Benefits and Challenges of Cannabis Use in the Treatment of Refractory Epilepsy

Introduction: Refractory epilepsy (RE) is a disease that causes continuous and debilitating seizures. Due to the ineffectiveness of antiepileptic therapies, there is a growing interest in drugs made with cannabidiol (CBD), a substance extracted from Cannabis. Objective: To point out benefits and challenges of the use of CBD in the treatment of RE. Methods: Literature review performed at PubMed, with the descriptors Epilepsy, Drug Therapy and Cannabis. Results: It is suggested that CBD is mediated by cannabinoid receptors coupled to protein G, by blockade of NMDA receptors, by GABAergic modulation, glutamatergic synapses and / or mechanisms involving noncannabinoid receptors. CBD can also oppose the actions of exogenous and endogenous cannabinoid agonists, due to the negative allosteric modulation. The benefits of CBD are: great therapeutic diversity, safety and tolerability, rare and mild side effects, low risk of drug interactions, and milder cognitive effects, when compared to other antiepileptic drugs. Despite the benefits, CBD has adverse effects such as drowsiness, appetite reduction, diarrhea, increased activity of liver enzymes and interaction with substances metabolized by cytochrome P450. Still, the inefficient regulation generates variation in the composition of the marketed drugs, which can lead to Δ9 - tetrahydrocannabinol (THC) intoxication. Conclusions: Thus, it is essential that the scientific community remains open to investigate the effects of CBD, given the advantages of its use for treating RE.

Incidence of severe nephrotoxicity with cisplatin vs. non-cisplatin regimens: A meta-analysis with sub-group analyses based on renal eligibility criteria.

e15549 Background: Serum Creatinine (SCr) is commonly used to screen patients for eligibility in trials of the nephrotoxic drug cisplatin despite the fact that glomerular filtration rate (GFR) is known to better estimate renal function. The objective of this meta-analysis was to indirectly compare incidence of nephrotoxicity in trials using cisplatin for treatment of solid tumors when renal function was assessed using SCr or GFR for eligibility criteria. Methods: A literature search was conducted in PubMed to identify randomized trials comparing cisplatin to non-cisplatin containing chemotherapy regimens. Studies were included if they were performed from 1990-2010, used SCr or GFR as eligibility criteria, and reported incidence of WHO or NCI grade ≥3 nephrotoxic events for both treatment arms. Review articles, non-randomized trials, observational, phase I, studies without a comparator group, or not reported in English were excluded. The relative risk (RR) of grade ≥3 nephrotoxicity associated with cisplatin vs. non-cisplatin regimens was examined using inverse variance weighted fixed effects (FE) and random effects (RE) methods. Subgroup analyses of studies using SCr, GFR, and either SCr or GFR for screening were performed. Results: The literature search identified 2,359 studies, and 42 studies met all inclusion and exclusion criterion (N=9,521 patients). SCr was used as eligibility criteria in 20 studies (N=4,704), GFR was used by 9 studies (N=1,650), and either SCr or GFR was used by 13 studies (N=3,167). The overall RR for developing nephrotoxicity with cisplatin vs. non-cisplatin treatment was 1.75 (95%CI 1.18-2.58, p=0.005). Results from subgroup analyses showed the RR was 2.60 (95%CI 1.34-5.03, p=0.005) when SCr was used as eligibility criteria compared to 1.50 (95%CI 0.82-2.74, p=0.19) when GFR was used and 1.26 (95%CI 0.55-2.85, p=0.59) when either SCr or GFR was used. Results did not vary between FE and RE methods. Conclusions: Cisplatin based therapy is associated with a significant increase in severe nephrotoxicity. The risk of severe nephrotoxicity is higher in trials that utilize SCr as eligibility criteria compared to those that utilize GFR.

Cisplatin-associated nephrotoxicity in clinical trials using serum creatinine (SCr) versus calculated glomerular filtration rate (GFR) as inclusion criterion: A meta-analysis.

272 Background: Treatment with cisplatin (CIS) is associated with increased risk of nephrotoxicity and SCr is commonly used to screen patients for renal dysfunction prior to enrollment in trials using CIS. However, GFR is known to better estimate renal function than SCr. The objective of this trial-level meta-analysis was to indirectly compare incidence of WHO grade ≥3 nephrotoxicity associated with CIS therapy when renal function was assessed using SCr vs. calculated GFR during screening for these trials. Methods: A PubMed literature search was used to identify randomized trials comparing treatment regimens including CIS to those without CIS. Studies were included if they were performed between 1990 and 2005, reported SCr or GFR as inclusion criteria, and reported WHO grade ≥3 nephrotoxic events for both the CIS and non-CIS treatment arms. Studies were excluded if they were review articles, observational, phase 1, non-randomized, did not have a comparator group, or were not reported in English. Inverse variance weighted fixed effects (FE) and random effects (RE) methods were used to estimate the relative risk (RR) associated with CIS vs. non-CIS containing regimens with sub-group analyses of studies using SCr, GFR, and either SCr or GFR for screening. Results: The literature search identified 2359 studies. After exclusion criteria, 549 were reviewed and 24 studies (N=5524 patients) met all inclusion criteria for analysis. Of these, 16 studies used SCr (N=3955), 3 used GFR (N=692), and 5 used SCr or GFR (N=877) for screening. Overall incidence proportion of nephrotoxicity was higher for CIS vs. non-CIS regimens (2.1% vs. 0.7%). Overall RR for CIS vs. non-CIS regimens was 2.49 (95%CI 1.37-4.51, p=0.003). In sub-group analyses, the RR was 2.63 (95%CI 1.29-5.39, p=0.008) for SCr compared to 2.39 (95%CI 0.53-10.64, p=0.26) for GFR and 2.03 (95%CI 0.46-9.02, p=0.35) for either SCr or GFR. The RRs did not differ between the FE and RE methods. Conclusions: This indirect comparison meta-analysis shows CIS is associated with a higher likelihood of nephrotoxicity vs. non-CIS regimens, and may be higher when SCr is used instead of GFR as eligibility criteria.

Clinical and neuropsychological correlation in patients with rolandic epilepsy

OBJECTIVES: To evaluate the presence of neurological soft signs (NSS) and to correlate them with the Wechsler Intelligence Scale for Children (WISC III) in patients with rolandic epilepsy (RE). METHODS: Forty children and adolescents aged between 9 and 15 years were studied. They were divided into two groups: G1 - patients with RE (n=20) - and G2 - healthy controls without epilepsy (n=20). They were assessed with the Quick Neurological Screening Test (QNST II) - clinical trial to search for NSS -, and the WISC III - neuropsychological test. RESULTS: No statistical difference between groups was found in WISC III and QNST II. However, children with poorer motor skills had worse performance in the QNST II and also in the execution intelligence quotient - IQ (p=0.001) and in total IQ (p=0.004), thus showing a positive correlation between them. CONCLUSIONS: The QNST II is a good screening tool for the neurologist to detect abnormalities in fine motor skills.