Synthesis of thioether derivatives of quinazoline-4-one-2-thione and evaluation of their antiplatelet aggregation activity

A series of 2-(arylmethylthio)-3-phenylquinazolin-4-one derivatives have been synthesized and their antiplatelet aggregation activities were assessed against ADP and arachidonic acid-induced platelet aggregation in human plasma. Among the tested thioethers, derivative 2, 3, 5 and 16 were the most potent compounds with satisfactory IC₅₀ for inhibition of platelet aggregation induced by ADP. Analysis of global physicochemical parameters shows some correlations between activities and molecular volume and also surface area of the studied derivatives.     

Positive classic antineutrophil cytoplasmic antibody (C‐ANCA) titer at switch to azathioprine therapy associated with relapse in proteinase 3–related vasculitis

Objective

To analyze disease‐free survival in patients with antineutrophil cytoplasmic antibody (ANCA)–associated small‐vessel vasculitis (AAV) treated with cyclophosphamide only or switched to azathioprine after 3 months of full remission while taking cyclophosphamide.

Methods

We analyzed disease‐free survival in all consecutive patients diagnosed with AAV between 1990 and 2000 at our center. Patients were treated with cyclophosphamide only (1990–1996) or switched to azathioprine after 3 months of remission while taking cyclophosphamide (1997–2000). All patients received at least 12 months of followup.

Results

Of the total 128 patients, 53 (41%) relapsed. Forty‐four of the 128 patients (34%) had been switched to azathioprine therapy. Disease‐free survival at 2 and 4 years was 76% and 65% in the cyclophosphamide group compared with 76% and 51% in the azathioprine group. In patients with proteinase 3 (PR3) classic ANCA (C‐ANCA)–associated vasculitis who were switched to azathioprine (n = 33), a positive C‐ANCA titer at the moment of treatment switch (n = 13) was significantly associated with relapse (RR 2.6, 95% confidence interval 1.1–8.0; P = 0.04). In patients with a negative ANCA titer at the time of switch to azathioprine, disease‐free survival at 2 and 4 years was 80% and 62%, which was identical to that for patients treated with cyclophosphamide only. In patients who were ANCA‐positive at the time of treatment switch, disease‐free survival at 2 and 4 years was only 58% and 17%.

Conclusion

Switching cyclophosphamide to azathioprine after induction of remission in patients with PR3‐ANCA‐associated vasculitis who are still ANCA‐positive at the time of treatment switch is associated with a high risk of relapse.

     

Increased aortic stiffness and blood pressure in non-classic Pompe disease

Vascular abnormalities and glycogen accumulation in vascular smooth muscle fibres have been described in Pompe disease. Using carotid-femoral pulse wave velocity (cfPWV), the gold standard methodology for determining aortic stiffness, we studied whether aortic stiffness is increased in patients with Pompe disease. Eighty-four adult Pompe patients and 179 age- and gender-matched volunteers participated in this cross-sectional case-controlled study. Intima media thickness and the distensibility of the right common carotid artery were measured using a Duplex scanner. Aortic augmentation index, central pulse pressure, aortic reflexion time and cfPWV were assessed using the SphygmoCor® system. CfPWV was higher in patients than in volunteers (8.8 versus 7.4 m/s, p?<?0.001). This difference was still present after adjustment for age, gender, mean arterial blood pressure (MAP), heart rate and diabetes mellitus (p?=?0.001), and was shown by subgroup analysis to apply to the 40-59 years age group (p?=?0.004) and 60+ years age group (p?=?0.01), but not to younger age groups (p?=?0.99). Except for a shorter aortic reflexion time (p?=?0.02), indirect indicators of arterial stiffness did not differ between patients and volunteers. Relative to volunteers (20 %), more Pompe patients had a history of hypertension (36 %, p?=?0.005), and the MAP was higher than in volunteers (100 versus 92 mmHg, p?<?0.001). This study shows that patients with non-classic Pompe disease have increased aortic stiffness and blood pressure. Whether this is due to glycogen accumulation requires further investigation. To reduce the potential risk of cardiovascular diseases, we recommend that blood pressure and other common cardiovascular risk factors are monitored regularly.