Summary In a study designed to demonstrate the safety and pharmacokinetics of a recombinant factor VIII (Recombinate) manufactured in Andover, MA and Thousand Oaks, CA, two different methods of factor VIII assay (one-stage clotting and Chromogenic substrate) were compared in vivo. The study was performed in four centres in the UK: London, Oxford, Cardiff and Manchester. Two pharmacokinetic studies, at least one week apart, were performed in 30 patients with severe haemophilia A (VIII:C < 2 IU/dl). A dose of 50 IU/kg was administered with sampling pre-infusion, and +0.25, 0.5, 1, 3, 6, 9, 12 and 24 h post-infusion. The aggregate 60 pharmacokinetic study showed a half-life of 12.7 and 13.0 h (p = 0.28) and recovery of 127 and 161 IU/dl (p = 0.0001) using one-stage clotting or chromogenic substrate respectively. In a supplementary experiment, 20 post-infusion samples were re-assayed by 1-stage and chromogenic assay using two plasma (20th British plasma standard and an “in-house” pooled normal plasma) and two concentrate standards, derived from the same type, but different batch of infused concentrate (Recombinate) and pre-diluted in either individual pre-infusion sample or in pooled commercial haemophilic plasma. The use of the Recombinate concentrate standard overcame the significant difference in FVIII levels between 1-stage and chromogenic assay methods when a plasma standard was used (p <0.0001). It is concluded that where potency dosing designation is carried out by an assay system different to that used in the clinical situation, the use of the recombinant concentrate as a standard in post-infusion plasma samples is likely to give more reliable and reproducible results.
We present a case of fulminant pneumococcaemia and disseminated intravascular coagulopathy in a young adult man 17 years after splenectomy. The clinical presentation, laboratory and postmortem findings are discussed. The diagnosis, management and prophylaxis of overwhelming infections in splenectomized patients are reviewed. The advent of pneumococcal and other vaccines could contribute significantly to the successful protection of asplenic patients against certain severe infections.
Thrombotic occlusion is a frequent complication associated with the use of central venous catheters. The purpose of this study was to evaluate the efficacy of a continuous infusion of low-dose urokinase (200 U/kg/h) in clearing catheters that had not cleared after two bolus doses of urokinase in a pediatric oncology population. Fifty-eight incidents of catheter-related occlusions (49 Hickman-type catheters/nine implantable ports) as documented by radiographic dye study occurred in 227 pediatric oncology patients with 254 central venous catheters during a 1-year period. Fourteen of 58 catheters failed to clear after two bolus instillations of urokinase (5,000 U and 10,000 U). Thirteen catheters were treated for 24 hours with urokinase, 200 U/kg/h, and one catheter with urokinase, 100 U/kg/h for 24 hours. Twelve catheters were used for study. Coagulation studies were monitored preinfusion, 12 hours into the infusion, and postinfusion. Patency was reestablished in 11/12 catheters (92%) with a mean infusion time of 28.7 hours. No coagulation abnormalities or clinical bleeding associated with the urokinase infusion occurred. Only one patient exhibited a prolonged partial thromboplastin time (greater than 150 seconds); this was associated with a heparin effect. These data indicate that low-dose urokinase may be a safe and effective means to clear occluded central venous catheters in children.
Clinical reports indicate that the development of drug resistance to AZT after chronic administration is common. In order to study this phenomenon, the T-cell line Jurkat E6-1 was treated continuously in vitro with low, gradually increased, concentrations of azidothymidine (AZT). Initially, 1 microM AZT significantly retarded the cell line from reaching confluence. However, after 10 weeks the T-cell line was able to grow in 10 microM AZT without any evidence of growth inhibition. Subsequently, cell isolates could grow continuously in the presence of 20, 50, and 100 microM AZT without growth inhibition. These T-cell lines (Jurkat E6-1/AZT-10, Jurkat E6-1/AZT-20, Jurkat E6-1/AZT-50, and Jurkat E6-1/AZT-100) were tested for AZT anabolism using purified [3H]AZT, and the results were compared to the wild-type untreated Jurkat E6-1 cell line. Similar intracellular AZT anabolites concentrations were determined in all cell lines. However, a four- to sixfold lower cellular concentration of mono-, di-, and triphosphate anabolites of AZT was determined in the Jurkat E6-1/AZT-10 cell line after 1 microM AZT incubation and 6.5-fold lower after 10 microM AZT treatment. In general, a five- to sixfold reduction in the phosphorylation rates were estimated in the AZT resistant T-cell line. Pharmacology studies of [3H]AZT in the Jurkat E6-1/AZT-100 cell line showed a much lower level of activation of the pro-drug (28-fold), due to lack of thymidine kinase (TK) activity when compared to the Jurkat E6-1/AZT-10 T-cell line. A similar level of resistance was obtained at the thymidylate (dTMP) kinase level. Concurrently an additional mode of resistance (407-fold) was seen on the incorporation of the AZT triphosphate anabolite (AZTTP) into cellular DNA. The formation of this cell line in a period of < or = 4 months coincides with the evidence of the clinical development of "resistance" to AZT in patients who receive the drug continuously. In addition, these T-cell lines have been infected with HIV, and studies on the development of collaterally sensitive regimens are under way.
The first recognised outbreak of Marburg virus disease in Africa, and the first since the original epidemic in West Germany and Yugoslavia in 1967, occurred in South Africa in February 1975. The primary case was in a young Australian man , who was admitted to the Johannesburg Hospital after having toured Rhodesia. Two secondary cases occurred, one being in the first patient's travelling companion, and the other in a nurse. Features of the illness included high fever, myalgia, vomiting and diarrhoea, hepatitis, a characteristic maculopapular rash, leucopenia, thrombocytopenia, and a bleeding tendency. The first patient died on the seventh day from haemorrhage resulting from a combination of disseminated intravascular coagulation and hepatic failure. The other two patients were given vigorous supportive treatment and prophylactic heparin and recovered after an acute phase lasting about seven days. During this period on developed pancreatitis, the serum amylase remaining raised until the 32nd day after the onset of the illness. The other developed unilateral uveitis after having been asymptomatic for two months. This persisted for several weeks and Marburg virus was cultured from the anterior chamber of the eye.
Haemostatic factors in 33 Black and 32 White maturity-onset diabetics were analysed and compared with those in 19 normal Black and 19 White subjects. The Black-White diabetic group comparisons revealed depressed antithrombin (AT) III functional activity, a raised factor VII level and a raised factor V level in females in the White diabetic group. On comparing the White diabetics with their respective controls a rise in factor VIII and fibrinogen activity was demonstrated. These changes are suggestive of a hypercoagulable state in the White maturity-onset diabetic. In contrast, Black diabetics have higher functional AT III levels than their respective controls. This may indicate a protective reaction which would explain in part the reported lower incidence of occlusive vascular disease in this group. Platelet hyperactivity was not demonstrated in the majority of White and Black diabetics. Black diabetics and controls demonstrated higher factor VIII levels than the corresponding White groups, confirming previous observations of raised factor VIII levels among Blacks and suggesting that this feature is a racial characteristic.
The levels of factor VIII-related antigen (ERA) in normal White females, in White and Black obligatory haemorphilia carriers and in possible haemophilia carriers compared with the functional factor VIII activity. The results obtained compared favourably with those previously reported, in that the obligatory carrier group demonstrated excess antigen compared with functional factor VIII activity. The F VIII/ERA ration obtained for each obligatory carrier was compared statistically with the ratio of normal group. A ratio of 0,65 was the level below which haemophilia carrier status could be predicted within the 95% confidence limits.
Screening coagulation studies were carried out on 69 long-term survivors who had received renal allografts. Fibrinogen levels were significantly raised in this group. Factor VIII activity was increased in 7 of the 11 patients studied. Six long-term survivors of renal allografts demonstrated arterial thrombotic phenomena. The onset of the thrombotic episode occurred at a relatively young age. It is considered that the hypercoagulable state may contribute to the observed increased tendency towards arterial thrombotic phenomena.
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