Comparison of feline and human immunodeficiency virus reverse transcriptase enzymes through chemical screening and computational analysis.

Feline immunodeficiency virus (FIV) is a common infection found in domesticated and wild cats worldwide. Despite the wealth of therapeutic understanding of the disease in humans, considerably less information exists regarding the treatment of the disease in felines. Current treatment relies on drugs developed for the related human immunodeficiency virus (HIV) and includes compounds of the popular non-nucleotide reverse transcriptase (NNRTI) class. This is despite FIV-RT being only 67% similar to HIV-1 RT at the enzyme level, increasing to 88% for the allosteric pocket targeted by NNRTIs. The goal of this project was to try to quantify how well the more extensive pharmacological knowledge available for human disease translates to felines. To this end we screened known NNRTIs and 10 diverse pyrimidine analogs identified virtually. We use this chemo-centric probe approach to (a) assess the similarity between the two related RT targets based on the observed experimental inhibition values, (b) try to identify more potent inhibitors at FIV, and (c) gain a better appreciation of the structure-activity relationships (SAR). We found the correlation between IC50s at the two targets to be strong (r2 = 0.87) and identified compound 1 as the most potent inhibitor of FIV with IC50 of 0.030 µM ± 0.009. This compared to FIV IC50 values of 0.22 ± 0.17 µM, 0.040 ± 0.010 µM and >160 µM for known anti HIV-1 RT drugs Efavirenz, Rilpivirine, and Nevirapine, respectively. This knowledge, along with an understanding of the structural origin that give rise to any differences could improve the way HIV drugs are repurposed for FIV.

Clinical study of 400mg efavirenz treatment in newly diagnosed patients with HIV/AIDS.

The efficacy of 400mg efavirenz (EFV) once daily is reported to be similar to that of 600mg EFV. However, EFV-related toxic and side effects of 400mg EFV are significantly reduced. Here, the feasibility of reducing EFV to 400mg once a day in HIV-infected/AIDS patients was evaluated. Fifty patients were included. Patients were given 3TC+TDF+400mg EFV (n=25) or 3TC+TDF+600mg EFV (n=25). The proportion of patients with HIV RNA < 40 copies/mL and the adverse events served as the primary and secondary outcomes, respectively. HIV inhibition rates of the 3TC+TDF+400mg EFV group and 3TC+TDF+600mg EFV group were both 56.52% at week 24 and respectively 100%, 91.3% at week 48. During 48 weeks, 27 cases of adverse events were reported in the 3TC+TDF+400mg EFV group, lower than those in the 3TC+TDF+600mg EFV group, which had 39 cases. Compared with the 3TC+TDF+400mg EFV group, the incidence of transaminase, dizziness, hyperlipidemia and rashes all increased in the 3TC+TDF+600mg EFV group (P>0.05). No serious adverse events of the central nervous system occurred. The incidence of depression, sleep disturbance, and vertigo were similar (P>0.05). The efficacy of 400mg EFV is comparable to 600mg EFV. However, patients receiving 400mg EFV have fewer adverse events.

Eosinophilic granulomatosis with polyangiitis and its association with montelukast: a case-based review.

The association between the use of certain medications (including sulfonamides, hydralazine, and procainamide) and the occurrence of drug-induced lupus or hepatitis is well established. More recently, cases of immune-related adverse events ranging from inflammatory polyarthritis to necrotizing myositis in patients taking checkpoint inhibitors have been reported. However, data linking drugs to systemic vasculitis are scarce and at times debatable. Propylthiouracil, hydralazine, and minocycline have been associated with rare cases of ANCA-associated syndromes, including life-threatening pulmonary-renal syndromes and systemic polyarteritis nodosa-like diseases. Eosinophilic granulomatosis with polyangiitis (EGPA) has been reported in patients taking leukotriene inhibitors. Since the link between the use of leukotriene inhibitors and occurrence of EGPA remains highly controversial, we performed a literature review for cases of EGPA in patients taking montelukast without prior history of oral corticosteroid use. We found 24 cases, along with our own two cases described, making 26 cases in total. The mean age was 43 and a majority (18/26) were female. In majority of cases EGPA-like disease never relapsed after they were taken off leukotriene inhibitors suggesting a clear causal relationship between the use of these drugs and occurrence of eosinophil-rich systemic EGPA.

Evaluating human landing catches as a measure of mosquito biting and the importance of considering additional modes of action.

Entomological evaluations of vector control tools often use human landing catches (HLCs) as a standard measure of a direct human-vector contact. However, some tools have additional characteristics, such as mortality, and HLCS are not sensitive for measuring other effects beyond landing inhibition. Therefore, additional measures may need to be considered when evaluating these tools for public health use. This study has two main aims (1) the evaluate the accuracy of HLCs as a proxy for feeding and (2) to compare the predicted reduction in vectorial capacity when we do and do not consider these additional characteristics. To achieve this, we analyse previously published semi-field data from an experiment which used HLCs and another where mosquitoes were allowed to feed in the presence of different dosages of the volatile pyrethroid spatial repellent, transfluthrin. We compare results for two mathematical models: one which only considers the reduction in feeding effect and one which also considers mortality before and after feeding (using data gathered by the aspiration of mosquitoes after the semi-field feeding/landing period and 24 h survival monitoring). These Bayesian hierarchical models are parameterised using Bayesian inference. We observe that, for susceptible mosquitoes, reduction in landing is underestimated by HLCs. For knockdown resistant mosquitoes the relationship is less clear; with HLCs sometimes appearing to overestimate this characteristic. We find HLCs tend to under-predict the relative reduction in vectorial capacity in susceptible mosquitoes while over-predicting this impact in knockdown-resistant mosquitoes. Models without secondary effects have lower predicted relative reductions in vectorial capacities. Overall, this study highlights the importance of considering additional characteristics to reduction in biting of volatile pyrethroid spatial repellents. We recommend that these are considered when evaluating novel vector control tools.

Feasibility, safety, efficacy and potential scaling-up of sofosbuvir-based HCV treatment in Central and West Africa: (TAC ANRS 12311 trial).

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

Adsorption of antiretroviral drugs, abacavir, nevirapine, and efavirenz from river water and wastewater using exfoliated graphite: Isotherm and kinetic studies.

In this work, exfoliated graphite was used to adsorb antiretroviral drugs from river water and wastewater. The exfoliated graphite was prepared from natural graphite by intercalating it with the acids and exfoliating it at 800 °C. It was characterized using Fourier Transform Infrared Spectroscopy which showed phenolic, alcoholic, and carboxylic functional groups between 1000 cm-1 and 1700 cm-1. Energy-dispersive X-ray spectroscopy results showed carbon as the main element with splashes of oxygen. The Scanning Electron Microscopy images showed increased c-axis distance between graphene layers after intercalation, which further increased after the exfoliation. The exfoliation resulted in elongated distorted cylinders, which were confirmed by the lower density (0.0068 g/mL) of exfoliated graphite material compared to the natural graphite (0.54 g/mL). The X-ray diffraction pattern showed the characteristics of hexagonal phase graphitic structure by the diffraction plane (002) at 26.74°. Raman spectroscopy results showed the natural graphite, graphite intercalated, and exfoliated graphite contained the D, G, D', and G' peaks at about 1350 cm-1, 1570 cm-1, 2440 cm-1, and 2720 cm-1, respectively indicating that the material's crystallinity was not affected by the modification. The highest antiretroviral drugs removal (95-99%), from the water was achieved with a solution pH of 7, an adsorbent mass of 30 mg, and an adsorption time of 30 min. The kinetic model and adsorption isotherm studies showed that the experimental data fit well in pseudo-second-order kinetics and is well explained by Freundlich's adsorption isotherm. The maximum adsorption capacity of the exfoliated graphite for antiretroviral drugs ranges between 1.660 and 197.0, 1.660-232.5, and 1.650-237.7 mg/g for abacavir, nevirapine, and efavirenz, respectively. The obtained removal percentages were 100% in river water, 63-100% in influent and 70-100% in effluent wastewater unspiked samples.

Entomological assessment of hessian fabric transfluthrin vapour emanators as a means to protect against outdoor-biting Aedes after providing them to households for routine use in Port-au-Prince, Haiti.

BACKGROUND: A simple treated fabric device for passively emanating the volatile pyrethroid transfluthrin was recently developed in Tanzania that protected against nocturnal Anopheles and Culex mosquitoes for several months. Here these transfluthrin emanators were assessed in Port-au-Prince, Haiti against outdoor-biting Aedes. METHODS: Transfluthrin emanators were distributed to participating households in poor-to-middle class urban neighbourhoods and evaluated once every two months in terms of their effects on human landing rates of wild Aedes populations. A series of three such entomological assessment experiments were conducted, to examine the influence of changing weather conditions, various transfluthrin formulations and emanator placement on protective efficacy measurements. Laboratory experiments assessed resistance of local Aedes aegypti to transfluthrin and deltamethrin, and the irritancy and repellency of the transfluthrin-treated fabric used in the field. RESULTS: Across all three entomological field assessments, little evidence of protection against wild Ae. aegypti was observed, regardless of weather conditions, transfluthrin formulation or emanator placement: A generalized linear mixed model fitted to the pooled data from all three assessment rounds (921 females caught over 5129 hours) estimated a relative landing rate [95% Confidence interval] of 0.87 [0.73, 1.04] for users of treated versus untreated emanators (P = 0.1241). Wild Ae. aegypti in this setting were clearly resistant to transfluthrin when compared to a fully susceptible colony. CONCLUSIONS: Transfluthrin emanators had little if any apparent effect upon Aedes landing rates by wild Ae. aegypti in urban Haiti, and similar results have been obtained by comparable studies in Tanzania, Brazil and Peru. In stark contrast, however, parallel sociological assessments of perspectives among these same end-users in urban Haitian communities indicate strong satisfaction in terms of perceived protection against mosquitoes. It remains unclear why the results obtained from these complementary entomological and sociological assessments in Haiti differ so much, as do those from a similar set of studies in Brazil. It is encouraging, however, that similar contrasts between the entomological and epidemiological results of a recent large-scale assessment of another transfluthrin emanator product in Peru, which indicate they provide useful protection against Aedes-borne arboviral infections, despite apparently providing only modest protection against Aedes mosquito bites.

Programmed cell death-1 is involved with peripheral blood immune cell profiles in patients with hepatitis C virus antiviral therapy.

Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.

MnO2 and roflumilast-loaded probiotic membrane vesicles mitigate experimental colitis by synergistically augmenting cAMP in macrophage.

BACKGROUND: Ulcerative colitis (UC) is one chronic and relapsing inflammatory bowel disease. Macrophage has been reputed as one trigger for UC. Recently, phosphodiesterase 4 (PDE4) inhibitors, for instance roflumilast, have been regarded as one latent approach to modulating macrophage in UC treatment. Roflumilast can decelerate cyclic adenosine monophosphate (cAMP) degradation, which impedes TNF-α synthesis in macrophage. However, roflumilast is devoid of macrophage-target and consequently causes some unavoidable adverse reactions, which restrict the utilization in UC. RESULTS: Membrane vesicles (MVs) from probiotic Escherichia coli Nissle 1917 (EcN 1917) served as a drug delivery platform for targeting macrophage. As model drugs, roflumilast and MnO2 were encapsulated in MVs (Rof&MnO2@MVs). Roflumilast inhibited cAMP degradation via PDE4 deactivation and MnO2 boosted cAMP generation by activating adenylate cyclase (AC). Compared with roflumilast, co-delivery of roflumilast and MnO2 apparently produced more cAMP and less TNF-α in macrophage. Besides, Rof&MnO2@MVs could ameliorate colitis in mouse model and regulate gut microbe such as mitigating pathogenic Escherichia-Shigella and elevating probiotic Akkermansia. CONCLUSIONS: A probiotic-based nanoparticle was prepared for precise codelivery of roflumilast and MnO2 into macrophage. This biomimetic nanoparticle could synergistically modulate cAMP in macrophage and ameliorate experimental colitis.

Ameliorative potential of galangin in murine model of ovalbumin-induced allergic rhinitis: a role of PI3K-PKB pathway.

OBJECTIVE: To examine the potential of galangin in a mouse model of ovalbumin (OVA)-induced allergic rhinitis (AR), as chronic AR, induced by immunoglobulin-E (IgE), leads to histamine release and nasal inflammation, and although galangin exhibits antiasthmatic and anti-inflammatory potential, its effect on AR is yet to be investigated. ANIMALS: 126 BALB/c mice. METHODS: AR induction involved sensitizing female mice with OVA (5%, 500 µL, IP) for 14 days. Post OVA challenge, the mice were divided into 7 groups (n = 18/group), including normal, AR control, montelukast (10 mg/kg), galangin (5, 10, and 20 mg/kg), and per se (galangin [20 mg/kg] treatment. Various outcomes were evaluated, including nasal symptoms, histopathology, biochemistry, and nasal lavage fluid inflammatory cytokines and signaling pathways in nasal mucosal to assess galangin potential in AR. RESULTS: In AR mice, galangin (10 and 20 mg/kg) significantly (P < .05) reduced sneezing, rubbing, and nasal discharge post-OVA challenge. Galangin treatment attenuated (P < .05) elevated serum histamine, ß-hexosaminidase, IgE, and Immunoglobulin G1 levels in AR control mice. Additionally, galangin significantly (P < .05) decreased OVA-induced alterations in IL-4, IL-6, IL-13, and interferon-γ levels in nasal lavage fluid compared to AR control mice. Western blot analysis demonstrated that galangin lowered OVA-induced AR by significantly (P < .05) downregulating the phosphorylated protein kinase B and mammalian target of rapamycin-protein expressions while markedly (P < .05) upregulating the glycogen synthase kinase-3ß protein expressions in nasal mucosal. Galangin also significantly ameliorated (P < .05) the OVA-induced histological aberrations in the nasal mucosa, reflected by reduced eosinophil infiltration, hyperplasia, and edema. CLINICAL RELEVANCE: Galangin exhibits antihistaminic and anti-inflammatory effects in AR mice by regulating IgE-mediated histamine and inflammatory release and modulating the phosphatidylinositol 3-kinase/Ak strain transforming/mammalian target of rapamycin pathways.

Clinical Characteristics, Investigations and Treatment in Children with Chronic Urticaria: An Observational Study.

Background and Objectives: The guidelines for chronic urticaria in children contain recommendations that are often based on adult studies. The diagnostic pathway has not been standardized and the effectiveness of anti-H1, omalizumab, montelukast, and systemic glucocorticoids is rarely reported in the pediatric population. There is a wide variation in the rate of remission of chronic urticaria between studies. The aim of this study is to enhance our understanding of pediatric chronic urticaria. Materials and Methods: This study enrolled 37 children with chronic urticaria aged from 0 to 18 years. Demographic parameters, medical history, clinical features, laboratory data and treatment information were collected. Children were treated with the recommended dosage of second-generation H1-antihistamines, which was increased by up to twofold. Omalizumab was added for refractory anti-H1 patients. A three-day course with systemic glucocorticoids was administered for severe exacerbations. Montelukast was administered to some children. Results: Wheals without angioedema were common. Chronic urticaria was spontaneous in 32 children (86.48%), inducible in 2 (5.41%), induced by a parasite in 1 and vasculitic in 2. Treatment of the potential causes of chronic urticaria was of no benefit, except for eradication of Dientamoeba fragilis. Chronic urticaria was resolved within three years in 45.9% of cases. Allergic diseases were present in nine children (24.32%) and autoimmune diseases were present in three (8.11%). All children were treated with anti-H1 at the licensed dose or at a higher dose. A partial or complete response to anti-H1 was observed in 29 (78.38%) patients. Montelukast showed no benefit. All children treated with omalizumab responded. Systemic glucocorticoids were successfully used to treat exacerbations. Conclusions: Our findings indicate that laboratory tests should not be routinely performed in children with chronic urticaria without clinical suspicion. However, comorbidities such as thyroid autoimmune disease and coeliac disease are suggested to be monitored over the chronic urticaria course. These clinical conditions could be diagnosed from the diagnostic framework of chronic urticaria. Increasing the dosage of anti-H1 and omalizumab was effective in children resistant to standard treatment but we still need further studies to generate a standard patient-centered treatment.

Montelukast Influence on Lung in Experimental Diabetes.

Background and Objectives: The influence of montelukast (MK), an antagonist of cysLT1 leukotriene receptors, on lung lesions caused by experimental diabetes was studied. Materials and Methods: The study was conducted on four groups of six adult male Wistar rats. Diabetes was produced by administration of streptozotocin 65 mg/kg ip. in a single dose. Before the administration of streptozotocin, after 72 h, and after 8 weeks, the serum values of glucose, SOD, MDA, and total antioxidant capacity (TAS) were determined. After 8 weeks, the animals were anesthetized and sacrificed, and the lungs were harvested and examined by optical microscopy. Pulmonary fibrosis, the extent of lung lesions, and the lung wet-weight/dry-weight ratio were evaluated. Results: The obtained results showed that MK significantly reduced pulmonary fibrosis (3.34 ± 0.41 in the STZ group vs. 1.73 ± 0.24 in the STZ+MK group p < 0.01) and lung lesion scores and also decreased the lung wet-weight/dry-weight (W/D) ratio. SOD and TAS values increased significantly when MK was administered to animals with diabetes (77.2 ± 11 U/mL in the STZ group vs. 95.7 ± 13.3 U/mL in the STZ+MK group, p < 0.05, and 25.52 ± 2.09 Trolox units in the STZ group vs. 33.29 ± 1.64 Trolox units in the STZ+MK group, respectively, p < 0.01), and MDA values decreased. MK administered alone did not significantly alter any of these parameters in normal animals. Conclusions: The obtained data showed that by blocking the action of peptide leukotrienes on cysLT1 receptors, montelukast significantly reduced the lung lesions caused by diabetes. The involvement of these leukotrienes in the pathogenesis of fibrosis and other lung diabetic lesions was also demonstrated.

Fluorescence based methodology with greenness consideration for concurrent estimation of anti-allergic medication; application to dosage form.

A green, sensitive and rapid spectrofluorimetric method for quantitative assay of an anti-allergic medication composed of montelukast and fexofenadine mixture in raw materials and dosage form was developed. The method was based on measuring the synchronous fluorimetric peak without interference, pre-separation or pre-extraction procedures. Montelukast was analyzed at 360 nm while fexofenadine was measured at 263 nm using Δλ = 20 nm for both drugs using ethanol as diluting solvent and acetate buffer of pH 4. The assay was rectilinear over the concentration range of 1.0-10.0 µg/mL for fexofenadine and 0.1-0.6 µg/mL for montelukast. The method was full validated according to ICH guidelines. The applicability of the method enables the assay of both drugs in raw materials, synthetic mixture as well as combined tablets. Moreover, the greenness of the method was assessed using different methods including; analytical eco-scale, GAPI and AGREE. All of these methods confirm that the proposed method is an eco-friendly method.

Entomological assessment of hessian fabric transfluthrin vapour emanators for protecting against outdoor-biting Aedes aegypti in coastal Tanzania.

BACKGROUND: A low technology emanator device for slowly releasing vapour of the volatile pyrethroid transfluthrin was recently developed in Tanzania that provides robust protection against night biting Anopheles and Culex vectors of malaria and filariasis for several months. Here these same emanator devices were assessed in Dar es Salaam city, as a means of protection against outdoor-biting Aedes (Stegomia) aegypti, the most important vector of human arboviruses worldwide, in parallel with similar studies in Haiti and Brazil. METHODS: A series of entomological experiments were conducted under field and semi-field conditions, to evaluate whether transfluthrin emanators protect against wild Ae. aegypti, and also compare the transfluthrin responsiveness of Ae. aegypti originating from wild-caught eggs to established pyrethroid-susceptible Ae. aegypti and Anopheles gambiae colonies. Preliminary measurements of transfluthrin vapour concentration in air samples collected near treated emanators were conducted by gas chromatography-mass spectrometry. RESULTS: Two full field experiments with four different emanator designs and three different transfluthrin formulations consistently indicated negligible reduction of human landing rates by wild Ae. aegypti. Under semi-field conditions in large cages, 50 to 60% reductions of landing rates were observed, regardless of which transfluthrin dose, capture method, emanator placement position, or source of mosquitoes (mildly pyrethroid resistant wild caught Ae. aegypti or pyrethroid-susceptible colonies of Ae. aegypti and An. gambiae) was used. Air samples collected immediately downwind from an emanator treated with the highest transfluthrin dose (15g), contained 12 to 19 µg/m3 transfluthrin vapour. CONCLUSIONS: It appears unlikely that the moderate levels of pyrethroid resistance observed in wild Ae. aegypti can explain the modest-to-undetectable levels of protection exhibited. While potential inhalation exposure could be of concern for the highest (15g) dose evaluated, 3g of transfluthrin appears sufficient to achieve the modest levels of protection that were demonstrated entomologically. While the generally low levels of protection against Aedes reported here from Tanzania, and from similar entomological studies in Haiti and Brazil, are discouraging, complementary social science studies in Haiti and Brazil suggest end-users perceive valuable levels of protection against mosquitoes. It therefore remains unclear whether transfluthrin emanators have potential for protecting against Aedes vectors of important human arboviruses.

Optimizing removal of antiretroviral drugs from tertiary wastewater using chlorination and AI-based prediction with response surface methodology.

Chemical and pharmaceutical chemicals found in water sources create substantial risks to human health and the environment. The presence of pharmaceutical contaminants in water can cause antibiotic resistance development, toxicity to aquatic organisms, and endocrine disruption. Hence, the elimination of chemicals and other contaminants from wastewater prior to its release is a burgeoning concern in the domains of engineering and science. The use of treatment technologies in wastewater treatment plants can remove pharmaceutical contaminants through the oxidation process. However, many traditional wastewater treatment plants lack the advanced monitoring tools required to detect low concentrations of pharmaceuticals. Without the ability to detect these compounds, it's challenging to treat them effectively. The goal of this study was to use Response Surface Methodology (RSM) and Artificial Neural Networks (ANN) algorithms to model and improve how Nevirapine and Efavirenz break down in different chlorination conditions. The RSM analysis revealed statistically significant models (F-values: Nevirapine, pH-t: 108.15, T-t: 76.55, ICC-t: 110.84), indicating a strong correlation between operational parameters (pH, temperature, and initial chlorine concentration) and degradation behavior. The ANN model accurately predicted the degradation of both Nevirapine and Efavirenz under various chlorination conditions, as confirmed by analyzing actual-predicted graphs, residual plots, and Mean Squared Error (MSE) values. The ANN model using ICC-t achieved the highest MOD value of 31.31 % for Nevirapine. The ANN model based on ICC-t yielded a maximum MOD value of 16.06 % for Efavirenz. These findings provide valuable insights into optimizing chlorination processes for better removal of these pharmaceutical contaminants from water.

Removal of antiretroviral drugs from wastewater using activated macadamia nutshells: Adsorption kinetics, adsorption isotherms, and thermodynamic studies.

Antiretroviral drugs (ARVDs) have been extensively employed in health care to improve the quality of life and lifecycle longevity. However, overuse and improper disposal of ARVDs have been recognized as an emerging concern whereby wastewater treatment major recipients. Therefore, in this work, the activated macadamia nutshells (MCNs) were explored as low-cost adsorbents for the removal of ARVDs in wastewater samples. Fourier transform infrared spectroscopy (FTIR), Scanning Electron microscopy (SEM), Brunauer-Emmet-Teller (BET), and Powder X-ray diffraction (PXRD). The highest removal efficiency (R.E) was above 86% for the selected analytes nevirapine, abacavir, and efavirenz. The maximum adsorption capacity of the functionalized MCN adsorbent was 10.79, 27.44, and 38.17 mg/g for nevirapine, abacavir, and efavirenz for HCl-modified adsorbent. In contrast, NaOH modified had adsorption capacities of 13.67, 14.25, and 20.79 mg/g. The FTIR showed distinct functional groups OH and CO, which facilitate the removal of selected ARVDs. From studying kinetics parameters, the pseudo-second-order (R2 = 0.990-0.996) was more dominant than the pseudo-first-order (R2 = 0.872-0.994). The experimental data was most fitted in the Freundlich model with (R2 close to 1). The thermodynamic parameters indicated that the adsorption process was spontaneous and exothermic. The study indicated that MCNs are an eco-friendly, low-cost, and effective adsorbent for the removal of nevirapine, abacavir, and efavirenz. PRACTITIONER POINTS: Modification macadamia nutshell with HCl and NaOH improved physio-chemical properties that yielded high removal efficiency compared with raw macadamia nutshells. Modification of macadamia by HCl showed high removal efficiency, which could be attributed to high interaction such as H-bonding that improves adsorption. The macadamia nutshell as an adsorbent showed so much robustness with regeneration studies yielding to about 69.64% of selected compounds.

Biophysical mechanisms underlying tefluthrin-induced modulation of gating changes and resurgent current generation in the human Nav1.4 channel.

Human skeletal muscle contraction is triggered by activation of Nav1.4 channels. Nav1.4 channels can generate resurgent currents by channel reopening at hyperpolarized potentials through a gating transition dependent on the intracellular Navß4 peptide in the physiological conditions. Tefluthrin (TEF) is a pyrethroid insecticide that can disrupt electrical signaling in nerves and skeletal muscle, resulting in seizures, muscle spasms, fasciculations, and mental confusion. TEF can also induce tail currents through other voltage-gated sodium channels in the absence of Navß4 peptide, suggesting that muscle spasms may be caused by resurgent currents. Further, intracellular Navß4 peptide and extracellular TEF may show competitive or synergistic effects; however, their binding sites are still unknown. To address these issues, electrophysiological recordings were performed on CHO-K1 cells expressing Nav1.4 channels with intracellular Navß4 peptide, extracellular TEF, or both. TEF and Navß4 peptide induced a hyperpolarizing shift of activation and inactivation curves in the Nav1.4 channel. TEF also substantially prolonged the inactivation time constants, while simultaneous application of Navß4 peptide partially reversed this effect. Resurgent currents were enhanced by TEF and Navß4 peptide at negative potentials, but TEF more potently enhances resurgent currents and dampens decay of resurgent currents. With longer depolarization, peak resurgent currents decay was fastest with the TEF alone. Molecular docking suggested that TEF and Navß4 peptide binding site(s) are not in the narrowest part of the channel pore, but rather in the bundle-crossing regions and in the domain linkers, respectively. TEF can induce resurgent currents independently and synergistically with Navß4 peptide, which may explain the muscle spasms observed in TEF intoxication.