Fundamental & Clinical Pharmacology最新文献

Background

Seizures after the use of cannabinoids are reported, but no precise descriptions of the characteristics of subjects and factors that may trigger seizures are available.

Objectives

To study the characteristics and circumstances associated with the occurrence of seizures in individuals using cannabinoids for medical or recreational purposes.

Methods

A retrospective analysis of spontaneous reports of adverse drug effects issued by the French pharmacovigilance and addictovigilance systems, and by manufacturers, extracted data from the Eudravigilance database (01/01/1985–21/07/2023). The request used the broad MedDRA SMQ term ‘convulsive’, with all products containing cannabinoids (THC, CBD, cannabis or natural cannabinoids).

Results

Among 4296 notifications with cannabinoids, 130 (3%) reports of convulsive effects were analysed: 29 cases (23.3%) related to medical use (27 CBD, 1 THC and 2 combined THC/CBD preparations) and 98 (75.4%) related to recreational use. The median age was 29.0 years (min-max: 3–75), 78.7% were men and 81.1% were serious cases. Among the recreational users, 38.8% used Cannabis sativa with a history of epilepsy, and 68.4% of them were taking antiepileptics. In total, 67.7% of individuals had at least one risk factor for seizures, i.e., 31.0% among medical users and 78.6% among recreational users. The main risk factors with medical use were inefficacy of CBD (17.2%), fatigue (13.8%) and concomitant epileptogenic medications (10.3%). The main risk with recreational use was concomitant epileptogenic medications (39.8%), consumption of illicit drugs (33.7%) and alcohol (32.7%).

Conclusion

This analysis demonstrates the importance of alerting cannabinoid users, particularly recreational cannabis users and those with a history of epilepsy, about seizure-associated risks. Moreover, educational information should be provided together with the prescription of licensed cannabinoids and medical cannabis.

Background

Paclitaxel is a potent agent against ovarian cancer. Hydrogen sulfide (H₂S) is of particular interest in cancer treatment research. It is known that H₂S has apoptotic and antiproliferative effects.

Objectives

We aimed to examine the potential effects of H₂S donor NaHS and paclitaxel, both individually and when co-administered, on the ID8 murine epithelial ovarian cancer cell line.

Methods

We examined the effects of the co-administration of paclitaxel and NaHS on cell viability, cytotoxicity, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), apoptosis, and proliferation in the ID8 ovarian cancer cell line. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase tests were performed to ascertain the effect of NaHS and paclitaxel on cell viability and cytotoxicity. Caspase 3/7 levels were quantified in order to detect whether apoptosis is caspase dependent. Quantitative real-time polymerase chain reaction (qPCR) method was used to ascertain relative mRNA levels of Bcl-2, Bcl-xL, Bax, and Bak genes.

Results

The viability of ID-8 cells showed a significant reduction following the co-administration of paclitaxel and NaHS, compared to the paclitaxel administration only. The results of qPCR analysis demonstrated significant alterations in the Bcl-2, Bcl-xL, Bax, Bak, Casp3, Casp8, and Casp9 genes' mRNA levels following cotreatment. In contrast to paclitaxel alone, its co-administration with NaHS resulted in increased apoptosis and decreased ROS levels. The presence of NaHS has been observed to enhance the apoptotic impact of paclitaxel by amplifying the decline in MMP.

Conclusion

These data indicate that co-administration of H₂S with paclitaxel could be useful as a potential agent in the treatment of ovarian cancer. We found that the presence of H₂S enhanced the antitumor efficacy of paclitaxel.

Background

COVID-19 vaccination raises questions in patients with autoimmune or inflammatory diseases (AIID), not included in clinical trials. Concern exists about the risk of activating the immune system or worsening the AIID. However, cases of AIID flare-ups or new-onset reported in literature are limited and do not allow conclusions to be drawn on the potential effect of vaccination.

Objective

To explore the clinical features of AIID that occurred after vaccination.

Methods

We performed a retrospective analysis of adverse event following immunization (AEFI) reported in the French National Pharmacovigilance Database (BNPV) following vaccination with SPIKEVAX (mRNA-1273/Moderna), regardless of the dose received, between Jan 31, 2021 and Jan 31, 2022.

Results

Among the 20 169 AEFI cases recorded in BNPV, 2594 cases identified with Standardized MedDRA Queries “Immune/Mediated/Autoimmune Conditions” were analyzed to select cases of interest. After review by two experts, 368 cases of AIID were finally retained for analysis [age 54 (42–69); female 234 (63.6%); onset median time 4 days (from < 24 h to 179d); serious cases 226 (61.4%)] and divided into two groups: AIID flare-ups (n = 174) and AIID new-onset (n = 194). SOCs “Musculoskeletal and connective tissue disorders” and “Nervous system disorders” recorded the most of AIID cases whatever flare-up or new-onset. Cases reported are mainly ankylosing spondylitis (n = 20), rheumatoid arthritis (n = 17), multiple sclerosis (n = 19) for flare-ups and Guillain-Barre syndrome (n = 27) for new-onset.

Conclusion

No safety concerns related to AIID following vaccination with SPIKEVAX were found after the reviewing of 368 French cases.

Background

The results of randomized controlled trials (RCTs) evaluating the effect of vitamin D on the prevention of acute respiratory tract infections (RTIs) are conflicting. The aim of this study was to assess the level of evidence for the efficacy of vitamin D in preventing acute RTIs by performing a sensitivity analysis of the meta-analysis carried out by Jolliffe and al., using the Rebuild the Evidence Base (REB) method.

Methods

The main inclusion criteria were double-blind, placebo-controlled, open-label RCTs. The exclusion criteria were RCTs in which vitamin D was associated with other nutrients and unpublished RCTs.

The primary outcome was the number of people who had at least one RTI, including upper and lower RTIs. A bias analysis was performed of the included RCTs, followed by a hypothetico-deductive analysis to determine whether they were confirmatory or exploratory. Then, we used the REB method to determine the level of evidence for the effectiveness of vitamin D in preventing RTIs.

Results

The main meta-analysis included 25 RCTs with a low risk of bias, involving 41 847 people. There was no significant difference between groups in the number of patients who had at least one RTI. According to the REB, there was a lack of evidence when assessing the effectiveness of vitamin D in preventing RTI.

Conclusion

According to the REB, the analysis of the RCTs, considering the risk of bias, showed that there is a lack of evidence to justify the prescription of vitamin D for the preventing of RTIs.

Background

We aimed to elucidate the role of Angiotensin II type 1 receptor (AT1R) blocker usage in muscle wasting and dysfunction related to HIV.

Research Design and Methods

Appendicular skeletal muscle mass, higher and lower limb strength, and physical fitness were determined in people living with HIV (PWH) using AT1R blockers users (n = 33), angiotensin-converting enzyme (ACE) inhibitors (n = 28), or not using antihypertensive drugs (n = 33). Groups had similar age, sex, race, BMI, and time of HIV infection. Muscle biopsies were performed to determine the abundance of AT1R, the relative abundance of selected proteins related to proteolysis, antioxidant enzymes, and oxidative stress. Plasma angiotensin II, IL-6, and TNF-alpha were also determined.

Results

PWH using AT1R blocker presented higher strength, physical fitness, and muscle mass than PWH using ACE inhibitors or not using antihypertensive drugs. Although both PWH using AT1R blockers and ACE inhibitors presented reduced angiotensin II plasma levels, only PWH using AT1R blockers presented lower skeletal muscle AT1R activation, lower plasma oxidative stress markers, lower skeletal muscle oxidative stress (4-HNE), and proteolysis markers (Atrogin-1, Murf-1).

Conclusion

AT1R blocker usage protects against oxidative stress and activated proteolysis, contributing to the prevention of muscle wasting and dysfunction among PWH.

Background

Opioid use disorder (OUD) is an emerging and global public health concern, and its management remains inadequate, notably due to a lack of biomarkers, except for the CYP2B6 genetic polymorphisms.

Objectives

Hence, the aim of this study was to assess the influence of genetic polymorphisms of ABCB1, SLC22A1, COMT, and OPRM1 on biological parameters and clinical response in patients receiving methadone maintenance treatment (MMT).

Methods

A subgroup of 72 patients treated by MMT was genotyped for ABCB1 (rs1045642; rs2032582), SLC22A1 (rs12208357; rs72552763; rs113569197), COMT (rs4680), and OPRM1 (rs1799971) from Opioid PhArmacoLogy (OPAL), a clinical survey of patients suffering from OUD. Associations of these polymorphisms and both clinical and pharmacological (plasma methadone levels) responses were investigated.

Results

All polymorphisms tested were not associated with (R,S)-methadone concentrations/doses (concentrations relative to doses), (R)-methadone concentrations/doses nor (S)-methadone concentrations/doses in bivariate analyses with codominant and recessive models. Also, polymorphisms tested were not related to clinical response (opiate cessation) during MMT in treated patients. The main limitations of our study were the sample size and the absence of polygenic analyses.

Conclusion

This study found no evidence to support the use of genotyping for polymorphisms in the ABCB1, SLC22A1, COMT, and OPRM1 genes in a clinical setting for the management of MMT in OUD.

Background

Radiation exposure can cause inflammation, which etoricoxib (ET), an anti-inflammatory drug, could potentially mitigate.

Objective

This study aimed to evaluate the potential effectiveness of etoricoxib-loaded nanostructured lipid carriers (ET-NLCs) in mitigating radiation-induced acute lung inflammation in rats.

Methods

Thirty-six rats were divided into six groups. Group 1 (C): control; group 2 (ET): normal rats given ET (10 mg/kg) orally for 14 days; group 3 (ET-NLC): normal rats administered ET-NLCs orally (10 mg/kg) for 14 days. Group 4 (R): rats exposed to 6 Gy whole-body gamma radiation, untreated thereafter to induce lung inflammation and injury. Group 5 (ET-R), irradiated rats, were administered ET (10 mg/kg) orally daily for 14 days. Group 6 (ET-NLC-R), irradiated rats, were administered ET-NLCs (10 mg/kg) orally daily for 14 days. Molecular, biochemical, and histopathological analyses were performed to assess inflammation, apoptosis, oxidative stress, and lung tissue architecture.

Results

Radiation exposure led to a 1053% increase in Bax expression and an 81.5% decrease in Bcl-2, indicating heightened apoptosis. ET-NLCs treatment reversed these effects, reducing Bax by 59.9% and increasing Bcl-2 by 337.4%. Additionally, ET-NLCs reduced caspase-3 and caspase-8 activation by 54.5% and 62.9%, respectively, compared to radiation exposure alone. Furthermore, ET-NLCs demonstrated potent anti-inflammatory effects by reducing interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels by 49% and 39%, respectively, compared to the irradiated group. Radiation increased malondialdehyde (MDA) levels by 388%, indicating oxidative damage, and suppressed antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD). ET-NLC treatment decreased MDA levels and increased CAT, GPX, and SOD by 35.7%, 4766.7%, and 765.9%, respectively, restoring antioxidant balance. Radiation reduced surfactant protein (SP-D) levels to 4.9% of control values, but ET-NLCs treatment restored them to 14%. Histopathological analysis revealed that radiation-exposed lungs showed thickened inter-alveolar septa, emphysematous areas, and inflammatory infiltration. ET-NLCs treatment exhibited only mild thickening and limited inflammatory cell infiltration, suggesting significant improvement in lung architecture.

Conclusions

Based on these results, NLCs