Medicine in Drug Discovery最新文献

In the etiology of nosocomial infections, the leading role belongs to such microorganisms as Staphylococcus aureus. Insufficient effectiveness of antimicrobial chemotherapy and practical absence of drugs with an antibiofilm activity encourage the development of new remedies. The study presents results on antibiofilm activity of the adamantane derivative 1-[4-(1-adamantyl)phenoxy]-3-(N-benzyl,N-dimethylamino)-2-propanol chloride (KVM-97) against methicillin-resistant S. aureus (MRSA) and the effect of this agent on the expression genes that provide regulatory and biosynthetic functions of biofilms. The ability of adamantane derivative to affect S. aureus biofilms was tested by microtiter dish biofilm formation assay. The effect of KVM-97 on expression level of genes icaA, icaD, icaR, agrA, sarA, clfB, fib, fnbB, ebpS, and eno was detected by the real-time PCR. The KVM-97 inhibits the formation of S. aureus biofilms at 5.0 MIC by 95.1 % and at 0.5 MIC – by 22.4 %. Under the action of KVM-97, destruction of the mature biofilms was not detected. It inhibits expression of the icaADBC operon and agrA gene, as well as stimulates a transcriptional activity of the icaR regulator. Subinhibitory concentrations of the KVM-97 significantly inhibit the expression of clfB, fib, fnbB, ebpS, and eno, but does not change the sarA gene expression. Thus, 1-[4-(1-adamantyl)phenoxy]-3-(N-benzyl,N-dimethylamino)-2-propanol chloride shows pronounced antibiofilm activity against MRSA at the early stages of the biofilm forming. This effect may be relating to influence on the expression of genes that regulate adhesion to the substrate and formation of S. aureus biofilms.

Cancer patients have a shorter life expectancy because of metastasis, which is the dynamic chain of events that leads to the spread of tumour cells to distant places inside the body. Cancer's development, spread, metastasis, and treatment all involve fluid mechanics in some way. Cancer cells and their associated components take advantage of the body's many fluid systems as a means of dissemination throughout the body and colonisation of distant organs. Cancerous tissues rely on the blood supply for oxygen and nutrition, metastasis to other organs, and medication delivery. Cancer cells' ability to travel from the main tumour, extravasate, and seed metastases can be enhanced by exploiting the flow mechanics of the blood and lymphatic circulatory systems. Cancer cell survival in the circulation and the regulation of organotropic seeding patterns are affected by flow rates, channel size, and shear stress. Therefore, cancer cells not only use these fluids as a mode of transport throughout the body, but also as a fertile ground to seed distant metastases by taking advantage of the fundamental physical forces among these fluids. Metastasis, tumor growth, & nanoparticle-mediated medication delivery is all under the control of multiscale flow-structure interaction processes, whereas an increase in interstitial pressure is caused by the tumour vasculature's irregularity and leakiness. This Review discusses the role that fluids play in metastasis, including the forces and stresses that are utilised by circulating tumour cells & tumour-associated factors. Given the intriguing concerns raised by the role of physiological fluids and their mechanics in the biology of the metastatic cascade, gaining insight into this process may reveal a novel strategy for intercepting cancer cells on their route.

Only 5% of orphan diseases have approved drugs, leading to a high demand for new treatment. As a result, pharmaceutical companies have shifted their focus of drug development to orphan diseases. This study conducted a database search to analyze the modality and development strategy of orphan drugs approved by the Food and Drug Administration from 2011 to 2022. The analysis showed that the modalities used for orphan drugs have diversified with increasing emergence of nucleic acid drugs, gene therapies, cell therapies, antibody drugs including next-generation antibodies, and engineered proteins, suggesting that modality diversification enhances the drug development for orphan diseases that are otherwise challenging to treat with conventional drugs. The ratio of orphan drugs targeting only a single disease has increased, likely due to the emergence of gene-specific treatments such as nucleic acid drugs and gene therapies. Moreover, this study found that orphan drugs using different modalities have been competitively developed with the same mechanism of action targeting only a single orphan disease in recent years. In several cases, small-molecule drugs with unique characteristics offer advantages such as dosing convenience and non-genetic patient coverage over nucleic acid drugs, antibody drugs, and gene therapy. These trends suggest the importance of modality technology development and advancement of small molecule optimization technology for future orphan drug development.

Atrial fibrillation (AF) is a life-changing and life-threatening cardiac electropathological condition, especially in patients with prior history of cardiovascular diseases. This multifaceted condition is one of the top 5 leading causes of cardiovascular death with a rapidly increasing prevalence and death rate. From inception till now, numerous clinical trials have been conducted to explore novel therapeutic targets and strategies along with pre-existing treatments for patients suffering from atrial fibrillation. The pharmacotherapy approach to treat AF (acute, chronic, persistent, paroxysmal, non-valvular, nonrheumatic, and rapid) comprises mainly antiarrhythmic drugs (AAD) and anticoagulant drugs (ACD) for rate and rhythm control along with the prevention of strokes. This narrative review aims to discuss monotherapeutic clinical trials that compared AADs (class II: carvedilol and xamoterol; class III: amiodarone; class IV: verapamil, diltiazem, and nifedipine) and ACDs (vitamin K antagonist: warfarin; factor Xa inhibitor: apixaban; factor IIa and Xa inhibitor: heparin) with cardiac glycoside (digoxin), angiotensin II receptor antagonist (telmisartan), platelet inhibitor (indobufen), anti-convulsant (magnesium sulfate), anti-inflammatory (aspirin), and antipyretic drugs (aspirin) to treat various types of AF in patients with a diverse history of cardiovascular diseases. This study provides a review of all clinical trials on this topic and provides a comparative chart for healthcare professionals to determine the best-suited treatment for their patients.

Obesity impacts pharmacokinetic and pharmacodynamic parameters, changing the drug-binding state via plasma proteins, which is critical for drug effectiveness and toxicity. Albumin and α1-acid glycoprotein (AAG) are the two main proteins accountable for drug binding in humans. Previous studies have shown higher values of AAG in individuals with obesity, but the interference of AAG in the pharmacokinetics of drugs remains unclear. We, therefore, aimed to analyze the pharmacotherapeutic profile and interfering factors in patients undergoing bariatric surgery in the pre-operative period and after 12 months. A retrospective cross-sectional study design was conducted and serum AAG was determined, and potential drug-drug interactions were monitored in patients with severe obesity who underwent bariatric surgery. The drug classes most used were antidepressants, cardiovascular agents, and lipid-modifying agents, with a decrease in use after 12 months of surgery. Before surgery, it was found that more than half of the patients had at least one drug interaction in their therapeutic regimen. Of these, most were classified as moderate. After surgery, a decrease in drug interaction was observed. Serum AAG showed a significant reduction after 12 months, which can influence the free fraction of drugs with a high-affinity rate and how they impact therapeutic efficacy.

Toxoplasmosis is a disease requiring therapeutic innovation, and thiosemicarbazones with antimicrobial activity are candidates to control Toxoplasma gondii infection. Here, the anti-T. gondii activities of (E)-2-(1-(4-chlorophenylthio)propan-2-ylidene)-hydrazinecarbothioamides (Ca and Cb) were investigated. T. gondii-infected macrophages (MOs) or glial cells treated with Ca or Cb showed a decrease in the number of intracellular parasites. A deficiency in the chemokine receptor CCR2, but not CCR5, partially reduced anti-T. gondii activity induced by Ca or Cb. In contrast, a deficiency in 5-lipoxygenase (5-LO) activity potentiated anti-T. gondii activities induced by these compounds. In vivo treatment with Ca increased the survival of T. gondii-infected wild-type mice, and this was associated with increased IFN-γ and IL-12 production. A deficiency in CCR5 or CCR2 abolished the protective effect of Ca treatment in vivo, while a deficiency in 5-LO increased Cb anti-T. gondii effects. Collectively, our data suggest that Ca and Cb are potential therapeutic candidates for the treatment of toxoplasmosis.

Significant progress in understanding cancer pathogenesis, it remains one of the leading causes of death after cardiovascular diseases. Similarly viral infections have emerged from wildlife or re-emerged, generating serious threats to the global health. As a result, there is an urgent need for the development of novel, more effective anticancer and antiviral therapeutics. Scientists, medicinal chemists and researchers are continuously finding novel targets, mechanisms and molecules against theses severe and dangerous infections. Therefore, ongoing extensively study and research emphasizes 1,3,4 thiadiazole pharmacophore have versatile pharmacological actions. Due to mesoionic behaviour of 1,3,4 thiadiazole pharmacophore allows to enter and easily cross biological membrane which allow to interact various biological proteins. In this review study an attempt has been made of various mechanisms involved in cancer and viral prevalence with updated studies done so far. This review study also findings the role of 1,3,4 thiadiazole motif in the management of various cancers and viral infection. This study also highlighting research statics on clinical trials and various patents containing 1,3,4 thiadiazole derivatives.

Nowadays, combining multiple drugs is the optimal therapy to decelerate the pathologic process, which contains various underlying adverse effects due to drug-drug interactions (DDIs). Artificial intelligence (AI) has the potential to evaluate the interaction, pharmacodynamics, and possible side effects between drugs. Over the past years, many AI-based DDI prediction techniques, including both machine learning and deep learning, that harness available big data have been presented. Although significant progressives have been gained through previous methods, improvements are still crucial. In this work, we introduce an ensemble deep neural network that can help to improve the predictive performance of DDIs. As a result, our prediction model could predict 86 types of DDIs on a benchmark dataset with an average accuracy of 93.80%. Our ensemble classifier produces better performance when compared with the existing proposed methods on the same dataset. Our model's high performance places it among the top list of those well-built pharmacovigilance-assisted tools that facilitate the detection of DDIs to support medical decisions and drug development. We released our source codes and models at https://github.com/khanhlee/edn-ddi.

There is mounting evidence that cancer patients co-administer herbal drugs with chemotherapy, however, information on the pharmacodynamic (PD) effects of such combination therapy is scarce. Natural products including crude extracts, herbal formulas, and bioactive compounds from plants hold great potential to prevent and treat cancers. More importantly, some herbal drugs can reduce the incidence of chemotherapy-induced toxicity including oral mucositis, gastrointestinal toxicity, hepatotoxicity etc. This review focuses on the effectiveness of some herbal products as adjuvant therapy and describes the possible mechanisms of chemo-herbal drug PD interactions in enhancing the efficacy/ or reducing the side effects of chemotherapy. We also highlighted recent advances in preclinical in vitro and in vivo studies to establish the effectiveness of herbal medicine to enhance efficacy or counteract chemotherapy-induced side effects. In addition, we draw particular attention to the synergistic effects of chemo-herbal drug combination therapy to prevent and treat cancers using evidence from clinical trials. We concluded that herbal drugs hold great potential as adjuvant therapy for the prevention and treatment of chemotherapy-induced side effects. It is important to also highlight that the clinical evidence on chemo-herbal drug combination therapy is limited. There is an urgent need for an in-depth PD evaluation including the safety pharmacology of chemo-herbal drug combination therapy as well as reliable evidence from multicentre clinical trials to establish the beneficial or negative effects of chemo-herbal drug combination therapy in the ongoing fight against cancer.

Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) induced cytokine storm is the major cause of COVID-19 related deaths. Patients have been treated with drugs that work by inhibiting a specific protein partly responsible for the cytokines production. This approach provided very limited success, since there are multiple proteins involved in the complex cell signaling disease mechanisms. We targeted five proteins: Angiotensin II receptor type 1 (AT1R), A disintegrin and metalloprotease 17 (ADAM17), Nuclear Factor‑Kappa B (NF‑κB), Janus kinase 1 (JAK1) and Signal Transducer and Activator of Transcription 3 (STAT3), which are involved in the SARS‑CoV‑2 induced cytokine storm pathway. We developed machine-learning (ML) models for these five proteins, using known active inhibitors. After developing the model for each of these proteins, FDA-approved drugs were screened to find novel therapeutics for COVID‑19. We identified twenty drugs that are active for four proteins with predicted scores greater than 0.8 and eight drugs active for all five proteins with predicted scores over 0.85. Mitomycin C is the most active drug across all five proteins with an average prediction score of 0.886. For further validation of these results, we used the PyRx software to conduct protein–ligand docking experiments and calculated the binding affinity. The docking results support findings by the ML model. This research study predicted that several drugs can target multiple proteins simultaneously in cytokine storm-related pathway. These may be useful drugs to treat patients because these therapies can fight cytokine storm caused by the virus at multiple points of inhibition, leading to synergistically effective treatments.