Real-world experience with use of Antihemophilic Factor (Recombinant), PEGylated for prophylaxis in severe haemophilia A.

INTRODUCTION: Prophylaxis with extended half-life factor VIII (FVIII) is approved for haemophilia A, but data regarding routine clinical use are limited. AIM: To assess real-world experience of ADYNOVATE® (Antihemophilic Factor (Recombinant), PEGylated prophylaxis in children and adults with haemophilia A. METHODS: A retrospective chart review was conducted in three US haemophilia treatment centres. Records of all patients who began Adynovate prophylaxis in routine clinical practice were identified. Demographic, clinical and patient-reported information beginning 6 months before initiation of Adynovate until the record review was analysed. RESULTS: Fifteen patients (aged 9 months to 28 years), with median 9 months' use of Adynovate (range 1-15 months), were identified. All had switched from another prophylactic regimen, 13 (87%) from standard half-life recombinant FVIII. Nine (60%) patients had ≥1 bleed within 6 months preswitch. The most frequent reason for switching was to reduce infusion frequency (14 patients). After switching, infusion frequency reduced for 13 patients, and overall weekly factor consumption decreased by 19%. Eight (53%) patients had no bleeds postswitch, three (20%) had spontaneous joint bleeds (vs four pre-switch), and three (20%) had only mild traumatic bleeds. Patient/parental satisfaction with Adynovate was documented as positive in 13 of 15 (87%) cases; 2 patients were not satisfied and discontinued Adynovate. No adverse events were considered related to Adynovate. CONCLUSION: In patients who switched from a standard half-life FVIII to Adynovate prophylaxis in routine clinical practice, bleeding control was generally improved or maintained, with a lower infusion frequency and factor consumption in most patients.

Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors-A retrospective analysis.

INTRODUCTION: Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. AIM: Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. METHODS: Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. RESULTS: Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. CONCLUSIONS: Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI.

Effects of intravenously administered fructose and glucose on splanchnic amino acid and carbohydrate metabolism in hypertriglyceridemic men.

Splanchnic metabolism was studied in the fed state during prolonged intravenous administration (30 g/h) of either fructose or glucose to hypertriglyceridemic men who had been maintained on a high-carbohydrate diet for 2 wk. Splanchnic exchange of amino acids and carbohydrates was quantified by measurement of splanchnic flow and of blood or plasma arteriohepatic venous concentration gradients. Results obtained in subjects receiving fructose were compared with those obtained in (a) similar subjects receiving glucose and (b) postabsorptive controls maintained on isocaloric, balanced diets. Mean arterial plasma levels of alanine, glycine, serine, threonine, methionine, proline, valine, leucine, histidine, lysine, and ornithine were significantly higher in subjects given fructose than in those give glucose (P less than 0.05). The mean arterial concentration and splanchnic uptake of alanine were significantly higher in subjects given fructose than in postabsorptive controls, despite a significantly lower fractional extraction of alanine in the former (P less than 0.05). The mean arterial plasma levels of serine and ornithine were significantly lower in subjects receiving fructose than in postabsorptive controls (P less than 0.05). About half of the administered fructose or glucose was taken up in the splanchnic region, where approximately 15% was converted to CO2 and 10% to lactate. Half of the fructose taken up in the splanchnic region was converted to glucose released from the liver. The amount of hexose carbon remaining for hepatic synthesis of liquids in subjects given fructose was less than half of that of subjects given glucose. These studies demonstrate that fructose and glucose have divergent effects on amino acid metabolism and that during hypercaloric infusion of glucose (as with fructose), the human liver is a major site of lactate production.

Effects of a 3-day fast and of ethanol on splanchnic metabolism of FFA, amino acids, and carbohydrates in healthy young men.

Splanchnic metabolism was studied to quantify changes underlying the fatty liver, hyperlipemia, and hypoglycemia produced by ethanol. Four subjects fasted for 15 h were compared with five subjects fasted for 69 h under basal conditions and during continuous intravenous infusion of sufficient ethanol to give a concentration of 3-5 mM in arterial blood plasma. Splanchnic storage of fatty acids was estimated from the difference between uptake of FFA and secretion of derived products. Basal values for splanchnic uptake of FFA were twofold higher after the 69-h fast while splanchnic storage of fatty acids and production of ketone bodies increased threefold. Values for basal secreation into the blood of triglycerides derived from FFA were similar in the two groups. In both nutritional states, the fraction of FFA taken up in the splanchnic region oxidized to ketone bodies and to CO2 fell when ethanol was given because of preferential oxidation of ethanol to acetate, and the fraction esterified rose. However, systemic transport and splanchnic uptake of FFA fell with ethanol in subjects fasted 15 h, so that neither storage of triglycerides in splanchnic tissues nor secretion into the blood increased. In subjects fasted 69 h, ethanol increased transport of FFA and splanchnic storage of fat. In all but one subject it also increased secretion of triglycerides into the blood. The concentration of glucose in blood fell during ethanol infusion in all five subjects undergoing the 69-h fast. Mean splanchnic glucose production was maintained at about one-half of the pre-ethanol value, despite virtual cessation of splanchnic uptake of lactate and of those amino acids that are metabolized via malate. Quantitative estimates of extrasplanchnic metabolism suggest that enhanced formation of alpha-glycerophosphate from glucose, in addition to impaired hepatic gluconeogenesis, may contribute to ethanol-induced hypoglycemia in man.

Malfunction of tricuspid valve prosthesis shown by isotope angiocardiography.

Isotope angiocardiography established prosthetic tricuspid valve obstruction in a patient 6 years after triple valve replacement. Thrombus formation is a common complication of prosthetic cardiac valves, particularly in the tricuspid position where engagement of cage with myocardium is an additional potentially obstructive hazard. Comparison is made between the information yield of the isotope investigation and cardiac catheterization with contrast cineangiography. It is suggested that the isotope technique can noninvasively provide valuable anatomic and functional data, particularly where the right side of the heart is to be examined.

Renal and biochemical changes produced in broilers by high-protein, high-calcium, urea-containing, and vitamin-A-deficient diets.

Three hundred 18-day-old male chicks (Arbor Acre) were divided into five groups of 60 each and given high-protein (42.28%), high-calcium (3.37%), urea-containing (5%), vitamin-A-deficient, or control diets to study the effect of nutritional imbalances on the development of nephritis and related biochemical changes over 15 weeks. The first four diets increased the levels of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, uric acid, and nonprotein nitrogen in serum. Blood urea was increased by only the urea diet. Hypoglycemia and a decrease in hepatic glucose-6-phosphatase were also observed in chicks fed the first four diets. The vitamin-A-deficient diet resulted in a depletion of vitamin A in the liver and kidneys. These changes were directly correlated with the prolonged feeding of experimental diets and also with the severity of nephritis and degenerative changes in various organs. It was concluded that increasing the intake of nitrogen or calcium in order to increase production may in fact have the opposite effect, leading to degenerative changes in various tissues and to nephritis.

Clinicopathological, hematological, and biochemical studies in some outbreaks of nephritis in poultry.

Hematological, biochemical, histoenzymological, and histopathological changes in serum and tissues were studied in chickens during outbreaks of nephritis. Hematological studies revealed normocytic-normochromic anemia characterized by increased total erythrocyte counts, hemoglobin, packed cell volume, and erythrocyte sedimentation rate. Albumin-to-globulin ratio and sodium levels in serum, glucose in blood, and alkaline phosphatase and glucose-6-phosphatase in liver and kidneys were decreased. Glutamate pyruvate transaminase, uric acid, non-protein-nitrogen, and potassium levels in serum were increased. No significant change in the calcium, phosphorus, and total protein levels in serum was observed. These changes were directly related to the severity of the nephritis.

Hematological changes in nephritis in poultry induced by diets high in protein, high in calcium, containing urea, or deficient in vitamin A.

Nephritis was induced in 300, 18-day-old male Arbor Acre broiler chicks by feeding diets high (42.28%) in protein, high (3.27%) in calcium, containing urea (5%), or deficient in vitamin A. Various hematological parameters were studied at weekly intervals. Normocytic-normochromic anemia, characterized by a decrease in total erythrocyte counts, hemoglobin, packed cell volume, and an increase in erythrocyte sedimentation rate, was evident in the birds kept on diets high in protein, high in calcium, or deficient in vitamin A. Increased total erythrocytes, hemoglobin packed cell volume, and erythrocyte sedimentation rate was observed in birds fed urea. Differential leucocyte counts revealed lymphopenia, heterophilia and monocytosis in birds kept on diets high in protein, containing urea, or deficient in vitamin A. However, lymphocytosis, heteropenia , and monocytosis were recorded in birds fed the high calcium diet.

Biochemical changes of the milk in experimental caprine mastitis induced by Mycoplasma serogroup 11 (2-D).

Biochemical changes of the milk were studied in 7 lactating goats. The right udder halves of the animals were inoculated through the teat canal with 1 ml of Mycoplasma ovine/caprine serogroup 11 (2-D) culture containing 6x10(6) colony forming units ml-1. The left udder halves of these goats were kept as control. The experiment was continued for 35 days during which period one goat was killed every 5th day. All the goats developed clinical mastitis within 24 h and the infected udder halves remained enlarged for 4-5 days. The milk from these halves was yellow-tinged and showed slight separation of proteins. Subsequently, there was marked reduction in the size and secretion of the infected udder halves, followed by agalactia from post-inoculation (PI) day 22. The mycoplasmas were reisolated from milk samples of the infected halves up to PI day 20. Histopathological examination of these halves revealed changes indicative of acute and chronic mastitis. Biochemical analysis of mastitic milk/mammary secretions showed a marked increase in the concentration of total proteins, immunoglobulins, free fatty acids and phospholipids, while the concentration of total lipids and glycerides initially underwent a considerable decrease as compared to the basal and control values. However, the level of total cholesterol decreased sharply during the initial days while later, from PI day 5, it markedly increased. This study shows that Mycoplasma ovine/caprine serogroup 11 is pathogenic to the lactating udder of goats and produces marked biochemical alterations in the milk.