ABSTRACT
For the approval of a drug, the stability data must be submitted to regulatory authorities. Such analyses are often time-consuming and cost-intensive. Forced degradation studies are mainly carried out under harsh conditions in the dissolved state, often leading to extraneous degradation profiles for a solid drug. Oxidative mechanochemical degradation offers the possibility of generating realistic degradation profiles. In this study, a sustainable mechanochemical procedure is presented for the degradation of five active pharmaceutical ingredients (APIs) from the sartan family: losartan potassium, irbesartan, valsartan, olmesartan medoxomil, and telmisartan. High-resolution mass spectrometry enabled the detection of impurities already present in untreated APIs and allowed the elucidation of degradation products. Significant degradation profiles could already be obtained after 15-60 min of ball milling time. Many of the identified degradation products are described in the literature and pharmacopoeias, emphasizing the significance of our results and the applicability of this approach to predict degradation profiles for drugs in the solid state.
Subject(s)
Benzimidazoles , Biphenyl Compounds , Losartan , Telmisartan , Tetrazoles , Valsartan , Benzimidazoles/chemistry , Benzimidazoles/analysis , Tetrazoles/chemistry , Telmisartan/chemistry , Valsartan/chemistry , Losartan/chemistry , Losartan/analysis , Biphenyl Compounds/chemistry , Irbesartan/chemistry , Irbesartan/analysis , Imidazoles/chemistry , Benzoates/chemistry , Valine/chemistry , Valine/analysis , Solvents/chemistry , Drug StabilityABSTRACT
Pyrethroids are widely used against agricultural pests and human disease vectors due to their broad insecticidal spectrum, fast action, and low mammalian toxicity. Unfortunately, overuse of pyrethroids has led to knockdown resistance (kdr) caused by mutations in voltage-gated sodium channels. Mutation I1011M was repeatedly detected in numerous pyrethroid-resistant Aedes aegypti populations from Latin American and Brazil. In addition, mutation G923V was first reported to coexist with I1011M in permethrin/DDT-resistant Ae. aegypti, whether G923V enhances the I1011M-mediated pyrethroid resistance in sodium channels remains unclear. In this study, we introduced mutations G923V and I1011M alone or in combination into the pyrethroid-sensitive sodium channel AaNav1-1 and examined the effects of these mutations on gating properties and pyrethroid sensitivity. We found mutations I1011M and G923V + I1011M shifted the voltage dependence of activation in the depolarizing direction, and none of mutations affect the voltage-dependence of inactivation. G923V and G923V + I1011M mutations reduced the channel sensitivity to both Type I and Type II pyrethroids. However, I1011M alone conferred resistance to Type I pyrethroids, not to Type II pyrethroids. Interestingly, significant synergism effects on Type I pyrethroids were observed between mutations G923V and I1011M. The effects of all mutations on channel sensitivity to DDT were identical with those to Type I pyrethroids. Our results confirm the molecular basis of resistance mediated by mutations G923V and I1011M and may contribute to develop molecular markers for monitoring pest resistance to pyrethroids.
Subject(s)
Aedes , Insecticide Resistance , Insecticides , Pyrethrins , Pyrethrins/pharmacology , Animals , Insecticide Resistance/genetics , Aedes/genetics , Aedes/drug effects , Insecticides/pharmacology , Glycine/pharmacology , Glycine/analogs & derivatives , Sodium Channels/genetics , Sodium Channels/metabolism , Sodium Channels/drug effects , Valine/genetics , Mutation , Amino Acid Substitution , Insect Proteins/genetics , Insect Proteins/metabolism , Protein DomainsABSTRACT
Background: The protective role of gut microbiota and its metabolites against intestinal damage in sepsis patients remain unclear. Methods: Fecal samples were acquired from patients categorized into sepsis and non-sepsis groups for analysis of microbial composition via 16S rRNA sequencing and untargeted metabolomics analysis. We assessed the impact of gut microbiota from sepsis patients on intestinal barriers in antibiotic-treated mice. Furthermore, We conducted spearman's correlation analysis to examine the relationship between metabolites and the severity of sepsis. Additionally, we performed animal experiments to validate the functionality of identified metabolites. Results: The diversity of intestinal flora is decreased in patients with sepsis compared to the control group. Through fecal microbiota transplantation experiments, it was discovered that the gut microbiota derived from sepsis patients could induce intestinal damage in antibiotic-treated mice. Metabolomics analysis of the microbiota revealed a significant enrichment of the Valine, leucine, and isoleucine biosynthesis pathway. Further analysis showed a significant decrease in the abundance of L-valine in sepsis patients, which was negatively correlated with APACHE-II and SOFA scores. In sepsis mouse experiments, it was found that L-valine could alleviate sepsis-induced intestinal damage. Conclusion: Alterations in microbial and metabolic features in the gut can affect the severity of sepsis. Furthermore, L-valine can protect against sepsis-induced intestinal injury.
Subject(s)
Gastrointestinal Microbiome , Sepsis , Valine , Gastrointestinal Microbiome/drug effects , Sepsis/microbiology , Animals , Mice , Humans , Valine/pharmacology , Valine/therapeutic use , Male , Female , Middle Aged , Fecal Microbiota Transplantation , Severity of Illness Index , Metabolomics/methods , Aged , Feces/microbiology , Disease Models, Animal , Mice, Inbred C57BL , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Intestines/microbiology , RNA, Ribosomal, 16S/geneticsABSTRACT
Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) affect the efficacy of direct-acting antivirals (DAAs). In this study, we aimed to clarify the susceptibility of the coexistence of nonstructural (NS) 5A Q24K/L28M/R30Q (or R30E)/A92K RASs, which were observed in patients with DAAs re-treatment failure and to consider new therapeutic agents. We used a subgenomic replicon system in which HCV genotype 1B strain 1B-4 was electroporated into OR6c cells derived from HuH-7 cells (Wild-type [WT]). We converted WT genes to NS5A Q24K/L28M/R30Q/A92K or Q24/L28K/R30E/A92K. Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Compared with the WT, the Q24K/L28M/R30E/A92K RASs was 640,000-fold resistant to daclatasvir and ledipasvir, 150,000-fold resistant to velpatasvir, 44,000-fold resistant to elbasvir, and 1500-fold resistant to pibrentasvir. The Q24K/L28M/R30E/A92K RASs was 816.3 times more resistant to pibrentasvir than the Q24K/L28M/R30Q/A92K RASs. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs.
Subject(s)
Antiviral Agents , Benzimidazoles , Drug Resistance, Viral , Hepacivirus , Imidazoles , Viral Nonstructural Proteins , Hepacivirus/drug effects , Hepacivirus/genetics , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/antagonists & inhibitors , Humans , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Drug Resistance, Viral/genetics , Drug Resistance, Viral/drug effects , Benzimidazoles/pharmacology , Imidazoles/pharmacology , Carbamates/pharmacology , Fluorenes/pharmacology , Sofosbuvir/pharmacology , Pyrrolidines/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Valine/analogs & derivatives , Valine/pharmacology , Genotype , Replicon/drug effects , Replicon/genetics , Sulfonamides/pharmacology , Benzofurans/pharmacology , Pyrazines/pharmacology , Benzopyrans , RNA-Dependent RNA PolymeraseABSTRACT
Pseudopeptides are emerging next-generation soft bioinspired materials for biological applications. Therefore, a new class of C2-symmetric L-valine-derived pseudopeptides has been designed and developed. The newly developed pseudopeptides exhibit intracellular Cu(II) ion detection in live-cell fluorescence studies on RAW264.7 cells. We find that the changes in the amino acid side chain in desired pseudopeptidic moieties lead to a drastic change in their selectivity towards different metal ions. The L-valine-derived pseudopeptides exhibit selectivity towards Cu(II) ions through turn-off fluorescence, and the L-phenylalanine-derived pseudopeptides exhibit selectivity towards Zn(II) ions through turn-on fluorescence. In addition, the L-valine-derived pseudopeptides show an increase in spherical-shaped structures upon incubation with Cu(II) ions during supramolecular nano-assembly formation. In contrast, the L-phenylalanine-derived pseudopeptides show a decrease in spherical-shaped structures upon adding Zn(II) ions. The judiciously designed L-valine-derived and L-phenylalanine-derived bioinspired pseudopeptides are promising for exploring similar effects in various peptidomimetics in advanced biological applications.
Subject(s)
Copper , Peptides , Copper/chemistry , Mice , Animals , Peptides/chemistry , Peptides/chemical synthesis , Nanostructures/chemistry , RAW 264.7 Cells , Phenylalanine/chemistry , Valine/chemistryABSTRACT
BACKGROUND: The link between diabetes mellitus and chronic hepatitis C infection remains well established. It is estimated that up to one third of chronic hepatitis C patients have type II diabetes mellitus. Hepatitis C virus infection is one of the main global health burdens. Sofosbuvir and Daclatasvir are used as effective antiviral inhibitors of hepatitis C virus. The cardiovascular effects of those drugs are not well studied. We used electrocardiography and echocardiography with global longitudinal strain assessment by speckle tracking to detect their effect on cardiac function. METHODS AND RESULTS: One hundred diabetic patients with hepatitis C infection were included in the study. Abdominal ultrasound and laboratory work up were carried out for all participants. Left ventricular systolic and diastolic function were assessed by 2D-echocardiography and global longitudinal strain, before and 3 months after treatment. Results showed significant decrease in global longitudinal strain 3 months after therapy (-21 ± 4 vs. -18 ± 7; P < 0.001) but other echocardiographic findings showed no significant changes. CONCLUSIONS: Sofosbuvir and Daclatasvir were associated with early left ventricular systolic dysfunction as assessed by global longitudinal strain in diabetic patients. More deterioration in left ventricular systolic function was detected among those with Child-Pough class B. Further long-term follow-up may be required.
Subject(s)
Antiviral Agents , Carbamates , Diabetes Mellitus, Type 2 , Hepatitis C, Chronic , Imidazoles , Pyrrolidines , Sofosbuvir , Valine , Ventricular Dysfunction, Left , Ventricular Function, Left , Humans , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/complications , Male , Female , Middle Aged , Sofosbuvir/therapeutic use , Sofosbuvir/adverse effects , Valine/analogs & derivatives , Valine/therapeutic use , Pyrrolidines/therapeutic use , Imidazoles/therapeutic use , Treatment Outcome , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/diagnosis , Carbamates/therapeutic use , Ventricular Function, Left/drug effects , Ventricular Dysfunction, Left/physiopathology , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/etiology , Ventricular Dysfunction, Left/diagnosis , Time Factors , Aged , Electrocardiography , AdultABSTRACT
We present a case of a primigravida in her 30s who had a caesarean delivery of dichorionic diamniotic twins at 33 weeks of gestation. Her postpartum course was complicated by a herpes simplex virus (HSV) infection of her nipple, found after her neonates were diagnosed with HSV encephalitis. She was evaluated at her 3-week postpartum visit and reported that her neonates were concurrently admitted to the neonatal intensive care unit with disseminated neonatal HSV-1. The patient and her partner were in a monogamous relationship with no known history of HSV. Physical examination demonstrated a vertical fissure on the face of her right nipple and a small cluster of vesicles on her left hand. PCR swabs of the lesions were positive for HSV-1 at both locations. The patient was started on oral valacyclovir 1000 mg two times per day, topical acyclovir ointment applied 4-6 times per day and mupirocin ointment applied 3 times per day to her breast with resolution of her breast lesions. She was able to continue expressing her breastmilk with the help of a pump and then resumed breastfeeding once her infection was cleared. Her infants recovered after prolonged parenteral antiviral therapy with age-appropriate development at follow-up.
Subject(s)
Acyclovir , Antiviral Agents , Encephalitis, Herpes Simplex , Herpes Simplex , Herpesvirus 1, Human , Nipples , Humans , Female , Antiviral Agents/therapeutic use , Antiviral Agents/administration & dosage , Infant, Newborn , Acyclovir/therapeutic use , Acyclovir/administration & dosage , Herpes Simplex/diagnosis , Herpes Simplex/drug therapy , Herpesvirus 1, Human/isolation & purification , Encephalitis, Herpes Simplex/diagnosis , Encephalitis, Herpes Simplex/drug therapy , Valacyclovir/therapeutic use , Valacyclovir/administration & dosage , Pregnancy Complications, Infectious/diagnosis , Adult , Pregnancy , Infectious Disease Transmission, Vertical , Valine/analogs & derivatives , Valine/therapeutic use , Valine/administration & dosage , Breast FeedingABSTRACT
BACKGROUND: Branched-chain amino acids (BCAAs) have been affected epilepsy, yet conclusions remain inconclusive, lacking causal evidence regarding whether BCAAs affect epilepsy. Systematic exploration of the causal relationship between BCAAs and epilepsy could hand out new ideas for the treatment of epilepsy. METHODS: Utilizing bidirectional Mendelian randomization (MR) study, we investigated the causal relationship between BCAA levels and epilepsy. BCAA levels from genome-wide association studies (GWAS), including total BCAAs, leucine levels, isoleucine levels, and valine levels, were employed. Causal relationships were explored applying the method of inverse variance-weighted (IVW) and MR-Egger, followed by sensitivity analyses of the results to evaluate heterogeneity and pleiotropy. RESULTS: Through strict genetic variant selection, we find some related SNPs, total BCAA levels (9), leucine levels (11), isoleucine levels (7), and valine levels (6) as instrumental variables for our MR analysis. Following IVW and sensitivity analysis, total BCAAs levels (OR = 1.14, 95 % CI = 1.019 â¼ 1.285, P = 0.022) and leucine levels (OR = 1.15, 95 % CI = 1.018 â¼ 1.304, P = 0.025) had significant correlation with epilepsy. CONCLUSIONS: There exists a causal relationship between the levels of total BCAAs and leucine with epilepsy, offering the new ideas into epilepsy potential mechanisms, holding significant implications for its prevention and treatment.
Subject(s)
Amino Acids, Branched-Chain , Epilepsy , Genome-Wide Association Study , Humans , Amino Acids, Branched-Chain/blood , Epilepsy/genetics , Isoleucine/genetics , Leucine/genetics , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Valine/geneticsABSTRACT
INTRODUCTION: Protonitazene is an opioid belonging to the 2-benzylbenzimidazole structural class. We describe two cases of opioid toxicity involving the reported inhalation of a delta-9-tetrahydrocannabinol vape product in which protonitazene was detected. CASE REPORTS: Case 1 was a young male found unconscious after the reported use of a delta-9-tetrahydrocannabinol vape. He suffered two subsequent apnoeic episodes requiring bag-valve-mask ventilation before eventual recovery. Only protonitazene was detected in blood at a concentration of 0.74 µg/L. Case 2 was a young male who died shortly after being found unresponsive. The postmortem femoral blood concentrations of protonitazene and delta-9-tetrahydrocannabinol were 0.33 µg/L and 2 µg/L, respectively. Analysis of a pod vaping device found in the decedent's hand and a separate e-liquid bottle labelled as delta-9-tetrahydrocannabinol showed a mixture of protonitazene and delta-9-tetrahydrocannabinol. DISCUSSION: The opioid effects of protonitazene are mediated through ß-arrestin2 and mu opioid receptor signalling pathways. Benzimidazole opioids are lipophilic and, when mixed with a suitable solvent, can be used in a vape device. It is anticipated that naloxone would have provided effective reversal of toxicity in our cases. CONCLUSIONS: Novel routes of opioid administration, like vaping, may appear relatively innocuous in comparison to intravenous administration, but opioids may still be absorbed at high concentrations, resulting in severe opioid toxicity or death.
Subject(s)
Dronabinol , Humans , Male , Dronabinol/blood , Adult , Analgesics, Opioid/poisoning , Analgesics, Opioid/blood , Vaping/adverse effects , Australia , Fatal Outcome , Young Adult , Benzimidazoles/poisoning , Indazoles/poisoning , Indazoles/blood , Valine/analogs & derivativesABSTRACT
Metabolic reprogramming and energetic rewiring are hallmarks of cancer that fuel disease progression and facilitate therapy evasion. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipid metabolism. Through the suppression of BCAA availability, we report significantly reduced lipid content, strongly indicating that BCAAs are important lipogenic fuels in PCa. This work also uncovered a novel compensatory mechanism, whereby fatty acid uptake is increased in response to extracellular valine deprivation. Inhibition of valine degradation via suppression of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) resulted in a selective reduction of malignant prostate cell proliferation, decreased intracellular succinate and impaired cellular respiration. In combination with a comprehensive multi-omic investigation that incorporates next-generation sequencing, metabolomics, and high-content quantitative single-cell imaging, our work highlights a novel therapeutic target for selective inhibition of metabolic reprogramming in PCa.
Subject(s)
Prostatic Neoplasms , Valine , Male , Humans , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms/genetics , Valine/pharmacology , Valine/metabolism , Cell Line, Tumor , Cell Proliferation , Mitochondria/metabolism , Amino Acids, Branched-Chain/metabolism , Lipid Metabolism/drug effects , Succinic Acid/metabolism , Metabolic ReprogrammingABSTRACT
It has been assumed that exercise intensity variation throughout a cycling time trial (TT) occurs in alignment of various metabolic changes to prevent premature task failure. However, this assumption is based on target metabolite responses, which limits our understanding of the complex interconnection of metabolic responses during exercise. The current study characterized the metabolomic profile, an untargeted metabolic analysis, after specific phases of a cycling 4-km TT. Eleven male cyclists performed three separated TTs in a crossover counterbalanced design, which were interrupted at the end of the fast-start (FS, 600 ± 205 m), even-pace (EP, 3600 ± 190 m), or end-spurt (ES, 4000 m) phases. Blood samples were taken before any exercise and 5 min after exercise cessation, and the metabolomic profile characterization was performed using Nuclear Magnetic Resonance metabolomics. Power output (PO) was also continually recorded. There were higher PO values during the FS and ES compared to the EP (all p < 0.05), which were accompanied by distinct metabolomic profiles. FS showed high metabolite expression in TCA cycle and its related pathways (e.g., glutamate, citric acid, and valine metabolism); whereas, the EP elicited changes associated with antioxidant effects and oxygen delivery adjustment. Finally, ES was related to pathways involved in NAD turnover and serotonin metabolism. These findings suggest that the specific phases of a cycling TT are accompanied by distinct metabolomic profiles, providing novel insights regarding the relevance of specific metabolic pathways on the process of exercise intensity regulation.
Subject(s)
Bicycling , Cross-Over Studies , Metabolome , Humans , Male , Metabolome/physiology , Adult , Bicycling/physiology , Citric Acid Cycle , Serotonin/blood , NAD/blood , NAD/metabolism , Young Adult , Glutamic Acid/blood , Glutamic Acid/metabolism , Metabolomics , Valine/blood , Citric Acid/bloodABSTRACT
Globin adducts of various chemicals, persisting in organism over the whole lifetime of erythrocytes, have been used as biomarkers of cumulative exposures to parent compounds. After removal of aged erythrocytes from the bloodstream, cleavage products of these adducts are excreted with urine as alternative, non-invasively accessible biomarkers. In our biomonitoring studies on workers exposed to ethylene oxide, its adduct with globin, N-(2-hydroxyethyl)valine, and the related urinary cleavage product N-(2-hydroxyethyl)-L-valyl-L-leucine have been determined. To describe a toxicokinetic relationship between the above types of biomarkers, a general compartmental model for simulation of formation and removal of globin adducts has been constructed in the form of code in R statistical computing environment. The essential input variables include lifetime of erythrocytes, extent of adduct formation following a single defined exposure, and parameters of exposure scenario, while other possible variables are optional. It was shown that both biomarkers reflect the past exposures differently as the adduct level in globin is a mean value of adduct levels across all compartments (subpopulations of erythrocytes of the same age) while excretion of cleavage products reflects the adduct level in the oldest compartment. Application of the model to various scenarios of continuous exposure demonstrated its usefulness for human biomonitoring data interpretation.
Subject(s)
Biological Monitoring , Biomarkers , Erythrocytes , Occupational Exposure , Humans , Biomarkers/urine , Biomarkers/blood , Erythrocytes/metabolism , Erythrocytes/drug effects , Models, Biological , Ethylene Oxide/toxicity , Ethylene Oxide/pharmacokinetics , Ethylene Oxide/urine , Toxicokinetics , Globins/metabolism , Valine/analogs & derivatives , Valine/pharmacokinetics , Valine/urine , Valine/blood , Computer SimulationABSTRACT
Central administration of valine has been shown to cause hyperphagia in fish. Although mechanistic target of rapamycin (mTOR) is involved in this response, the contributions to feed intake of central and peripheral metabolite changes due to excess valine are unknown. Here, we investigated whether intracerebroventricular injection of valine modulates central and peripheral metabolite profiles and may provide insights into feeding response in fish. Juvenile rainbow trout (Oncorhynchus mykiss) were administered an intracerebroventricular injection of valine (10 µg·µL-1 at 1 µL·100·g-1 body wt), and the metabolite profile in plasma, hypothalamus, and rest of the brain (composing of telencephalon, optic tectum, cerebellum, and medulla oblongata) was carried out by liquid chromatography-mass spectrometry (LC/MS)-based metabolomics. Valine administration led to a spatially distinct metabolite profile at 1 h postinjection in the brain: enrichment of amino acid metabolism and energy production pathways in the rest of the brain but not in hypothalamus. This suggests a role for extrahypothalamic input in the regulation of feed intake. Also, there was enrichment of several amino acids, including tyrosine, proline, valine, phenylalanine, and methionine, in plasma in response to valine. Changes in liver transcript abundance and protein expression reflect an increased metabolic capacity, including energy production from glucose and fatty acids, and a lower protein kinase B (Akt) phosphorylation in the valine group. Altogether, valine intracerebroventricular administration affects central and peripheral metabolism in rainbow trout, and we propose a role for the altered metabolite profile in modulating the feeding response to this branched-chain amino acid.NEW & NOTEWORTHY Valine causes hyperphagia in fish when it is centrally administered; however, the exact mechanisms are far from clear. We tested how intracerebroventricular injection of valine in rainbow trout affected the brain and plasma metabolome. The metabolite changes in response to valine were more evident in the rest of the brain compared with the hypothalamus. Furthermore, we demonstrated for the first time that central valine administration affects peripheral metabolism in rainbow trout.
Subject(s)
Hypothalamus , Oncorhynchus mykiss , Valine , Animals , Oncorhynchus mykiss/metabolism , Oncorhynchus mykiss/blood , Valine/pharmacology , Valine/administration & dosage , Hypothalamus/metabolism , Hypothalamus/drug effects , Metabolome/drug effects , Brain/metabolism , Brain/drug effects , Metabolomics , Injections, Intraventricular , Energy Metabolism/drug effectsABSTRACT
OBJECTIVE: This study aims to evaluate the efficacy and safety of JAK inhibitors in the treatment of patients with RA. METHODS: The databases CNKI, VIP, Wanfang, CBM, and PubMed, Embase, Cochrane Library and Web of Science were searched to identify relevant randomized controlled trials (RCTs), all from the time of database creation to April 2024. Screening, data extraction, and risk of bias assessment (using Review Manager-5.3 software) were independently performed by at least two authors. The network meta-analysis was conducted using R 4.1.3 software. PROSPERO registration number: CRD42022370444. RESULTS: Thirty-three RCTs included 15,961 patients The experimental groups involved six JAK inhibitors (filgotinib, tofacitinib, decernotinib, baricitinib, upadacitinib and peficitinib) and 12 interventions (different doses of the six JAK inhibitors), and the control group involved adalimumab (ADA) and placebo. Compared with placebo, all JAK inhibitors showed a significant increase in efficacy measures (ACR20/50/70). Compared with ADA, only tofacitinib, low-dose decernotinib, and high-dose peficitinib showed a significant increase in ACR20/50/70. Decernotinib ranked first in the SUCRA ranking of ACR20/50/70. In terms of safety indicators, only those differences between low-dose filgotinib and high-dose upadacitinib, low-dose tofacitinib and high-dose upadacitinib were statistically significant. Low-dose filgotinib ranked first in the SUCRA ranking with adverse events as safety indicators. Only the efficacy and safety of tofacitinib ranked higher among different SUCRA rankings. CONCLUSION: Six JAK inhibitors have better efficacy than placebo. The superior efficacy of decernotinib and safety of low-dose filgotinib can be found in the SUCRA. However, there are no significant differences in safety between the different JAK inhibitors. Head-to-head trials, directly comparing one against each other, are required to provide more certain evidence.
Subject(s)
Arthritis, Rheumatoid , Azetidines , Bayes Theorem , Janus Kinase Inhibitors , Network Meta-Analysis , Piperidines , Pyrimidines , Humans , Arthritis, Rheumatoid/drug therapy , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Piperidines/therapeutic use , Piperidines/adverse effects , Azetidines/therapeutic use , Azetidines/adverse effects , Purines/therapeutic use , Purines/adverse effects , Pyrroles/therapeutic use , Pyrroles/adverse effects , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Randomized Controlled Trials as Topic , Treatment Outcome , Heterocyclic Compounds, 2-Ring/therapeutic use , Heterocyclic Compounds, 2-Ring/adverse effects , Niacinamide/analogs & derivatives , Niacinamide/therapeutic use , Niacinamide/adverse effects , Benzamides/therapeutic use , Benzamides/adverse effects , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/adverse effects , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/adverse effects , Triazoles/therapeutic use , Triazoles/adverse effects , Triazoles/administration & dosage , Adamantane/analogs & derivatives , Pyridines , Valine/analogs & derivativesABSTRACT
Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched transcripts, among which hydroxyacyl-CoA dehydrogenase mRNA encodes for a key enzyme in fatty acid oxidation. Resistant melanoma cultures rely on fatty acid oxidation and hydroxyacyl-CoA dehydrogenase for their survival upon MAPK treatment. Together, our data demonstrate that VARS may represent an attractive therapeutic target for the treatment of therapy-resistant melanoma.
Subject(s)
Drug Resistance, Neoplasm , Melanoma , Animals , Humans , Mice , Amino Acyl-tRNA Synthetases/metabolism , Amino Acyl-tRNA Synthetases/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic , Melanoma/genetics , Melanoma/pathology , Melanoma/enzymology , Melanoma/drug therapy , Melanoma/metabolism , Protein Biosynthesis , Protein Kinase Inhibitors/pharmacology , Valine/metabolism , Valine/genetics , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: We previously reported that, among all the naturally occurring amino acids, L-valine is the most powerful luminal stimulator of glucagon-like peptide 1 (GLP-1) release from the upper part of the rat small intestine. This makes L-valine an interesting target for nutritional-based modulation of GLP-1 secretion. However, the molecular mechanism of L-valine-induced secretion remains unknown. METHODS: We aimed to investigate the effect of orally given L-valine in mice and to identify the molecular details of L-valine stimulated GLP-1 release using the isolated perfused rat small intestine and GLUTag cells. In addition, the effect of L-valine on hormone secretion from the distal intestine was investigated using a perfused rat colon. RESULTS: Orally given L-valine (1 g/kg) increased plasma levels of active GLP-1 comparably to orally given glucose (2 g/kg) in male mice, supporting that L-valine is a powerful stimulator of GLP-1 release in vivo (P > 0.05). Luminal L-valine (50 mM) strongly stimulated GLP-1 release from the perfused rat small intestine (P < 0.0001), and inhibition of voltage-gated Ca2+-channels with nifedipine (10 µM) inhibited the GLP-1 response (P < 0.01). Depletion of luminal Na+ did not affect L-valine-induced GLP-1 secretion (P > 0.05), suggesting that co-transport of L-valine and Na+ is not important for the depolarization necessary to activate the voltage-gated Ca2+-channels. Administration of the KATP-channel opener diazoxide (250 µM) completely blocked the L-valine induced GLP-1 response (P < 0.05), suggesting that L-valine induced depolarization arises from metabolism and opening of KATP-channels. Similar to the perfused rat small intestine, L-valine tended to stimulate peptide tyrosine-tyrosine (PYY) and GLP-1 release from the perfused rat colon. CONCLUSIONS: L-valine is a powerful stimulator of GLP-1 release in rodents. We propose that intracellular metabolism of L-valine leading to closure of KATP-channels and opening of voltage-gated Ca2+-channels are involved in L-valine induced GLP-1 secretion.
Subject(s)
Glucagon-Like Peptide 1 , Intestine, Small , KATP Channels , Valine , Animals , Glucagon-Like Peptide 1/metabolism , Male , Valine/pharmacology , Rats , Mice , Intestine, Small/metabolism , Intestine, Small/drug effects , KATP Channels/metabolism , Calcium Channels/metabolism , Colon/metabolism , Colon/drug effects , Mice, Inbred C57BL , Rats, WistarABSTRACT
Hepatitis C virus core antigen (HCVcAg) testing can simplify and decrease costs of HCV infection confirmation compared to molecular testing (nucleic acid testing). We piloted HCVcAg testing for the confirmation of active infection. The study was conducted during June through December 2022 among the police and the general population of Islamabad, Pakistan age 18 years and older. Initial screening for HCV antibody was conducted using a rapid diagnostic test (RDT) for all consenting participants. Those who tested positive had venous blood samples tested for HCVcAg, platelets and aspartate aminotransferase (AST). Persons with HCVcAg values ≥3 fmol/L were defined as viremic, and they were offered treatment with direct acting antiviral (DAA) medications, sofosbuvir and daclatasvir. Aspartate aminotransferase to platelet ratio index (APRI) was calculated for each HCV infected person, and those with an APRI score <1.5 received treatment for 12 weeks, while those with APRI ≥ to 1.5 received 24 weeks of treatment. A total of 15,628 persons were screened for anti-HCV using RDT and 643 (4.1%) tested positive. HCVcAg values of ≥3 fmol/L was found in 399/643 (62.1%), and all were offered and accepted treatment. Of those treated, 273/399 (68.4%) returned for a follow-up SVR and HCVcAg was not detected in 261/273, a 95.6% cure rate. The pilot study demonstrated the effectiveness of reaching and treating an urban population using RDT for screening and HCVcAg for confirmation of infection and test of cure.
Subject(s)
Antiviral Agents , Hepacivirus , Hepatitis C , Police , Humans , Pakistan/epidemiology , Male , Female , Adult , Middle Aged , Antiviral Agents/therapeutic use , Hepatitis C/diagnosis , Hepatitis C/drug therapy , Hepacivirus/genetics , Hepacivirus/immunology , Young Adult , Viral Core Proteins/blood , Hepatitis C Antigens/blood , Aged , Adolescent , Pilot Projects , Mass Screening/methods , Hepatitis C Antibodies/blood , Carbamates , Imidazoles , Pyrrolidines , Valine/analogs & derivativesABSTRACT
INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD. AREAS COVERED: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'ALZ-801' or 'valiltramiprosate.' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate's active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aß42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate's phase II biomarker trial show: (1) significant reductions in plasma p-tau181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion. EXPERT OPINION: Valiltramiprosate's clinical trial data show early indications of efficacy with potential disease modifying effect in AD.
Subject(s)
Alzheimer Disease , Prodrugs , Alzheimer Disease/drug therapy , Humans , Prodrugs/pharmacokinetics , Animals , Amyloid beta-Peptides/metabolism , Cyclopropanes/therapeutic use , Cyclopropanes/pharmacokinetics , Cyclopropanes/pharmacology , Cyclopropanes/administration & dosage , Drug Combinations , Peptide Fragments , Biological Availability , Half-Life , Valine/analogs & derivatives , Valine/pharmacokinetics , Valine/administration & dosage , Taurine/analogs & derivativesABSTRACT
Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an N-alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular N-alkylation (of the indole/indazole/7-azaindole core) ensures that novel SCRAs continue to enter the illicit drug market rapidly. In response to the large number of SCRAs that have been detected, pharmacological evaluation of this NPS class has become increasingly common. Adamantane-derived SCRAs have consistently appeared throughout the market since 2011, and as such, a systematic set of these derivatives was synthesized and pharmacologically evaluated. Deuterated and fluorinated adamantane derivatives were prepared to evaluate typical hydrogen bioisosteres, as well as evaluation of the newly detected AFUBIATA.
Subject(s)
Cannabinoid Receptor Agonists , Halogenation , Indazoles , Indoles , Cannabinoid Receptor Agonists/pharmacology , Cannabinoid Receptor Agonists/chemistry , Cannabinoid Receptor Agonists/chemical synthesis , Structure-Activity Relationship , Animals , Indazoles/pharmacology , Indazoles/chemistry , Indazoles/chemical synthesis , Humans , Indoles/pharmacology , Indoles/chemistry , Adamantane/analogs & derivatives , Adamantane/pharmacology , Adamantane/chemistry , Deuterium , Mice , Valine/analogs & derivativesABSTRACT
Ravidasvir (RDV) is a novel NS5A inhibitor that exhibits potent pan-genotypic inhibition of hepatitis C virus (HCV) replication. Sofosbuvir (SOF) plus RDV was demonstrated to be efficacious and safe in adults with active HCV infection, including those living with HIV (LWHIV), in the STORM-C-1 trial. We assessed the population pharmacokinetics (PK) of RDV in a sub-study nested within STORM-C-1 conducted in Thailand and Malaysia. SOF (400 mg) plus RDV (200 mg) was administered orally once daily for 12 weeks to adults with chronic HCV infection, but without cirrhosis and for 24 weeks to those with compensated cirrhosis. Intensive and sparse PK samples were collected at 4, 8, and 12 weeks after treatment initiation. Population PK parameters of RDV and the impact of covariates were evaluated using nonlinear mixed-effects modeling. Five hundred ninety-four participants were included, 235 (40%) had compensated cirrhosis, and 189 (32%) were LWHIV. RDV plasma concentrations were best described by a two-compartment model with first-order elimination. Oral clearance (CL/F) and volume of distribution (Vd/F) parameters were allometrically scaled on fat-free mass. Concomitant antiretroviral treatment (ART) increased RDV CL/F by 30%-60%, with efavirenz-based ART having the largest impact. Females had 16% lower RDV CL/F than males, and higher albumin levels reduced RDV central volume of distribution. While several covariates impact RDV CL/F and Vd/F, the effect on RDV exposures was not clinically relevant based on the efficacy data reported in this diverse Asian adult population. There were no meaningful drug-drug interactions in adults LWHIV on ART.