Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.     

Multi-centre research surveillance project to reduce infections/phlebitis associated with peripheral vascular catheters

A surveillance project was undertaken on 37 surgical wards by infection control nurses with the aim of reducing phlebitis/infections associated with peripheral vascular catheters, and to identify risk factors. Data on 2934 catheters in situ longer than 24h was collected in two separate surveillance periods and results were fed back after each surveillance period. Four significant risk factors were identified; what the catheters were used for, the duration the catheters were in situ, the surveillance period (the first surveillance period had a higher phlebitis rate than the second) and whether an infusion pump was used. Logistic regression analysis showed that each of these had a significant effect after adjusting for the effects of the other three factors.     

The growth of breast fed and artificially fed infants from birth to twelve months

Growth data collected from 394 healthy infants were analysed in relation to feeding practices. Infants were grouped on the basis of sex, if breast fed or artificially fed, and duration of breast feeding. From birth to 3 months, weight gains were similar for boys (2.5 kg) and also for girls (2.3 kg) irrespective of feeding method. From 3 to 6 months weight gains were greater in infants who were artificially fed from birth (2.0 kg both sexes) or breast fed for only a short time (1.9 kg) than for those exclusively breast fed for 6 months (1.6 kg) or longer (1.7 kg). Weight gains continued to be greater in artificially fed infants after 6 months. Over 12 months, artificially fed boys gained 410 g and girls 750 g more than those who were breast fed from birth. These differences occurred even though the artificial feedings that prevailed to 6 months and longer were low-solute ('humanized') formulas.     

A population based study of the impact of corticosteroid therapy and delayed diagnosis on the outcome of childhood pneumococcal meningitis.

BACKGROUND: Despite an extensive literature, the impact of both adjunctive steroid therapy and delayed diagnosis on the outcome of childhood pneumococcal meningitis is controversial. AIM: To determine the independent contribution of corticosteroid therapy and delayed diagnosis on the outcome of childhood pneumococcal meningitis in a representative population with good access to medical services. METHODS: Data were obtained from laboratories and hospital records to assemble a population register in Sydney, Australia, 1994-99. Follow up questionnaires were completed by attending physicians. RESULTS: A total of 122 cases of pneumococcal meningitis aged 0-14 years were identified. Almost 50% of 120 children with available records either died (n = 15) or had permanent neurological impairment (n = 39). Early use (before or with parenteral antibiotics) of corticosteroids protected against death or severe morbidity (adjusted OR 0.21, 95% CI 0.05 to 0.77). Delayed diagnosis was associated with increased morbidity in survivors (OR 3.4, 95% CI 1.03 to 11.4) but not with increased mortality. CONCLUSION: In a population with good access to health care and after adjusting for other known prognostic variables, early recognition of pneumococcal meningitis and treatment with adjunctive dexamethasone significantly improves outcomes. These data add to those from randomised controlled trials. Implementation requires development of protocols and guidelines for use in emergency departments.     

Hydrogen bonding in salicylsalicylic acid (salsalate) crystals

An X-ray crystallographic study of the drug salsalicylic acid (salsalate) has been performed. Crystal formation of the drug is influenced by both inter- and intra-molecular hydrogen bonding. In addition an OH group in salsalate can occupy alternate ortho positions resulting in two hydrogen bonding motifs within a single crystal.     

Electronmicroscopy of the surface of Pasteurella haemolytica

The surfaces of Pasteurella haemolytica, biotype A, serotypes 1, 2, 6, 7 and 9 and of P. haemolytica, biotype T serotypes 3, 4, 10 and 15 were examined by transmission electronmicroscopy with ruthenium red staining and polycationic ferritin labelling, by scanning electronmicroscopy, and by light microscopy. Electronmicroscopy showed that the surface of strains of P. haemolytica biotype A was covered by irregular protrusions which were probably capsular material. The surface and general morphology of P. haemolytica biotype T were distinct from those of biotype A.