physician.

Fabrication, evaluation, and enhanced penetration of vinyl and cellulose-engineered transdermal patch of nifedipine using essential oil as penetration enhancer.

The aim of this study was to develop and evaluate the transdermal patch formulations of nifedipine. The patch formulations containing nifedipine were prepared and optimized with different ratios of vinyl and cellulose-derived polymers, drug contents, and permeation enhancers. Among the various formulations, the patch formulation containing a 1:5 ratio of ethyl cellulose and polyvinyl pyrrolidone was selected for ex vivo pharmacokinetic study based on in vitro permeation studies using stratum corneum of the pig's skin. The cumulative percentage release after the transdermal administration of the optimized patch formulation was 71.43%, and the plasma concentration of nifedipine was maintained for 16 hrs. The physicochemical evaluation study including flatness, thickness, moisture content and uptake, drug content in vitro release, and ex vivo permeation indicated satisfactory results. The formulation batch with clove oil as a penetration enhancer has shown better ex vivo permeation as compared to the formulations without enhancers and another synthetic enhancer. These results suggest that the optimized patch formulation Q3 could be further developed for clinical applications, providing the therapeutic plasma level of nifedipine over an extended period. Hence analyzing the results of the evaluation tests, in vitro and ex vivo data on the preparation and optimization of nifedipine-loaded transdermal patch, it can be concluded that the formulation shows its feasibility as an effective transdermal delivery system for nifedipine.

Oral Lichen Planus: An Updated Review of Etiopathogenesis, Clinical Presentation, and Management.

Lichen planus (LP) is a chronic idiopathic immune-mediated inflammatory condition. LP is a heterogeneous disease with varied clinical presentations having different natural history, prognosis, sequelae, and outcomes. It can affect skin, hair, nails, and mucosae. Mucosal LP (including oral LP) tends to be persistent and resistant to treatment, compared to cutaneous LP. Oral LP (OLP) is broadly divided into two main categories: hyperkeratotic (usually asymptomatic) and erosive (commonly symptomatic). It can present with symptoms including odynophagia, dysphagia, dysgeusia, and sensitivity to hot spicy foods. Apart from the superficial epidermal changes, which vary with the type of clinical presentation, histopathologically oral LP shows a unifying similar and consistent feature of a lichenoid interface dermatitis. Recently, researchers have highlighted the critical role played by IL-17 in the pathogenesis of OLP. World Health Organization has categorized oral LP as one of the oral potentially malignant disorders (OPMD), albeit with a low risk of malignant transformation. Also, in the last couple of years there have been various reports on the usage of newer drugs like anti-IL17, anti-IL12/23, anti-IL 23, PDE4 inhibitors, and JAK inhibitors in the management of refractory OLP. The principal aim of treatment still remains to resolve the symptoms, prolong the symptoms free period, and reduce the risk of potential malignant transformation. We have described many new revelations made in recent times regarding the etiopathogenesis, associated conditions as well as management of OLP. Thus, the objective of this review is to present a comprehensive up-to-date knowledge including the recent advances made regarding OLP.

Effect of Yoga and Walking on Glycemic Control for the Management of Type 2 Diabetes: A Systematic Review and Meta-analysis.

Background: A daily habit of yogic practice or walking, along with an oral hypoglycemic agent (OHA) could be beneficial for better control of type 2 diabetes mellitus (T2DM). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to find out the efficiency of yoga or walking on glycemic control in T2DM. Methodology: The present systematic review and meta-analysis were completed according to the PRISMA guidelines. The risk of bias in included studies was evaluated, by using the revised Cochrane risk-of-bias tool for randomized trials. Meta-analysis was implemented using RevMan software. Forest plots were used to illustrate the study findings and meta-analysis results. Results: Sixteen studies were included in this systematic review, where 1820 participants were allocated to one of the following interventions: yoga, walking, and without any regular exercise (control group). Participants were between 17-75 years of age. Compared to the control group, the yoga group had a significant reduction in fasting blood glucose (FBG) by 31.98 mg/dL (95% CI = -47.93 to -16.03), postprandial blood glucose (PPBG) by 25.59 mg/dL (95% CI = -44.00 to -7.18], glycosylated hemoglobin (HbAlc) by 0.73% (95% CI = -1.24 to -0.22), fasting insulin by 7.19 µIU/mL (95% CI = -12.10 to -2.28), and homeostatic model assessment for insulin resistance (HOMA-IR) by 3.87 (95% CI = -8.40 to -0.66). Compared to the control group, the walking group had a significant reduction in FBG by 12.37 mg/dL (95% CI = -20.06 to -4.68) and HbA1c by 0.35% (95% CI = -0.70 to -0.01). Compared to the walking group, the yoga group had a significant reduction in FBG by 12.07 mg/dL (95% CI = -24.34 to - 0.20), HbA1c by 0.20% (95% CI = -0.37 to -0.04), fasting insulin by 10.06 µIU/mL (95% CI = -23.84 to 3.71) and HOMA-IR by 5.97 (95% CI = -16.92 to 4.99). Conclusions: Yoga or walking with OHA has positive effects on glycemic control. For the management of T2DM, yoga has relatively more significant effects on glycemic control than walking.Review registration number: PROSPERO registration number CRD42022310213.

Rare Cause of Skull Base Osteomyelitis: A Challenging Diagnosis and Management With a Literature Review.

This is a case of skull base osteomyelitis (SBO) caused by a rare fungal species, Scedosporium apiospermum. This is a clinical case report with a review of the literature. SBO is a potentially life-threatening infection of the temporal bone. The patient presented to our hospital with a two-month history of left otalgia, otorrhea and reduced hearing, after failed initial intravenous antibiotic therapy. Thorough examination and further investigation confirmed the diagnosis of SBO caused by a rare fungal species, S. apiospermum. The patient was subsequently started on a long-term course of antifungals which led to an improvement of symptoms. This case highlights the importance of early recognition and considering early antifungal treatment in patients with persistent otalgia and otorrhea, particularly in those who have failed to respond to intravenous antibiotics. Further research is needed to better understand the optimal timing and duration of antifungal therapy in these patients.

Topical Therapy in Psoriasis.

Psoriasis is a chronic condition that progresses in remitting and relapsing phases. Most of these patients have mild-to-moderate illness, which can be managed with topical medications or could be thought of as continuing therapy after remission. Potential therapeutic efficacy is offered, and systemic treatment's negative side effects are constrained. Topical therapies have recently advanced in tandem with recent advancements in our understanding of psoriasis. To improve the quality of life of patients, appropriate knowledge and application of these topical agents are crucial.

Disease Assessment in Psoriasis.

Researchers are making all out efforts worldwide, to find a serological marker to monitor the disease severity and/or measure efficacy of the drug. There are many potential molecular targets being investigated as a candidate marker. However, till date there has been no significant breakthrough. Thus, various scoring systems have been devised to evaluate the disease severity in psoriasis. In spite of constant revisions of the scores being currently used, from time to time. None of the scores yet satisfy all the validation criteria desired of an ideal scoring system. And this is partly also because of the fact that the psoriasis has such a huge range of clinical variants. Nevertheless, in the recent past, significant progress has been made in this direction.

Biologics and Biosimilars in Psoriasis.

Psoriasis is a chronic, debilitating, relapsing, inflammatory dermatosis, which affects approximately 2-3% of the population. The burgeoning research on pathogenesis of psoriasis has opened up new directions in management of this common condition. The introduction of biologics has given additional elements to the arsenal of psoriatic disease treatments. TNF-α inhibitors, IL-12/23 inhibitors, IL-17 inhibitors, CD-6 inhibitor proved highly efficient and have a good safety profile in numerous clinical trials. Biosimilar drugs are structurally almost similar to their reference biologic and are also made from living organism. Long-term follow-up and post-marketing surveillance are required to understand, long-term efficacy, adverse events of these powerful potent molecules.

Psoriasis and its Association with Metabolic Syndrome.

Psoriasis is a multifactorial, chronic, immune-mediated inflammatory condition. Psoriasis often goes beyond the skin, nails and scalp and involves the eyes (uveitis), joints (arthritis) and several metabolic derangements, as seen in various studies. It is strongly associated with features of the metabolic syndrome (MetS) like hypertension, obesity, dyslipidaemia, type 2 diabetes, insulin resistance and non-alcoholic fatty liver disease. Amongst various skin diseases, MetS has the strongest association with psoriasis. The risk of having MetS is almost doubled in patients with psoriasis as compared to healthy individuals. Both conditions share a common pathophysiological background in terms of genetics, inflammatory markers, lifestyle choices, etc. The association of psoriasis with MetS is clinically important as it influences the prognosis, quality of life and choice of treatment. Systemic conventional drugs should be used with caution in such patients, as their long-term use may contribute to metabolic impairment. The treating dermatologist should be aware of such associations and their implications, and a more holistic approach should be taken to manage psoriasis where equal importance is given to lifestyle and dietary modifications and comorbid conditions, in addition to the pharmacological therapy so as to decrease the burden of the disease for both the patient and the health system.

Extra Orbital Periocular Tuberculosis - A Rare Case Report.

Tuberculosis is a known bacterial infection caused by Mycobacterium tuberculosis complex and has varied clinical presentation. Though pulmonary from is the commonest, extra orbital form is a rare presentation of the same. Here we present a case of extra orbital tuberculosis in a young female, presenting as a painless swelling lateral to the lateral canthus of right eye, along with right preauricular lymphadenopathy. The mass was excised, sent for histopathological examination and culture of M. tuberculosis, which yielded positive results.

Oral Tranexamic Acid for the Treatment of Melasma: Evidence and Experience-Based Consensus Statement from Indian Experts.

Melasma, a chronic pigmentary skin condition mainly affecting the face, remains a challenge despite the availability of several options for treatment. Many melasma patients are not satisfied with treatment outcomes. Tranexamic acid (TXA), an anti-fibrinolytic drug has shown promising results in patients with melasma. Evidence from several clinical studies has surfaced on efficacy and tolerability of TXA in these patients. It can be used as monotherapy or adjuvant with other therapies. Currently, there is no published consensus or guideline document for its use in the treatment of melasma. TXA is available for oral use, topical use as well as an injection. In this article, a consensus of Indian experts is prepared based on the available literature and experience with use of oral TXA in melasma. This review article might help clinicians for use of oral TXA appropriately while treating melasma.

A single ascending dose study of single-stranded oligodeoxyribonucleotide RO7062931 in Chinese healthy volunteers.

RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded oligodeoxyribonucleotide complementary to hepatitis B virus RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This phase I single ascending dose (SAD) study evaluated the safety, tolerability, and pharmacokinetics of RO7062931 in Chinese healthy volunteers. There were four SAD cohorts (0.3, 1.0, 2.0, and 4.0 mg/kg), in each of which healthy volunteers were randomized to a single subcutaneous (s.c.) injection of RO7062931 or matching placebo in a 4:1 ratio. Placebo recipients were pooled as one treatment group for safety assessments. A total of 41 healthy Chinese men received one dose of RO7062931 (n = 33) or placebo (n = 8) and completed the study (85-day follow-up). Adverse events (AEs) were reported in 22 of 33 (66.6%) RO7062931 recipients (n = 80 treatment-related) and seven of eight (87.5%) placebo recipients (n = 1 treatment-related). Apart from two moderate-intensity AEs, all AEs were mild. The most frequently reported AEs were influenza, injection-related reactions, and headache. Dose-proportional increases in plasma RO7062931 exposure were observed between the 0.3 and 1.0 mg/kg doses, whereas a supra-dose-proportional increase occurred at doses greater than or equal to 2.0 mg/kg, along with a marked increase in urinary excretion. Single s.c. dose of RO7062931 up to 4.0 mg/kg were safe and well-tolerated in healthy Chinese volunteers. Pharmacokinetic data suggested that ASGPR saturation had commenced between doses of 2.0 and 4.0 mg/kg. Results were broadly consistent with observations in primarily White subjects in the global first-in-human study of RO7062931.

Structurally Induced Chirality of an Achiral Chromophore on Self-Assembled Nanofibers: A Twist Makes It Chiral.

The surface domains of self-assembled amphiphiles are well-organized and can perform many physical, chemical, and biological functions. Here, we present the significance of chiral surface domains of these self-assemblies in transferring chirality to achiral chromophores. These aspects are probed using l- and d-isomers of alkyl alanine amphiphiles which self-assemble in water as nanofibers, possessing a negative surface charge. When bound on these nanofibers, positively charged cyanine dyes (CY524 and CY600), each having two quinoline rings bridged by conjugated double bonds, show contrasting chiroptical features. Interestingly, CY600 displays a bisignated circular dichroic (CD) signal with mirror-image symmetry, while CY524 is CD silent. Molecular dynamics simulations reveal that the model cylindrical micelles (CM) derived from the two isomers exhibit surface chirality and the chromophores are buried as monomers in mirror-imaged pockets on their surfaces. The monomeric nature of template-bound chromophores and their binding reversibility are established by concentration- and temperature-dependent spectroscopies and calorimetry. On the CM, CY524 displays two equally populated conformers with opposite sense, whereas CY600 is present as two pairs of twisted conformers in each of which one is in excess, due to differences in weak dye-amphiphile hydrogen bonding interactions. Infrared and NMR spectroscopies support these findings. Reduction of electronic conjugation caused by the twist establishes the two quinoline rings as independent entities. On-resonance coupling between the transition dipoles of these units generates bisignated CD signals with mirror-image symmetry. The results presented herein provide insight on the little-known structurally induced chirality of achiral chromophores through transfer of chiral surface information.

Deep Divergence and Genomic Diversification of Gut Symbionts of Neotropical Stingless Bees.

Social bees harbor conserved gut microbiotas that may have been acquired in a common ancestor of social bees and subsequently codiversified with their hosts. However, most of this knowledge is based on studies on the gut microbiotas of honey bees and bumblebees. Much less is known about the gut microbiotas of the third and most diverse group of social bees, the stingless bees. Specifically, the absence of genomic data from their microbiotas presents an important knowledge gap in understanding the evolution and functional diversity of the social bee microbiota. Here, we combined community profiling with culturing and genome sequencing of gut bacteria from six neotropical stingless bee species from Brazil. Phylogenomic analyses show that most stingless bee gut isolates form deep-branching sister clades of core members of the honey bee and bumblebee gut microbiota with conserved functional capabilities, confirming the common ancestry and ecology of their microbiota. However, our bacterial phylogenies were not congruent with those of the host, indicating that the evolution of the social bee gut microbiota was not driven by strict codiversification but included host switches and independent symbiont gain and losses. Finally, as reported for the honey bee and bumblebee microbiotas, we found substantial genomic divergence among strains of stingless bee gut bacteria, suggesting adaptation to different host species and glycan niches. Our study offers first insights into the genomic diversity of the stingless bee microbiota and highlights the need for broader samplings to understand the evolution of the social bee gut microbiota. IMPORTANCE Stingless bees are the most diverse group of the corbiculate bees and represent important pollinator species throughout the tropics and subtropics. They harbor specialized microbial communities in their gut that are related to those found in honey bees and bumblebees and that are likely important for bee health. Few bacteria have been cultured from the gut of stingless bees, which has prevented characterization of their genomic diversity and functional potential. Here, we established cultures of major members of the gut microbiotas of six stingless bee species and sequenced their genomes. We found that most stingless bee isolates belong to novel bacterial species distantly related to those found in honey bees and bumblebees and encoding similar functional capabilities. Our study offers a new perspective on the evolution of the social bee gut microbiota and presents a basis for characterizing the symbiotic relationships between gut bacteria and stingless bees.

Effect of complex nutrients, amino acids, vitamins on Ni(II) biosorption from aqueous solution by Ni(II) resistant Saccharomyces cerevisiae AJ208.

The paper aims to establish and enhance the microorganism's successful growth, proper activity, and biosorption potency for Ni(II) biosorption from an aqueous solution using 5,000 mg/l Ni(II) resistant Saccharomyces cerevisiae AJ208. Complex nutrients, amino acids, and vitamins were added to the specifically optimized fermentation media as essential growth factors. Amino acids such as L-cysteine (0.0002 g/ml), L-Proline (0.0002 g/ml), L-Lysine (0.0002 g/ml), L-tryptophan (0.0001 g/ml) and L-Histidine (0.0003 g/ml) led to an increase of more than 87% biosorption. Vitamins such as, Ascorbic acids (0.01 × 10-8 g/ml), folic acids (0.01 × 10-8 g/ml), pyridoxine-HCl (0.01 × 10-8 g/ml),Thiamin-HCl (0.05 × 10-8 g/ml) promotes biosorption more than 91%. The Ni(II) bio-removal increased with complex nutrients like soybean meal, malt extract, and yeast extract at the concentration of 0.03, 0.4, 0.05 in g/ml, and nickel removal reached more than 85%. The multiple linear regression (MLR) and ANN application of the experimental data have predicted Ni(II) percentage removal well. This adsorption shows that the proposed Ni(II) removal process using complex nutrients is environmentally friendly and economically feasible.Novelty statement: This study evaluates a cost-effective approach to bioremediation of Ni(II) by using complex nutrients as a growth factor. Media enriched with complex nutrients is cheap than chemical media. Ni(II) Removal significant increased up to 87%, 88.34%, 96% with soybean meal, L-proline, and L-ascorbic acids at 3,000 mg/l initial Ni(II) concentration using newly developed 5,000 mg/l Ni(II) resistant Saccharomyces cerevisiae AJ208 and their NCBI accession number: MZ027228 (AJ208 ITS 1) and MZ027229 (AJ208 ITS 2).