Simultaneous quantification of delta-9-THC, THC-acid A, CBN and CBD in seized drugs using HPLC-DAD

An HPLC-DAD method for the quantitative analysis of Δ(9)-tetrahydrocannabinol (THC), Δ(9)-tetrahydrocannabinolic acid-A (THCA-A), cannabidiol (CBD), and cannabinol (CBN) in confiscated cannabis products has been developed, fully validated and applied to analyse seized cannabis products. For determination of the THC content of plant material, this method combines quantitation of THCA-A, which is the inactive precursor of THC, and free THC. Plant material was dried, homogenized and extracted with methanol by ultrasonication. Chromatographic separation was achieved with a Waters Alliance 2695 HPLC equipped with a Merck LiChrospher 60 RP-Select B (5μm) precolumn and a Merck LiChroCart 125-4 LiChrospher 60 RP-Select B (5μm) analytical column. Analytes were detected and quantified using a Waters 2996 photo diode array detector. This method has been accepted by the public authorities of Switzerland (Bundesamt für Gesundheit, Federal Office of Public Health), and has been used to analyse 9092 samples since 2000. Since no thermal decarboxylation of THCA-A occurs, the method is highly reproducible for different cannabis materials. Two calibration ranges are used, a lower one for THC, CBN and CBD, and a higher one for THCA-A, due to its dominant presence in fresh plant material. As provider of the Swiss proficiency test, the robustness of this method has been tested over several years, and homogeneity tests even in the low calibration range (1%) show high precision (RSD≤4.3%, except CBD) and accuracy (bias≤4.1%, except CBN).

Arzneimittel für seltene Krankheiten (orphan drugs) : Das schweizerische Heilmittelrecht im Vergleich mit der orphan drug Regulierung der EU

Arzneimittel für seltene Krankheiten (orphan drugs) lassen sich unter normalen Marktbedingungen kaum kostendeckend erforschen, entwickeln und vermarkten, was zu einem Mangel an geeigneten Therapien und zugelassenen Arzneimitteln für seltene Krankheiten führt. Um den fortdauernden Ausschluss von betroffenen Patienten vom medizinischen Fortschritt zu verhindern und die Defizite in der Erforschung und Entwicklung von orphan drugs zu beseitigen, schuf die Europäische Union – nach US-amerikanischem Vorbild – ein Anreizsystem. Der vorliegende Beitrag erläutert die regulatorischen Rahmenbedingungen für orphan drugs in der EU und zeigt auf, dass die Schweiz in der Schaffung günstiger Rahmenbedingungen für Patientinnen und Patienten, die an einer seltenen Krankheit leiden, anderen Ländern um Jahre hinter her hinkt, sich aber allmählich etwas tut.

Orphan drugs and paediatric medicinal products

While the safety and availability of medicinal products for the majority of adult patients has steadily improved in recent decades, for children and people suffering from rare diseases (orphan diseases) there is a lack of approved medicinal products for these patient populations. Since the research and development of medicinal products is associated with high costs, the costs for paediatric medicinal products and medicines for rare diseases (orphan drugs) may barely be covered under normal market conditions due to the small patient populations. In order to prevent the continued exclusion of children and persons suffering from rare diseases from medical progress and to eliminate the deficits in the research and development of medicinal products for these patient groups, the European Union created, along the lines of the U.S. model, a system of incentives and constraints. Since 2000, under Regulation (EC) No. 141/2000 (Orphan Drug Regulation) there has been an incentive system to encourage the research and development of orphan drugs. With the goal of improving the health of children in Europe, Regulation (EC) No. 1901/2006 (Paediatric Regulation) combines economic incentives with the requirement to conduct paediatric studies. This article explains and comments on the specific regulatory framework for orphan drugs and paediatric medicinal products in the European Union.

Electrochemical simulation of phase I metabolism for 21 drugs using four different working electrodes in an automated screening setup with MS detection.

BACKGROUND Electrochemical conversion of xenobiotics has been shown to mimic human phase I metabolism for a few compounds. MATERIALS & METHODS Twenty-one compounds were analyzed with a semiautomated electrochemical setup and mass spectrometry detection. RESULTS The system was able to mimic some metabolic pathways, such as oxygen gain, dealkylation and deiodination, but many of the expected and known metabolites were not produced. CONCLUSION Electrochemical conversion is a useful approach for the preparative synthesis of some types of metabolites, but as a screening method for unknown phase I metabolites, the method is, in our opinion, inferior to incubation with human liver microsomes and in vivo experiments with laboratory animals, for example.

The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT 3 receptors

Background and Purpose: The antimalarial compounds quinine, chloroquine and mefloquine affect the electrophysiological properties of Cys-loop receptors and have structural similarities to 5-HT3 receptor antagonists. They may therefore act at 5-HT3 receptors. Experimental Approach: The effects of quinine, chloroquine and mefloquine on electrophysiological and ligand binding properties of 5-HT3A receptors expressed in HEK 293 cells and Xenopus oocytes were examined. The compounds were also docked into models of the binding site. Key Results: 5-HT3 responses were blocked with IC50 values of 13.4 μM, 11.8 μM and 9.36 μM for quinine, chloroquine and mefloquine. Schild plots indicated quinine and chloroquine behaved competitively with pA2 values of 4.92 (KB=12.0 μM) and 4.97 (KB=16.4 μM). Mefloquine displayed weakly voltage-dependent, non-competitive inhibition consistent with channel block. On and off rates for quinine and chloroquine indicated a simple bimolecular reaction scheme. Quinine, chloroquine and mefloquine displaced [3H]granisetron with Ki values of 15.0, 24.2 and 35.7 μM. Docking of quinine into a homology model of the 5-HT3 receptor binding site located the tertiary ammonium between W183 and Y234, and the quinoline ring towards the membrane, stabilised by a hydrogen bond with E129. For chloroquine, the quinoline ring was positioned between W183 and Y234 and the tertiary ammonium stabilised by interactions with F226. Conclusions and Implications: This study shows that quinine and chloroquine competitively inhibit 5-HT3 receptors, while mefloquine inhibits predominantly non-competitively. Both quinine and chloroquine can be docked into a receptor binding site model, consistent with their structural homology to 5-HT3 receptor antagonists.

Oral hygiene products, medications and drugs - hidden aetiological factors for dental erosion.

Acidic or EDTA-containing oral hygiene products and acidic medicines have the potential to soften dental hard tissues. The low pH of oral care products increases the chemical stability of some fluoride compounds and favours the incorporation of fluoride ions in the lattice of hydroxyapatite and the precipitation of calcium fluoride on the tooth surface. This layer has some protective effect against an erosive attack. However, when the pH is too low or when no fluoride is present these protecting effects are replaced by direct softening of the tooth surface. Oral dryness can occur as a consequence of medication such as tranquilizers, antihistamines, antiemetics and antiparkinsonian medicaments or of salivary gland dysfunction. Above all, patients should be aware of the potential demineralization effects of oral hygiene products with low pH. Acetyl salicylic acid taken regularly in the form of multiple chewable tablets or in the form of headache powder, as well as chewing hydrochloric acids tablets for the treatment of stomach disorders, can cause erosion. There is most probably no direct association between asthmatic drugs and erosion on the population level. Consumers and health professionals should be aware of the potential of tooth damage not only by oral hygiene products and salivary substitutes but also by chewable and effervescent tablets. Several paediatric medications show a direct erosive potential in vitro. Clinical proof of the occurrence of erosion after use of these medicaments is still lacking. However, regular and prolonged use of these medicaments might bear the risk of causing erosion. Additionally, it can be assumed that patients suffering from xerostomia should be aware of the potential effects of oral hygiene products with low pH and high titratable acidity.

Vitamin D status among children and adolescents on anticonvulsant drugs in southern Switzerland.

INTRODUCTION It is recognised that vitamin D status is often inadequate (<50 nmol/l) in epileptic children, mainly because some anticonvulsant drugs induce the enzymes responsible for its metabolism. The purpose of the present study was to address vitamin D status among children and adolescents treated with anticonvulsant drugs and control subjects who reside in southern Switzerland, a high solar radiation region. METHODS Between January and May 2013, total serum 25-hydroxyvitamin D was assessed by liquid chromatography-tandem mass spectrometry in 58 children and adolescents with epilepsy and 29 controls residing in southern Switzerland. Dark-skinned individuals, females wearing dress styles covering practically the whole body and subjects with body mass index ≥85th percentile for age and sex were excluded. RESULTS Concentration of serum 25-hydroxyvitamin D was similar in epilepsy patients (48 [37-62] nmol/l; median and interquartile range) and controls (53 [47-64] nmol/l). An inadequate serum 25-hydroxyvitamin D concentration was common both among patients (55%) and control subjects (34%). Serum 25-hydroxyvitamin D was significantly lower among patients treated with anticonvulsant drugs that induce the metabolism of vitamin D (30 [21-51] nmol/l) than among the remaining patients (51 [40-65] nmol/l) and controls. CONCLUSIONS The present study indicates a relevant tendency towards inadequate vitamin D status among children with and without anticonvulsant drug management who reside in southern Switzerland. This tendency is more prominent in patients treated with anticonvulsant drugs that induce the metabolism of 25-hydroxyvitamin D.

Taste acceptability of pulverized brand-name and generic drugs containing amlodipine or candesartan.

Trials with pulverized brand-name antihypertensive drugs suggest that, from the perspective of taste acceptability, crushed candesartan, chlortalidon, hydrochlorothiazide, lercanidipine and lisinopril should be preferred to pulverized amlodipine, atenolol, bisoprolol, enalapril, irbesartan, losartan, ramipril, telmisartan and valsartan. Brand-name antihypertensive drugs and the corresponding generic medicines have never been compared with respect to their taste acceptability. We therefore investigated among healthy health care workers the taste acceptability of a pulverized 1 mg-test dose of the brand-name and two generics containing either the dihydropyridine calcium-channel blocker amlodipine (Norvasc(®), Amlodipin-Mepha(®) and Amlodipin Pfizer(®)) or the angiotensin receptor antagonist candesartan (Atacand(®), Cansartan-Mepha(®) and Pemzek(®)). For this purpose, a smiley-face scale depicting four degrees of pleasure was used. Between November and December 2013, the taste test was performed among 19 nurses (15 female and 4 male subjects) and 12 physicians (5 female and 7 male subjects) aged between 25 and 49 years. Pulverized brand-names and generics containing either amlodipine or candesartan did not differ with respect to their taste acceptability.

Thiolato-bridged dinuclear arene ruthenium complexes and their potential as anticancer drugs

Water-soluble arene ruthenium complexes have been intensively studied as cytotoxic compounds for the last fifteen years, notably owing to the promising in vitro and in vivo evaluations of, respectively, RAPTA-C (η6-p-MeC6H4Pri)Ru(P-pta)Cl2 (pta = 1,3,5-triaza-7-phospha-tricyclo-[3.3.1.1]decane) from Dyson's laboratory, and the (η6-arene)Ru(en)Cl]+ (en = ethylenediamine, RAED) family of compounds from Sadler's laboratory. In this account we describe the discovery of thiolato-bridged dinuclear arene ruthenium complexes and highlight subsequent developments in the field, including their syntheses, structures, and the recent strategies for the design of thiolato-bridged dinuclear arene ruthenium bioconjugates.

Report of the WPA section of pharmacopsychiatry on the relationship of antiepileptic drugs with suicidality in epilepsy

INTRODUCTION This report from the World Psychiatric Association Section on Pharmacopsychiatry examines the possible relationship of antiepileptic drugs with suicide-related clinical features and behaviors in patients with epilepsy. MATERIALS AND METHODS A systematic review of the MEDLINE search returned 1039 papers, of which only 8 were considered relevant. A critical analysis of the Food and Drug Administration (FDA) report on the increase risk for patients under antiepileptics to manifest suicidality is also included in this report. RESULTS The analysis of these studies revealed that the data are not supportive of the presence of a "class effect" on suicide-related behavior; on the contrary, there are some data suggesting such an effect concerning treatment with topiramate, lamotrigine, and levetiracetam for which further research is needed. DISCUSSION For the majority of people with epilepsy, anticonvulsant treatment is necessary and its failure for any reason is expected to have deleterious consequences. Therefore, clinicians should inform patients and their families of this increased risk of suicidal ideation and behavior, but should not overemphasize the issue. Specific subgroups of patients with epilepsy might be at a higher risk, and deserve closer monitoring and follow-up. Future research with antiepileptics should specifically focus on depression and suicidal thoughts.

Use of antiarrhythmic drugs during ablation of persistent atrial fibrillation: observations from a large single-centre cohort

Catheter ablation of complex fractionated atrial electrograms (CFAE), also known as defragmentation ablation, may be considered for the treatment of persistent atrial fibrillation (AF) beyond pulmonary vein isolation (PVI). Concomitant antiarrhythmic drug (AAD) therapy is common, but the relevance of AAD administration and its optimal timing during ablation remain unclear. Therefore, we investigated the use and timing of AADs during defragmentation ablation and their possible implications for AF termination and ablation success in a large cohort of patients. Retrospectively, we included 200 consecutive patients (age: 61 ± 12 years, LA diameter: 47 ± 8 mm) with persistent AF (episode duration 47 ± 72 weeks) who underwent de novo ablation including CFAE ablation. In all patients, PVI was performed prior to CFAE ablation. The use and timing of AADs were registered. The follow-ups consisted of Holter ECGs and clinical visits. Termination of AF was achieved in 132 patients (66 %). Intraprocedural AADs were administered in 168/200 patients (84 %) 45 ± 27 min after completion of PVI. Amiodarone was used in the majority of the patients (160/168). The timing of AAD administration was predicted by the atrial fibrillation cycle length (AFCL). At follow-up, 88 patients (46 %) were free from atrial arrhythmia. Multivariate logistic regression analysis revealed that administration of AAD early after PVI, LA size, duration of AF history, sex and AFCL were predictors of AF termination. The administration of AAD and its timing were not predictive of outcome, and age was the sole independent predictor of AF recurrence. The administration of AAD during ablation was common in this large cohort of persistent AF patients. The choice to administer AAD therapy and the timing of the administration during ablation were influenced by AFCL, and these factors did not significantly influence the moderate single procedure success rate in this retrospective analysis.

Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs

Although platinum-based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume-regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E. Cell swelling strongly enhanced LRRC8-dependent cisplatin uptake, bolstering the notion that cisplatin enters cells through VRAC. LRRC8A disruption also suppressed drug-induced apoptosis independently from drug uptake, possibly by impairing VRAC-dependent apoptotic cell volume decrease. Hence, by mediating cisplatin uptake and facilitating apoptosis, VRAC plays a dual role in the cellular drug response. Incorporation of the LRRC8D subunit into VRAC substantially increased its permeability for cisplatin and the cellular osmolyte taurine, indicating that LRRC8 proteins form the channel pore. Our work suggests that LRRC8D-containing VRACs are crucial for cell volume regulation by an important organic osmolyte and may influence cisplatin/carboplatin responsiveness of tumors.

Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis.

AIMS The preferred antithrombotic strategy for secondary prevention in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) is unknown. We pooled multiple observational studies and used propensity score-based methods to estimate the comparative effectiveness of oral anticoagulation (OAC) compared with antiplatelet therapy (APT). METHODS AND RESULTS Individual participant data from 12 databases of medically treated patients with CS and PFO were analysed with Cox regression models, to estimate database-specific hazard ratios (HRs) comparing OAC with APT, for both the primary composite outcome [recurrent stroke, transient ischaemic attack (TIA), or death] and stroke alone. Propensity scores were applied via inverse probability of treatment weighting to control for confounding. We synthesized database-specific HRs using random-effects meta-analysis models. This analysis included 2385 (OAC = 804 and APT = 1581) patients with 227 composite endpoints (stroke/TIA/death). The difference between OAC and APT was not statistically significant for the primary composite outcome [adjusted HR = 0.76, 95% confidence interval (CI) 0.52-1.12] or for the secondary outcome of stroke alone (adjusted HR = 0.75, 95% CI 0.44-1.27). Results were consistent in analyses applying alternative weighting schemes, with the exception that OAC had a statistically significant beneficial effect on the composite outcome in analyses standardized to the patient population who actually received APT (adjusted HR = 0.64, 95% CI 0.42-0.99). Subgroup analyses did not detect statistically significant heterogeneity of treatment effects across clinically important patient groups. CONCLUSION We did not find a statistically significant difference comparing OAC with APT; our results justify randomized trials comparing different antithrombotic approaches in these patients.