Magnetic resonance imaging and joint outcomes in boys with severe hemophilia A treated with tailored primary prophylaxis in Canada.

BACKGROUND/OBJECTIVES: Tailored primary prophylaxis (TPP) is a reduced-intensity treatment program for hemophiliacs with the goal of preventing arthropathy. Our primary aim was to evaluate the joint outcomes of treated subjects using magnetic resonance imaging (MRI) and physical examination as outcome measures. METHODS: Ankles, elbows and knees (index joints) of 24 subjects (median [range] age at start of therapy, 1.6 [1-2.5] years) with severe hemophilia A enrolled in the Canadian Hemophilia Primary Prophylaxis Study (CHPS) were examined by MRI at a median age of 8.8 years (range 6.2-11.5 years). Subjects were treated with TPP using a recombinant factor VIII concentrate, starting once weekly and escalating in frequency and dose according to frequency of bleeding. RESULTS: Osteochondral changes (cartilage loss/subchondral bone damage) were detected in 9% (13/140) of the index joints and 50% (12/24) of study subjects. Osteochondral changes were restricted to joints with a history of clinically reported joint bleeding. Soft tissue changes were detected in 31% (20/65) of index joints with no history of clinically reported bleeding (ankles 75% (12/16); elbows 19% (6/32); and knees 12% (2/17)). In these apparently 'bleed free' index joints hemosiderin deposition was detected by MRI in 26% (17/65) of joints (ankles 63% (10/16); elbows 16% (5/32), and knees 12% (2/17)). CONCLUSION: TPP did not completely avoid the development of MRI-detected structural joint changes in hemophilic boys in this prospective study. A longer period of follow-up is required for assessment of the longitudinal course of these early changes in hemophilic arthropathy, detected using a sensitive imaging technique (MRI).

Effects of hydralazine on canine muscarinic ganglion stimulation.

The effects of hydralazine upon the caudal pressor responses during occlusion of the abdominal aorta and vena cava evoked by: (1) preganglionic electrical stimulation of the lumbar sympathetic chain, (2) neostigmine and (3) McN-A-343 were investigated in the anesthetized dog. Hydralazine (10 microgram/kg, i.v.) produced a small but significant reduction of the pressor response to lumbar electrical stimulation prior and following blockade of nicotinic transmission with chlorisondamine (1.0 mg/kg). However, hydralazine was not effective in blocking the pressor responses elicited by neostigmine and McN-A-343. On the other hand, small doses of atropine (20 microgram/kg) produced a blockade of residual pressor responses evoked by all three stimuli. On the basis of these findings, the site of action of hydralazine appears to be different from that of atropine. It is proposed that hydralazine affects ganglionic transmission by acting at sites other than muscarinic in nature.

Effects of hydralazines on canine muscarinic ganglion transmission.

The effects of hydralazine, dihydralazine and 4-propyl-1-hydrazinophthalazine (4-propylhydralazine) were investigated on reflex pressor responses to increased intracranial fluid pressure (IIP) during occlusion of the abdominal aorta and the vena cava (MVO). It has been shown that application of MVO, caudal to the renal arteries, produces two independent vascular zones in the animal (Steinberg and Hilton, 1966a). Increasing intracranial fluid pressure during MVO elicits a reflex pressor response which consists of two components. One component is blocked by the nicotinic ganglionic blocking agent, chlorisondamine, and the other component is blocked by small doses of atropine. It was found that hydralazine and dihydralazine were effective in blocking residual pressor responses following partial blockade of reflex pressor responses to IIP with chlorisondamine. 4-Propylhydralazine, which is chemically similar to hydralazine and dihydralazine, was less active in inhibiting the residual pressor responses. It is suggested that hydralazine may act in part by interfering with muscarinic ganglionic transmission.