Cannabinoid levels description in a cohort of patients with chronic and neuropathic pain treated with Cannabis decoction: A possible role of TDM.

The phytocomplex of Cannabis is made up of approximately 500 substances: terpeno-phenols metabolites, including Δ-9-tetrahydrocannabinol and cannabidiol, exhibit pharmacological activity. Medical Cannabis has several pharmacological potential applications, in particular in the management of chronic and neuropathic pain. In the literature, a few data are available concerning cannabis pharmacokinetics, efficacy and safety. Thus, aim of the present study was the evaluation of cannabinoid pharmacokinetics in a cohort of patients, with chronic and neuropathic pain, treated with inhaled medical cannabis and decoction, as a galenic preparation. In this study, 67 patients were enrolled. Dried flower tops with different THC and CBD concentrations were used: Bedrocan® medical cannabis with THC level standardized at 19% and with a CBD level below 1%, Bediol® medical cannabis with THC and CBD level standardized at similar concentration of 6.5% and 8%, respectively. Cannabis was administered as a decoction in 47 patients and inhaled in 11 patients. The blood withdrawn was obtained before the new dose administration at the steady state and metabolites plasma concentrations were measured with an UHPLC-MS/MS method. Statistically significant differences were found in cannabinoids plasma exposure between inhaled and oral administration of medical cannabis, between male and female and cigarette smokers. For the first time, differences in cannabinoid metabolites exposures between different galenic formulations were suggested in patients. Therapeutic drug monitoring could be useful to allow for dose adjustment, but further studies in larger cohorts of patients are required in order to confirm these data.

Vitamin D impact in affecting clozapine plasma exposure: A potential contribution of seasonality.

Schizophrenia affects approximately 24 million people worldwide and clozapine is the most effective antipsychotic drug. Nevertheless, its use in therapy is limited due to adverse effects.Therapeutic drug monitoring is a clinical tool useful to reduce the clozapine toxicity. In the literature, papers showed how psychiatric disorders could be associated with low vitamin D levels, but a few studies focusing on its role in affecting clozapine exposure are available. A TDM repository was analyzed: clozapine and vitamin D levels measured with liquid chromatography were considered. 1261 samples obtained from 228 individuals were evaluated: 624 patients (49.5%) showed clozapine plasma levels in therapeutic range (350-600 ng/mL). Clozapine toxic plasma levels (>1000 ng/mL) were more present in winter (p = 0.025), compared to other seasons. Concerning vitamin D, a sub-analysis of 859 samples was performed: 326 (37.81%) were deficient ( ng/mL), 490 (57.12%) had insufficient concentrations (10-30 ng/mL), while 43 (5.02%) had sufficient (>30 ng/mL) levels. A correlation between vitamin D and clozapine plasma levels (p = 0.007, Pearson coefficient=0.093) was observed. The role of seasonal variation in clozapine plasma exposure in psychiatric patients treated with clozapine was suggested. Further studies in larger cohorts are needed in order to clarify these aspects.

Ceftobiprole and daptomycin concentrations in valve tissue in a patient with mitralic native valve endocarditis.

Ceftobiprole (CFB), especially in combination, could be a promising alternative treatment for infective endocarditis. A main determinant of clinical response to antibiotic treatment is drug concentration at the infected site. Data on CFB and Daptomycin (DPT) heart valve penetration are lacking.Here we report a clinical case of CFB and DPT treatment combination for endocarditis. Then, we measured CFB and DPT concentrations in a native infected valve to verify their pharmacokinetic penetration and relationship with pharmacodynamic microbiological markers.The isolated microorganism was a MRSA with CFB and DPT MIC < 2 mg/L and <1 mg/L, respectively. The CFB and DPT plasma concentrations were 36.2 and 14.1 mg/L, respectively and the extrapolated concentration, based on each half-life, at the operatory time were 16.4 and 19.1 mg/L for CFB and DPT, respectively; the corresponding median CFB and DPT valve concentrations were 2.26 (IQR 2.14-2.69) and 12.9 µg/g (IQR 5.69-20.9), respectively; the estimated tissue/plasma ratios for CFB and DTP were 0.14 and 0.67, respectively.The association of CFB and DPT showed a good efficacy in this single endocarditis clinical case, confirmed by plasma and tissue PK/PD data.This report shows the first data on CFB valve tissue penetration, and it needs to be confirmed in other patient valve tissues. Moreover, relative studies of correlation with clinical efficacy are needed.

Correlation between Thiopurine S-Methyltransferase Genotype and Adverse Events in Inflammatory Bowel Disease Patients.

Background and Objectives: In patients with inflammatory bowel diseases (IBD), the use of azathioprine results in adverse events at a rate of 5% to 20%. The aim of the study was to assess a possible correlation between genetic variability of the enzyme thiopurine S-methyltransferase (TPMT) and the development of toxicity to azathioprine. Materials and Methods: A retrospective, single center, blind, case-control study was conducted on 200 IBD patients, of whom 60 cases suspended azathioprine due to toxicity (leukopenia, pancreatitis, hepatitis, and nausea or vomiting), and 140 controls continued treatment with the drug without adverse events. Results: In the entire cohort, only 8 cases of heterozygous mutations of TPMT were observed, corresponding to 4% mutated haplotype rate, much lower than that reported in literature (close to 10%). No homozygous mutation was found. Regarding the TPMT allelic variants, we did not find any statistically significant difference between patients who tolerated azathioprine and those who suffered from adverse events. (OR = 0.77, 95% CI = 0.08-7.72; p = 0.82). Conclusions: According to our study, in IBD patients, the search for TPMT gene mutations before starting treatment with azathioprine is not helpful in predicting the occurrence of adverse events. Importantly, patients with allelic variants should not be denied the therapeutic option of azathioprine, as they may tolerate this drug.

Pharmacogenetic of voriconazole antifungal agent in pediatric patients.

AIM: We explored the role of SNPs within the SLCO1B3, SLCO1B1, SLC22A6, ABCB1, ABCG2, SLCO3A1, CYP2C19, ABCC2, SLC22A1, ABCB11 and NR1I2 genes on voriconazole pharmacokinetics. PATIENTS & METHODS: 233 pediatric patients were enrolled. Drug plasma Ctrough was measured by a HPLC-MS method. Allelic discrimination was performed by qualitative real-time PCR. RESULTS: SLCO1B3 rs4149117 c.334 GT/TT (p = 0.046), ABCG2 rs13120400 c.1194 + 928 CC (p = 0.029) and ABCC2 rs717620 c.-24 GA/AA (p = 0.025) genotype groups significantly influenced Ctrough. ethnicity (p = 0.042), sex (p = 0.033), SLCO1B3 rs4149117 c.334 GT/TT (p = 0.041) and ABCB1 rs1045642 c.3435 TT (p = 0.016) have been retained in linear regression model as voriconazole predictor factors. CONCLUSION: Understanding how some gene polymorphisms affect the voriconazole pharmacokinetic is essential to optimally dose this agent.

Precision medicine for HIV: where are we?

To date, antiretroviral therapy is highly effective in HIV-affected patients, but the individualization of such a life-long therapy may be advised. This review briefly summarizes the main factors involved in the potential personalization of antiretroviral treatment. Relevant articles in English were identified by PubMed and recent congresses' abstracts. Foremost influences concerning pharmacodynamics, therapeutic drug monitoring, pharmacogenetics, comorbidities, immune recovery and viral characteristics affecting the healthcare of HIV-positive patients are listed here. Furthermore, pharmacoeconomic aspects are mentioned. Applying pharmacokinetic and pharmacogenetic knowledge may be informative and guide the better choice of treatment in order to achieve long-term efficacy and avoid adverse events. Randomized investigations of the clinical relevance of tailored antiretroviral regimens are needed in order to obtain a better management of HIV/AIDS-affected patients.