When should a substance be designated as sensitizing for the skin ('Sh') or for the airways ('Sa')?

In the List of MAK and BAT Values compounds are designated with 'Sa' ('sensitizing for the airways') or 'Sh' ('sensitizing for the skin') if, according to scientific evidence, they are allergens. Mainly based on suggestions by a WHO working group and based on our own experience, extended criteria have been elaborated by the working group 'skin and allergy' of the Commission of the Deutsche Forschungsgemeinschaft for the Investigation of Health Hazards of Chemical Compounds in the Work Area, which are presented in this article. They serve as guidelines for deciding which substances have to be labelled 'Sa' and 'Sh', respectively, for the prevention of sensitization and subsequent allergic diseases in workers. Although in some special cases their strict application may not be deemed necessary or possible, the proposed new criteria should be used to make the procedure of classification of substances: 1) more rational, 2) more consistent, 3) more comprehensible, and 4) more transparent. This paper informs readers working scientifically or administratively in this field and invites a critical discussion of the issue.     

α(1)-Adrenoceptors in the urinary tract

α(1)-Adrenoceptors have been identified and characterized extensively by functional, radioligand-binding, and molecular biological techniques. Molecular clones have been isolated for three α(1)-subtypes (α(1a), α(1b), and α(1d)), and these subtypes are also functionally characterized. α(1)-Adrenoceptors are present in the prostate, urethra, bladder (urothelium, smooth muscle, and afferent nerves), ureter, vas deferens, peripheral ganglia, nerve terminals, vascular tissues, and central nervous system (CNS), and they could all potentially influence overall urinary function and contribute to both the therapeutic and adverse effects of α(1)-adrenoceptor antagonists in patients with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). This review aimed to discuss the relevant physiological and pharmacological roles and molecular biology of α(1)-adrenoceptor subtypes in the prostate, urethra, bladder, ureter, and CNS.     

α-adrenoceptors mediating the positive inotropic effect of phenylephrine in the right ventricular muscle of the monkey (Macaca fuscata)

Summary The property of adrenoceptors mediating the positive inotropic effect (PIE) in the ventricular muscle of the Japanese monkey (Macaca fuscata) was investigated by the use of phenylephrine (PE) and adrenoceptor antagonists. The intrinsic activity (0.6) and the pD₂-value (5.41) for PE were comparable to those in other mammalian species. The -adrenoceptor antagonist, pindolol (3×10^–8 mol/l) shifted only the upper part of the concentration-response curve (CRC) for PE to the right; the pD₂-value for PE was not significantly affected by pindolol. On the other hand, phentolamine (10^–6 mol/l) shifted the lower part of the CRC for PE more than the upper part. In the presence of both pindolol and phentolamine the curve was shifted to the right in a parallel manner. The time required for twitch relaxation was negatively correlated to the degree of PIE of PE in the presence of phentolamine but not pindolol. These results indicate that both - and -adrenoceptors mediate the positive inotropic action in the ventricular muscle of the Japanese monkey and that in contrast to the action via -adrenoceptors the action via -adrenoceptors is not accompanied by the relaxant effect.     

Dynorphin A (2–17) attenuates the unconditioned but not the conditioned effects of opiate withdrawal in the rat

OBJECTIVES: An unbiased place preference conditioning procedure was used to examine the influence of the non-opioid peptide, dynorphin A 2-17 (DYN 2-17), upon the conditioned and unconditioned effects of opiate withdrawal in the rat. METHODS: Rats were implanted SC with two pellets containing 75 mg morphine or placebo. Single-trial place conditioning sessions with saline and the opioid receptor antagonist naloxone (0.1-1.0 mg/kg; SC) commenced 4 days later. Ten minutes before SC injections, animals received an IV infusion of saline or DYN 2-17 (0.1-5.0 mg/kg). Additional groups of placebo- and morphine-pelleted animals were conditioned with saline and DYN 2-17. During each 30-min conditioning session, somatic signs of withdrawal were quantified. Tests of place conditioning were conducted in pelleted animals 24 h later. RESULTS: Naloxone produced wet-dog shakes, body weight loss, ptosis and diarrhea in morphine-pelleted animals. Morphine-pelleted animals also exhibited significant aversions for an environment previously associated with the administration of naloxone. These effects were not observed in placebo-pelleted animals. DYN 2-17 pretreatment resulted in a dose-related attenuation of somatic withdrawal signs. However, conditioned place aversions were still observed in morphine-pelleted animals that had received DYN 2-17 in combination with naloxone. Furthermore, the magnitude of this effect did not differ from control animals. CONCLUSIONS: These data demonstrate that the administration of DYN 2-17 attenuates the somatic, but not the conditioned aversive effects of antagonist-precipitated withdrawal from morphine in the rat. Differential effects of this peptide in modulating the conditioned and unconditioned effects of opiate withdrawal are suggested.     

Population pharmacokinetics of S(−)-carvedilol in healthy volunteers after administration of the immediate-release (IR) and the new controlled-release (CR) dosage forms of the racemate

Carvedilol is a beta(1)-, beta(2)-, and alpha(1)-adrenoreceptor blocker indicated for treatment of hypertension and mild-to-severe congestive heart failure. The objective of this study was to develop and evaluate a single population model that describes S(-)-carvedilol pharmacokinetics from both the immediate-release (IR) and the new controlled-release dosage forms of the racemate. Carvedilol IR data (1270 measurements) were obtained from 2 open-label studies (50 mg/25 mg Q12 hours for 2 doses). Carvedilol CR data (2058 measurements) were obtained from an open-label, nonrandomized, dose-rising (10, 20, 40, and 80 mg), 4-period balanced crossover study. All data were simultaneously analyzed using NONMEM V. Leverage analysis and internal evaluations were conducted for the final model. A 2-compartment model with first-order absorption and elimination provided the best fit. The model included different absorption rates (KAs) for the CR and IR morning (IR(AM)) and evening (IR(PM)) doses; incorporating change-points at certain times. Estimates of KAs indicated that the absorption was slower at equivalent times and extended for CR relative to IR carvedilol. Oral clearance of S(-)-carvedilol was 149 L/h. The IR(PM) and the CR doses had bioavailability (F(rel)) of 0.80 and 0.76, respectively, relative to the IR(AM) dose. The inter-subject variability in KAs was lower for the CR dosage form than the original IR dosage form. Estimation of interoccasion variability on KAs and F(rel) for the CR dosage form improved the fit. The model performed well in simulation and leverage analysis indicated its robustness. The model will be a useful tool for future simulation studies.     

Nuclear import of the pre-integration complex (PIC): the Achilles heel of HIV?

Current treatments against the Aquired immune deficiency syndrome (AIDS) are reasonably effective in reducing the amount of human immunodeficiency virus (HIV) present in infected patients, but their side-effects, and the emergence of drug-resistant HIV strains have intensified the renewed search for novel anti-HIV therapies. An essential step in HIV infection is the integration of the viral genome into the host cell chromosomes within the nucleus. Unlike other retroviruses, HIV can transport its genetic material, in the form of the large nucleoprotein pre-integration complex (PIC), into the nucleus through the intact nuclear envelope (NE). This enables HIV to infect non-dividing cells such as macrophages and microglial cells. Detailed knowledge of the signal-dependent pathways by which cellular proteins and RNAs cross the NE has accumulated in the past decade, but although several different components of the PIC have been implicated in its nuclear import, the mechanism of nuclear entry remains unclear. Since specifically inhibiting PIC nuclear import would undoubtedly block HIV infection in non-dividing cells, this critical step of HIV replication is of great interest as a drug target. This review examines the complex and controversial literature regarding three PIC components--the HIV proteins matrix, integrase and Vpr--proposed to facilitate PIC nuclear import, and existing models of HIV PIC nuclear import. It also suggests approaches to move towards a better understanding of PIC nuclear import, through examining the role of individual PIC components in the context of the intact PIC by direct visualisation, in order to develop new anti-HIV therapeutics.     

Alkaloids from the Roots of Aristolochia Triangularis(I)

从马兜铃科植物Ａｒｉｓｔｏｌｏｃｈｉａｔｒｉａｎｇｕｌａｒｉｓ的根部分离出十五个生物碱成分。其中两种成分ｔｒｉａｎｇｕｌａｒｉｎｅ－Ａ和ｔｒｉａｎｇｕｌａｒｉｎｅ－Ｂ系新生物碱，三种系阿卟啡类季铵碱。这些化合物的结构经各种波谱（ＩＲ，ＵＶ，ＭＳ，２ＤＮＭＲ）解析和化学转化技术得以确定。     

Advances in the study of drug metabolism – symposium report of the 12th Meeting of the International Society for the Study of Xenobiotics (ISSX)

Abstract

The 12th International Society for the Study of Xenobiotics (ISSX) meeting, held in Portland, OR, USA from July 28 to 31, 2019, was attended by diverse members of the pharmaceutical sciences community. The ISSX New Investigators Group provides learning and professional growth opportunities for student and early career members of ISSX. To share meeting content with those who were unable to attend, the ISSX New Investigators herein elected to highlight the “Advances in the Study of Drug Metabolism” symposium, as it engaged attendees with diverse backgrounds. This session covered a wide range of current topics in drug metabolism research including predicting sites and routes of metabolism, metabolite identification, ligand docking, and medicinal and natural products chemistry, and highlighted approaches complemented by computational modeling. In silico tools have been increasingly applied in both academic and industrial settings, alongside traditional and evolving in vitro techniques, to strengthen and streamline pharmaceutical research. Approaches such as quantum mechanics simulations facilitate understanding of reaction energetics toward prediction of routes and sites of drug metabolism. Furthermore, in tandem with crystallographic and orthogonal wet lab techniques for structural validation of drug metabolizing enzymes, in silico models can aid understanding of substrate recognition by particular enzymes, identify metabolic soft spots and predict toxic metabolites for improved molecular design. Of note, integration of chemical synthesis and biosynthesis using natural products remains an important approach for identifying new chemical scaffolds in drug discovery. These subjects, compiled by the symposium organizers, presenters, and the ISSX New Investigators Group, are discussed in this review.     

Calcium signaling: the role of inositol phosphates and the mechanisms of Ca~(2+) entry

<正> Activation of surface membrane receptors provokes a variety of cellular responses by initiating a series of specific biochemical reactions which are responsible for the membrane transducing mechanisms and the subsequent Ca~(2+)signaling process. Ca~(2+) is well known as a second messenger that an early consequence of receptor activation is usually the synthesis or     

Contribution of the β-ureidopropionase (UPB1) gene alterations to the development of fluoropyrimidine-related toxicity

BackgroundAn impairment of the 5-fluorouracil (5-FU) catabolic pathway, represented by alterations in the dihydropyrimidine dehydrogenase (DPYD) gene, is considered a crucial factor contributing to the development of 5-FU-related toxicity. The β-ureidopropionase (BUP1) enzyme catalyzes the final step in the 5-FU catabolic pathway; however, alterations in the UPB1 gene coding for the BUP1 enzyme have not yet been analyzed in fluoropyrimidine (FP)-treated patients suffering from 5-FU-related toxicity.MethodsWe have performed a mutation analysis of the entire coding sequence of UPB1 based on denaturing high-performance liquid chromatography in 113 cancer patients treated by FP-containing regimes. These patients included 67 individuals suffering from severe 5-FU-related toxicity and 46 individuals with excellent tolerance of chemotherapy.ResultsNine UPB1 variants were detected in the subpopulation of patients with severe toxicity, including a novel mutation affecting the coding sequence (c.872_873 + 11del13). An analysis of UPB1 variants on 5-FU-related toxicity in the population of all analyzed patients revealed an association between the c.-80C > G (rs2070474) variant and gastrointestinal toxicity. A strong positive correlation was found between the carriers of the c.-80 GG genotype and the development of severe (grade 3–4) mucositis (OR = 7.5; 95% CI = 2.60 – 21.60; p = 0.0002).ConclusionOur results suggest that UPB1 variants may contribute to the development of 5-FU-related toxicity in some FP-treated patients; however, the role of UPB1 alterations is probably less significant than that of DPYD alterations.     

What do we (need to) know about the kinetic properties of nanoparticles in the body?

Nowadays the development and applications of nanotechnology are of major importance in both industrial and consumer areas. However, the knowledge on human exposure and possible toxicity of nanotechnology products is limited. To understand the mechanism of toxicity, thorough knowledge of the toxicokinetic properties of nanoparticles is warranted. There is a need for information on the absorption, distribution, metabolism and excretion (ADME) of nanoparticles and validated detection methods of these man-made nanoparticles. Determination of the ADME properties of nanoparticles requires specialised detection methods in different biological matrices (e.g. blood and organs). In this paper, the current knowledge on the kinetic properties of nanoparticles is reviewed. Moreover, knowledge gaps from a kinetic point of view (detection, dose, ADME processes) are identified.     

Does EU legislation allow the use of the Benchmark dose (BMD) approach for risk assessment?

Hazard characterisation is largely based on an approach of (statistically) comparing dose groups with the controls in order to derive points of departure such as no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs). This approach suggests the absence of any relevant effect at the NOAEL. The NOAEL approach has been debated for decades. A recent Scientific Opinion by the European Food Safety Authority (EFSA) concluded that the Benchmark Dose (BMD) approach should be preferred over the NOAEL approach for deriving human (health-based) limit or guidance values. Nonetheless, the BMD approach is used infrequently within European regulatory frameworks. The reason for this may lie in legislation or guidelines requiring the use of the NOAEL approach. In this context, various EU regulatory frameworks were examined on such demands. Interestingly, no single legislation was identified containing statutory requirements in conflict with the use of the BMD approach.     

Siderite (FeCO₃) and magnetite (Fe₃O₄) overload-dependent pulmonary toxicity is determined by the poorly soluble particle not the iron content

The two poorly soluble iron containing solid aerosols of siderite (FeCO?) and magnetite (Fe?O?) were compared in a 4-week inhalation study on rats at similar particle mass concentrations of approximately 30 or 100?mg/m3. The particle size distributions were essentially identical (MMAD ≈1.4 μm). The iron-based concentrations were 12 or 38 and 22 or 66?mg Fe/m3 for FeCO? and Fe?O?, respectively. Modeled and empirically determined iron lung burdens were compared with endpoints suggestive of pulmonary inflammation by determinations in bronchoalveolar lavage (BAL) and oxidative stress in lung tissue during a postexposure period of 3 months. The objective of study was to identify the most germane exposure metrics, that are the concentration of elemental iron (mg Fe/m3), total particle mass (mg PM/m3) or particle volume (μl PM/m3) and their associations with the effects observed. From this analysis it was apparent that the intensity of pulmonary inflammation was clearly dependent on the concentration of particle-mass or -volume and not of iron. Despite its lower iron content, the exposure to FeCO? caused a more pronounced and sustained inflammation as compared to Fe?O?. Similarly, borderline evidence of increased oxidative stress and inflammation occurred especially following exposure to FeCO? at moderate lung overload levels. The in situ analysis of 8-oxoguanine in epithelial cells of alveolar and bronchiolar regions supports the conclusion that both FeCO? and Fe?O? particles are effectively endocytosed by macrophages as opposed to epithelial cells. Evidence of intracellular or nuclear sources of redox-active iron did not exist. In summary, this mechanistic study supports previous conclusions, namely that the repeated inhalation exposure of rats to highly respirable pigment-type iron oxides cause nonspecific pulmonary inflammation which shows a clear dependence on the particle volume-dependent lung overload rather than any increased dissolution and/or bioavailability of redox-active iron.     

Is the 5-HT(7) receptor involved in the pathogenesis and prophylactic treatment of migraine?

The mechanisms underlying the pathogenesis of migraine and their possible association with serotonin (5-hydroxytryptamine; 5-HT) have not yet been elucidated. One of the major obstacles in achieving this goal is the lack of information on the mechanisms by which the monoamine could possibly trigger and/or modulate the basic pathophysiological features of the condition, that is, cranial vasodilatation and neurogenic inflammation. This information should provide a useful theoretical framework to insight the nature of the postulated fundamental triggering mechanism in the brain that ultimately results in head pain. Novel avenues for research and drug development may be envisaged upon the recent observations showing that 5-HT is actually able to produce vasodilatation of intra- and extra-cranial blood vessels through a mechanism pharmacologically resembling the 5-HT(7) receptor type, and that the messenger RNA (mRNA) encoding for this receptor is highly expressed in cranial vessels. Other lines of evidence have suggested that the 5-HT(7) receptor may play an excitatory role in neuronal systems and that it may be involved in hyperalgesic pain and neurogenic inflammation. On the basis of these observations, it is proposed that the 5-HT(7) receptor may well represent a link between the abnormal phenomena of 5-HT processing and neurotransmission that are observed in migraine patients, and the vascular and neurogenic alterations that account for migraine headache. This view is supported by the fact that most of the migraine prophylactic 5-HT receptor antagonists display relatively high affinity for the 5-HT(7) receptor, which significantly correlates with their pharmaceutically active oral doses.