First-line Drug For Treatment Research Articles

Tumor hypoxia: The major culprit behind cisplatin resistance in cancer patients.

Cisplatin is the most commonly used first-line drug for cancer treatment. However, many patients develop resistance to cisplatin therapy which ultimately results in therapy failure and increased mortality. A growing body of evidence shows that the hypoxic microenvironment is the prime factor underlying tumor insensitivity to cisplatin treatment. Since tumors in the majority of cancer patients are under hypoxic stress (low oxygen supply), it becomes necessary to understand the pathobiology behind hypoxia-induced cisplatin resistance in cancer cells. Here, we discuss the molecular events that render hypoxic tumors insensitive to cisplatin therapy. Furthermore, various drugs and tumor oxygenation techniques have been developed to circumvent cisplatin resistance in hypoxic tumors. However, their pharmaceutical applications are limited due to failures in clinical investigations and a lack of preclinical studies in the hypoxic tumor microenvironment. This review addresses these challenges and provides new directions for the strategic deployment of cisplatin sensitizers in the hypoxic tumor microenvironment.

Miscibility and thermal properties of poly(vinylpyrrolidone-vinyl acetate)/lamivudine and tenofovir binary blends prepared by hot melt extrusion

Preparation of amorphous solid dispersions (ASD) by hot melt extrusion (HME) of poly(vinylpyrrolidone-vinyl acetate) (Kollidon) and the active pharmaceutical ingredients (API) Lamivudine (3TC) and Tenofovir Disoproxyl Fumarate (TDF) was investigated aiming to study their miscibility and thermal behavior. These two drugs are currently used as drugs in first line treatment of patients with Acquired Immunodeficiency Syndrome (AIDS). In order to predetermine parameters for extrusion and the maximum concentration of API to be used without any recrystallization, binary blends were first processed in the mixing chamber at 130°C using a roller type rotor at 10, 20 and 30 rpm for 7 min, giving rise to ASD of both API, at least up to 20 wt% of the drug. Both 3TC and TDF were then extruded individually with Kollidon in a single screw extruder. HME produced ASD with high concentration of both Kollidon/API combinations, being part of the API soluble in the polymer matrix. From HME, Kollidon/3TC forms ASD in concentration up to 50 wt%, but from 30 wt% 3TC, the ASD has no time stability, showing recrystallization in less than 5 months, while the Kollidon/TDF system forms ASD up to 30 wt% of TDF, but it has aging stability inferior to 4 months.

Improving drug utilization platform with injectable mucoadhesive hydrogel for treating ulcerative colitis

Owing to the low solubility of 5-aminosalicylic acid (5-ASA), a first-line drug for treatment of ulcerative colitis (UC), oral and local administration are challenging, leading to a low utilization rate. Here, we applied generation 4 polyamidoamine (G4 PAMAM) dendrimer to construct a G4-ASA nanoparticle, via a host–guest interaction, containing surface amino groups to crosslink the aldehyde group of the oxidized dextran by a Schiff base reaction, yielding an injectable adhesive 5-ASA-loaded hydrogel (G4-ASA/Dex). This slow-release 5-ASA agent was then injected rectally to dextran sulfate sodium (DSS)-induced UC mice. 5-ASA solubility increased 25.62-fold (from 0.903 mg/mL to 23.131 mg/mL) in G4-ASA nanoparticles, while the hydrogel exhibited structural stability, mucoadhesivity, and acid-responsive drug release. Thus, the G4-ASA/Dex was injectable, convenient for rectal delivery, and exhibited an outstanding adhesive effect. Furthermore, G4-ASA/Dex more effectively maintained colon length and reduced intestinal inflammatory cell infiltration compared with traditional administration, while exhibiting optimal performance in terms of the disease activity index, histological scoring, and immunohistochemical results. Hence, this new model could improve the solubility and utilization of 5-ASA for clinical use, thereby, serving as an effective local treatment strategy for intestinal inflammation.

Fecal microbiota in children with juvenile idiopathic arthritis treated with methotrexate or etanercept

BackgroundAlterations in the composition of the fecal microbiota in children with juvenile idiopathic arthritis (JIA) have been observed in several studies, but it has not been determined whether the standard treatment for JIA changes the composition or function of the microbiota.The first-line disease-modifying anti-rheumatic drug for treatment of JIA is usually methotrexate, followed or supplemented by anti-tumor necrosis factor alpha drugs, such as etanercept. The aim of this study was to investigate the effects of methotrexate and etanercept treatments on the fecal microbiota and the fecal short-chain fatty acids (SCFAs) in children with JIA.MethodsIn this multicenter study, the composition of fecal microbiota from 45 treatment-naïve children with JIA was compared with that from 29 children treated with methotrexate and 12 children treated with etanercept. We also made pairwise comparisons of 15 children sampled before and during methotrexate treatment and 7 children sampled before and during etanercept treatment.The microbiota was determined using sequencing amplicons from the V3 and V4 regions of the 16S rRNA gene. Alpha-diversity, community composition, and relative abundances of bacterial taxa were analyzed in all comparisons. Analyses of fecal SCFAs, using a high-performance liquid chromatograph, were performed for the pairwise comparisons.ResultsWe did not find any significant differences in α-diversity or community composition of microbiota. However, principal coordinate analysis indicated a change in community composition in 7 of the 15 paired samples before and during methotrexate and 2 of the 7 paired samples before and during etanercept.Comparisons of the relative abundance of taxa revealed minor differences before and during treatment with methotrexate or etanercept, but they were not significant after correction for multiple analyses, and the unpaired and paired analyses did not show similar changes.There were no significant differences in levels of fecal SCFAs before and during treatment with methotrexate or etanercept.ConclusionsTreatment with methotrexate or etanercept had minor, but no significant or consistent changes either on composition of microbiota or on levels of SCFAs, suggesting that these changes are not related to the therapeutic effects of methotrexate or etanercept.

Can parents believe websites’ information about methylphenidate’s side effects?

BackgroundAttention deficit and hyperactivity disorder (ADHD) is one of the most common behavioural disorders, affecting around 5% of the global population. Methylphenidate is recommended as the first-line drug treatment for...

HER2 Expression, Test Deviations, and Their Impact on Survival in Metastatic Gastric Cancer: Results From the Prospective Multicenter VARIANZ Study.

PURPOSETrastuzumab is the only approved targeted drug for first-line treatment of human epidermal growth factor receptor 2–positive (HER2+) metastatic gastric cancer (mGC). However, not all patients respond and most eventually progress. The multicenter VARIANZ study aimed to investigate the background of response and resistance to trastuzumab in mGC.METHODSPatients receiving medical treatment for mGC were prospectively recruited in 35 German sites and followed for up to 48 months. HER2 status was assessed centrally by immunohistochemistry and chromogenic in situ hybridization. In addition, HER2 gene expression was assessed using qPCR.RESULTSFive hundred forty-eight patients were enrolled, and 77 had HER2+ mGC by central assessment (14.1%). A high deviation rate of 22.7% between central and local test results was seen. Patients who received trastuzumab for centrally confirmed HER2+ mGC (central HER2+/local HER2+) lived significantly longer as compared with patients who received trastuzumab for local HER2+ but central HER2− mGC (20.5 months, n = 60 v 10.9 months, n = 65; hazard ratio, 0.42; 95% CI, 8.2 to 14.4; P < .001). In the centrally confirmed cohort, significantly more tumor cells stained HER2+ than in the unconfirmed cohort, and the HER2 amplification ratio was significantly higher. A minimum of 40% HER2+ tumor cells and a HER2 amplification ratio of ≥ 3.0 were calculated as optimized thresholds for predicting benefit from trastuzumab.CONCLUSIONSignificant discrepancies in HER2 assessment of mGC were found in tumor specimens with intermediate HER2 expression. Borderline HER2 positivity and heterogeneity of HER2 expression should be considered as resistance factors for HER2-targeting treatment of mGC. HER2 thresholds should be reconsidered. Detailed reports with quantification of HER2 expression and amplification levels may improve selection of patients for HER2-directed treatment.

Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at −8.3 kcal/mol, followed by Zn and Ca at −8.0 kcal/mol, and Fe and Mg at −7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn–Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.

The Impact of Antiosteoporotic Drugs on Glucose Metabolism and Fracture Risk in Diabetes: Good or Bad News?

Osteoporosis and diabetes mellitus represent global health problems due to their high, and increasing with aging, prevalence in the general population. Osteoporosis can be successfully treated with both antiresorptive and anabolic drugs. While these drugs are clearly effective in reducing the risk of fracture in patients with postmenopausal and male osteoporosis, it is still unclear whether they may have the same efficacy in patients with diabetic osteopathy. Furthermore, as bone-derived cytokines (osteokines) are able to influence glucose metabolism, it is conceivable that antiosteoporotic drugs may have an effect on glycemic control through their modulation of bone turnover that affects the osteokines’ release. These aspects are addressed in this narrative review by means of an unrestricted computerized literature search in the PubMed database. Our findings indicate a balance between good and bad news. Active bone therapies and their modulation of bone turnover do not appear to play a clinically significant role in glucose metabolism in humans. Moreover, there are insufficient data to clarify whether there are any differences in the efficacy of antiosteoporotic drugs on fracture incidence between diabetic and nondiabetic patients with osteoporosis. Although more studies are required for stronger recommendations to be issued, bisphosphonates appear to be the first-line drug for treatment of osteoporosis in diabetic patients, while denosumab seems preferable for older patients, particularly for those with impaired renal function, and osteoanabolic agents should be reserved for patients with more severe forms of osteoporosis.

Development of a Sensitive Enzyme-linked Immunosorbent Assay for Daptomycin

Daptomycin (DAP) has a completely different mechanism of action compared with conventional drugs for methicillin-resistant Staphylococcus aureus (MRSA) and is widely used as the first-line drug for treatment of dermal soft tissue infection and sepsis caused by MRSA infection in clinical practice. However, DAP has serious side effects, including renal dysfunction and rhabdomyolysis, and thus therapeutic drug monitoring of DAP is recommended. The purpose of this study was to develop an enzyme-linked immunosorbent assay (ELISA) for DAP that is simpler and more sensitive compared with existing assay methods and can be used in pharmacokinetic studies. Anti-DAP antibody was obtained by immunizing mice with an antigen conjugated with mercaptosuccinyl bovine serum albumin using N-(4-maleimidobutyryloxy) succinimide as a heterobifunctional coupling agent. Enzyme labeling of DAP with horseradish peroxidase was performed using pyromellitic dianhydride. The generated antibody and enzyme conjugate were used to develop a highly sensitive and specific ELISA for DAP in human serum. This ELISA shows a linear range of detection from 0.3 to 72.9 ng/mL, and a limit of quantification of approximately 0.3 ng/mL. The developed ELISA should be a valuable tool for pharmacokinetic studies and therapeutic drug monitoring of DAP.

Novel and emerging therapeutic drug targets for management of type 2 Diabetes Mellitus

DM (Diabetes Mellitus) can be divided to type 1 and type 2, but out of both, type 2 is more predominant form of diabetes. At present approximate more than 451 million people (1 in 11 of world's adult population) are in the grip of type 2 diabetes (T2D) and responsible for worldwide morbidity and mortality. As per the estimate of the WHO, this epidemic will be placed on the top ten leading causes of death by 2030. A combination of improvements in life style and pharmacological therapy is required to combat with disease effectively and keep it for long term. Still metformin is the first line drug (contraindicated in lactic acidosis) among all available medication used to treat the elevated sugar level. Apart from these sulfonylureas, meglitinides, thiazolidinediones, alpha glucosidase inhibitors and DPP4 inhibitors are widely used classes of antihyperglycemic agents used either alone or in combination with metformin. There are many other emerging drug targets being reported recently for the treatment of T2D like 5′ AMP-activated protein kinase, fructose-1, 6-bisphosphatase, glucagon-like-peptide 1, glucokinase, G protein-coupled receptor 119, glycogen synthase kinase 3, PTP1B, SGLT2, etc. This review is focused to discuss these emerging therapeutic targets of T2D along with recent potent chemical entities of concerned therapeutic target. • Diabetes will be placed on the top ten leading causes of death by 2030. • Currently metformin is the first line drug for treatment of T2D. • Emerging drug targets for T2D include AMPK, FBPase, GLP-1, GK, GPR-119, GSK-3, PTP1B, SGLT2, etc.

Efficacy and safety of Shi-style cervical manipulation therapy for treating acute and subacute neck pain: study protocol for a randomized controlled trial

BackgroundNeck pain is a common clinical disease, which seriously affects people’s mental health and quality of life and results in loss of social productivity. Improving neck pain’s curative effect and reducing its recurrence rate are major medical problems. Shi’s manipulation therapy has unique advantages and technical features that aid in the diagnosis and treatment of neck pain. Compared with first-line non-steroidal anti-inflammatory drug (NSAID) treatment of neck pain, Shi’s cervical manipulation lacks the relevant research basis of therapeutic advantage, safety, and satisfaction for treating acute and subacute neck pain. Herein, we aim to confirm our hypothesis in a clinical trial that the safety and efficacy of Shi’s cervical manipulation will be more effective, safer, and more satisfactory than NSAIDs to treat acute and subacute neck pain.MethodsIn this multicenter, positive-controlled, randomized clinical trial, traditional analgesic drug (NSAID) is used to evaluate and show that Shi’s manipulation is more effective, safe, and satisfactory for treating acute and subacute neck pain. Overall, 240 subjects are randomly divided into the trial and control groups, with both groups treated by the corresponding main intervention method for up to 12 weeks. Clinical data will be collected before the intervention and immediately after the first treatment; at 3 days and 1, 2, 4, 8, and 12 weeks after the intervention; and at 26 and 52 weeks after treatment follow-up of clinical observation index data collection. The clinical observation indices are as follows: (1) cervical pain is the primary observation index, measured by Numerical Rating Scale. The secondary indices include the following: (2) cervical dysfunction index, measured by patient self-evaluation using cervical Neck Disability Index; (3) cervical activity measurement, measured by the cervical vertebra mobility measurement program of Android mobile phone system; (4) overall improvement, measured by patient self-evaluation with SF-36; and (5) satisfactory treatment, determined by patient self-evaluation.DiscussionWe will discuss whether Shi’s cervical manipulation has greater advantages in efficacy, safety, and satisfaction of acute and subacute neck pain than traditional NSAIDs, to provide a scientific basis for the dissemination and application of Shi’s cervical manipulation.Trial registrationChina Registered Clinical Trial Registration Center ChiCTR1900021371. Registered on 17 February 2019

Epilepsias mioclónicas progresivas

Las epilepsias mioclónicas progresivas (EMP) son enfermedades neurodegenerativas infrecuentes, clínica y genéticamente heterogéneas, caracterizadas por presentar mioclonías de acción, crisis epilépticas y deterioro neurológico progresivo. Afectan principalmente a niños y adolescentes. Su cuadro clínico inicial dificulta un adecuado diagnóstico diferencial con otras enfermedades neurológicas genéticas más frecuentes como la epilepsia mioclónica juvenil. Se sabe que la mayoría de mutaciones genéticas que causan estas enfermedades reflejan una herencia autosómica recesiva, con variantes dominante o mitocondrial de excepcional frecuencia. El diagnóstico tiene lugar cuando se identifican las mutaciones en un paciente con un cuadro clínico característico (como es el caso de la enfermedad de Unverritch-Lundborg o la EMP del Mar del Norte). Por otro lado, en algunos casos son más útiles la anatomía patológica (para la enfermedad de cuerpos de Lafora o la epilepsia mioclónica con fibras rojas rasgadas) o exámenes auxiliares específicos (vgr., ácido siálico en orina para Sialidosis). Es importante hacer el diagnóstico específico ya que ello permite un tratamiento genético definido para algunas de estas enfermedades. El manejo de las crisis epilépticas incluye el uso de valproato como fármaco de primera línea, en tanto que otros como zonisamida y levetiracetam constituyen una segunda línea; sin embargo, la falta de respuesta al tratamiento médico antiepiléptico es relativamente común. El pronóstico puede variar entre una enfermedad y otra, pero, por lo general, suele ser desfavorable conduciendo a discapacidad severa o muerte temprana.

Principles of pharmacological therapy of comorbid diseases in patients with orthopedic pathology

Comorbidity is one of the leading problems in clinical practice. Interaction of diseases, involutive processes of natural aging and pathomorphosis of drugs significantly change clinical picture and course of the disease, the nature and severity of complications, limit or complicate the treatment and diagnostic process. Objective. To analyze current information on available recommendations for the treatment of comorbid diseases in patients with orthopedic pathology. Materials. An overview of the recommendations of the European Society of Cardiology, European Society of Hypertension, European Society for Vascular Surgery, Ukrainian Gastroenterological Association and American Diabetes Association for the period 2017–2019 is presented. Results. The first stage in the treatment of arterial hypertension is the lifestyle optimization, and the initial therapy of most patients with hypertension should be a combination of two drugs. Management of patients with lower extremity artery disease is associated with an increased risk of any cardiovascular events. Therefore, preventive measures are of particular importance. Gastropathies induced by non-steroidal anti-inflammatory drugs are widespread in orthopedic practice. In the prevention of their occurrence, a well-chosen gastroprotective therapy is important. Once the diagnosis of diabetes is made, lifestyle modification should be started immediately along with the start of pharmacotherapy. Metformin remains the first-line drug for treatment, drugs of other groups can be prescribed when there are contraindications to metformin. In the treatment of neuropathic pain in diabetes or pre-diabetes, only pharmacological treatment strategies are effective. Conclusions. In most cases, a number of comorbidities with timely diagnosis and compliance with the algorithms of medical care can be corrected and treated. Properly selected conservative therapy can reduce the risk of peri- and postoperative complications.

Metabolite Profiling of Dihydroartemisinin in Blood of Plasmodium-Infected and Healthy Mice Using UPLC-Q-TOF-MSE.

Dihydroartemisinin (DHA) and its’ derivatives have been employed as the most powerful first-line drugs for malarial treatment for several decades. The metabolism of DHA has not been studied clearly. Previous reports were focused on the pharmacokinetics procedure of DHA in healthy rats. The metabolites of DHA in red blood cells (RBC), especially in the RBC from Plasmodium-infected models, have rarely been studied. The Plasmodium species parasitize inside RBC, and these cells should be the final place where DHA performs its activity. In this study, the profile of DHA metabolites in biosample (blood, plasma, and RBC) of the infected and healthy mice was investigated with UPLC-Q-TOF-MS and UNIFI platform to gain insight into DHA metabolism. Results show that a total of 25 metabolites were successfully identified in infected (30 in healthy) blood, 27 in infected (27 in healthy) plasma, and 15 in infected (22 in healthy) RBC. Results show that hydroxylation, OH-dehydration, and glucuronidation reactions were important in the metabolic pathway in vivo. Significantly, DHA metabolites inside RBC were identified for the first time. 8-Hydroxy (8-OH) DHA, 4α-OH deoxy ART, and 6β-OH deoxy ART were identified in vivo for the first time.

A Cross-sectional Study on Prevalence of Vitamin B12 Deficiency and Peripheral Neuropathy between Metformin Users and Non Users in Participants with Type 2 Diabetes Mellitus

Introduction: Metformin is a first line drug for treatment of Type 2 Diabetes Mellitus (T2DM) which acts by decreasing insulin resistance. Metformin use can lead to vitamin B12 deficiency. Aim: To evaluate the difference in proportion of vitamin B12 deficiency and clinical neuropathy between metformin users and metformin non users in patients with T2DM. Materials and Methods: This cross-sectional study was conducted at Department of General Medicine, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, Karnataka, India, from Jul 2015 to June 2017. Hundred patients with T2DM were recruited in the study, and divided into two groups i.e., T2DM patients on metformin (n=50) and without metformin (n=50). One group were patients of diabetes who were on metformin for more than three years, and the other group were those who had not taken metformin in last three months. All participants were evaluated with serum vitamin B12. Toronto Clinical Neuropathy (TCN) score was used to diagnose peripheral neuropathy. Multivariable logistic regression was done to look for association between metformin use and vitamin B12 deficiency and peripheral neuropathy separately. Results: Between the metformin users and non metformin user group, the proportion of males (72% vs 66%, p-value=0.66) and the age (56.02±9.19 vs 56.16±8.33 years, p-value=0.93) were similar in both groups. Median duration of diabetes among metformin users was 10.18 years (IQR=6.68-16.68 year) and non metformin user group was 7.68 years (IQR=5.68-12.68 year). There was a significantly higher prevalence of vitamin B12 deficiency in metformin users (38,76%) than non metformin users (21,42%). The prevalence of vitamin B12 deficiency was highest (11,100%) in those with metformin use for more than 15 years. Association of vitamin B12 deficiency in metformin users was significant {(OR=7.17 (2.46-20.92), p-value &lt;0.001}. Peripheral neuropathy assessed by TCN scoring was significantly more common in metformin users (37,74% vs 23,46%; p-value=0.004). Conclusion: This study reports high prevalence of vitamin B12 deficiency in T2DM patients with significantly higher prevalence among metformin users. Peripheral neuropathy was significantly more common in metformin users and was associated with vitamin B12 deficiency. Hence, metformin treated T2DM patients, especially those with peripheral neuropathy should be evaluated for vitamin B12 deficiency.

Efficacy and safety of immunological checkpoint inhibitors combined with anti-angiogenic drugs in first-line treatment of metastatic renal cell carcinoma: a systematic review and meta-analysis.

BackgroundImmune checkpoint inhibitors (ICIs) have shown promising results for the second-line treatment of metastatic renal cell carcinoma (mRCC). Several randomized controlled trials have so far also evaluated the efficacy of ICIs for first-line treatment of mRCC. In this study, we conducted a meta-analysis of relevant studies to further clarify the efficacy and safety of ICIs combined with anti-angiogenic drugs for the treatment of mRCC.MethodsWe searched the PubMed, Embase, and Cochrane libraries for RCT trials of ICIs combined with anti-angiogenic drugs for first-line treatment of mRCC published before November 20, 2019. A meta-analysis was conducted based on methodological recommendations by the Cochrane Collaboration.ResultsFour articles with a total of 2,967 patients met the inclusion criteria. Our meta-analysis revealed that progression-free survival (PFS) and objective response rate (ORR) were significantly improved in the experimental group while there was no significant difference in overall survival (OS) (HR 0.75, 95% CI: 0.67–0.84; HR 1.43, 95% CI: 1.07–1.91; HR 0.74, 95% CI: 0.53–1.03). After stratification for PD-L1 expression, OS, PFS, and ORR of PD-L1 positive patients were significantly increased in the experimental group (HR 0.74, 95% CI: 0.56–0.96; HR 1.66, 95% CI: 1.11–2.49; HR 0.65, 95% CI: 0.57–0.75).ConclusionsImmunological checkpoint inhibitors combined with anti-angiogenic drugs as a first-line treatment for mRCC improve PFS and ORR. This effect is more pronounced in PD-L1 positive patients, where ICIs also improve OS. ICIs do not increase the incidence of adverse events.

Clinical descriptive analysis of severe Pneumocystis jirovecii pneumonia in renal transplantation recipients

ABSTRACT Pneumocystis jirovecii (P. jirovecii) pneumonia (PJP) is an opportunistic fungal infection after renal transplantation, which is always severe, difficult to diagnose, combined with multiple complications and have poor prognosis. We retrospectively analyzed clinical data, including risk factors, diagnosis, treatment and complications of seven clinical cases suffered with severe PJP after renal transplantation in our department in 2019. All the seven recipients were routinely prescribed with PJP prophylaxis after renal transplantation, and six of them suffered acute graft rejection before the infection. P. jirovecii sequence was identified in blood or broncho-alveolar lavage fluid (BALF) by the metagenomic next-generation sequencing (mNGS) in all patients. All the patients were improved with the therapy trimethoprim-sulfamethoxazole (TMP-SMX) combined with caspofungin for the PJP treatment, but suffered with complications including renal insufficiency, leukopenia, thrombocytopenia, gastrointestinal bleeding, mediastinalemphysema, pulmonary hemorrhage, and hemophagocytic syndrome and other severe infections. Taken together, mNGS is a powerful tool that could be used to diagnose PJP in renal transplantation recipients. And PJP prophylaxis should be prescribed during and after treatment for acute rejection. TMP-SMX is the first-line and effective drug for PJP treatment, but the complications are always life-threatening and lead to poor prognosis. We should pay attention to these life-threatening complications.

Circulating microRNA profile unveils mechanisms of action of acitretin for psoriasis vulgaris

ABSTRACT Psoriasis vulgaris is a common chronic and recurrent inflammatory skin disease. In clinical practice, acitretin is the first-line treatment drug for psoriasis vulgaris. MicroRNAs (miRNAs) play a vital role in the initiation and development of psoriasis vulgaris. However few studies focused on the mechanisms of acitretin in the treatment of psoriasis vulgaris from the perspective of miRNAs. Here, the expression profiles of circulating miRNAs in the plasma of 12 patients with psoriasis vulgaris before and after acitretin treatment were sequenced. Three miRNAs (miR-146a-5p, miR-122-5p and miR-21-5p) were identified using expression pattern analysis, and the levels were significantly decreased after acitretin treatment (P< 0.001). Receiver operating characteristic (ROC) analyses indicated that the three miRNAs have the potential to be utilized as molecular markers to evaluate the therapeutic effect of acitretin, and the values of the area under the curve (AUC) were 0.825, 0.831, and 0.796, respectively. In addition, we predicted target genes of the three miRNAs and performed signaling pathway enrichment analyses. The results demonstrated that the target genes were mainly involved in the MAPK, JAK-STAT, and NF-κB signaling pathways, which were further validated through in vitro experiments. In conclusion, acitretin can suppress miRNA-mediated MAPK, JAK-STAT, and NF-κB signaling pathways by decreasing miRNAs expression, thereby inhibiting the proliferation and inflammatory response of keratinocytes.

Botulinum toxin type A for hand tremor: a meta-analysis of randomised controlled trials.

Tremor is one of the most common movement disorders. It does not usually respond to first-line drug treatments (e.g. propranolol, primidone, anticholinergics, gabapentin and clonazepam) due to side effects and frequent dose limitations. Botulinum toxin type A (BoNT-A) has been widely used to treat tremor, but its efficacy and safety are uncertain. To evaluate the efficacy and safety of BoNT-A in the treatment of hand tremor. We searched the MEDLINE, EMBASE, PsycINFO and Cochrane Library databases for relevant randomised controlled trials of the effects of BoNT-A injections on tremors, up to 20 February 2020. A meta-analysis of comparative effects was performed using R studio software, and publication bias was examined using Egger's test. Six studies examining a total of 245 participants with tremor were included in the meta-analysis. The primary outcome of meta-analysis showed no difference in clinical tremor scale scores between the BoNT-A group versus the placebo group (standardised mean difference (SMD): -0.42, 95% confidence interval (CI): -1.94 to 1.10; I2 = 96%). For clinical tremor scale scores, subgroup analyses suggested that the BoNT-A group may differ in terms of multiple sclerosis (MS) related tremor (SMD: -1.10; 95% CI: -2.17 to -0.04; I2 = 79%) compared to a placebo, but the difference did not exist in the outcome of essential tremor (ET) or hand tremor (MD: -1.31; 95% CI: -3.39; 1.31; I2 = 97%). Grip strength (MD: -1.25, 95% CI: -5.99 to 3.50, I2 = 97%) was slightly lower in the BoNT-A group, but the difference was not significant. The incidence of adverse events (AEs), including hand weakness (RR: 2.96, 95% CI: 1.40 to 6.24, I2 = 37%), was significantly greater in the BoNT-A group than in the placebo group. Two studies were assessed as having an overall low risk of bias. Our study confirms that BoNT-A injections are unlikely to have an impact on patients with hand tremors. However, subgroup analysis suggested that BoNT-A injections could have possible benefits in MS-related tremor. While moderate to severe hand weakness AEs often limits their use in clinical practice, additional well-designed double-blind, placebo-controlled trials are needed to provide more robust conclusions.

Relevance of first-line drugs for treatment of multiple sclerosis in present-day conditions

Multiple sclerosis (MS) is a chronic demyelinating disease of young employable people. Demyelination develops as a result of the autoimmune mechanisms of the damage to nerve fibers, while the neurodegenerative changes in the brain matter begin from the first days of the disease. MS in most cases has a wavy course (periods of exacerbations and remissions), over time the progression of disease worses the quality of life of patients. Usually, there are remitting, secondary progressive, and primary progressive MS. The «gold standard» of treatment after the diagnosis of MS is first-line drugs disease-modifying therapies (DMT) of the first line -glatiramer acetate and в —interferons. These drugs have been used for more than 20 years and have proven their effectiveness, safety and good tolerability in long-term continuous observational clinical studies. It is important to note that therapy should be started as early as possible, from the moment of diagnosis, since in most patients, even with a stable clinical picture and no symptoms, the disease progresses. Over time, this can lead to persistent, irreversible neurological deficits and disability. The use of active immune -modulating drugs requires constant monitoring of the patient’s condition by qualified neurologists. This article presents the results of clinical trials of Timexon® (glatiramer acetate) and Teberif ® (interferon beta- 1а) in patients with remitting multiple sclerosis and discusses the issues of prescribing first-line drugs, switching from one therapy to another within the first-line, monitoring the effectiveness and safety of treatment.