Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2003-03-24
2004-06-22
Henley, III, Raymond J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06753350
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to methods to reduce the incidence of Intraventricular Hemorrhage (IVH) in preterm infants. The present invention also relates to the supplementation with docosahexaenoic acid and arachidonic acid of infant formulas designed for preterm infants.
2. Description of Related Art
Intraventricular Hemorrhage (IVH), a bleeding from fragile blood vessels in the brain, is a significant cause of morbidity and mortality in premature infants and may have life-long neurological consequences such as cerebral palsy, mental retardation, and seizures. These vessels are especially fragile in preterm infants, particularly those born more than 8 weeks early, i.e., before 32 weeks of gestation. IVH is more commonly seen in extremely premature infants; its incidence is over 50% in preterm infants with birth weight less than 750 grams, and up to 25% in infants with birth weight less than 1000 to 1500 grams.
IVH encompasses a wide spectrum of intra-cranial vascular injuries with bleeding into the brain ventricles, a pair of C-shaped reservoirs, located in each half of the brain near its center, that contain cerebrospinal fluid. The bleeding occurs in the subependymal germinal matrix, a region of the developing brain located in close proximity to the ventricles. Within the germinal matrix, during fetal development, there is intense neuronal proliferation as neuroblasts divide and migrate into the cerebral parenchyma. This migration is about complete by about the 24
th
week of gestation, although glial cells can still be found within the germinal matrix until term. The germinal matrix undergoes rapid involution from the 26
th
to the 32
nd
week of gestation, at which time regression is nearly complete, as glial precursors migrate out to populate the cerebral hemispheres.
Supporting this intense cell differentiation and proliferation activity there is a primitive and fragile capillary network. These vessels have thin walls for their relatively large size, lack a muscularis layer, have immature interendothelial junctions and basal laminae, and often lack direct contact with perivascular glial structures, suggesting diminished extravascular support. It is in this fragile capillary network where IVH originates. When a fetus is born prematurely, the infant is suddenly thrust from a well-controlled, protective environment into a stimulating, hostile one. Because of this physiologic stress and shock, the infant may lose the ability to regulate cerebral blood flow and may suffer alterations in blood flow and pressure and in the amounts of substances dissolved in the blood such as oxygen, glucose and sodium. The fragile capillaries may, and often do, rupture.
The severity of the condition depends on the extent of the vascular injury. There are four grades, or stages, of IVH as can be seen using ultrasound or brain computer tomography. Grade I IVH, the less severe stage, involves bleeding in the subependymal germinal matrix, with less than 10% involvement of the adjacent ventricles. Grade II IVH results when 10 to 40% of the ventricles are filled with blood, but without enlargement of the ventricles. Grade III IVH involves filling of over 50% of the ventricles with blood, with significant ventricular enlargement. In Grade IV IVH, the bleeding extends beyond the intraventricular area into the brain parenchyma (intraparenchymal hemorrhage).
The major complications of IVH relate to the destruction of the cerebral parenchyma and the development of posthemorrhagic hydrocephalus. Following parenchymal hemorrhages (Grade IV IVH), necrotic areas may form cysts that can become contiguous with the ventricles. Cerebral palsy is the primary neurological disorder observed in those cases, although mental retardation and seizures may also occur. In addition, infants affected with Grade III to IV IVH may develop posthemorrhagic hydrocephalus, a condition characterized by rapid growth of the lateral ventricles and excessive head growth within two weeks of the hemorrhage. Likely causes are obstruction of the cerebrospinal fluid conduits by blood clots or debris, impaired absorption of the cerebrospinal fluid at the arachnoid villi, or both. Another form of the hydrocephalus condition may develop weeks after the injury. In this case the likely cause is obstruction of the cerebrospinal fluid flow due to an obliterative arachnoiditis in the posterior fossa.
There is no specific treatment of IVH once it develops. Surgery will not prevent or cure the bleeding. Treatment of hydrocephalus may require use of spinal taps, ventricular reservoirs, or ventricular peritoneal shunts. A spinal tap is used to remove fluid from the spinal canal to reduce pressure. A needle is inserted in the infant's back to let fluid drip out. The procedure may allow time for the blood clots to clear by themselves and the fluid conduits to clear up. If the blockage is so severe that the fluid cannot circulate from the ventricles to the spinal canal, tubing can be surgically implanted into the ventricles (ventricular reservoirs). If the condition persists, a permanent tubing (shunt) can be placed in the ventricles. One end ot the tubing is placed in a ventricle, and the other is placed into the abdominal cavity. The tubing is tunneled under the skin.
Prevention of IVH is, thus, the favored approach. Prevention of prematurity, optimal management of labor and delivery, and the administration to mothers at risk of early delivery of drugs such as corticosteroids and phenobarbital are some of the methods of prenatal intervention aiming to reduce the incidence of IVH. Postnatal intervention on the premature infant is also possible. For example, indomethacin may be administered, a few hours after birth, to those premature infants that are at high risk of developing IVH. Indomethacin inhibits the formation of prostaglandins by decreasing the activity of the cyclooxygenase, may cause the maturation of the germinal matrix microvasculature, and is associated with decreased cerebral blood flow. Its use, however, is controversial as it may cause acute renal failure and other serious side effects.
Thus, there is a present need for a method to reduce the incidence of Intraventricular Hemorrhage in preterm infants. The method must not negatively affect growth pattern, must be safe to be administered to infants, and, if administered as part of the nutritional intake of the infants, this feeding must be well tolerated by the infants.
It is now known in the art that polyunsaturated fatty acids (PUFA) of both the n-3 and n-6 families are required for normal growth and development. See Innis, S. M. et al., Prog Lipid Res 1991; 30:39-103; see also Neuringer, M. and Conner, W. E. Nutr Rev 1986; 44:285-294. The n-3 long chain polyunsaturated fatty acid (LCPUFA), docosahexaenoic acid (DHA, 22:6n-3) is required for optimal brain, neural, and retinal development (See Innis et al. (1991),
opus cit
.; see also Neuringer and Connor (1986),
opus cit
.) and the n-6 LCPUFA arachidonic acid (ARA, 20:4n-6) is needed to support good growth and development (See Carlson, S. E. et al., Am J Clin Nutr 1993; 58:35-42). Infants who are breast-fed receive these LCPUFA in their diet because human milk contains low levels of DHA and ARA. While the amounts of DHA and ARA in human milk vary among individual women and populations depending upon maternal diets, studies across many population groups have shown the median levels of DHA and ARA in human milk to be approximately 0.3% and 0.5-0.6% of total fatty acid content, respectively. See Innis, S. M., J Pediatr 1992; 120:S56-61; see also Koletzko, B. et al., J Pediatr 1992; 120:S62-70.
Infant formulas currently marketed in the United States did not until recently contain any preformed DHA or ARA. Thus, infants solely fed these infant formulas ingest no DHA or ARA. The formulas do, however, contain the 18-carbon chain length essential fatty acids, alpha linolenic (linolenic) acid (ALA, 18:3n-3) and linoleic acid (LA, 18:2n-6), at levels equal to or greater th
Hansen James W.
Knauff Karen H.
Schade Deborah A.
Bristol--Myers Squibb Company
Henley III Raymond J.
Nelson Mullins Riley & Scarborough LLP
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