Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various immunological parameters were determined in 46 patients with severe hemophilia A and in 9 patients with severe hemophilia B. All patients were treated over many years with commercial factor VIII or IX concentrates. Patients with severe classic hemophilia had a significantly reduced relative and absolute number of T-helper cells and a significantly increased relative and absolute number of T-suppressor cells. About half of these patients had an inverse T-helper/suppressor cell ratio. Patients with moderate hemophilia A and severe hemophilia B did not show these abnormalities. Hemophiliacs with an inverse ratio had a significantly higher concentration of serum total protein, IgG and IgM. No relationship between the amount of factor VIII concentrate administered, the HLA-type of the patient, the presence or absence of CMV-antibodies, hepatitis markers, thrombocytopenia and abnormal liver function tests to the T-cell abnormalities could be established. Lymphadenopathy was frequently associated with an inverse ratio. Indirect evidence suggests that the alterations of the immune system began in 1979/80.
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PMID:T-cell alterations in hemophiliacs treated with commercial clotting factor concentrates. 631 82

Of 120 patients presenting with mild bleeding disorders, 63 were found to have a definite coagulopathy. The commonest disorders were haemophilia, Christmas disease and von Willebrand's disease (vWd), the latter being predominant. Diagnosis led to prophylactic treatment prior to surgery in 18 patients with prevention of excessive haemorrhage. Three patients who had received blood products developed hepatitis. DDAVP (desamino-cys-1-8-D-arginine vasopressin) is the treatment of choice in suitable mildly affected patients with haemophilia A and vWd. Examination of blood group distribution suggests an excess of group O among patients with bleeding disorders, especially those with vWd.
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PMID:Mild bleeding disorders: review of 120 patients. 633 71

Prothrombin complex concentrates (PCCs) have been used for the treatment of hemorrhagic episodes in patients with hemophilia B but have been associated with a high incidence of thrombotic complications. Newer, ultrapure concentrates of factor IX contain less extraneous proteins than PCCs and are less thrombogenic in vitro. In this report, the results of clinical studies with Mononine (Armour Pharmaceutical Company), a purified factor IX concentrate prepared by monoclonal affinity chromatography, are described. Two studies were performed, a phase I/II clinical trial in 10 patients and a compassionate use study in 72 patients. The pharmacokinetics of Mononine were found to be similar to the pharmacokinetics of factor IX after administration of PCCs. In both studies, Mononine was well-tolerated and hemostatically effective when used in doses of up to 161 IU/kg in treatment courses of up to 67 infusions of Mononine. Patients with hepatitis and a prior history of thrombosis with PCCs tolerated Mononine with no evidence of thrombosis. The only thrombotic complication attributed to Mononine in the two studies was an episode of phlebitis at the site of an intravenous line in one patient. These studies indicate that Mononine is safe and effective in the treatment of hemorrhagic episodes in patients with hemophilia B.
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PMID:Safety and recovery of mononine in multiple-dose, high-dose regimens. 757 96

Hemophilia A and B patients seen at nine US regional treatment centers were tested for serologic markers of hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) during 1987 and 1988. Because human immunodeficiency virus (HIV) infection, a potentially confounding variable, was present in 53% of the group, the population was divided by HIV status for analysis purposes. In the HIV-positive group (N = 382), less than 1% had not been infected with HBV, HCV, or HDV, whereas 75% had evidence of infection with HBV and 98% with HCV. HBsAg, a marker of active HBV infection, was present in 12% of subjects; 96% of these were HCV positive. Anti-HDV was detected in 35 subjects (9.1%); all were anti-HBc positive. Ten of the 35 (29%) also were positive for IgM anti-HDV, indicating current infection. All 10 were HBsAg positive and 7 of the 9 tested were HDV RNA positive. Severe/moderate hemophilia B patients were more likely to have experienced an HBV infection and to be anti-HDV positive than were similar hemophilia A patients (22% v 8%, P < .05). In the HIV-negative group (N = 345), the subjects were younger and had less severe hemophilia than the HIV-positive patients. No evidence of HBV, HCV, or HDV infection was found in 18%, whereas 33% had experienced HBV infection and 79% were anti-HCV positive. Within this group, 4% were HBsAg positive. All 13 subjects with anti-HDV (4% of the HIV-negative group) also possessed anti-HBc. One (7.7%) was IgM anti-HDV positive and the serum from another contained HDV RNA. Both of these individuals were HBsAg positive. As in the HIV-positive group, severe/moderate hemophilia B patients were more likely to be HBV and HDV positive than were hemophilia A patients (9% v 3%, P < .05). A prevalence study of viral hepatitis in a large US hemophilic population showed that active infection with HCV is common, occurring in 89% of all study patients regardless of HIV status. Evidence of active HBV infection was found in 8%; 19% of these were actively infected with HDV. HDV was more common in hemophilia B patients after controlling for disease severity.
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PMID:A multicenter study of viral hepatitis in a United States hemophilic population. 767 17

The management of hemorrhagic episodes in patients with hemophilia B is in transition as a result of the availability of new products for replacement therapy. Although the basic principles of therapy have not changed, the new highly purified Factor IX concentrates, AlphaNine and Mononine, represent a break-through, as they appear to be safe in terms of viral transmission and thromboembolic side-effects. These products are now widely available, and although expensive, are regarded by some physicians as the preferred therapy for Hemophilia B. Less pure and less expensive Factor IX products, however, are also available and can be used safely in previously treated patients who have already been exposed to the hepatitis viruses.
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PMID:Current management of hemophilia B. 829 16

The safety and efficacy of a monoclonal antibody purified factor IX concentrate were evaluated in two continuing trials of 32 previously untreated patients with mild, moderate, or severe hemophilia B. Patients were evaluated every 2 weeks for 24 weeks and every 3 months thereafter for at least 1 year. No patients became positive for human immunodeficiency virus antibody or hepatitis C virus antibody during the trial. Two patients developed a false-positive hepatitis B core antibody, one transiently, but neither had elevated levels of alanine aminotransferase (ALT). None of the 25 patients evaluable for non-A, non-B, non-C hepatitis by strict International Society of Thrombosis and Hemostasis criteria developed elevated levels of ALT indicative of posttransfusion infection. Anaphylaxis occurred in one subject who also developed an inhibitor to factor IX (19.3 Bethesda units). Five of the eight adverse events reported (63%) were mild in severity, and the relationship of three of these to therapy was considered remote. Hemostasis with monoclonal antibody purified factor IX concentrate was excellent in all patients.
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PMID:Safety and efficacy of monoclonal antibody purified factor IX concentrate in previously untreated patients with hemophilia B. 871 76

Previous experiments have demonstrated the stable expression of factor IX (FIX) protein in mice and canine models of hemophilia B following portal vein gene transfer with a recombinant adeno-associated virus (rAAV) vector encoding FIX. Here, we present the results of studies that further optimized the rAAV vector transgene cassette used to express FIX and explored the use of the less-invasive intravenous (i.v.) route of vector administration for the treatment of hemophilia B. First, a liver-specific promoter was evaluated in conjunction with cis-acting regulatory elements in mice. Constructs that included both the beta-globin intron and the woodchuck hepatitis virus post-transcriptional regulatory element resulted in the highest level of FIX expression in vivo. Using this optimized vector, we demonstrate that i.v. injection was feasible for hepatic gene transfer in mice, achieving 70-80% of portal vein expression levels of FIX. In further studies using the Chapel Hill strain of hemophilia B dogs, we demonstrate for the first time FIX expression and partial correction of the bleeding disorder following i.v. administration of an AAV vector.
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PMID:Intravenous administration of an AAV-2 vector for the expression of factor IX in mice and a dog model of hemophilia B. 1471 5

Arthropathies and joint deformities in patients with severe hemophilia result in prolonged immobilization, reduced physical activity, and predispose them for osteoporosis. This can lead to an increasing tendency of bone fragility and fractures in patients after trivial trauma. The aim of this study was to find out (i) the prevalence of osteoporosis in hemophilia patients and (ii) the association of osteoporosis with hemophilic arthropathy and related restricted physical activity. In this case-control study, 50 consecutive severe hemophilia patients aged between 20 and 50 years were evaluated for osteoporosis with measurement of bone mass density (BMD) by a DEXA scan and values were compared with that of 50 sex matched normal healthy controls. Major joints of the limbs were evaluated to determine the extent of joint damage and related disability. Forty-two patients had severe hemophilia A and 8 patients severe hemophilia B (efficient factor activity < 0.01 U/ml). BMD values (gms/cm(2)) of lumbar spine and left hip of the patients were significantly lower than that of controls (0.825 vs. 0.939; P < 0.0001 and 0.725 vs. 0.938; P < 0.0001, respectively). The incidence of osteoporosis (T score: -2.5 or more) was significantly higher in hemophiliacs. Incidence of fractures in adult life was also significantly higher in hemophiliacs compared to controls (12% vs. 0%). There was statistically significant correlation between joint evaluation scores and BMD of hip, but not with that of the lumbar spine. There was no correlation between Hepatitis-C virus status and BMD of any site. This shows that development of osteoporosis is a significant problem in patients with severe hemophilia in this country. Hence appropriate preventive measures such as early treatment and adequate mobilization, exercises, encouragement to participate in sporting activities, early assessment of bone density, and administration of anti-osteoporotic therapy is recommended.
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PMID:Osteoporosis in young haemophiliacs from western India. 1727 14

Hemophilia B is an X-linked genetic disorder that typically results from chronic circulating deficiency of blood coagulation factor IX (FIX) (1). While the occurrence of hemophilia B is significantly less frequent than hemophilia A (factor VIII, deficiency) it has received special attention as a model for gene therapy. This is because hemophilia B is one of the least complicated genetic diseases from the point of view of demonstrating the proof of principle of a gene therapy protocol. Specifically, hemophilia B is a single gene recessive disorder and a wide range of tissues can be targeted for FIX gene delivery and strict regulation of FIX expression is not required. In addition, the 2.8 kb FIX cDNA is much smaller than the 9 kb FVIII cDNA, and FIX expression in transfected mammalian cells has been less problematic than FVIII expression (2). Since clinical severity of bleeding episodes closely corresponds to a patient's FIX activity, achieving even partial restoration of normal FIX levels in the bloodstream can alleviate internal bleeding. Individuals with FIX levels less than 1% of normal experience severe symptomatic episodes but providing roughly 5% of normal levels (i.e., 250 ng/mL plasma) can significantly reduce the frequency and severity of bleeding episodes and reduce long term complications (3). Treatment of hemophilia B primarily relies on intravenous injections of FIX protein purified from pooled human plasma, or very recently, on newly developed recombinant FIX. Treatment is applied typically only when bleeding episodes have occurred or are expected, for example, in case of a trauma or surgery. Although the risk of viral transmission of HIV and hepatitis viruses has been largely eliminated the absolute safety of any product derived from blood cannot be guaranteed. Furthermore, supplies of factor concentrates are limited and costs (especially if prophylactic treatment is being considered) are high. Thus, the application of gene therapy to hemophilia, whereby long-term correction of factor IX deficiency might be achieved, would be extremely useful.
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PMID:Ex Vivo Stromal Cell Electroporation of Factor IX cDNA for Treatment of Hemophilia B. 2144 54

The liver is a target for gene therapy of inborn errors of metabolism, of hemophilia, and of acquired diseases such as liver cancer and hepatitis. The ideal gene transfer strategy should deliver the transgene DNA to parenchymal liver cells with accuracy and precision in the absence of side effects. Liver sinusoids are highly specialized capillaries with a particular endothelial lining: the endothelium contains open fenestrae, whereas a basal lamina is lacking. Fenestrae provide a direct access of gene transfer vectors to the space of Disse, in which numerous microvilli from parenchymal liver cells protrude. The small diameter of fenestrae in humans constitutes an anatomical barrier for most gene transfer vectors with the exception of adeno-associated viral (AAV) vectors. Recent studies have demonstrated the superiority of novel AAV serotypes for hepatocyte-directed gene transfer applications based on enhanced transduction, reduced prevalence of neutralizing antibodies, and diminished capsid immune responses. In a landmark clinical trial, hemophilia B was successfully treated with an AAV8 human factor IX expressing vector. Notwithstanding significant progress, clinical experience with these technologies remains very limited and many unanswered questions warrant further study. Therefore, the field should continue to progress as it has over the past decade, cautiously and diligently.
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PMID:The liver as a target organ for gene therapy: state of the art, challenges, and future perspectives. 2428 41


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