Decoding hereditary spastic paraplegia pathogenicity through transcriptomic profiling.

Hereditary spastic paraplegia (HSP) is a group of genetic motor neuron diseases resulting from length-dependent axonal degeneration of the corticospinal upper motor neurons. Due to the advancement of next-generation sequencing, more than 70 novel HSP disease-causing genes have been identified in the past decade. Despite this, our understanding of HSP physiopathology and the development of efficient management and treatment strategies remain poor. One major challenge in studying HSP pathogenicity is selective neuronal vulnerability, characterized by the manifestation of clinical symptoms that are restricted to specific neuronal populations, despite the presence of germline disease-causing variants in every cell of the patient. Furthermore, disease genes may exhibit ubiquitous expression patterns and involve a myriad of different pathways to cause motor neuron degeneration. In the current review, we explore the correlation between transcriptomic data and clinical manifestations, as well as the importance of interspecies models by comparing tissue-specific transcriptomic profiles of humans and mice, expression patterns of different genes in the brain during development, and single-cell transcriptomic data from related tissues. Furthermore, we discuss the potential of emerging single-cell RNA sequencing technologies to resolve unanswered questions related to HSP pathogenicity.

Screening of Bioequivalent Extended-Release Formulations for Metformin by Principal Component Analysis and Convolution-Based IVIVC Approach.

Bioequivalence (BE) is usually hard to achieve for extended-release (ER) dosage form products due to not only its complicated formulation but also to the BCS classification of the investigated drugs. Considering the difficulties in establishing full-scale IVIVC and limited in vivo pharmacokinetics data in the early stage of formulation development, we have selected BCS III drug metformin as a model drug to demonstrate a novel approach for the selection of BE formulations. Firstly, dissolution tests in both standard and biorelevant media were performed followed by identification of the most similar formulation WM to the reference product (GXR) based on principal component analysis (PCA) of the dissolution data. Then, we developed an IVIVC model using the reported GXR pharmacokinetics profiles via a convolution-based approach. Based on our established IVIVC and in vitro dissolution profiles of generic metformin ER products, we were able to predict their in vivo pharmacokinetic profiles and quantitatively compare the differences in AUC and Cmax to ensure the correct selection of BE product. Finally, the selection of WM as the BE formulation of GXR was confirmed with a pilot BE study in healthy volunteers under fasting state. Moreover, the in vivo data from the fed state study were further integrated into our IVIVC model to identify FeSSIF-V2 as the biorelevant media for WM. Our novel integrative approach of PCA with a convolution-based IVIVC was successfully adopted for the screening of the BE metformin ER formulation and such an approach could be further utilized for the effective selection of BE formulation for other drugs/formulations with complex in vivo absorption processes.

Is it safe to take Radix Salvia Miltiorrhiza - Radix Pueraria Lobate product with warfarin and aspirin? A pilot study in healthy human subjects.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix Salvia Miltiorrhiza (Danshen) and Radix Pueraria Lobate (Gegen) are officially listed in the Chinese Pharmacopoeia and have long been used together as a Compound Chinese Traditional Medicine (CCTM) for treatment of coronary heart diseases, which are often co-administered with aspirin or warfarin to patients suffering from cardiovascular diseases. AIM OF STUDY: Since significant pharmacokinetic and pharmacodynamic interactions between Danshen-Gegen (DG) formula and aspirin/warfarin have been observed in our previous rat studies, the current study was proposed aiming to further verify such pharmacokinetic and pharmacodynamic interactions in healthy human subjects and explore related mechanisms. MATERIALS AND METHODS: A 5-day, multiple dose, five-session clinical trial has been carried out (n = 14) with 2-week washout periods between sessions, during which the subjects would receive different combinations of the medications. Plasma samples were collected for pharmacokinetic evaluation, and whole blood samples were collected for pharmacodynamic evaluation. In addition, an in-vitro mechanistic study is conducted to investigate the role of danshensu on the anti-thrombotic and anti-platelet aggregation effects of warfarin and aspirin respectively. RESULTS: Significant pharmacokinetic and pharmacodynamic herb-drug interactions were observed in healthy human subjects. pharmacokinetically, co-administration of DG with aspirin or warfarin could lead to a moderately increased AUC0→t of aspirin and a decreased AUC0→t of 7-hydroxyl warfarin respectively. The systemic exposure of danshensu (DSS, the marker component of DG) would be significantly increased after co-administration with warfarin. Pharmacodynamically, a reduction in systemic thromboxane B2 concentration was noticed after administration of DG with aspirin, which could be associated with the increased systemic exposure of aspirin and the synergistic effect of danshensu, aspirin and salicylic acid on cyclooxygenase (COX) inhibition. An offset on the warfarin induced soluble thrombomodulin induction was observed after its co-administration with DG, which could be partially attributed to the COX-2 inhibition effect of danshensu. CONCLUSION: Our results indicated that co-administration of DG with aspirin/warfarin would lead to significant pharmacokinetic and pharmacodynamic herb-drug interactions in healthy human subjects.

Evaluation of potential herb-drug interactions between oseltamivir and commonly used anti-influenza Chinese medicinal herbs.

ETHNOPHARMACOLOGICAL RELEVANCE: According to Traditional Chinese Medicine theory, influenza is categorized as a warm disease or Wen Bing. The Wen Bing formulas, such as Yin-Qiao-San and Sang-Ju-Yin, are still first-line herbal therapies in combating variant influenza virus. To continue our study on the pharmacokinetic and pharmacodynamic interactions between Wen Bing formulas and oseltamivir (OS), the first-line western drug for the treatment of influenza, further interactions between OS and the eight single herbs and their relevant marker components from Wen Bing formulas were investigated in the current study. AIM OF STUDY: To establish an in-vitro screening platform for investigation of the potential anti-influenza herbs/herbal components that may have pharmacokinetic and pharmacodynamic interactions with OS. MATERIALS AND METHODS: To screen potential inhibition on OS hydrolysis, 1 µg/mL of OS is incubated with herbs/herbal components in diluted rat plasma, microsomes and human recombinant carboxylesterase 1(hCE1) under optimized conditions. MDCK-WT and MDCK-MDR1 cell lines are utilized to identify potential modification on P-gp mediated transport of OS by herbs/herbal components. Caco-2 cells with and without Gly-Sar inhibition are performed to study the uptake of OS via PEPT1 transporters. Modification on OAT3 mediated transport is verified by the uptake of OS on HEK293-MOCK/HEK293-OAT3 cells. Anti-virus effects were evaluated using plaque reduction assay on H1N1 and H3N2 viruses. Potential pharmacokinetic and pharmacodynamic interaction between OS (30 mg/kg) and the selected herb, Radix Scutellariae (RS), at 300-600 mg/kg were carried out on rats. All samples are analyzed by an LC/MS/MS method for the contents of OS and OSA. A mechanistic PK model was developed to interpret the HDI between OS and RS in rats. RESULTS: Our developed platform was successfully applied to screen the eight herbal extracts and their ten marker components on metabolic inhibition of OS and modification of OS transport mediated by P-gp, OAT3 and PEPT1. Results from six in-vitro experiments were analyzed after converting raw data from each experiment to corresponding fold-change (FC) values, based on which Radix Scutellariae (RS) were selected to have the most HDI potential with OS. By analyzing the plasma and urine pharmacokinetic data after co-administration of OS with a standardized RS extract in rats using an integrated population pharmacokinetics model, it is suggested that RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which leads to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine. Never the less, the anti-virus effects of 2.5 h post-dose rat plasma were not influenced by co-administration of OS with RS. CONCLUSION: A six-dimension in-vitro screening platform has been developed and successfully applied to find RS as a potential herb that would influence the co-administrated OS in rats. Although co-administered RS could inhibit OS hydrolysis during absorption and increase the absorbed fraction of OS, which lead to the increased ratio of OS concentration versus that of OSA in both rat plasma and urine, the anti-virus effect of OS was not influenced by co-administered RS.

Piperine-loaded nanoparticles with enhanced dissolution and oral bioavailability for epilepsy control.

Piperine, an alkaloid from black pepper, has demonstrated beneficial effects in central nervous system, especially in epilepsy control. However, its therapeutic application remains limited due to the low aqueous solubility of piperine. Thus, the present study aimed to formulate piperine into a more solubilized form to enhance its oral bioavailability and facilitate its development as a potential anti-epileptic treatment. The nanoprecipitation method was applied to prepare piperine nanoparticles, which were then examined under transmission electron microscopy. A spherical nanosized particle was obtained with small particle size (average particle size 130.20 ±â€¯1.57 nm), narrow size distribution (polydispersity index 0.195 ±â€¯0.002) and efficient entrapment (entrapment efficiency 92.2 ±â€¯2.5%). Compared with the unformulated piperine, nanosized piperine had a much faster dissolution rate with 3 times higher accumulated drug release after 24 h. After oral administration at 3.5 mg/kg in rats, the nanosized piperine formulations could improve its oral bioavailability by 2.7-fold with 16 times higher concentrations in brain at 10 h postdosing. Moreover, the piperine nanoparticles exhibited effective protection against pentylenetetrazol-induced seizures in both zebrafish and mice. In summary, the present study provided a simple formulation strategy for oral administration of piperine to overcome its limitation in water solubility. The developed formulations could effectively enhance oral bioavailability of piperine with promising anti-epileptic effect, which could be applied as a potential therapy in epilepsy control.