Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Novel sulfated polysaccharides, sulfated bacterial glycosaminoglycan (Org 31581) and chemically degraded heparin (Org 31733), have proved to be potent and selective inhibitors of human immunodeficiency virus (HIV) in vitro. Their 50% inhibitory concentrations for HIV type 1 (HIV-1) in MT-4 cells were 0.67 and 0.52 micrograms/ml, respectively. These values are comparable to those obtained for dextran sulfate and standard heparin (0.39 and 0.89 micrograms/ml, respectively). Org 31581 and Org 31733 showed much less antithrombin activity than did dextran sulfate and standard heparin. These results indicate that the anti-HIV activity of sulfated polysaccharides can be dissociated from their antithrombin activity. Org 31581 and Org 31733 were equally inhibitory to HIV-2 and HIV-1 and were also inhibitory to the replication of human cytomegalovirus. Syncytium formation, induced by cocultivation of MOLT-4 (clone 8) cells with chronically HIV-1-infected HuT 78 cells, was also inhibited by Org 31581. As previously demonstrated with dextran sulfate and heparin, both Org 31581 and Org 31733 blocked virus adsorption to the host cells. These compounds offer great promise as candidate drugs for the chemotherapy of HIV infections.
 ...
PMID:Novel sulfated polysaccharides: dissociation of anti-human immunodeficiency virus activity from antithrombin activity. 240 68

The array of clinicopathologic factors associated with acquired immune deficiency syndrome (AIDS) patients continues to increase and surprise many physicians. The recent literature contains reports of thrombotic episodes occurring in patients with human immunodeficiency virus (HIV) infection. Various abnormalities predisposing to a hypercoagulable state have also been reported in AIDS patients including the presence of antiphospholipid antibodies and the lupus anticoagulant; deficiencies of protein C, protein S, heparin cofactor II, and antithrombin and increased levels of von Willebrand factor, and d-dimers. These abnormalities correlate with the severity of HIV-associated immunosuppression as measured by the CD4 cell counts and with the presence of concurrent infectious or neoplastic diseases. The authors reviewed the medical literature and describe various abnormalities predisposing to a hypercoagulable state in AIDS patients along with the management of such complications. This issue is important because deep venous thrombosis (DVT), pulmonary embolus (PE), or thrombosis at other sites can develop in patients with AIDS who are ambulatory and have no known risk factors for pathologic thrombus formation, providing another challenge in an already difficult clinical situation. This also provides a strong rationale for careful prospective studies focusing on the prevalence and risk factors involved in the development of thromboembolic complications in patients with AIDS.
 ...
PMID:HIV and thrombosis: a review. 1117 84

Hirudin, the anticoagulatory polypeptide of the leech Hirudo medicinalis, strongly inhibits thrombus formation by specifically interacting with thrombin. For diagnostic purposes, hirudin should be superior to other anticlotting compounds because it only minimally alters the mineral, protein, and cellular blood constituents. To test this hypothesis, hirudinized and routinely processed venous blood from 80 healthy volunteers and patients was subjected to a variety of automated blood tests. A strong correlation was found between the results of automated complete blood counts obtained from K(2)-ethylenediaminetetraacetic acid (EDTA) anticoagulated and hirudinized blood (1000 antithrombin units [ATU] hirudin/ml). In addition, clinical chemistry and serological infection parameters (asparlat amintransferase [ASAT], lactate dehydrogenase [LDH], sodium, and so on, and antibodies against hepatitis B and C and human immunodeficiency virus [HIV]1/2, respectively) correlated well when measured in serum as compared with hirudinized plasma. Contrary to single clotting factors, global coagulation parameters (activated partial thromboplastin time [aPTT], prothrombin time [PT]) could not be measured in hirudinized blood. Recombinant hirudin neither interfered with immunophenotyping of mononuclear cells using FACScan analysis, nor did it alter the detection of Wilms' tumor gene expression by RT-PCR technology even at high doses (5000 ATU hirudin). Thus, a hirudin-containing blood sampling tube can be designed as a universal blood sampling tube (UBT) for testing the majority of diagnostic blood parameters.
 ...
PMID:Measurement of hematological, clinical chemistry, and infection parameters from hirudinized blood collected in universal blood sampling tubes. 1154 57

A condition of oxidative stress, due to perturbation of oxidant/antioxidant balance, has been suggested to play a role not only in the pathogenesis of human immunodeficiency virus (HIV) infection, but also in the promotion of a thrombophilic condition. Because various hemostatic dysfunctions usually considered as risk factors for thrombotic events were reported in HIV infection, this study was undertaken to investigate whether the oxidative phenomenon could promote a prothrombotic state in such condition. Erythrocyte glutathione peroxidase (GSH-Px), the major free-radical scavenger enzyme, and serum tumor necrosis factor-alpha (TNF-alpha) were evaluated in 33 consecutive HIV-infected out-patients and 35 matched HIV-negative healthy controls at a distance of any acute episode. Thrombin generation was explored by measuring the plasma levels of prothrombin fragment 1 + 2 (F1 + 2), whereas fibrin degradation products (D-dimer) and plasminogen activator inhibitor (PAI-1) activity were evaluated as indices of plasmin activity and fibrinolytic derangement. The anticoagulant pathway was investigated by measuring the plasma levels of antithrombin and protein C. Erythrocyte GSH-Px activity and serum TNF-alpha were significantly higher in HIV-infected patients when compared to controls. F1 + 2, D-dimer, and PAI-1 activity were increased in HIV-infected patients by comparison with controls. Normal antithrombin, but decreased protein C, was instead detected in HIV-infected patients. In the latter patients, serum TNF-alpha negatively correlated with both erythrocyte GSH-Px activity and plasma D-dimer. On the other hand, a positive correlation was shown between F1 + 2 and D-dimer and between D-dimer and GSH-Px activity. Furthermore, a trend toward increasing levels of GSH-Px with increasing PAI-1 activity was reported. These findings suggest a relationship between erythrocyte oxidative stress and the hypercoagulable condition during HIV infection.
 ...
PMID:Increased erythrocyte glutathione peroxidase activity and serum tumor necrosis factor-alpha in HIV-infected patients: relationship to on-going prothrombotic state. 1198 8

Fresh frozen plasma (FFP) contains higher levels of intact coagulation factors and coagulation and fibrinolysis inhibitors than solvent/detergent-treated plasma (SD plasma), and also greater residual cell contamination. SD plasma is a particle-free plasma of uniform quality. SD treatment, however, has the specific result of reducing the activities of some inhibitors. Both plasma types carry a minimal residual risk of transmitting human immunodeficiency virus (HIV)-1/2, hepatitis virus B (HBV), and hepatitis virus C (HCV), but SDP is, in addition, also safe with respect to other lipid-enveloped viruses and perhaps with respect to hepatitis virus A (HAV), also due to its antibody (Ab) content. Future revisions of therapeutic plasma safety and quality standards should consider the following points:For FFP:reduce residual cell count in all FFP units to values below 5 x 10(6) leukocytes/l;screen donors for Parvovirus B19 genome and antibodies in order to establish a sufficiently large collection of genome-negative and antibody-positive donors whose FFP can be used for selected patients;For SDP:introduce pool testing for Parvovirus B19 genome; fix an upper limit for genome and a lower limit for antibody content;in addition to the standard quality control methods for therapeutic plasma, focus on assays to test for functionally intact proteinase inhibitors such as alpha(2)antiplasmin (alpha(2)AP) and alpha(1)proteinase inhibitor (alpha(1)PI) that are important for plasma indications. Commercially available kits may not be sufficient to show changes in inhibition kinetics. For both types:introduce an activation marker such as thrombin-antithrombin complex (TAT) as a random test to monitor activation processes during withdrawal, separation, manufacturing, and storage;abolish inappropriate parameters like Antithrombin III (AT III) and coagulation factor XI that are not relevant for changes in plasma quality;finally, support every effort towards establishing an efficient documentation and reporting system on efficacy and side effects of plasma transfusions. Effective reporting alone might help to reveal deficiencies of specific plasma quality and to overcome them through modifications to manufacturing processes and testing, or by defining its indications more precisely.
 ...
PMID:Quality of therapeutic plasma-requirements for marketing authorization. 1237 93

Major histocompatibility (MHC)-restricted cytotoxic T-lymphocytes (CTL) kill human immunodeficiency virus (HIV)-infected cells. In addition, activated CD8(+) T-lymphocytes from HIV-infected individuals suppress virus replication in vitro by producing antiviral factor (CAF). The effector mechanism(s) of CAF involves modulation of HIV gene transcription, is non-cytolytic and mediated in part by soluble antiviral factors. Initially, CAF activity was shown to be more vigorous in activated CD8(+) cells and cell free supernatants (SNs) from asymptomatic individuals compared to those with AIDS, suggesting a protective role in vivo. CAF-mediated suppression is also evident in animal models of immunodeficiency virus infection. Several soluble molecules that contribute to non-cytolytic virus suppression have been characterised, including alpha- and beta-chemokines and interleukin-16 (IL-16), but these are distinct from CAF. Two agents possessing certain CAF-like characteristics, modified antithrombin 111 (AT111) and the human alpha-defensins, have been described but their antiviral mechanisms are not fully understood. CAF-secretion may not be virus-specific as similar activity is found in activated CD8(+) cells/SNs from humans and chimpanzees seronegative for HIV-1. Recent data indicates that the secretion of CAF is MHC-restricted and both cytolytic and non-cytolytic mechanisms are mediated by CTL. If the latter is correct, a single appropriate stimulus could be used to enhance both effector mechanisms in vivo. This paper reviews research aimed at characterising HIV-suppressive factors and raises other questions that must be considered for the development of prophylactic and therapeutic strategies leading to the safe and effective control of HIV.
 ...
PMID:CD8+ T-cell-mediated non-cytolytic suppression of human immuno-deficiency viruses. 1276 88

Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG(12)-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.
 ...
PMID:Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity. 1980 67

Blood products are those biologicals derived from plasma or obtained by recombinant technologies. This overview covers the characteristics and classification of plasma proteins, the current status of products (albumin, immunoglobulins, coagulation factors and microcontent proteins), as well as the likely trends in the near future. Human serum albumin is one of the earliest, safest and most widely used proteins in the pharmaceutical field. The approval and development of high-purity plasma albumin, recombinant human albumin and HSA fusion proteins provide a favorable prospect for the therapeutic protein. Normal immunoglobulin contains antibodies to all the micro-organisms prevalent in the donor population. The IMIG is relatively simple to prepare and use, and the side effects are acceptable; IVIG is used mainly to treat patients with primary immunodeficiency syndromes; SCIG preparations can be used in selecting suitable patients for home therapy and have occurred fewer adverse systemic reactions; specific immunoglobulins contain concentrations of antibody to an individual organism or toxin at a higher titer than normal immunoglobulin and can not be replaced in clinical use. The plasma-derived or recombinant coagulation factors are used to treat the patients with congenital or acquired factor deficiency. The products such as Fibrinogen, FVII, FVIII, von Willebrand complex, FIX/PCC, FXI, FXIII and so on, have been widely used and proved to be effective. The development of recombinant FVIIa is now as a good bypassing product to haemophilia with inhibitors. The Fibrinogen and thrombin play a very important role in surgery hemostasis. Moreover, microcontent proteins including protein C, antithrombin, alpha 1-AT, tPA have been licensed and used in clinical treatment; a number of other small field proteins are under produced research or pre-clinical investment. The ongoing development of new recombinant plasma proteins is providing alternatives for patients, but the distinct position and the potential impact of plasma-derived preparations are unique, furthermore the development of new plasma protein is still a hot spot in global pharmaceutics. Nowadays, a relative difference exists in the development of blood products between our nation and developed countries, so the domestic manufacturers are faced with chances and challenges.
 ...
PMID:[Current status and trends in blood biologicals]. 2184 40

Introduction Human immunodeficiency virus (HIV) patients are at risk of developing thrombosis than general population. There are several intersecting mechanisms associated with HIV infection and antiviral therapy that are emerging, which may lead to vasculopathy and hypercoagulability in these patients. Methods We analyzed the HIV patients who followed up with our Vascular Medicine outpatient clinic with venous thromboembolism (VTE) over the past 3 years and followed them prospectively. The patients included were those who had minimum, regular follow-up of 3 months, with a Doppler scan in the beginning and last follow-up. Patients were analyzed for age, gender, race, site of thrombosis, coagulation factors, lipid panel, type of antiretroviral treatment, past or present history of infections or malignancy, CD4 absolute and helper cell counts at the beginning of thrombosis, response to treatment and outcome. Patients with HIV with arterial thrombosis were excluded. Results A total of eight patients were analyzed. The mean age was 49.87 years (range, 38-58 years). All were male patients with six patients having lower limb thrombosis, one patient with upper limb thrombosis related to peripheral inserted central catheter (PICC), and one patient had pulmonary embolism with no deep vein thrombosis. Most common venous thrombosis was popliteal vein thrombosis, followed by common femoral, superficial femoral and external iliac thrombosis. Two patients had deficiency of protein S, two had high homocysteine levels, one had deficiency of antithrombin 3, and one had increase in anticardiolipin Immunoglobulin antibody. All patients were taking nucleoside and nonnucleoside inhibitors but only two patients were taking protease inhibitors. There was history of lymphoma in one and nonsmall cell lung carcinoma in one patient. Three patients had past history of tuberculosis and one of these patients also had pneumocystis carinii pneumonia. The mean absolute CD4 counts were 383.25 cells/UL (range, 103-908 cells/UL) and helper CD4 counts were 22.5 cells/UL (range, 12-45 cells/UL). All were anticoagulated with warfarin or enoxaparin. There was complete resolution of deep vein thrombosis in two patients (one with PICC line thrombosis in 3 months and other with popliteal vein thrombosis in 1 year). There was extension of clot in one patient and no resolution in others. Seven patients are still alive and on regular follow-up. Conclusion Thrombosis in HIV patients is seen more commonly in middle aged, community ambulant male patients. Left lower limb involvement with involvement of popliteal vein is most common. Deficiency of protein S and hyperhomocystenaemia were noted in these patients. Most of these patients did not respond to therapeutic anticoagulation, but the extension of the thrombosis was prevented in majority of cases.
...
PMID:Risk of Venous Thromboembolism in Patients Infected with HIV: A Cohort Study. 2443 91

Patients with human immunodeficiency virus (HIV) are at risk of developing thrombosis and are 8 to 10 times more likely to develop thrombosis than the general population. Moreover, if they have hypercoagulable state they can have severe thrombosis and life-threatening thrombotic events. The purpose of this retrospective study is to analyze hypercoagulable state in HIV-seropositive patients who have been diagnosed with venous thromboembolism (VTE). This study is a subgroup study of a larger cohort group of HIV-seropositive patients with VTE followed up with our vascular medicine outpatient clinic. The patients included for this study were HIV-seropositive patients with hypercoagulable state, analyzed over the past 3 years, and followed prospectively. HIV-seropositive patients with arterial thrombosis were excluded. These patients had minimum, regular follow-up of 3 months, with a Doppler scan in the beginning and last follow-up. All the patients were analyzed for hypercoagulable state and the patients selected in this study were those who were tested positive for hypercoagulable state. All patients were analyzed for age, gender, race, site of thrombosis, coagulation factors, lipid panel, type of antiretroviral treatment, past or present history of infections or malignancy, CD4 absolute and helper cell counts at the beginning of thrombosis, and response to treatment and outcome. Patients with HIV with arterial thrombosis were excluded. The study was approved by the ethics committee. Five patients were included in this study. The mean age was 47.8 years (range 38 to 58 years). All were male patients with lower limb thrombosis. Most common venous thrombosis was popliteal vein thrombosis, followed by common femoral, superficial femoral, and external iliac thrombosis. Two patients had deficiency of protein S, two had high homocysteine levels, one had deficiency of antithrombin 3, and one had increase in anticardiolipin immunoglobulin G antibody. All the patients were taking nucleoside and nonnucleoside inhibitors but only one patient was taking protease inhibitors. There was no history of malignancy but two patients had past history of tuberculosis. The mean absolute CD4 counts were 244 cells/UL (range 103 to 392 cells/UL) and helper CD4 counts were 19.6 cells/UL (range 15 to 30 cells/UL). All were anticoagulated with warfarin or enoxaparin. There was complete resolution of deep vein thrombosis only in one patient on long-term anticoagulation but there was no resolution of thrombosis in the other four patients despite of therapeutic anticoagulation for more than 6 months. All the patients are alive and on regular follow-up. Thrombosis in HIV patients is seen more commonly in middle aged, community ambulant male patients. The most common hypercoagulable state was noted as deficiency of protein S and hyperhomocysteinemia. Eighty percent of the patients did not respond to therapeutic anticoagulation.
...
PMID:A Case Series of HIV-Seropositive Patients and Hypercoagulable State-Is It Difficult to Treat Even with Therapeutic Anticoagulation? 2443 93


1 2 Next >>