Drug Design, Development and Therapy最新文献

Trofinetide is a first-in-class pharmacological treatment proposed for patients with Rett Syndrome. It is a long half-life derivative of glycine-proline-glutamate, the tripeptide normally excided from Insulin-like Growth Factor 1 upon degradation. Due to containing glutamate and glycine in its structure, trofinetide is thought to act through NMDA receptor modulation, thus providing a normalization of neuronal activity and survival. Trofinetide was tested in a series of short and long-term trials, showing good efficacy at improving scores on the Clinical Global Impression-Improvement scale and Rett Syndrome Behavior Questionnaire, with specific effect only on some subscales, ie General Mood subscale and Repetitive Face Movement subscale. No effects were documented on other subscales or on epilepsy, heart and bone -related symptoms. The main adverse effects of trofinetide, severe enough to determine discontinuation, include diarrhea, vomiting, and consequent weight loss. These may be scarcely avoidable, given the need to assume a very large amount of trofinetide per day. Other inherent limitations of use possibly regard the limited duration of drug supplies, as one bottle may last three days only, depending on weight, and the relatively high cost per bottle. Trofinetide has no direct competitors: single symptoms of the Rett Syndrome, for instance, seizures or aggressive behaviors, are currently treated with drugs that have been developed for patients without the Rett Syndrome. This leads to suboptimal efficacy and increased risk of adverse effects. The place in therapy of trofinetide is yet to be determined, based on the results of clinical trials, on its practical usability, and on the windows of opportunity for intervention. Moreover, trofinetide may be curative if given early enough during brain development, or merely symptomatic if given to young adults, and no data exist on this aspect. The place in therapy of trofinetide will require reassessment after competing treatments enter the market.

Purpose: Ciprofol, a new sedative anesthetic developed in China, offers rapid onset and recovery, reduced injection pain, and stable circulation. However, its effect on blood pressure during anesthesia induction in older adults remains unclear. To compare the effects of propofol and ciprofol on hypotension induced by general anesthesia in older adults.

Patients and methods: This prospective, single-center, double-blind, randomized, controlled clinical study enrolled 117 older adults undergoing surgery. Patients in the ciprofol group (group C) received an intravenous injection of ciprofol (0.3 mg/kg, n=57), while the propofol group (group P) received an intravenous injection of propofol (1.5 mg/kg, n=58). The primary outcome was the incidence of hypotension (mean arterial pressure (MAP) decreased by > 30% from baseline or MAP< 65 mmHg). Secondary outcomes included induction success rate (bispectral index (BIS) value ≤60 and Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) score ≤1), injection pain, number of drug additions, time to BIS 60, time to eyelash reflex disappearance, blood pressure changes, incidence of hypertension, tachycardia and BIS values before and after administration.

Results: The incidence of induced hypotension was 26.3% (15/57) in group C and 48.3% (28/58) in group P (OR=0.383, 95% CI:175-0.837, P =0.015). Group C had significantly lower injection pain incidence (5.3% vs 20.7%, OR=0.213, 95% CI: 0.057-0.801, p=0.014). Both groups had a 100% induction success rate, with no significant difference in the number of additional doses. Post-intubation hypertension and tachycardia incidence were not significantly different. Group C showed less blood pressure decrease during induction and a deeper anesthesia level.

Conclusion: Compared to propofol, ciprofol reduces the incidence of induced hypotension in older adults and maintains more stable blood pressure during induction. Additionally, ciprofol reduces injection pain and provides a good depth of anesthesia, making it a safe and effective option for anesthesia induction in older adults.

Trial registration clinicaltrialsgov identifier: ChiCTR2200066053.

Introduction: Neonatal hypoxic-ischemic encephalopathy (HIE), caused by perinatal asphyxia, is characterized by high morbidity and mortality, but there are still no effective therapeutic drugs. Mitochondrial biogenesis and apoptosis play key roles in the pathogenesis of HIE. Protopine (Pro), an isoquinoline alkaloid, has anti-apoptotic and neuro-protective effects. However, the protective roles of Pro on neonatal hypoxic-ischemic brain injury remain unclear.

Methods: In this study, we established a CoCl₂-induced PC12 cell model in vitro and a neonatal rat hypoxic-ischemic (HI) brain damage model in vivo to explore the neuro-protective effects of Pro and try to elucidate the potential mechanisms.

Results: Our results showed that Pro significantly reduced cerebral infarct volume, alleviated brain edema, inhibited glia activation, improved mitochondrial biogenesis, relieved neuron cell loss, decreased cell apoptosis and reactive oxygen species (ROS) after HI damage. In addition, Pro intervention upregulated the levels of p-AMPK/AMPK and PGC1α as well as the downstream mitochondrial biogenesis related factors, such as nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), but the AMPK inhibitor compound c (CC) could significantly reverse these effects of Pro.

Discussion: Pro may exert neuroprotective effects on neonatal hypoxic-ischemic brain damage via activation of the AMPK/PGC1α pathway, suggesting that Pro may be a promising therapeutic candidate for HIE, and our study firstly demonstrate the neuro-protective roles of Pro in HIE models.

Heart failure (HF) is a disease with high morbidity and mortality rates worldwide and significantly affects human health. Currently, the treatment options for HF are limited, and there is an urgent need to discover new therapeutic targets and strategies. Macrophages are innate immune cells involved in the development of HF. They play a crucial role in maintaining cardiac homeostasis and regulating cardiac stress. Recently, macrophages have received increasing attention as potential targets for treating HF. With the improvement of technological means, the study of macrophages in HF has made great progress. This article discusses the biological functions of macrophage phagocytosis, immune response, and tissue repair. The polarization, pyroptosis, autophagy, and apoptosis are of macrophages, deeply involved in the pathogenesis of HF. Modulation of the phenotypic changes of macrophages can improve immune-inflammation, myocardial fibrosis, energy metabolism, apoptosis, and angiogenesis in HF.

Background: Many studies have been conducted on the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression. However, the overall trends in research publications in this field remain elusive. There is still little quantitative analysis of the literature in this field. Therefore, we conducted a bibliometric analysis to explore the research patterns surrounding SSRIs for depression, aiming to gain a deeper understanding of their development and impact.

Methods: Publications about the use of SSRIs for the treatment of depression were identified in the Web of Science Core Collection. Visualization analysis was performed with Bibliometrix, VOSviewer, and CiteSpace.

Results: A total of 1149 publications published from 1990 to 2024 were included in the bibliometric analysis. Since 1990, the annual number of published papers has increased annually, reaching the maximum value of output in 2004. Fitted curve showed that after 2004, the number of publications per year was essentially stable The United States dominates the field. Among these institutions, University of Pittsburgh excels in this field. Fava M has the highest scientific productivity and extensive academic influence. European Neuropsychopharmacology is the most active journal in this field. The three most relevant keywords were "fluoxetine", "double-blind", and "major depression". The trend topics in recent years were "connectivity", "c-reactive protein", and "anhedonia".

Conclusion: Research on the use of SSRIs for the treatment of depression continues to receive increased attention but still requiraes further exploration and innovation. We further analyze the current research hotspots and frontiers in this field.

Background: Pain intensity after temporomandibular joint (TMJ) surgery is often underestimated, and inadequate pain control may relate to poor recovery quality, increased opioid consumption, and longer hospital stay. This trial aims to evaluate whether non-opiate anesthesia provides a promising option of pain management for patients undergoing TMJ surgery.

Methods: Sixty patients receiving TMJ surgery were randomly assigned to either the control group or the non-opiate group. Non-opiate anesthesia used lidocaine, dexmedetomidine, and ketamine infusion therapy for pain management. The primary outcome was the highest documented pain score while in the post-anesthesia care unit (PACU). Secondary outcomes included perioperative opioid consumption, utilization, dosage, and timing of rescue analgesia in the PACU, incidence of postoperative nausea and vomiting in the PACU and at home, pain satisfaction levels, occurrence of opioid-related adverse effects, duration of PACU and hospital stays, and total consumption of oxycodone-acetaminophen tablets at 24 and 48 hours post-surgery.

Results: Patients were predominantly female (88.3%) and had a median age of 37.5 [IQR 26.0, 52.5] years. There were no significant differences observed in the highest documented pain scores (mean difference [MD] -0.36 points, 95% CI: -1.84, 1.12, p = 0.63), postoperative oxycodone-acetaminophen consumption (MD 6.68 mg, 95% CI: -2.48, 15.84, p = 0.15), pain satisfaction (odds ratio [OR] 0.81, 95% CI: 0.23, 2.81, p = 0.74), time to PACU discharge (hazard ratio [HR] 1.24, 95% CI: 0.67, 2.30, p = 0.49) or time to hospital discharge (HR 1.48, 95% CI: 0.80, 2.75, p = 0.21) between the two groups. Similarly, no significant difference was observed in time to rescue analgesia, calculated in minutes from the end of surgery (HR 1.69, 95% CI: 0.79, 3.61, p = 0.18).

Conclusion: Non-opiate anesthesia for pain management shows a similar postoperative analgesia effect, compared to opioid-based anesthesia, in patients undergoing arthroscopic TMJ surgery.

Vitiligo is a chronic autoimmune disorder characterized by depigmented patches of the skin. The treatment of vitiligo remains challenging, partly owing to the lack of efficient drug delivery system. Microneedles (MNs), an ideal transdermal drug delivery system, have emerged as promising drug delivery platform for vitiligo. Recently, the emergence of novel MNs with increased biocompatibility, including hydrogel and hollow MNs, further enhance the translational value of MNs in the treatment of vitiligo. However, up-to-date review of these advancements remains lacking. This review aims to summarize the most recent studies of MN-based drug delivery systems for vitiligo, highlighting the translational potential of MNs as a therapeutic platform for the treatment of vitiligo in the near future.

Objective: The polymorphism of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene exerts a marked influence on drug transport, thus playing a pivotal role in personalized drug dosing. This study endeavours to establish a rapid, precise, and straightforward method for detecting SLCO1B1 genetic variants utilizing Duplex Fluorescence Melting Curve Analysis (DFMCA).

Methods: Whole blood samples were collected from 54 individuals from Meizhou People's Hospital (2023.01-2023.03), with a mean age of 58.90 years (SD = 7.86), including 28 men and 26 women. DNA was extracted from these samples and subjected to PCR amplification targeting two allelic regions. Primers, fluorescent probes, and corresponding allelic target sequences were designed specifically for two common SLCO1B1 polymorphisms (rs2306283 and rs4149056). The functionality of the fluorescent probes in binding to their respective allelic targets was verified using melting curve analysis, enabling the identification of distinct melting temperatures for different genotypes. Subsequently, DFMCA was employed to differentiate genotypes based on the melting temperature shifts of the corresponding fluorescent probes. The sensitivity, accuracy, and consistency of the method were evaluated, with sequencing validation performed on a subset of samples.

Results: DFMCA facilitated the concurrent detection and accurate genotyping of both polymorphisms within 2 hours, demonstrating concordance with sequencing results from randomly selected samples. Importantly, stable detection performance was achieved for human genomic DNA at concentrations ≥ 3.125 ng. In a cohort comprising Han Chinese individuals from southern China, the allele frequencies for rs2306283 (A: 28.7%, G: 71.3%) and rs4149056 (T: 88.89%, C: 11.11%) concurred well with previous studies in the Han Chinese population.

Conclusion: The SNP typing system utilizing DFMCA technology presents advantages in terms of speed, ease of use, accuracy, and cost-effectiveness, making it a suitable tool.

Colistin is the last-line option for the treatment of multidrug-resistant gram-negative bacterial infections with narrow therapeutic window. It is essential to ensure its efficacy and safety by therapeutic drug monitoring (TDM). Quantitative determination of colistin is difficult due to its complex ingredients. Previous determination methods demand intricate sample pre-treatment which are not only time-consuming but also costly, and is difficult to apply in clinical practice. Therefore, in order to carry out quantitative determination of colistin accurately and quickly, we establish a rapid high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) with simple sample pre-treatment process. The sample was purified by acetonitrile to remove the plasma protein. Then purified colistin was effectively separated from terfenadine, an internal standard (IS) using Phenomenex Kinetex C18 column (50.0×2.1mm, 5µm) with acetonitrile and water mobile phase at a flow rate of 0.5 mL/min and 40°C column temperature. Colistin and IS were monitored in positive ion mode. Our method expressed good linearity in 50.0~6000 ng/mL of colistin B and 28.31~3397.51 ng/mL of colistin A in plasma. Methodology validations, including selectivity, precision, accuracy, recovery, stability, matrix effect, and dilution integrity met acceptance criteria of Bioanalytical Method Validation (M10) of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).