Backscattering-Induced Dissipative Solitons in Ring Quantum Cascade Lasers.

Ring quantum cascade lasers have recently gained considerable attention, showing ultrastable frequency comb and soliton operation, thus opening a way to integrated spectrometers in the midinfrared and terahertz fingerprint regions. Thanks to a self-consistent Maxwell-Bloch model, we demonstrate, in excellent agreement with the experimental data, that a small but finite coupling between the counterpropagating waves arising from distributed backscattering is essential to stabilize the soliton solution.

Rapid isolation of acidic cannabinoids from Cannabis sativa L. using pH-zone-refining centrifugal partition chromatography.

This work introduces an effective methodology for the isolation of acidic cannabinoids from fiber-type Cannabis sativa L. Supercritical fluid extraction (SFE) was initially employed to obtain an enriched extract of acidic cannabinoids. Subsequently, fractionation was performed by using centrifugal partition chromatography (CPC) with the pH-zone-refining method. The biphasic solvent system that was selected consisted of n-hexane/ethyl acetate/ethanol/water 8:2:5:5 (v/v/v/v). Trifluoroacetic acid was added as retainer in the organic stationary phase, while triethylamine was used as eluter in the aqueous mobile phase. The most promising CPC fractions containing cannabidiolic acid (CBDA) and cannabidivarinic acid (CBDVA) were further purified by liquid-liquid extraction. Following this procedure, 1.86 g of CBDA (>85%) were recovered from 9 g of extract, with 1.08 g thereof having a purity of more than 95%, as determined by HPLC-PDA analysis. Moreover, 91 mg of CBDVA with greater than 85% purity were obtained. This methodology can be efficiently used for the large-scale purification of CBDA and after minor modifications could be readily adaptable for the isolation of other acidic cannabinoids, based on their ionizable character.

Serotonin transporter polymorphisms and side effects in antidepressant therapy--a pilot study.

OBJECTIVES: To assess the influence of the serotonin transporter variable number of tandem repeat (HTT-VNTR) polymorphism and the serotonin transporter-gene-linked polymorphic region (HTTLPR) polymorphism on development of side effects under antidepressant therapy. METHODS: A total of 109 depressive in-patients treated with various antidepressants according to local clinical practice were included in the investigation. Four weeks after admission to hospital, side effects were assessed by using a modified version of the dosage record and treatment emergent symptoms scale (DOTES). Differences in side effects between the genotype groups of both polymorphisms were analyzed using the Fisher's exact test. RESULTS: A total of 65 patients received mirtazapine (25 of them in combination with other antidepressants), and 44 patients were predominantly treated with antidepressants acting via HTT, such as selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). When patients were treated with HTT-blocking antidepressants, a significantly higher occurrence of side effects in patients with the HTTVNTR 2.10/2.10 genotype (52.6%) than in patients with the 2.10/2.12 (12.5%) and 2.12/2.12 (0%) genotypes (p = 0.004) was found. With regard to the HTTLPR polymorphism, patients predominantly on HTT-blocking antidepressants with the s/s genotype suffered more frequently from side effects (50.0%) than heterozygotes (40.0%) and homozygotes for the l-allele (0%) (p = 0.002). In contrast, no association of the HTTVNTR polymorphism was found in patients treated with mirtazapine. The risk groups defined by a combined genotype from both polymorphisms demonstrated a major effect on the incidence of adverse drug events in patients treated with predominantly HTT-blocking antidepressants (p = 0.00018; low risk: 0%, 0/13, medium risk: 13.3%, 2/15, high risk: 62.5%, 10/16). CONCLUSION: These results support the hypothesis that both polymorphisms influence tolerability to drugs primarily acting via HTT inhibition, such as SSRIs, TCAs and venlafaxine. Tolerability to mirtazapine was not influenced, probably owing to a different mode of action. As there are limitations due to the heterogeneity of treatment and concomitant therapy, further studies are required to confirm the obtained results.

Amitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy.

BACKGROUND: Amitriptyline has been replaced in many countries by alternative and more expensive drugs based on claims of improved tolerability and toxicity and despite slightly reduced efficacy. Preliminary studies indicate that adverse effects could be linked to polymorphisms of drug-metabolizing enzymes, but information on their clinical impact remains scanty and includes mainly case reports. We conducted a prospective blinded two-center study seeking correlations between CYP2C19 and CYP2D6 genotypes, drug concentrations, adverse events, and therapy response. METHODS: Fifty Caucasian inpatients with at least medium-grade depressive disorder received amitriptyline at a fixed dose of 75 mg twice a day. Blood samples for concentration monitoring of amitriptyline and nortriptyline were taken weekly until discharge along with evaluations of depression (Hamilton Depression Scale and Clinical Global Impression Scale) and side effect (Dosage Record and Treatment Emergent Symptoms Scale; DOTES) scores. RESULTS: In a ROC analysis, nortriptyline but not amitriptyline concentrations correlated with side effects (DOTES sum score >or=5; area under the curve, 0.733; P = 0.008). Carriers of two functional CYP2D6 alleles had a significantly lower risk of side effects than carriers of only one functional allele (12.1% vs 76.5%; P = 0.00001). The lowest risk was observed for carriers of two functional CYP2D6 alleles combined with only one functional CYP2C19 allele [0 of 13 (0%) vs 9 of 11 (81.8%) for the high-risk group; P = 0.00004]. We found no correlations between drug concentrations or genotypes and therapeutic response. CONCLUSIONS: Combined pharmacogenetic testing for CYP2D6 and CYP2C19 identifies patients with low risk for side effects in amitriptyline therapy and could possibly be used to individualize antidepressive regimens and reduce treatment cost. Identification of genotypes associated with slightly reduced intermediate metabolism may be more important than currently anticipated. It could also be the key to demonstrating cost-effectiveness for CYP2D6 genotyping in critical dose drugs.

Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers.

BACKGROUND: Recently, new polymorphisms were described in connection with intermediate and ultrarapid CYP2D6 metabolism. These may allow a much desired prediction of metabolic activity within the extensive metabolizer group. The functional consequences are still being discussed with few data available for clinical patients. METHODS: We conducted a prospective, blinded two-center study seeking correlations between CYP2C19 (*2,*3, and *4; conventional PCR) and CYP2D6 genotypes (*1 to *10, *35, and *41; real-time and multiplex PCR) and drug concentrations (Emit and HPLC) in 50 Caucasians receiving amitriptyline (AT; 75 mg twice a day). RESULTS: Eighteen CYP2C19 heterozygotes (*1/*2) had higher AT (P = 0.033) and lower nortriptyline (NT; P = 0.059) concentrations than 30 homozygotes (*1/*1). For CYP2D6, we calculated two new indices, i.e., the allele-specific change of concentration on identical background (ASCOC) and a quantitative functional gene dose. The ASCOC describes the change in NT concentration attributable to a mutant allele compared with the wild type. We found significantly higher concentrations for alleles *4 (95.6%; P <0.0001), *10 (63.3%; P <0.001), and *41 (39.8%; P <0.0001) but not for *2 and *35. Assigning of semiquantitative gene doses of 0, 0.5, or 1 to each allele instead of applying the current classification system (predicted phenotypes: 3 intermediate metabolizers, 46 extensive metabolizers, and 1 ultrarapid metabolizer) produced significant NT concentration differences: gene doses of 0.5 (n =3), 1 (n = 14), 1.5 (n = 11), 2 (n = 21) and 3 (n = 1; P <0.00001). CONCLUSIONS: AT and NT concentrations can be predicted within the group of CYP2D6 extensive metabolizers. The ASCOC provides substantial advantages compared with current methods of analysis. CYP2D6 but not CYP2C19 correlates with the sum of both concentrations used to guide AT therapy.

High-speed genotyping of CYP1A2*1F mutation with fluorescent hybridization probes using the LightCycler.

The polymorphism CYP1A2*1F of the cytochrome 1A2 gene affects the inducibility of this cytochrome, which is involved in the metabolism of many commonly used drugs. We developed a rapid-cycle polymerase chain reaction (PCR) and fluorescent probe melting curve analysis on the LightCycler instrument for identification of this mutation. This new method was confirmed by genotyping 101 samples in parallel to restriction enzyme digestion. The 100% concordance of both methods showed the reliability of our high-speed genotyping assay, which is suitable for large epidemiological studies or routine clinical use.