Subcutaneous factor IX administration to patients with hemophilia B

Abstract

equilibrium between the h/A3 genes is "back lit" by a strong selective force originating approximately 400 generations ago.The "reconstructed' location of the h-allele remarkably corresponds to the calculation that in 400 generations a biological fitness 1% greater than average would produce a change in frequency of the gene for adult lactase persistence from 0.05 (in lactase intolerant populations) to 0.60 in tolerant populations [ 121. Prior to the domestication of animals and the invention of dairying, lactose was not available to adults in significant quantities. Therefore, adult man, like other adult mammals, was naturally lactase deficient. Dairying cultures tended to select for adult lactose tolerance. The milk is a poor source of iron and may actually inhibit absorption of the metal. A separate, and easily disproved, argument for selection would be a proposition that the frequency of the h-allele should be high in populations depending on milk and cereals in their diet. The higher the proportion of lactose tolerance in the population, the higher the frequency of the h-allele in it. So far unsuspected, the evolutionary rivalry between the h-allele and the gene for lactase persistence is likely. It would suggest that these genes coevolved and probably originated some 400 generations ago. In conclusion, the h-allele evolved as an evolutionary rehabilitation of iron carency in farming and pastoralist populations. Its location is approximately 401 kb centromeric from the HLA A genes. REFERENCES 1 . Edwards CQ, Griffen LM, Dadone MM, Skolnick MH, Kushner JP: Mapping the locus for hereditary hemochromatosis: Localization between HLA-B and HLA-A. Am J Hum Genet 38:805-811, 1986. 2. Cox TM: Prevalence of the hemochromatosis gene. N Engl J Med 302695496, 1980. 3. JankoviC GM, coloviC MD, PetroviC MD, SuvajdiiC N, BogdanoviC G , Rado-vanEeviC R, TomaSeviC R, Trpinac D P Selective advantage for females with h-allele? Eur J Haematol43:265-266, 1989. 4. JankoviC GM, PetroviC MD, colovii. MD, MiloSeviC R, JanoSevii. S, Trpinac D P Increased transplacental and breast milk iron delivery in hereditary hemochromatosis. Am J Hematol 38:153-155, 1991.

Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs

“…Cheung et al 26 built on the studies of Heimark et al 27 and Stern et al 28 to document that FIX binds to type IV collagen via lysine at position 5 or valine at position 10, identifying the mechanism of extravascular and endothelial binding of hFIX. 26,29,30 The published data [23][24][25] and this report support the hypothesis that FIX can traverse not only from the extravascular space to the systemic circulation but also from the systemic circulation to the extravascular space. Whether or not FIX in the extravascular space has a function For personal use only.…”

“…A series of studies that administer the FIX protein subcutaneously have been reported in animals and humans with dosing that ranges from 15 to 200 IU/kg. [23][24][25] All these studies detected measurable FIX in the recipient's plasma following subcutaneous administration. In the study by Liles et al, 25 a single adult patient with hemophilia B (cross-reacting material negative, CRMϪ) given a high-purity plasma-derived hFIX subcutaneously developed a transient, low titer inhibitor (1-2 Bethesda units) months after the clinical study while being treated for a traumatic bleed.…”

Safety and pharmacokinetics of subcutaneously administered recombinant activated factor VII (rFVIIa)

“…Subcutaneous FIX has also demonstrated prophylactic efficacy during long‐term treatment in tolerized hemophilic dogs [7]. Application in humans has only occasionally been reported [8,9] and rigorous clinical trials have not been performed, probably because concerns exist that subcutaneous administration of FIX, a neoantigen in patients with hemophilia B, could increase its immunogenicity.…”

Perioperative haemostatic management of haemophilic mice using normal mouse plasma

“…The plasma FIX:C levels obtained in the SC group were markedly lower than that in the IV group. The low levels observed in the SC group might be attributed to slow and inefficient transport of FIX protein into the plasma compartment, and protein degradation and FIX clearance at the administration site [22,23]. In the IP group, the obtained levels were relatively higher than those of the SC group, but significantly lower than those of the IV group.…”