Linear IgA bullous dermatosis in a latin adolescent treated with cyclosporine and prednisone.

INTRODUCTION: Linear IgA bullous dermatosis (LABD) is a rare autoimmune disease. Although dapsone is the initial treatment, other immunomodulators are used in resistant cases or when dapsone is unavailable. CASE REPORT: A 12-year-old Mexican child, with no relevant medical history, developed in May 2023 a disseminated dermatosis affecting all body segments, including mucous membranes, characterized by erythematous patches and plaques evolving into the formation of serous and serosanguinous blisters and vesicles, distributed in a "string of pearls" pattern. LABD was suspected and confirmed by skin biopsy, which showed a subepidermal blister with neutrophilic infiltration and linear Immunoglobulin A deposits at the dermo-epidermal junction by direct immunofluorescence. Treatment with prednisone (2 mg/kg/day) and cyclosporine (5 mg/kg/day) resulted in improvement and lesion remission within 2 weeks. Both drugs needed to be discontinued for 3 months due to intermittent blistering. Cyclosporine was continued as maintenance therapy at a dose of 4 mg/kg/day for 8 months. CONCLUSIONS: The report highlights the use of cyclosporine as an alternative immunomodulator for DAAL, an immunosuppressive agent used in autoimmune disorders. Few cases, including this one, have described complete remission and control of the dermatosis with cyclosporine, accompanied by prednisone at the start of treatment.

INTRODUCCIÓN: La dermatosis ampollosa por IgA lineal es una enfermedad autoinmunitaria rara. Aunque la dapsona es el tratamiento inicial, se usan otros inmunomoduladores en casos resistentes o cuando la dapsona no está disponible. CASO CLÍNICO: Un niño mexicano de 12 años, sin antecedentes relevantes, desarrolló en mayo de 2023 una dermatosis diseminada a todos los segmentos corporales, incluyendo las mucosas, caracterizada por manchas y placas eritematosas que evolucionaron hacia la formación de ampollas y vesículas serosas y serohemáticas, distribuidas en forma de «cadena de perlas¼. Se sospechó dermatosis ampollosa por IgA lineal y se confirmó mediante biopsia cutánea, que mostró una ampolla subepidérmica con infiltrado neutrófilo y depósitos lineales de IgA en la unión dermoepidérmica mediante inmunofluorescencia directa. El tratamiento con prednisona (2 mg/kg al día) y ciclosporina (5 mg/kg al día) resultó en mejoría y la remisión de las lesiones a las 2 semanas. Fue necesario dejar ambos fármacos durante 3 meses debido a la aparición intermitente de ampollas. Se dejó ciclosporina como terapia de mantenimiento a dosis de 4 mg/kg al día por 8 meses. CONCLUSIONES: El reporte destaca el uso de ciclosporina como inmunomodulador alternativo para la dermatosis ampollosa por IgA lineal, un agente inmunosupresor utilizado en trastornos autoinmunitarios. Pocos casos, incluido este, han descrito la remisión completa y el control de la dermatosis con ciclosporina, acompañada de prednisona al inicio del tratamiento.

[Argentinean registry on the management of Helicobacter pylori infection: effectiveness and safety of first line treatment]. / Registro argentino para el manejo de la infección por Helicobacter pylori: efectividad y seguridad de los esquemas de primera línea de tratamiento.

INTRODUCTION: The optimal management of Helicobacter pylori (H pylori) infection remains unclear. Updated information concerning local data is needed to design the best strategy to treat H. pylori infection to reach high eradication rates. The Argentinean Registry (Hp-ArgReg) on H. pylori management was launched to monitor the eradication practices of gastroenterologists. The objective was to assess the effectiveness and safety of firstline H. pylori treatment in Argentina. MATERIALS AND METHODS: A multicenter prospective registry of the clinical practice of the Argentinean gastroenterologists concerning H. pylori infection (Hp-ArgReg) was developed. Variables included: patient demographic information, previous eradication attempts, prescribed treatment, adverse events, compliance and outcome. RESULTS: Overall, 800 patients were included and 727 patients received first-line empirical treatment. The most frequent treatment indications were dyspepsia (78%) and gastroduodenal ulcer (12%). Among first-line treatments, quadruple therapies (with or without bismuth) achieved eradication rates of 94.9%, while triple therapies achieved eradication rates of 78.9%. Quadruple therapies were significantly more effective than triple therapies (P < 0.01, OR 5, CI 2.95-8.6). Sequential therapy with zinc showed an effectiveness of 95.6%. Adverse events were reported in 29% of the cases (mainly mild) and tolerance was quite similar among therapies. CONCLUSION: in Argentina, Quadruple therapies with or without bismuth and sequential therapy with zinc showed an H. pylori eradication effectiveness of over 90% in real clinical practice. Local Registries for H pylori management could help to control the spread of antibiotic resistance.

Introducción: El óptimo manejo de la infección por Helicobacter pylori (H. pylori) es objeto de debate. Contar con datos locales ayudaría a lograr altas tasas de erradicación. El Registro Argentino H. pylori (RegArg-Hp) se estableció con el objetivo de monitorear el manejo local de la infección. El objetivo fue describir la efectividad y seguridad de las terapias empíricas de primera línea para la erradicación del H. pylori utilizadas en Argentina. Materiales y métodos: Registro prospectivo, multicéntrico, de la práctica clínica de los gastroenterólogos argentinos. Se incluyeron datos demográficos de pacientes con infección por H. pylori, intentos previos de erradicación, tratamiento indicado, eventos adversos, cumplimiento y erradicación. Resultados: De 800 pacientes incluidos, 727 recibieron un tratamiento empírico de primera línea. Las indicaciones de tratamiento más frecuentes fueron dispepsia (78%) y úlcera gastroduodenal (12%). Entre los tratamientos de primera línea, las terapias cuádruples (con o sin bismuto) lograron tasas de erradicación del 94.9% mientras las terapias triples tasas de erradicación del 78.9%. Las terapias cuádruples fueron significativamente más efectivas que las triples (P < 0.01, OR 5, IC 2.95-8.6). La terapia secuencial con zinc mostró una efectividad del 95.6%. Se reportaron eventos adversos en el 29% de los pacientes, generalmente leves y con una tolerancia similar entre las diferentes terapias. Conclusiones: En Argentina, las terapias cuádruples con o sin bismuto y la secuencial con zinc presentaron una efectividad de erradicación de H. pylori superior al 90%. La implementación de registros locales podría contribuir al control de la resistencia a los antibióticos.

Synergistic antimicrobial combination of third-generation cephalosporins and polymyxin B against carbapenem-polymyxin-resistant Klebsiella pneumoniae: an in vitro and in vivo analysis.

Antibiotic combination therapy is a promising approach to address the urgent need for novel treatment options for infections caused by carbapenem-polymyxin-resistant Klebsiella pneumoniae (CPR-Kp). The present study aimed to investigate the synergistic potential of four cephalosporins in combination with polymyxin B (PMB). A checkerboard assay was performed to evaluate the synergistic effects of cephalexin (CLX), cefixime, cefotaxime (CTX), and cefmenoxime (CMX) in combination with PMB. Subsequently, experiments evaluating the use of CTX or CMX in combination with PMB (CTX-PMB or CMX-PMB, respectively), including growth curve and SynergyFinder analysis, antibiofilm activity assays, cell membrane integrity assays, and scanning electron microscopy, were performed. Safety assessments were also conducted, including hemolysis and toxicity evaluations, using Caenorhabditis elegans. Furthermore, an in vivo model in C. elegans was adopted to assess the treatment efficacy against CPR-Kp infections. CTX-PMB and CMX-PMB exhibited low fractional inhibitory concentration indexes ranging from 0.19 to 0.50 and from 0.25 to 1.5, respectively, and zero interaction potency scores of 37.484 and 15.076, respectively. The two combinations significantly reduced growth and biofilm formation in CPR-Kp. Neither CTX-PMB nor CMX-PMB compromised bacterial cell integrity. Safety assessments revealed a low hemolysis percentage and high survival rates in the C. elegans toxicity evaluations. The in vivo model revealed that the CTX-PMB and CMX-PMB treatments improved the survival rates of C. elegans. The synergistic effects of the CTX-PMB and CMX-PMB combinations, both in vitro and in vivo, indicate that these antibiotic pairings could represent effective therapeutic options for infections caused by CPR-Kp.

Short-term Dual Therapy or Mono Therapy With Acetaminophen and Ibuprofen for Fever: A Network Meta-Analysis.

CONTEXT: There is uncertainty whether acetaminophen and ibuprofen are similar in their effects and safety when used as single or dual (alternating or combined) therapies. OBJECTIVE: To assess the comparative efficacy of acetaminophen, ibuprofen alone, alternating, or combined through a systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, and CENTRAL from inception to September 20, 2023. STUDY SELECTION: Randomized trials comparing acetaminophen, ibuprofen, both alternating, and both combined, for treating children with fever. DATA EXTRACTION: Two reviewers independently screened abstracts and full texts, extracted the data, and assessed the risk of bias. We performed pairwise and network meta-analysis using the random-effects model. RESULTS: We included 31 trials (5009 children). We found that combined (odds ratio [OR], 0.19; confidence interval [CI], 0.09-0.42) and alternating therapies (OR, 0.20; CI, 0.06-0.63) may be superior to acetaminophen, whereas ibuprofen at a high dose may be comparable (OR, 0.98; CI, 0.63-1.59) in terms of proportion of afebrile children at the fourth hour. These results were similar at the sixth hour. There were no differences between ibuprofen (low or high dose), or alternating, or combined with acetaminophen in terms of adverse events. LIMITATIONS: We only evaluated the efficacy and safety during the first 6 hours. CONCLUSIONS: Dual may be superior to single therapies for treating fever in children. Acetaminophen may be inferior to combined or alternating therapies to get children afebrile at 4 and 6 hours. Compared with ibuprofen, acetaminophen was also inferior to ibuprofen alone at 4 hours, but similar at 6 hours. PROSPERO registration: CRD42016035236.

Acetylsalicylic acid and dihydroartemisinin combined therapy on experimental malaria-associated acute lung injury: analysis of lung function and the inflammatory process.

BACKGROUND: Severe malaria can cause respiratory symptoms, which may lead to malaria-acute lung injury (MA-ALI) due to inflammation and damage to the blood-gas barrier. Patients with severe malaria also often present thrombocytopenia, and the use of acetylsalicylic acid (ASA), a commonly used non-steroidal anti-inflammatory drug with immunomodulatory and antiplatelet effects, may pose a risk in regions where malaria is endemic. Thus, this study aimed to investigate the systemic impact of ASA and dihydroartemisinin (DHA) on ALI induced in mice by Plasmodium berghei NK65 (PbNK65). METHODS: C57BL/6 mice were randomly divided into control (C) and PbNK65 infected groups and were inoculated with uninfected or 104 infected erythrocytes, respectively. Then, the animals were treated with DHA (3 mg/kg) or vehicle (DMSO) at the 8-day post-infection (dpi) for 7 days and with ASA (100 mg/kg, single dose), and analyses were performed at 9 or 15 dpi. Lung mechanics were performed, and lungs were collected for oedema evaluation and histological analyses. RESULTS: PbNK65 infection led to lung oedema, as well as increased lung static elastance (Est, L), resistive (ΔP1, L) and viscoelastic (ΔP2, L) pressures, percentage of mononuclear cells, inflammatory infiltrate, hemorrhage, alveolar oedema, and alveolar thickening septum at 9 dpi. Mice that received DHA or DHA + ASA had an increase in Est, L, and CD36 expression on inflammatory monocytes and higher protein content on bronchoalveolar fluid (BALF). However, only the DHA-treated group presented a percentage of inflammatory monocytes similar to the control group and a decrease in ΔP1, L and ΔP2, L compared to Pb + DMSO. Also, combined treatment with DHA + ASA led to an impairment in diffuse alveolar damage score and lung function at 9 dpi. CONCLUSIONS: Therapy with ASA maintained lung morpho-functional impairment triggered by PbNK65 infection, leading to a large influx of inflammatory monocytes to the lung tissue. Based on its deleterious effects in experimental MA-ALI, ASA administration or its treatment maintenance might be carefully reconsidered and further investigated in human malaria cases.

LT4/LT3 Combination Therapy vs. Monotherapy with LT4 for Persistent Symptoms of Hypothyroidism: A Systematic Review.

Regardless of the cause, hypothyroidism should be treated with levothyroxine. The objectives of management are the normalization of TSH levels and the relief of symptoms. In general, the vast majority of patients who achieve normalization of TSH levels show a resolution of symptoms; however, for a small number of individuals, symptoms persist (despite adequate control of TSH). This scenario generates a dilemma in the therapeutic approach to these patients, because even when excluding other causes or concomitant diseases that can explain the persistence of symptoms, pharmacological management strategies are scarce. Consequently, the efficacy of some less conventional approaches to therapy, such as the use of LT3 monotherapy, desiccated thyroid extracts, and LT4/LT3 combinations, in addressing persistent hypothyroid symptoms have been evaluated in multiple studies. The majority of these studies did not observe a significant benefit from these "nonconventional" therapies in comparison to results with LT4 monotherapy alone. Nevertheless, some studies report that a significant proportion of patients prefer an alternative to monotherapy with LT4. The most common approach has been to prescribe a combination of LT4 and LT3, and this review describes and analyzes the current evidence of the efficacy of LT4/LT3 combination therapy vs. LT4 monotherapy in addressing persistent hypothyroidism symptoms to provide suggested guidelines for clinicians in the management of these patients.

TNFα and IL-8 vitreous concentrations variations with two antidiabetic therapies in patients with proliferative diabetic retinopathy: an observational study.

BACKGROUND: Antidiabetic therapies are effective, but could indirectly modify the inflammatory response in the ocular microenvironment; therefore, a study was developed to evaluate the inflammatory cytokine profile in the vitreous humor of diabetic patients with retinopathy under treatment with antidiabetic drugs. METHODS: Observational, comparative, retrospective, cross-sectional study. Interleukins 1ß, 6, 8, 10, and tumor necrosis factor-alpha (TNFα) were evaluated in the vitreous humor obtained from patients with type 2 diabetes mellitus, proliferative diabetic retinopathy, and concomitant retinal detachment or vitreous hemorrhage, and who were already on antidiabetic treatment with insulin or metformin + glibenclamide. The quantification analysis of each cytokine was performed by the cytometric bead array (CBA) technique; medians and interquartile ranges were obtained, and the results were compared between groups using the Mann-Whitney U test, where a p-value < 0.05 was considered significant. RESULTS: Thirty-eight samples; quantification of TNFα concentrations was higher in the group of patients administered insulin, while interleukin-8 was lower; in the metformin + glibenclamide combination therapy group, it occurred inversely. In the stratified analysis, the highest concentrations of interleukin-8 and TNFα occurred in patients with vitreous hemorrhage; however, the only statistical difference existed in patients with retinal detachment, whose TNFα concentration in the combined therapy group was the lowest value found (53.50 (33.03-86.66), p = 0.03). Interleukins 1ß, 6, and 10 were not detected. CONCLUSION: Interleukin-8 and TNFα concentrations are opposite between treatment groups; this change is more accentuated in patients with proliferative diabetic retinopathy and vitreous hemorrhage, where the highest concentrations of both cytokines are found, although only TNFα have statistical difference.

Relationship between obesity severity and Helicobacter pylori eradication in patients undergoing bariatric and metabolic surgery: A post hoc analysis.

BACKGROUND: The global prevalence of obesity is increasing and represents a major public health challenge. However, there is a paucity of data regarding Helicobacter pylori (H pylori) eradication in people with obesity. The aim of the study is to examine the influence of obesity degree on H. pylori eradication in patients undergoing bariatric and metabolic surgery. METHODS: A post hoc analysis was conducted in a cohort of 204 adults patients (129 individuals diagnosed with obesity, 75 normal weight) H. pylori positive, included in two multicenter, prospective studies. Patients underwent a 14-day quadruple concomitant treatment, and H. pylori eradication was assessed using the 13C-urea breath test. The cohort was stratified according to body mass index (BMI), and statistical analyses were performed using chi-squared test, Kruskal-Wallis test, and logistic regression. RESULTS: Eradication rates were significantly lower in patients with obesity compared with normal weight individuals (68.2% vs. 88.0%, OR 0.29, 95% CI 0.13-0.63, p < 0.01). Furthermore, within the population diagnosed with obesity, the degree of obesity correlated with decreased eradication rates, with class 3 (BMI 40.0-49.9) and class 4 (BMI ≥ 50.0) obesity showing the lowest rates (67% and 51%, with an OR 0.28 and 0.15 respectively, p < 0.01). CONCLUSIONS: Our results indicate that obesity may influence H. pylori eradication, especially among severe obesity patients undergoing bariatric surgery, which could have implications for the development of ulcers and gastritis as well as the risk of gastric cancer. Tailored eradication strategies may be necessary to improve treatment efficacy in this population.

Use of topical rSm29 in combination with intravenous meglumine antimoniate in the treatment of cutaneous leishmaniasis: A randomized controlled trial.

BACKGROUND: Cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis is associated with an inflammatory response. Granzyme (GzmB) and IL-1ß play a key role in the pathology. Meglumine antimoniate (MA) is the first-choice drug for the treatment of CL, but therapy failure is observed in up to 50% of the cases. The protein, rSm29 of Schistosoma mansoni, down-modulates pro-inflammatory cytokine production. We evaluate if the combination of topical rSm29 plus MA increases the cure rate of CL. METHODS: In this randomized clinical trial, 91 CL patients were allocated in 3 groups. All cases received MA (20 mg/kg/weight) for 20 days. Group 1 used topical rSm29 (10 µg), group 2 a placebo topically applied, and group 3 received only MA. RESULTS: The cure rate on day 90 was 71% in subjects treated with rSm29 plus MA, and 43% in patients who received MA plus placebo or MA alone (P < 0.05). There was a decrease in GzmB and an increase in IFN-γ (P < 0.05) in supernatants of skin biopsies of the lesions obtained on D7 of therapy (P < 0.05) in patients who received rSm29. CONCLUSION: rSm29 associated with MA reduces GzmB levels, is more effective than MA alone, and decreases CL healing time. CLINICAL TRIALS REGISTRATION: ClinicalTrial.gov under NCT06000514.

Quadruple therapies show a higher eradication rate compared to standard triple therapy for Helicobacter pylori infection within the LEGACy consortium. A multicenter observational study in European and Latin American countries.

INTRODUCTION: Gastric cancer (GC) is one of the most lethal malignancies worldwide. Helicobacter pylori is the primary cause of GC; therefore, its eradication reduces the risk of developing this neoplasia. There is extensive evidence regarding quadruple therapy with relevance to the European population. However, in Latin America, data are scarce. Furthermore, there is limited information about the eradication rates achieved by antibiotic schemes in European and Latin American populations. OBJECTIVE: To compare the effectiveness of standard triple therapy (STT), quadruple concomitant therapy (QCT), and bismuth quadruple therapy (QBT) in six centers in Europe and Latin America. METHODS: A retrospective study was carried out based on the LEGACy registry from 2017 to 2022. Data from adult patients recruited in Portugal, Spain, Chile, Mexico, and Paraguay with confirmed H. pylori infection who received eradication therapy and confirmatory tests at least 1 month apart were included. Treatment success by each scheme was compared using a mixed multilevel Poisson regression, adjusting for patient sex and age, together with country-specific variables, including prevalence of H. pylori antibiotic resistance (clarithromycin, metronidazole, and amoxicillin), and CYP2C19 polymorphisms. RESULTS: 772 patients were incorporated (64.64% females; mean age of 52.93 years). The total H. pylori eradication rates were 75.20% (255/339) with STT, 88.70% (159/178) with QCT, and 91.30% (191/209) with QBT. Both quadruple therapies (QCT-QBT) showed significantly higher eradication rates compared with STT, with an adjusted incidence risk ratio (IRR) of 1.25 (p: <0.05); and 1.24 (p: <0.05), respectively. The antibiotic-resistance prevalence by country, but not the prevalence of CYP2C19 polymorphism, showed a statistically significant impact on eradication success. CONCLUSIONS: Both QCT and QBT are superior to STT for H. pylori eradication when adjusted for country-specific antibiotic resistance and CYP2C19 polymorphism in a sample of individuals residing in five countries within two continents.

Neuroprotective effects of the combined treatment of resveratrol and urapidil in experimental cerebral ischemia-reperfusion injury in rats.

PURPOSE: To evaluate the neuroprotective effect of resveratrol, urapidil, and a combined administration of these drugs against middle cerebral artery occlusion (MCAO) induced ischemia/reperfusion (IR) injury model in rats. METHODS: Thirty-five rats were divided into five groups of seven animals each. Animals in IR, IR resveratrol (IRr), IR urapidil (IRu), and IR + combination of resveratrol and urapidil (IRc) were exposed to MCAO induced cerebral ischemia reperfusion injury model. Rats in IRr and IRu groups received 30-mg/kg resveratrol and 5-mg/kg urapidil respectively. Animals in IRc received a combined treatment of both drugs. At the end of the study, brain tissues were used for oxidative stress (malondialdehyde, glutathione, and superoxide dismutase), pro-apoptotic caspase-3, anti-apoptotic Bcl-2, and pro-inflammatory tumor necrosis factor-α cytokine level measurements. RESULTS: The MCAO model successfully replicated IR injury with significant histopathological changes, elevated tissue oxidative stress, and upregulated apoptotic and inflammatory protein expression in IR group compared to control group (p < 0.001). All parameters were significantly alleviated in IRr group compared to IR group (all p < 0.05). In IRu group, all parameters except for caspase-3 and Bcl-2 were also significantly different than IR group (all p < 0.05). The IRc group showed the biggest difference compared to IR group in all parameters (all p < 0.001). The IRc had higher superoxide dismutase and Bcl-2 levels, and lower caspase-3 levels compared to both IRr and IRu groups (all p < 0.05). Also, the IRc group had lower MDA and TNF-α levels compared to IRu group (all p < 0.05). CONCLUSIONS: The results indicate that combined treatment of resveratrol and urapidil may be a novel strategy to downregulate neurodegeneration in cerebral IR injury.

Cost-effectiveness study of therapeutic approaches for mucosal leishmaniasis.

This study aimed to estimate the cost-effectiveness of four therapeutic approaches available for mucosal leishmaniasis in Brazil: miltefosine, meglumine antimoniate, combined with and without pentoxifylline, and liposomal amphotericin B. The perspective adopted was that of the Brazilian Unified National Health System (SUS). The outcome of interest was "cured patient", which was analyzed using a decision tree model. Estimates of direct costs and effectiveness were obtained from the scientific literature. Meglumine antimoniate alone was the base comparator strategy; liposomal amphotericin B showed an incremental cost-effectiveness ratio (ICER) of USD 7,409.13 per cured patient, and the combination of meglumine antimoniate with pentoxifylline presented an ICER of USD 85.13. Miltefosine was absolutely dominated, with higher cost and similar effectiveness when compared to meglumine antimoniate. Sensitivity analyses, varying the cost by ±25%, did not change the results. However, when the cost of miltefosine was estimated at less than USD 171.23, this strategy was dominant over meglumine antimoniate alone. The results confirm that treatment with liposomal amphotericin B remains the option with the highest ICER among the approaches analyzed. Miltefosine may be cost-effective based on the variation in the acquisition price, which deserves attention because it is the only available oral option. The non-accounting of other aspects prevent the use of these results immediately to support decision-making, but they point out the need to negotiate the prices of drugs available for mucosal leishmaniasis and indicates the need of encouraging technology transfer or other actions aimed at expanding the performance of the Brazilian national industrial complex.

Budget impact of upadacitinib in patients with moderate to severe rheumatoid arthritis in Argentina. / Impacto presupuestario de upadacitinib en pacientes con artritis reumatoide moderada a severa en Argentina.

OBJECTIVES.: To analyze the budget impact of upadacitinib (UPA) 15 mg + methotrexate (MTX) for the treatment of moderate-to-severe rheumatoid arthritis (RA) in patients with an inadequate response to conventional disease-modifying antirheumatic drugs (cDMARD-IR) from the perspective of social security and the private health sector in Argentina. MATERIALS AND METHODS.: A budget impact analysis model was developed for a hypothetical cohort of 100,000 adults with health insurance coverage who were diagnosed with RA over a 5-year time horizon. The model parameters were obtained through literature review and validated by local experts. The costs are expressed in 2024 US dollars (USD). RESULTS.: The introduction of UPA 15 mg + MTX for the treatment of moderate-to-severe RA and cDMARD-IR resulted in minimal increase, with a five-year total cumulative incremental cost of USD 1,855 for social security and USD 1,812 for the private health sector, representing 2% of the total budget. The acquisition cost of UPA was the most influential variable in the sensitivity analysis. CONCLUSIONS.: The introduction of UPA 15 mg + MTX for the treatment of moderate-to-severe RA and cDMARD-IR can provide an effective treatment option with a minimal increase in costs for the healthcare system in Argentina, which is especially important in developing countries where health system budgets are more limited. Providing evidence-based estimates is a valuable tool for informing healthcare policies and can help policymakers make informed decisions about the allocation of healthcare resources to improve patient outcomes while also managing costs.Motivation for the study. Rheumatoid arthritis (RA) is a disease that hasn't cure, so it's important to know the budget impact of treatment with upadacitinib (UPA) 15 mg + methotrexate (MTX) in patients with moderate to severe RA who didn't respond well to conventional antirheumatic drugs. Main findings. UPA + MTX would entail a minimal increase in costs for the healthcare system in Argentina, potentially making this effective treatment option more accessible to patients with RA. Access to this treatment can improve the outcome of patients with RA. Public health implications. In resource-constrained settings such as Argentina, providing evidence-based cost estimates can help healthcare managers allocate resources efficiently while improving patient outcomes. This study provides evidence to inform healthcare policies and decisions regarding the inclusion of UPA + MTX in treatment guidelines or formularies for RA management.

Effects of N-Acetylcysteine combined with Ambroxol Hydrochloride on clinical symptoms, CRP, and PCT in children with pneumonia.

OBJECTIVE: This study investigated the effects of N-Acetylcysteine (NAC) combined with Ambroxol Hydrochloride (AH) on clinical symptoms, C-Reactive Protein (CRP), and Procalcitonin (PCT) levels in children with pneumonia. METHODS: A total of 98 children with pneumonia were assigned to the control group and observation group by random number table method. NAC was administered to the observation group and AH was given to the control group. The therapeutic effect was observed, the disappearance time of clinical symptoms and levels of inflammatory factors, lung function parameters, blood gas analysis parameters, and immunoglobulin were measured. The incidence of adverse reactions was statistically analyzed. RESULTS: A higher effective rate was observed in the observation group than in the control group (p < 0.05). Antipyretic time, cough disappearance time, and lung rale disappearance time in the observation group were shorter than those in the control group (p < 0.05). After treatment, CRP and PCT were lower (p < 0.05), FVC, FEV1, and FEV1/FVC were higher, PaCO2 was lower, PaO2 and SaO2 were higher, and IgA, IgG, IgM, and C3 were higher in the observation group than those in the control group (p < 0.05). The incidence of adverse reactions between the two groups was not significantly different (p > 0.05). CONCLUSION: NAC combined with AH is effective in the treatment of pediatric pneumonia by effectively alleviating clinical symptoms, reducing inflammatory factors, and improving lung function and immune function.

Neuroprotective Potential of a Novel Soluble Guanylate Cyclase Stimulator the Riociguat Alone or in a Combination Manner with Resveratrol in Experimental Stroke Model in Rats / Potencial Neuroprotector del Novedoso Estimulador de Guanilato Ciclasa Soluble, el Riociguat solo o en Combinación con Resveratrol en un Modelo Experimental de Ataque Cerebrovascular en Ratas

SUMMARY: In this study we aimed to examine the effect of novel vasodilatory drug Riociguat co-administration along resveratrol to recover neurodegeneration in experimental stroke injury. For that purpose, thirty-five adult female rats were divided into five groups (Control, MCAO, MCAO + R, MCAO + BAY, MCAO + C) of seven animals in each. Animals in Control group did not expose to any application during the experiment and sacrificed at the end of the study. Rats in the rest groups exposed to middle cerebral artery occlusion (MCAO) induced ischemic stroke. MCAO + R group received 30 mg/kg resveratrol, and MCAO + BAY group received 10 mg/kg Riociguat. The MCAO + C group received both drugs simultaneously. The drugs were administered just before the reperfusion, and the additional doses were administered 24h, and 48h hours of reperfusion. All animals in this study were sacrificed at the 72nd hour of experiment. Total brains were received for analysis. Results of this experiment indicated that MCAO led to severe injury in cerebral structure. Bax, IL-6 and IL-1ß tissue levels were up-regulated, but anti-apoptotic Bcl-2 immunoexpression was suppressed (p<0.05). In resveratrol and Riociguat treated animals, the neurodegenerations and apoptosis and inflammation associated protein expressions were improved compared to MCAO group, but the most success was obtained in combined treatment exposed animals in MCAO + C group. This study indicated that the novel soluble guanylate stimulator Riociguat is not only a potent neuroprotective drug in MCAO induced stroke, but also synergistic administration of Riociguat along with resveratrol have potential to increase the neuroprotective effect of resveratrol in experimental cerebral stroke exposed rats.

En este estudio, nuestro objetivo fue examinar el efecto de la coadministración del nuevo fármaco vasodilatador Riociguat junto con resveratrol para recuperar la neurodegeneración en lesiones por ataques cerebrovasculares experimentales. Para ello, se dividieron 35 ratas hembras adultas en cinco grupos (Control, MCAO, MCAO + R, MCAO + BAY, MCAO + C) de siete animales en cada uno. Los animales del grupo control no fueron sometidos a ninguna aplicación durante el experimento y se sacrificaron al final del estudio. Las ratas de los grupos expuestas a la oclusión de la arteria cerebral media (MCAO) indujeron un ataque cerebrovascular isquémico. El grupo MCAO + R recibió 30 mg/kg de resveratrol y el grupo MCAO + BAY recibió 10 mg/kg de Riociguat. El grupo MCAO + C recibió ambos fármacos simultáneamente. Los fármacos se administraron antes de la reperfusión y las dosis adicionales se administraron a las 24 y 48 horas de la reperfusión. Todos los animales en este estudio fueron sacrificados a las 72 horas del experimento. Se recibieron cerebros totales para su análisis. Los resultados indicaron que la MCAO provocaba lesiones graves en la estructura cerebral. Los niveles tisulares de Bax, IL-6 e IL- 1ß estaban regulados positivamente, pero se suprimió la inmunoexpresión antiapoptótica de Bcl-2 (p <0,05). En los animales tratados con resveratrol y Riociguat, las neurodegeneraciones y las expresiones de proteínas asociadas a la apoptosis y la inflamación mejoraron en comparación con el grupo MCAO, sin embargo el mayor éxito se obtuvo en el tratamiento combinado de animales expuestos en el grupo MCAO + C. Este estudio indicó que el nuevo estimulador de guanilato ciclasa soluble Riociguat no solo es un fármaco neuroprotector potente en el ataque cerebrovascular inducido por MCAO, sino que también la administración sinérgica de Riociguat junto con resveratrol tiene el potencial para aumentar el efecto neuroprotector del resveratrol en ratas experimentales expuestas a un ataque cerebrovascular.

Hipertensão arterial sistêmica: recomendações para o tratamento inicial em adultos / Systemic arterial hypertension: recommendations for initial treatment in adults

Pergunta - Quais são as evidências sobre o uso de monoterapia ou terapia combinada no tratamento farmacológico inicial da HAS? Métodos - As buscas de Guias de Prática Clínica (GPC) foram realizadas em junho de 2024 nas bases de dados LILACS - Literatura Latino-Americana e do Caribe em Ciências da Saúde, Pubmed, Embase, BIGG - Base Internacional de Guias GRADE e GIN - Guidelines International Network. Nesta revisão rápida, a seleção de GPC e a avaliação da qualidade metodológica foram realizadas em duplicidade e de modo independente. Resultados - De 3.671 registros recuperados nas buscas, cinco GPC foram incluídos. Quatro GPC foram conduzidos na Argentina, El Salvador, Irã, Tailândia, e um foi produzido pela Organização Mundial da Saúde (OMS). A qualidade geral metodológica dos GPC foi considerada baixa. Os achados foram categorizados segundo o esquema terapêutico analisado. Todas as classes de anti-hipertensivos são recomendadas para a monoterapia da HAS. Há evidências de melhores resultados da terapia combinada no controle da HAS inicial e menos eventos adversos. Porém, ainda faltam evidências robustas. Deve-se considerar também que a qualidade metodológica dos GPC foi considerada baixa.

Question - What is the evidence on the use of monotherapy or combination therapy in the initial pharmacological treatment of hypertension? Methods - Searches for Clinical Practice Guidelines (CGP) were conducted in June 2024 in the databases LILACS - Latin American and Caribbean Literature in Health Sciences, Pubmed, Embase, BIGG - International Database of GRADE Guidelines and GIN - Guidelines International Network. In this rapid review, CGP selection and methodological quality assessment were performed in duplicate and independently. Results - Of 3,671 records retrieved in the searches, five CGPs were included. Four CGPs were conducted in Argentina, El Salvador, Iran, Thailand, and one was produced by the World Health Organization (WHO). The overall methodological quality of the CGPs was considered low. The findings were categorized according to the therapeutic regimen analyzed. All classes of antihypertensives are recommended for monotherapy of hypertension. There is evidence of better results of combined therapy in controlling initial hypertension and fewer adverse events. However, robust evidence is still lacking. It should also be considered that the methodological quality of the GPC was considered low.

Safety and Pharmacokinetics of a Combined Antioxidant Therapy against Myocardial Reperfusion Injury: A Phase 1 Randomized Clinical Trial in Healthy Humans.

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

Cost-effectiveness of dapagliflozin plus standard treatment compared to standard therapy for the management of chronic kidney disease in Colombia.

BACKGROUND: The DAPA-CKD study showed that dapagliflozin added to standard treatment reduced the risk of chronic kidney disease progression, and death from renal or cardiovascular causes compared to placebo. OBJECTIVE: Assess the cost-effectiveness of dapagliflozin and standard treatment versus standard treatment alone for chronic kidney disease within the Colombian health system. METHODS: We employed a Markov model based on the DAPA-CKD study, tailored to the Colombian scenario. The model forecasted hospitalizations for heart failure, overall and cardiovascular mortality, and chronic kidney disease progression over a 10-year horizon with a 5% discount rate. RESULTS: Dapagliflozin combined with standard treatment is a cost-effective intervention in treating stage 2-4 CKD. In the base case, the ICER was US $5,366, below 1 GDP (US $6.558) per capita. This was consistent in the sensitivity analyses. CONCLUSION: Our study showed that dapagliflozin, when combined with standard treatment, is cost-effective against standard treatment alone, aligning with Colombia's willingness-to-pay threshold.

Renoprotective effect of a novel combination of 6-gingerol and metformin in high-fat diet/streptozotocin-induced diabetic nephropathy in rats via targeting miRNA-146a, miRNA-223, TLR4/TRAF6/NLRP3 inflammasome pathway and HIF-1α.

BACKGROUND: MiRNA-146a and miRNA-223 are key epigenetic regulators of toll-like receptor 4 (TLR4)/tumor necrosis factor-receptor-associated factor 6 (TRAF6)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway, which is involved in diabetic nephropathy (DN) pathogenesis. The currently available oral anti-diabetic treatments have been insufficient to halt DN development and progression. Therefore, this work aimed to assess the renoprotective effect of the natural compound 6-gingerol (GR) either alone or in combination with metformin (MET) in high-fat diet/streptozotocin-induced DN in rats. The proposed molecular mechanisms were also investigated. METHODS: Oral gavage of 6-gingerol (100 mg/kg) and metformin (300 mg/kg) were administered to rats daily for eight weeks. MiRNA-146a, miRNA-223, TLR4, TRAF6, nuclear factor-kappa B (NF-κB) (p65), NLRP3, caspase-1, and hypoxia-inducible factor-1 alpha (HIF-1α) mRNA expressions were measured using real-time PCR. ELISA was used to measure TLR4, TRAF6, NLRP3, caspase-1, tumor necrosis factor-alpha (TNF-α), and interleukin-1-beta (IL-1ß) renal tissue levels. Renal tissue histopathology and immunohistochemical examination of fibronectin and NF-κB (p65) were performed. RESULTS: 6-Gingerol treatment significantly reduced kidney tissue damage and fibrosis. 6-Gingerol up-regulated miRNA-146a and miRNA-223 and reduced TLR4, TRAF6, NF-κB (p65), NLRP3, caspase-1, TNF-α, IL-1ß, HIF-1α and fibronectin renal expressions. 6-Gingerol improved lipid profile and renal functions, attenuated renal hypertrophy, increased reduced glutathione, and decreased blood glucose and malondialdehyde levels. 6-Gingerol and metformin combination showed superior renoprotective effects than either alone. CONCLUSION: 6-Gingerol demonstrated a key protective role in DN by induction of miRNA-146a and miRNA-223 expression and inhibition of TLR4/TRAF6/NLRP3 inflammasome signaling. 6-Gingerol, a safe, affordable, and abundant natural compound, holds promise for use as an adjuvant therapy with metformin in diabetic patients to attenuate renal damage and stop the progression of DN.