Exploring the scope of new arylamino alcohol derivatives: Synthesis, antimalarial evaluation, toxicological studies, and target exploration.

Synthesis of new 1-aryl-3-substituted propanol derivatives followed by structure-activity relationship, in silico drug-likeness, cytotoxicity, genotoxicity, in silico metabolism, in silico pharmacophore modeling, and in vivo studies led to the identification of compounds 22 and 23 with significant in vitro antiplasmodial activity against drug sensitive (D6 IC50 ≤ 0.19 µM) and multidrug resistant (FCR-3 IC50 ≤ 0.40 µM and C235 IC50 ≤ 0.28 µM) strains of Plasmodium falciparum. Adequate selectivity index and absence of genotoxicity was also observed. Notably, compound 22 displays excellent parasitemia reduction (98 ± 1%), and complete cure with all treated mice surviving through the entire period with no signs of toxicity. One important factor is the agreement between in vitro potency and in vivo studies. Target exploration was performed; this chemotype series exhibits an alternative antimalarial mechanism.

Pharmacological effects of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator: results from a 12-week, open-label pilot study in multiple sclerosis patients.

CS-0777 is a selective sphingosine 1-phosphate receptor-1 modulator under investigation for treatment of multiple sclerosis (MS). We conducted an open-label, pilot study in 25 MS patients to assess the safety, pharmacokinetics, pharmacodynamics and exploratory efficacy of oral CS-0777 (0.1, 0.3 and 0.6 mg), administered once weekly or every other week for 12 weeks. CS-0777 resulted in a pronounced, dose-dependent decrease in lymphocytes and CD4 T cell subsets, which returned to baseline within 4 weeks after the last dose. Overall, CS-0777 was safe and well-tolerated. These results require confirmation in a double-blind, placebo-controlled and adequately powered phase 2 study in MS.

Pharmacological modulation of peripheral T and B lymphocytes by a selective sphingosine 1-phosphate receptor-1 modulator.

CS-0777 is a selective sphingosine 1-phosphate receptor-1 (S1P(1)) modulator under development for treatment of autoimmune conditions. A randomized, double-blind, placebo-controlled study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CS-0777 in escalating dose cohorts of healthy male participants (0.1, 0.3, 1.0, and 2.5 mg; 6 active, 2 placebo per cohort). Primary pharmacodynamic parameters were absolute lymphocyte counts and lymphocyte subsets (CD4 and CD8 T and B cells). CS-0777 resulted in a pronounced, dose-dependent decrease in absolute lymphocyte counts (mean percent decrease from baseline at 24 hours postdose: 7%, 26%, 52%, 79%, and 85%, for placebo and 0.1, 0.3, 1.0, and 2.5 mg, respectively). Dose-related decreases of similar magnitude were observed for T and B cell subsets. Mean total white blood cell and neutrophil counts remained within normal ranges for all dose levels. CS-0777 was well tolerated, and there were no serious or severe adverse events. Mild, asymptomatic bradycardia and transaminase elevations (<3-fold upper limit of normal), similar to findings for other S1P receptor modulators, were observed at the highest dose level (2.5 mg). Therefore, CS-0777 shows potent activity in humans and may hold potential for treatment of autoimmune conditions such as multiple sclerosis.

Characterization of pentoxyverine metabolites in urine using GC/MS after intoxication with Silomat cough drops.

A nearly two and a half year old boy was hospitalized after showing symptoms of disorientation and hallucination. The parents remembered the child playing with a bottle of Silomat cough drops, so that an intoxication was taken into consideration. After liquid/liquid extraction of a urine sample collected in hospital, the underivatized and the acetylated extracts were analyzed by gas chromatography-mass spectrometry (GC/MS) using electron ionization (EI) as well as chemical ionization (CI). In the urine sample high amounts of pentoxyverine (carbetapentane) and several of its metabolites, e.g., different hydrolyzed, desalkylated and ring-hydroxylated products have been identified. The correlation of the results, the observed symptoms, and the access to the Silomat cough drops reveal an intoxication after ingestion of an unknown amount of the antitussive pentoxyverine. Corresponding EI- and CI-GC/MS spectra are presented characterizing the structure of its metabolites.

Unclear loss of consciousness after clobutinol intake.

The case of a 13-month-old boy with a diagnosis of unclear unconsciousness is reported on. As the physical examination did not lead to any explanation of his condition, the administration of drugs in the context of Munchausen syndrome by proxy was suspected. Complex forensic-toxicological analyses using HPLC/UV, LC/MS/MS, and GC/MS identified ambroxol and clobutinol, two drugs that are indicated for acute respiratory diseases. No other central active compounds were detected. The accusation of intentional bodily injury raised against the parents could be rebutted, since the boy's unconsciousness could be explained with a rare but harmful side effect of the antitussive clobutinol.

[Risks of non-prescription medication. Clobutinol cough syrup as a recent example]. / Risiken nicht verschreibungspflichtiger Medikamente. Aktuelles Beispiel Silomat Hustensaft.

INTRODUCTION: The arbitrary use of additional drugs other than prescribed medication is known to be a huge part of drug sales. However, the interactions of such non-prescription medication with any daily medication or concomitant diseases remain often unclear. Recently, in accordance with the decision of the competent authority in Germany, clobutinol (e.g. Silomat), a drug against non-productive cough was withdrawn in all countries worldwide in which this medication had been available. The drug had first been approved in 1961 and estimated to have had 200 million patient exposures. A recent clinical study revealed that clobutinol can prolong the QT interval compared to placebo and may thus cause cardiac tachyarrhythmias. Even in therapeutic doses (240 mg daily) this effect was seen in healthy volunteers. Furthermore, this study was prematurely discontinued because of an epileptic grand mal seizure in one volunteer, suggesting neurological side effects of clobutinol. DISCUSSION: Clobutinol prolongs the QT interval and may cause life-threatening arrhythmias. This should serve as a warning to doctors to be careful when prescribing non-prescription medication. CONCLUSION: Non-prescription drugs can be a potential risk for patients who are also taking other pharmaceutical preparations or having concomitant disease. This is because such drugs may cause harmful interactions, most of them previously unknown. All doctors should avoid unsupervised use of non-prescription medication.

Allergy evaluation after emergency treatment: anaphylaxis to the over-the-counter medication clobutinol.

Anaphylaxis is traditionally diagnosed and treated as an acute emergency but should be always followed by a search for specific triggers, resulting in avoidance strategies. This case report highlights the relevance of a detailed evaluation after anaphylaxis for diagnosis of a rare but potentially life-threatening allergy. Considering the high frequency of clobutinol application, IgE-mediated allergic hypersensitivity seems extremely rare and has to be distinguished from infection-associated urticaria and angioedema as well as non-specific summation effects. Accidental re-exposure has to be strictly avoided and therefore after identification of clobutinol as the anaphylaxis trigger, the patient received detailed allergy documents including international non-proprietary and trade names of the culprit drug.

A common antitussive drug, clobutinol, precipitates the long QT syndrome 2.

QT prolongation, a classic risk factor for arrhythmias, can result from a mutation in one of the genes governing cardiac repolarization and also can result from the intake of a medication acting as blocker of the cardiac K(+) channel human ether-a-go-go-related gene (HERG). Here, we identified the arrhythmogenic potential of a nonopioid antitussive drug, clobutinol. The deleterious effects of clobutinol were suspected when a young boy, with a diagnosis of congenital long QT syndrome, experienced arrhythmias while being treated with this drug. Using the patch-clamp technique, we showed that clobutinol dose-dependently inhibited the HERG K(+) current with a half-maximum block concentration of 2.9 microM. In the proband, we identified a novel A561P HERG mutation. Two others long QT mutations (A561V and A561T) had been reported previously at the same position. None of the three mutants led to a sizeable current in heterologous expression system. When coexpressed with wild-type (WT) HERG channels, the three Ala561 mutants reduced the trafficking of WT and mutant heteromeric channels, resulting in decreased K(+) current amplitude (dominant-negative effects). In addition, A561P but not A561V and A561T mutants induced a approximately -11 mV shift of the current activation curve and accelerated deactivation, thereby partially counteracting the dominant-negative effects. A561P mutation and clobutinol effects on the human ventricular action potential characteristics were simulated using the Priebe-Beuckelmann model. Our work shows that clobutinol has limited effects on WT action potential but should be classified as a "drug to be avoided by congenital long QT patients" rather than as a "drug with risk of torsades de pointes".

Hypomania related to phenelzine and isoetharine interaction in one patient.

A case is reported of a man with apparent unipolar depression that was responsive to treatment with phenelzine who became hypomanic when isoetharine was added to treat his chronic obstructive pulmonary disease. The role of beta-adrenergic receptors in affective illness is reviewed in light of this case.

Textile chemical finish dermatitis.

Chemicals used on fabrics to improve 10 different performance characteristics have resulted in irritant or allergic contact dermatitis. The most significant problem is due to formaldehyde and N-methylol compounds to produce durable press fabrics. Little is known about incidence of finish dermatitis or mode and amount of transfer of chemicals from fabric to skin.

Clinical study of broncholytic effect and side-effects of isoetharine ('Numotac').

In thirty-nine adult asthmatics a clinical trial was carried out with 10 mg slow-release tablets of isoetharine ('Numotac', 3M Riker) at two dose levels: 10 mg and 20 mg four times a day. The trial was double-blind with crossover after six weeks. Twenty-three patients reported a positive effect on their respiratory symptoms when isoetharine had replaced their previous treatment; negative effect was reported by one patient while twelve patients were undecided. Tremor was a common side-effect but except in three cases it was slight. There was no difference in side-effects between the high and the low doses if the initial dose was low. However, there were significantly more side-effects when the trial was started with the high dose.