The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions.

We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non-CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P-value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients.

Effects of chronic administration of ß-blockers on airway responsiveness in a murine model of heart failure.

Lung function abnormalities, both at rest and during exercise, are frequently observed in patients with chronic heart failure (HF), also in absence of respiratory disease. It has been documented that, in HF, chronic adrenergic stimulation down-regulates ß-adrenoceptors (ß-ARs) and modifies airway relaxant responses. This study was designed to investigate in an animal model of HF whether a treatment with a ß-AR blocker, metoprolol, could modify the altered airway hyperresponsiveness. In rats, randomly assigned to 3 experimental groups sham-operated rats (SH), rats with HF induced by left anterior descending coronaric occlusion (HF n = 10), and rats treated with metoprolol 100 mg/kg/die (MET = 10), HF was evaluated after 10 weeks and resulted in increases in plasma norepinephrine and epinephrine and left ventricular end diastolic pressure. ß2-ARs and G-protein-ßAR2-kinase (GRK2) mRNA levels were determined by real time reverse transcriptase PCR. Carbachol-precontracted isolated tracheal rings were used to functionally assess airway smooth muscle relaxation. In pulmonary tissues, ß2-AR mRNA level was significantly decreased in HF groups (-48.73 ± 5.18%, P < 0.01); in the same groups the GRK2 mRNA-levels were significantly enhanced (+222.50 ± 6.13%, P < 0.001); in lung deriving from MET groups the levels of mRNA were significantly increased (+339.86 ± 11.26%, P < 0.001), while the GRK2 mRNA-levels unchanged (-59.02 ± 3.97%, P < 0.001), when compared to SH groups. Relaxation of tracheal strips in response to salbutamol was significantly reduced in HF groups; in tracheal rings, deriving from MET groups, the relaxant effects of salbutamol were significantly enhanced (SH, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; HF, Emax: 34.87 ± 2.98%, pD2: 7.45 ± 0.27; MET, Emax: 85.43 ± 6.80%, pD2: 6.95 ± 0.59, P < 0.001). In HF, the down-regulation of pulmonary ß-ARs results in a significant attenuation of airway relaxation. These effects have been reversed by a treatment with metoprolol, suggesting a potential role of ß-AR blockers in the treatment of patients suffering from HF and chronic obstructive airway diseases.

Cardiorespiratory effects of change in posture after spinal anesthesia with hyperbaric bupivacaine.

Spinal anesthesia is a special regional anesthetic technique that is applied in lower limb orthopedic and other surgical procedures made below the transverse umbilical line, which is able to produce a neuraxial central block. The patient's position, together with the baricity of the drug solution injected, is a variable that can affect the success of anaesthesia. According to clinical practice, lateral decubitus or the sitting position are to be maintained for a period ranging from 15 to 20 minutes to avoid any possible motion of the injected solution that could cause side effects due to anesthetic being distributed up to thoracic segments. We describe a case of cardiovascular and respiratory effects occurred approximately 65 min after spinal anesthesia with 7 mg of 1% hyperbaric bupivacaine in a patient during change in posture from mild anti-Trendelemburg to supine decubitus. These findings show that a change in posture after spinal anaesthesia with hyperbaric bupivacaine can affect the safety of this anesthesia technique, also after a longer period of time than is usually recommended to avoid the spread of anaesthetic drug.