Pulmonary arterial hypertension nanotherapeutics: New pharmacological targets and drug delivery strategies.

Pulmonary arterial hypertension (PAH) is a rare, serious, and incurable disease characterized by high lung pressure. PAH-approved drugs based on conventional pathways are still not exhibiting favorable therapeutic outcomes. Drawbacks like short half-lives, toxicity, and teratogenicity hamper effectiveness, clinical conventionality, and long-term safety. Hence, approaches like repurposing drugs targeting various and new pharmacological cascades and/or loaded in non-toxic/efficient nanocarrier systems are being investigated lately. This review summarizes the status of conventional, repurposed, either in vitro, in vivo, and/or in clinical trials of PAH treatment. In-depth description, discussion, and classification of the new pharmacological targets and nanomedicine strategies with a description of all the nanocarriers that showed promising efficiency in delivering drugs are discussed. Ultimately, an illustration of the different nucleic acids tailored and nanoencapsulated within different types of nanocarriers to restore the pathways affected by this disease is presented.

Lipid carriers for mRNA delivery.

Messenger RNA (mRNA) is the template for protein biosynthesis and is emerging as an essential active molecule to combat various diseases, including viral infection and cancer. Especially, mRNA-based vaccines, as a new type of vaccine, have played a leading role in fighting against the current global pandemic of COVID-19. However, the inherent drawbacks, including large size, negative charge, and instability, hinder its use as a therapeutic agent. Lipid carriers are distinguishable and promising vehicles for mRNA delivery, owning the capacity to encapsulate and deliver negatively charged drugs to the targeted tissues and release cargoes at the desired time. Here, we first summarized the structure and properties of different lipid carriers, such as liposomes, liposome-like nanoparticles, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles, nanoemulsions, exosomes and lipoprotein particles, and their applications in delivering mRNA. Then, the development of lipid-based formulations as vaccine delivery systems was discussed and highlighted. Recent advancements in the mRNA vaccine of COVID-19 were emphasized. Finally, we described our future vision and perspectives in this field.

Gout therapeutics and drug delivery.

Gout is a common inflammatory arthritis caused by persistently elevated uric acid levels. With the improvement of people's living standards, the consumption of processed food and the widespread use of drugs that induce elevated uric acid, gout rates are increasing, seriously affecting the human quality of life, and becoming a burden to health systems worldwide. Since the pathological mechanism of gout has been elucidated, there are relatively effective drug treatments in clinical practice. However, due to (bio)pharmaceutical shortcomings of these drugs, such as poor chemical stability and limited ability to target the pathophysiological pathways, traditional drug treatment strategies show low efficacy and safety. In this scenario, drug delivery systems (DDS) design that overcome these drawbacks is urgently called for. In this review, we initially describe the pathological features, the therapeutic targets, and the drugs currently in clinical use and under investigation to treat gout. We also comprehensively summarize recent research efforts utilizing lipid, polymeric and inorganic carriers to develop advanced DDS for improved gout management and therapy.

Approved Nanomedicine against Diseases.

Nanomedicine is a branch of medicine using nanotechnology to prevent and treat diseases. Nanotechnology represents one of the most effective approaches in elevating a drug's treatment efficacy and reducing toxicity by improving drug solubility, altering biodistribution, and controlling the release. The development of nanotechnology and materials has brought a profound revolution to medicine, significantly affecting the treatment of various major diseases such as cancer, injection, and cardiovascular diseases. Nanomedicine has experienced explosive growth in the past few years. Although the clinical transition of nanomedicine is not very satisfactory, traditional drugs still occupy a dominant position in formulation development, but increasingly active drugs have adopted nanoscale forms to limit side effects and improve efficacy. The review summarized the approved nanomedicine, its indications, and the properties of commonly used nanocarriers and nanotechnology.

Hepatotoxic metabolites in Polygoni Multiflori Radix- Comparative toxicology in mice.

Polygoni Multiflori Radix (PM) and Rhei radix et rhizoma (rhubarb) contain similar hepatocyte-toxic anthraquinones such as emodin (major free anthraquinone in PM), physcion and their glycosides. In clinical practice, PM hepatotoxicity has been widely reported, although rhubarb is not recognized as hepatotoxic. To clarify the substances basis (key components) of PM hepatotoxicity, based on the characteristic components' similarity within PM, rhubarb and their concocted forms, a comparative sub-acute toxicity study was designed in mice. Nine groups of mice with 28 days of oral administration of these herbal extracts or 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG, major and unique characteristic component in PM)-herb combinations were set as follows: Group-1, control; Group-2, PM ethanol-extract (PME); Group-3, PM praeparata ethanol-extract (PMPE); Group-4, Rhubarb ethanol-extract (RME); Group-5, Steamed rhubarb ethanol-extract (RMPE); Group-6, TSG; Group-7, PMPE-TSG combination; Group-8, RME-TSG combination; Group-9, RMPE-TSG combination. Each experimental group received an equivalent emodin dose of 29 mg/kg except for the TSG group, and an equivalent TSG dose of 1,345 mg/kg except for the PMPE, RME and RMPE groups. The results showed that PME, PMPE-TSG and RME-TSG induced liver lesions and biochemical abnormalities of liver function compared with the control. In contrast, PMPE, RME, RMPE, TSG and RMPE-TSG caused no liver lesions and fewer biochemical abnormalities. Considering the related components, only the co-administration of high doses of TSG and emodin-8-O-ß-D-glucoside (EMG, major anthraquinone glycoside in PM) in these groups could cause liver lesions. According to tissue distribution and correlation analysis, EMG dose was positively correlated with the high hepatic emodin and TSG exposure, and the hepatic emodin and TSG exposure were positively correlated with the biochemical abnormalities of liver function. Cell viability test in vitro showed emodin was more hepatotoxic than TSG and EMG, and mainly emodin and TSG of the three had synergistic hepatotoxic effects. Therefore, creatively using rhubarb as a reference, this study revealed that PM hepatotoxicity in mice mainly came from the integrative contribution of TSG, EMG and emodin.

Pharmacovigilance of Herb-Drug Interactions: A Pharmacokinetic Study on the Combined Administration of Tripterygium Glycosides Tablets and Leflunomide Tablets in Rats by LC-MS/MS.

A popular and widely used combination therapy of leflunomide (LEF) and Tripterygium glycosides tablets (TGTS) has become a valuable clinical tool in China for the treatment of rheumatoid arthritis. This regimen has not been evaluated either in terms of interaction or toxicity, even given the rising concerns about LEF's prolonged elimination half-life and TGT's narrow therapeutic index, in addition to the current trend of using high doses of LEF. Thus, this study determines the potential adverse drug reactions between these two medicines. Reliable validated LC-MS/MS methods were used for the determination of teriflunomide (TER, the only active metabolite of LEF), and the main components of TGT: wilforlide A, wilforgine, wilfortrine, wilfordine, and wilforine. The results obtained from this investigation, as paralleled with the control groups, revealed that the Cmax and AUC0-t of TER were significantly decreased with separate co-administration, as the Cmax and AUC0-t were 30.17 ± 1.55 µg/mL and 24.47 ± 2.50 µg/mL, 374.55 ± 15.54 µg h/mL and 336.94 ± 21.19 µg h/mL, respectively (p < 0.05). Meanwhile, the pharmacokinetic profiles of the main components of TGT have also been affected by separate co-administration in rats. Therefore, herb−drug interactions between LEF and TGT have been proven.

Simultaneous determination of nirmatrelvir and ritonavir in human plasma using LC-MS/MS and its pharmacokinetic application in healthy Chinese volunteers.

Paxlovid, a copackaged medication of nirmatrelvir tablets (150 mg) and ritonavir tablets (100 mg) developed by Pfizer, is one of the first orally accessible COVID-19 antiviral medicines to be approved for emergency usage. In this research, an efficient LC-MS/MS method for simultaneous determination of nirmatrelvir and ritonavir in human plasma was established and validated with remdesivir as an internal standard. Chromatographic separations were carried out on a Thermo BDS Hypersil C18 column (4.6 × 100 mm, 2.4 µm) using deionized water and methanol as mobile phase, both added with 0.1% (v/v) formic acid. Based on the positive electrospray ionization mode, nirmatrelvir and ritonavir were analyzed by selective reaction monitoring. Excellent precision, accuracy, recovery, and linearity were demonstrated, covering the range of 50-5000 ng/mL for nirmatrelvir and 10-1000 ng/mL for ritonavir. Then, the established method was used for determining the pharmacokinetic profile of Paxlovid in healthy Chinese volunteers. The pharmacokinetic parameters, including Cmax , Tmax , t1/2 , and AUC0 - ∞ of Western volunteers, correspond well with the results of this pharmacokinetic investigation.

Differences in Multicomponent Pharmacokinetics, Tissue Distribution, and Excretion of Tripterygium Glycosides Tablets in Normal and Adriamycin-Induced Nephrotic Syndrome Rat Models and Correlations With Efficacy and Hepatotoxicity.

Tripterygium glycosides tablets (TGT) are widely used for treating nephrotic syndrome (NS), but hepatotoxicity is frequently reported. The presence of underlying disease(s) can alter the disposition of drugs and affect their efficacy and toxicity. However, no studies have reported the impact of NS on the ADME profiles of TGT or its subsequent impact on the efficacy and toxicity. Thus, the efficacy and hepatotoxicity of TGT were evaluated in normal and NS rats after oral administration of TGT (10 mg/kg/day) for 4 weeks. The corresponding ADME profiles of the six key TGT components (triptolide (TPL), wilforlide A (WA), wilforgine (WFG), wilfortrine (WFT), wilfordine (WFD), and wilforine (WFR)) were also measured and compared in normal and NS rats after a single oral gavage of 10 mg/kg TGT. Canonical correlation analysis (CCA) of the severity of NS and the in vivo exposure of the six key TGT components was performed to screen the anti-NS and hepatotoxic material bases of TGT. Finally, the efficacy and hepatotoxicity of the target compounds were evaluated in vitro. The results showed that TGT decreased the NS symptoms in rats, but caused worse hepatotoxicity under the NS state. Significant differences in the ADME profiles of the six key TGT components between the normal and NS rats were as follows: higher plasma and tissue exposure, lower urinary and biliary excretion, and higher fecal excretion for NS rats. Based on CCA and in vitro verification, TPL, WA, WFG, WFT, WFD, and WFR were identified as the anti-NS material bases of TGT, whereas TPL, WFG, WFT, and WFD were recognized as the hepatotoxic material bases. In conclusion, NS significantly altered the ADME profiles of the six key TGT components detected in rats, which were related to the anti-NS and hepatotoxic effects of TGT. These results are useful for the rational clinical applications of TGT.

Identification of degradation products in flumazenil using LC-Q-TOF/MS and NMR: Degradation pathway elucidation.

Flumazenil is an imidazobenzodiazepine derivative that antagonizes the actions of benzodiazepines. The degradation pathway elucidation plays an important role in the drug quality control. In this work, a reliable LC-Q-TOF/MS method was developed to separate and identify the degradation products of flumazenil generated in the stress testing conducted according to the ICH Q1A(R2) guideline. Fifteen degradation products were detected in total including three reported impurities and twelve unknown impurities. Based on the chromatographic and mass spectrometric data acquired, the structures of all the degradation products were identified. Besides, two major degradants were synthetized and further confirmed by NMR. The degradation pathways of flumazenil were elucidated, and the degradation characteristics of benzodiazepines were also discussed. The obtained results are of both great importance for the quality control of flumazenil and good reference for the degradation study of other benzodiazepines.

Jatrorrhizine: a review of its pharmacological effects.

OBJECTIVES: Jatrorrhizine is an isoquinoline alkaloid found in medicinal plants. It is the main bioactive compound of the Chinese herbs, Coptis chinensis, Rhizoma coptidis, and Phellodendron chinense Schneid, plants that are predominantly used in traditional Chinese medicine (TCM) for the treatment of metabolic disorders, gastritis, stomachache among a host of others. This manuscript aims to provide a comprehensive review of the pharmacological effects of jatrorrhizine, proffer suggestions on research areas that need redress and potentially serve as a reference for future studies. KEY FINDINGS: Published scientific literature was therefore retrieved from all credible sources including Pubmed, Elsevier, Research Gate, Web of Science, Google Scholar, Science Direct, Europe PMC and Wiley Online library using key words such as 'jatrorrhizine', 'botanical sources', 'pharmacology', 'toxicology', 'pharmacokinetics' or their combinations. A cursory examination of relevant scientific literature using the aforementioned key words produced more than 400 publications. CONCLUSIONS: Using an inclusion/exclusion criteria the subject matter of this review was adequately addressed. It is our hope that this review will provide a good platform for further research on fully harnessing the potential of this bioactive compound.