A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload.

This was a 24-week, multicenter phase-2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was -0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators.

[Molecular mechanisms of circadian clock functioning].

Most physiological processes of all organisms are rhythmic with a period of about 24 h and are generated by an endogenous biological CLOCK present in all cells. However, there is also a central CLOCK--the primary circadian pacemaker which is localized in the suprachiasmatic nuclei of the mammalian hypothalamus. Factors of groups Period (PER1, PER2 and PER3), BMAL (BMAL1 and BMAL2), CRYptochromes (CRY1 and CRY2) as well as some other factors are the components of this circadian CLOCK system. Some of these genes contain E-box sequences and their expression is regulated by a transcription factor complex CLOCK-BMAL1. The enzymes responsible for the post-translational modification of circadian gene products are also the components of circadian CLOCK system. These enzymes define CLOCK's work and determine the duration of circadian biorhythm and functional state of the whole organism. The most important of these enzymes are casein kinase-1epsilon and -1delta. We have analysed data about the interconnection between the circadian CLOCK system, cell cycle, and cancerogenesis as well as about the sensitivity of circadian gene expression to the action of toxic agents and nanomaterials.

A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload.

BACKGROUND: There is still a clinical need for a well-tolerated and safe iron chelator for the treatment of transfusional iron overload. We describe the pharmacokinetic properties and safety data after 7 days of dosing of FBS0701, a novel oral, once-daily iron chelator. DESIGN AND METHODS: This phase 1b dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload, was conducted in 16 adult patients with iron overloaded consequent to transfusions. FBS0701 was given daily for 7 days at doses up to 32 mg/kg and was well tolerated at all dose levels. RESULTS: Pharmacokinetics showed dose-proportionality. The maxium plasma concentration (C(max)) was reached within 60-90 minutes of dosing and the drug was rapidly distributed at the predicted therapeutic doses. The plasma elimination half-life (t(1/2)) was approximately 19 hours. There were no serious adverse events associated with the drug. Conclusions On the basis of these safety and pharmacokinetic data, FBS0701 warrants further clinical evaluation in patients with transfusional iron overload. (Clinicaltrials.gov identifier: NCT01186419).

Characterisation of the chemical and biological properties of molecules with QSAR/QSPR and chemical grouping, and its application to a group of alkyl ethers.

This study presents a QSAR/QSPR modelling and chemical grouping (read-across) approach to provide information on the biological properties of a group of aliphatic ethers, with accurate biological predictions restricted to those physico-chemical and (eco)toxicological properties where the performance of QSAR/QSPR has been shown to be acceptable. The mathematical methods used ranged from multivariate regression models to PLS (partial least-squares), SVM (support vector machines) and Sammon's mapping. A novel grouping approach, based on a set of key descriptors, has been proposed to give a compact picture of the structural and biological properties of the compounds, and to provide a more mechanistic basis for the interpretations of chemical groups. Besides being a straightforward case study, the paper also exemplifies the capabilities and limitations of the methods in predictive toxicology on a more general level.

Correlation between urinary methoxyacetic acid and exposure of ethylene glycol dimethyl ether in a lithium battery plant.

OBJECTIVE: To examine the correlation between airborne ethylene glycol dimethyl ether (EGdiME) exposures and the urinary methoxyacetic acid (MAA) and to approach the issue of a permissible exposure limit for EGdiME. METHODS: The survey was conducted on Thursday. Workers occupationally exposed to EGdiME, as well as nonexposed controls, were studied in combination with one of the authors, who was coincidentally exposed to EGdiME while carrying out the study. Air levels of EGdiME were determined by personal sampling on passive gas tubes. Urine was collected from nine control subjects and ten workers immediately before and after the shift, and from one of the authors at intervals during 12 h. The analyses of EGdiME in air and MAA in urine were performed by gas chromatography with flame ionization detection. RESULTS: The time-weighted average (TWA) air levels of EGdiME ranged from 0.7 to 10.5 ppm during 8 h work shifts. The urinary levels of MAA in one of the authors increased continuously during exposure and after the end of exposure. The levels of urinary MAA in the exposed workers were significantly higher than those in the control subjects. On the other hand, the postshift values were higher than the preshift values in the exposed workers, but the difference was not significant. A linear correlation was found between the TWA air levels of EGdiME and creatinine-adjusted MAA levels in urine collected at the end of the shift (r = 0.933; P < 0.0001). According to our equation, a linear extrapolation to the biological limit value recommended by Shih et al. (1999) of 40 mg MAA/g crea indicated an average inhalation exposure to EGdiME over the workweek of 12 ppm. CONCLUSIONS: These results indicate that the determination of MAA in urine is suitable for use in the biological monitoring of EGdiME exposure.

Multicentre patch test study of air-oxidized ethoxylated surfactants.

Frequent exposure to water and surfactants is considered to be the main cause of hand eczema from wet work. Ethoxylated surfactants are susceptible to oxidation and some of the oxidation products formed have proved to be contact sensitizers in guinea pigs. The question of human sensitization to oxidized surfactants was addressed in a multicentre study in the Stockholm region. 528 consecutive dermatitis patients were patch tested with widely used ethoxylated surfactants in oxidized and non-oxidized form as well as certain identified oxidation compounds. 61 patients presented with mild, clearly irritant reactions to some of the surfactants tested. 18 patients showed not only erythema but also oedema and/or papules and vesicles, using a morphologic descriptive system for reading the patch test reactions. These reactions occurred mostly to oxidized surfactants and oxidation products. When retesting 9 of these 18 patients only an allergic reaction to acetaldehyde was confirmed. We conclude that oxidized ethoxylated surfactants have increased irritant potential compared to non-oxidized material. Our working hypothesis is that oxidized surfactants of technical quality exert a lower risk of sensitization than do oxidized homologous pure surfactants. Among the potential allergens formed during autoxidation, formaldehyde and acetaldehyde must be considered as a source of unexpected exposure.

Physiologically based toxicokinetic modeling of inhaled ethyl tertiary-butyl ether in humans.

A physiologically based toxicokinetic (PBTK) model was developed for evaluation of inhalation exposure in humans to the gasoline additive, ethyl tertiary-butyl ether (ETBE). PBTK models are useful tools to relate external exposure to internal doses and biological markers of exposure in humans. To describe the kinetics of ETBE, the following compartments were used: lungs (including arterial blood), liver, fat, rapidly perfused tissues, resting muscles, and working muscles. The same set of compartments and, in addition, a urinary excretion compartment were used for the metabolite tertiary-butyl alcohol (TBA). First order metabolism was assumed in the model, since linear kinetics has been shown experimentally in humans after inhalation exposure up to 50 ppm ETBE. Organ volumes and blood flows were calculated from individual body composition based on published equations, and tissue/blood partition coefficients were calculated from liquid/air partition coefficients and tissue composition. Estimates of individual metabolite parameters of 8 subjects were obtained by fitting the PBTK model to experimental data from humans (5, 25, 50 ppm ETBE, 2-h exposure; Nihlén et al., Toxicol. Sci., 1998; 46, 1-10). The PBTK model was then used to predict levels of the biomarkers ETBE and TBA in blood, urine, and exhaled air after various scenarios, such as prolonged exposure, fluctuating exposure, and exposure during physical activity. In addition, the interindividual variability in biomarker levels was predicted, in the eight experimentally exposed subjects after a working week. According to the model, raising the work load from rest to heavy exercise increases all biomarker levels by approximately 2-fold at the end of the work shift, and by 3-fold the next morning. A small accumulation of all biomarkers was seen during one week of simulated exposure. Further predictions suggested that the interindividual variability in biomarker levels would be higher the next morning than at the end of the work shift, and higher for TBA than for ETBE. Monte Carlo simulations were used to describe fluctuating exposure scenarios. These simulations suggest that ETBE levels in blood and exhaled air at the end of the working day are highly sensitive to exposure fluctuations, whereas ETBE levels the next morning and TBA in urine and blood are less sensitive. Considering these simulations, data from the previous toxicokinetic study and practical issues, we suggest that TBA in urine is a suitable biomarker for exposure to ETBE and gasoline vapor.

The utility of preliminary surveys to detect the cause of acute metalworking fluid hazards.

This paper describes preliminary studies undertaken to optimize a later epidemiologic study, the aim of which was to identify a causative agent of adverse respiratory effects and dermatitis among production machinists. Two methods were used to rate coolant system hazards. The results of a voluntary plantwide questionnaire with an 18% participation rate showed that both dermatologic and respiratory symptoms were higher among machine operators than among maintenance or assembly workers, that symptoms were not more prevalent early in the week, and that dermatitis may be associated with smoking status; however, the questionnaire was not helpful in rating individual coolant system hazards. The hazard ratings provided by an in-plant expert panel were strongly associated with particular synthetic coolant containing an ethoxylated phenol; however, the resulting design for a later epidemiologic study could not be implemented due to changes in coolants used at the plant.

[Leocaine--a new generation of local anesthetics]. / Leokain--mestnyi anestetik novogo pokoleniia.

Leocaine is a new crystal beta-modification of beta-dimethylaminoethyl ether of n-butylaminobenzoic acid hydrochloride. Its chemical formula is the same as for dicaine, but it has a number of advantages over this drug. The anesthetic activity of leocaine is 2.5 times higher than that of dicaine. By the duration and depth of anesthesia 0.3% leocaine solution corresponds to 1% dicaine. Leocaine exerts no toxic effect on the corneal epithelium and its instillation into the conjunctival cavity does not result in the reactive dilatation of corneal or episcleral vessels. Leocaine solution is stable for 2 years. Clinical trials of leocaine carried out on more than 2500 patients showed virtually complete absence of side effects. Commercial manufacture of leocaine is launched at present. One of the commercial preparations represents a 0.3% solution of the active substance in isotonic NaCl solution. Another drug contains, besides leocaine, methylcellulose. Eye drops with leocaine are recommended for practical ophthalmology instead of dicaine for local anesthesia. The drugs are permitted for medical use and commercial manufacture by the Ministry of Health and Medical Industry of Russia.

Prospective study of changes in serum calcium after diethyl-ether anaesthesia.

Changes in serum calcium after diethyl-ether anaesthesia given for various routine surgical operations, were studied in 30 patients. Mean (+/- SD) concentration (mg%) of serum calcium before induction of anaesthesia was 10.37 +/- 0.77. Serum calcium decreased by 0.05 per cent after 10 min of induction and by 3.33 per cent at the end of anaesthesia which was highly significant (P less than 0.001). There was a correlation (r = 0.63; P less than 0.01) between decline in serum calcium and duration of ether anaesthesia. Serum calcium returned to near normal levels after 24 h of ether anaesthesia. In view of the fall in serum calcium, it is emphasized that ether should be either avoided in patients with known or suspected hypocalcaemia or be used for as short a time as possible with due precaution and calcium supplementation.

A serious complication of vesical ether instillation: ether cystitis.

We report the fourth case of ether cystitis, which occurred after ether was used to dissolve a Foley catheter balloon. The severity of the lesions required an ileocystoplasty to preserve normal micturition. Ether dissolution of Foley catheter balloons should be replaced with mechanical disruption.

[Functional state of the liver in obese patients subjected to surgery under halothane and ether anesthesia]. / Funktsional'noe sostoianie pecheni u tuchnykh bol'nykh, operirovannykh pod ftorotanovym i éfirnym narkozom.

On the basis of an analysis of changes in biochemical indices of the hepatic function in 41 patients operated upon for obesity of the 3d or 4th stage the authors make a conclusion that ether narcosis exerts a less injuring effect on the liver as compared with fluothane and is believed to be preferable.