Unusual manifestations of giant cell arteritis and granulomatosis with polyangiitis.

Giant cell arteritis (GCA) is a type of large vessel vasculitis, and it involves the aorta, large vessels and terminal branches of the external carotid artery, especially the temporal artery. Temporal artery biopsy is a simple tool for the diagnosis of vasculitis, however, the histopathological findings do not always differentiate between the small-vessel vasculitis and GCA. We report the case of 72-year-old male who initially had a clinical diagnosis of GCA, then in the course of treatment, diagnostic histopathological approach revealed the necrotizing vasculitis with bronchocentric granulomatosis in the inflammatory nodule of the lung. The manifestations of patients with systemic vasculitis represent the disorders of multiple organ systems thus are diverse and may vary through the course of the disease. Presentation of unexpected features such as insufficient response to antibiotics, sinusitis, runny nose, discomfort of frontal region or pachymeningitis which anticipates re-evaluation of systemic vasculitis that may lead us to an appropriate diagnosis and the treatment.

Multiple Intestinal Ulcers Associated with Primary Epstein-Barr Virus Infection in a Patient with Rheumatoid Arthritis Undergoing Methotrexate Therapy.

A 47-year-old woman with a 2-year history of rheumatoid arthritis (RA) undergoing methotrexate treatment developed a perforated ulcer in the ileum for which she underwent emergency surgery. A histological analysis of the extirpated specimen presented a possible Epstein-Barr virus (EBV) infection in the ulcerative lesion without a feature of lymphoproliferative disorder. Interestingly, the patient's serological tests with a paired serum diagnosed a primary EBV infection. The present case emphasizes the importance of being aware of severe enteritis as a possibility for patients with RA, for an accurate diagnosis.

AT-1015, a novel serotonin2A receptor antagonist, improves resaturation of exercised ischemic muscle in hypercholesterolemic rabbits.

OBJECTIVE: The effect of AT-1015, a serotonin(2A) receptor antagonist, on the resaturation of ischemic muscle in a hypercholesterolemic rabbit model was examined with near-infrared spectroscopy. METHODS: New Zealand White male rabbits were fed normal chow or cholesterol-rich chow. Ischemia was induced in the right hindlimb by ligation of the femoral artery, accompanied by balloon injury of the iliac artery. At 3 days after induction of ischemia, the bilateral gastrocnemius muscles were subjected to passive contraction for 2 minutes. The oxygen resaturation time of the gastrocnemius muscle after exercise was measured by near-infrared spectroscopy. AT-1015 was orally administered for 3 days after induction of ischemia. Assay of serotonin level in platelet-poor plasma and histologic examination of muscle and artery were performed in another set of rabbits. RESULTS: Oxygen resaturation time of the ischemic gastrocnemius was significantly prolonged in hypercholesterolemic rabbits compared with in normal rabbits without AT-1015, whereas there was no difference between both groups of rabbits that were administered AT-1015. Plasma level of serotonin in hypercholesterolemic rabbits was significantly increased compared with that in normal rabbits. No histologic differences were found in both muscle and artery among all groups. CONCLUSIONS: A serotonin(2A) receptor antagonist improved the oxygen resaturation of ischemic calf muscle after exercise in hypercholesterolemia. The interaction between plasma free serotonin and the serotonin(2A) receptor may play an important role in muscle oxygenation in ischemic limbs.

Rational design, synthesis, and structure-activity relationships of novel factor Xa inhibitors: (2-substituted-4-amidinophenyl)pyruvic and -propionic acids.

An inhibitor of factor Xa (fXa), the m-substituted benzamidine AXC1578 (1a), was structurally modified with the aim of increasing its potency. In particular, pyruvic acid and propionic acid substituents were incorporated into the P1 benzamidine moiety to introduce a favorable interaction with the oxy-anion hole in the catalytic triad region of fXa. This strategy was based on computational docking studies using the extracted active site of fXa. The validity of the computational model was supported by the acquisition of X-ray crystal structures of the 1a-trypsin and 3b-trypsin complexes (the homology around the active sites of fXa and trypsin is high). The above modifications significantly increased the inhibitory activity toward fXa, whereas the high selectivity for fXa versus thrombin was maintained or enhanced. Compounds 3b, 3c, 3e, and 4b are considered to be potential lead compounds for the development of orally active anticoagulant drugs because they demonstrated potent activity when administered orally to cynomolgus monkeys.

Cardiac Ca(2+) channel-blocking effects of the cyproheptadine derivative AH-1058 in isolated guinea pig cardiomyocytes.

The Ca(2+) channel-blocking efficacy of the cyproheptadine derivative AH-1058 (4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride) was quantitatively assessed using isolated guinea pig cardiomyocytes. AH-1058 (0.001 - 10 microM) and its mother compound cyproheptadine (1 - 100 microM) reduced the Ca(2+) currents elicited from the holding potential of -80 or -40 mV. The IC(50) values for cyproheptadine at holding potentials of -80 and -40 mV were 42.44 and 7.75 microM, respectively, whereas those for AH-1058 were 4.91 and 0.32 microM, respectively, whose potency was equivalent to those of the typical Ca(2+) channel blocker verapamil. These results suggest that the introduction of the cinnamil structure to cyproheptadine can generate a potent L-type Ca(2+) channel-blocking compound as potent as verapamil.

Pharmacokinetics and pharmacodynamics of AJW200, a humanized monoclonal antibody to von Willebrand factor, in monkeys.

The interaction between platelet glycoprotein Ib and von Willebrand factor (vWF) plays a crucial role in platelet-mediated thrombus formation under high-shear-stress conditions. The aim of this study was to investigate the antiplatelet profile of a humanized anti-vWF monoclonal antibody, AJW200. In vitro studies were performed with a modified cone-and-plate viscometer and human platelets. AJW200 inhibited high-shear-stress-induced platelet adhesion, aggregation, and thrombin generation, but it did not have such effects under low-shear-stress conditions. Although abciximab inhibited platelet aggregation under both shear stress conditions, it did not inhibit platelet adhesion and thrombin generation. In addition, the pharmacokinetics and pharmacodynamics of AJW200 were evaluated in cynomolgus monkeys. Sustained inhibition of ristocetin-induced platelet aggregation was observed over 24 hours, 6 days, and 2 weeks after a single bolus injection of 0.3, 1, and 3 mg/kg, respectively. Moderate prolongation of the bleeding time was observed at the doses of 1 and 3 mg/kg. Abciximab markedly prolonged the bleeding time at 0.4 mg/kg, at which concentration complete inhibition of ADP-induced platelet aggregation was observed. These results suggest that glycoprotein Ib-vWF blockade with AJW200 results in a sustained antiplatelet effect without extensive prolongation of the bleeding time, probably due to a shear-stress-dependent inhibitory action.