MC9204对大鼠心肌肥厚模型的影响

目的：观察新的二氢吡啶类钙拮抗剂ＭＣ９２０４对大鼠心肌肥厚的影响。方法：建立大鼠腹主动脉狭窄左室肥厚（ＬＶＨ）模型，并给予新的二氢吡啶类钙拮抗剂ＭＣ９２０４治疗３ｍｏ，观察在鼠ＬＶＨ时心肌重量指数，心室厚度，氧自由基（ＯＦＲ）、心肌酶释放等的变化。     

Drug-induced Sweet's syndrome in acne caused by different tetracyclines: case report and review of the literature

Sweet's syndrome was first described in 1964. It is characterized by an acute onset of non-pruritic, painful reddish nodules on the head and neck, chest and/or the upper limbs, mostly accompanied by fever, general malaise and leucocytosis. Histopathological examination shows a diffuse dermal neutrophilic infiltrate. The pathogenesis is still not fully understood, and different diseases have been shown to be associated with this syndrome. However, although still very rare, there is an increase of reports on Sweet's syndrome induced by drugs. We describe a 30-year-old man who experienced acute neutrophilic dermatosis after systemic treatment with minocycline. Additionally, there is a strong possibility that the same patient developed a drug-induced Sweet's syndrome after oral administration of tetracycline and doxycycline.     

Central Hypotensive Effects of Nicardipine in Conscious Freely Moving Spontaneously Hypertensive Rat

The central cardiovascular effects of the calcium channel blocker nicardipine was studied in conscious freely moving normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Nicardipine was administered in a 1.5 μ1 volume into the lateral ventricle of the brain (i.c.v.) or intravenously (i.v.). The injection of vehicle alone did not significantly change mean arterial pressure (MAP) or heart rate (HR). Nicardipine (10,30,100 and 300 μg/kg), intravenously administered, dose-dependently decreased MAP and increased HR in WKY and SHR. However, when administered i.c.v., nicardipine (10 μg/kg) increased MAP and HR in WKY and decreased MAP without any significant change in HR in SHR. These results are consistent with previous work reporting an exaggerated hypotensive response to i.c.v. administration of dihydropyridine calcium channel blockers in anesthetized SHR as compared to WKY. They suggest that a 1,4–dihydropyridine-sensitive pressor system is present in the SHR but not in the WKY.     

JP‐45/JSRP1 Variants Affect Skeletal Muscle Excitation–Contraction Coupling by Decreasing the Sensitivity of the Dihydropyridine Receptor

JP‐45 (also JP45; encoded by JSRP1) is an integral protein constituent of the skeletal muscle sarcoplasmic reticulum junctional face membrane interacting with Ca_v1.1 (the α.1 subunit of the voltage‐sensing dihydropyridine receptor, DHPR) and the luminal calcium‐binding protein calsequestrin. Two JSRP1 variants have been found in the human population: c.323C>T (p.P108L) in exon 5 and c.449G>C (p.G150A) in exon 6, but nothing is known concerning the incidence of these polymorphisms in the general population or in patients with neuromuscular diseases nor the impact of the polymorphisms on excitation–contraction (EC) coupling. In the present report, we investigated the frequencies of these two JSRP1 polymorphisms in the Swiss malignant hyperthermia population and studied the functional impact of the variants on EC coupling. Our results show that the polymorphisms are equally distributed among malignant hyperthermia negative, malignant hyperthermia equivocal, and malignant hyperthermia susceptible individuals. Interestingly, however, the presence of either one of these JP‐45 variants decreased the sensitivity of the DHPR to activation. The presence of a JSRP1 variant may explain the variable phenotype seen in patients with malignant hyperthermia carrying the same mutation and, more importantly, may counteract the hypersensitivity of EC coupling caused by mutations in the RYR1 gene.     

Long‐term prophylaxis of hereditary angioedema with androgen derivates: a critical appraisal and potential alternatives

Androgen derivatives are regarded as standard in the long‐term prophylaxis of swelling attacks in patients with hereditary angioedema (HAE). Because of their relatively slow onset of action, they are not suitable for acute therapy. Long‐term prophylaxis with androgen derivatives must be regarded critically, especially on account of their androgenic and anabolic effects, some of which are severe. The risk of adverse events increases with the daily dose and the duration of treatment. Thus, treatment always calls for close monitoring of patients with regard to potential adverse events. In addition, androgens are subject to numerous contraindications and they show interactions with a large number of other drugs. Off‐label use, doping issues, clarification of reimbursement and the need to import the androgen derivatives, which are no longer marketed in Germany, result in additional effort for the treating physician in terms of logistics and time involved. In symptomatic treatment of acute attacks the intravenous substitution of C1‐INH and – since 2008 – subcutaneous administration of icatibant are available. The two substances are well tolerated and their effect occurs rapidly and, when the diagnosis has been confirmed, reliably. In the light of these two treatment options for controlling acute attacks, prophylactic treatment of HAE patients with androgen derivatives such as danazol should be reassessed. Patients might benefit from a dose reduction or the withdrawal of androgen prophylaxis and attacks can be controlled with demand‐oriented acute treatment using C1‐INH or icatibant.     

苯磺酸氨氯地平的合成

目的苯磺酸氨氯地平的合成。方法通过吡咯衍生物和氨基巴豆酸甲酯和2-氯苯甲醛进行Hantzsch反应获得高收率的氨氯地平。结果反应总收率在45%以上。目标化合物结构经1H-NMR确证。结论此工艺方法简便,适合工业化生产。     

MOLECULAR RECOGNITION OF THE DISORDERED DIHYDROPYRIDINE RECEPTOR II–III LOOP BY A CONSERVED SPRY DOMAIN OF THE TYPE 1 RYANODINE RECEPTOR

• 1 The dihydropyridine receptor (DHPR) II–III loop is an intrinsically unstructured region made up of α‐helical and β‐turn secondary structure elements with the N and C termini in close spatial proximity.
• 2 The DHPR II–III loop interacts in vitro with a ryanodine receptor (RyR) 1 SPRY domain through α‐helical segments located in the A and B regions. Mutations within the A and B regions in the DHPR II–III loop alter the binding affinity to the SPRY2 domain.
• 3 The A and C peptides derived from DHPR II–III loop show negative cooperativity in binding to the SPRY2 domain.
• 4 The SPRY2 domain of the RyR1 (1085–1208) forms a β‐sheet sandwich structure flanked by variable loop regions. An acidic loop region of SPRY2 (1107–1121) forms part of a negatively charged cleft that is implicated in the binding of the DHPR II–III loop.
• 5 The mutant E1108A located in the negatively charged loop of SPRY2 reduces the binding affinity to the DHPR II–III loop.

     

EFFECTS OF CALCIUM- AND ETa-RECEPTOR ANTAGONISTS ON ENDOTHELIN-INDUCED VASOCONSTRICTION AND LEVELS OF ENDOTHELIN IN THE HUMAN INTERNAL MAMMARY ARTERY

1. The effects of the ET_A receptor antagonist BQ123 and dihydropyridine calcium antagonists on the vasoconstrictor effect of endothlin-1 (ET-1) were studied in human isolated internal mammary artery (IMA). The effect of the calcium antagonist, nisoldipine, on ET-1 levels has also been examined in cultured IMA endothelial cells (IMAEC). 2. The results showed that BQ123 and the calcium antagonists nisoldipine, isradipine, nitrendipine and nifedipine fully relaxed IMA precontracted with 3 nmol/L ET-1 with the EC₅₀ values of 7.18 ± 0.09 (-log mol/L) for BQ123, and 7.68 ± 0.07, 7.02 ± 0.12, 6.96 ± 0.08 and 6.89 ± 0.09 for the calcium antagonists, respectively. 3. Pretreatment of IMA with 10, 30, 100 and 300 nmol/L nisoldipine significantly depressed the maximal response (Max; 88.3 ± 5.1, 75.2 ± 4.9, 59.3 ± 5.6 and 56.2 ± 4.8% of maximal noradrenaline response versus 99.1 ± 13.2% in control, P<0.01) of IMA to ET-1 without a significant change in the EC₅₀ values. 4. Pretreatment of IMA with 300 nmol/L BQ123 significantly increased both the EC₅₀ (7.97 ± 0.09 vs 8.36 ± 0.08 in the control, P<0.05) and the Max (138.1 ± 10.2%vs the control, P< 0.01) of IMA to ET-1. 5. Incubation of IMAEC with nisoldipine for 7h resulted in a dose-dependent (10^?8–10^?5 mol/L) reduction up to 93.1% in ET levels in the conditioned media. 6. ET levels in the cell lysates were not detectable either in the absence or in the presence of nisoldipine, suggesting the reduction of ET levels in the media could be due to inhibition of ET synthesis. 7. In conclusion, these studies demonstrate that: (i) both BQ123 and the calcium antagonists are potent relaxant agents of human IMA precontracted with ET-1; (ii) BQ123 also increases the Max of IMA to ET-1 and the mechanism is unknown; (iii) the calcium antagonist nisoldipine reduces ET levels in the cultured human IMAEC.     

Incidence of cancer among nitrate fertilizer workers

The results are presented from a historical prospective cohort study on the incidence of cancer among 1756 male workers at a nitrate fertilizer plant. Workers employed for 1 year or more between 1947 and 1980 were included in the cohort. Surrogates for individual exposure to nitrogen derivates and asbestos dust were recorded to identify subgroups. There were 195 cases of cancer observed versus 208.8 expected, as based on the rates among age-adjusted rural Norwegian males. A slight increase in stomach cancer was found: 28 observed versus 19.9 expected.