[Interindividual pharmacokinetic variability in long-term antibiotherapy]. / Variabilité pharmacocinétique intra-individuelle et traitement antibiotique prolongé.

OBJECTIVE: The authors wanted to assess intraindividual pharmacokinetic variability, with a case of long-term amikacin therapy. DESIGN: A 92-year-old female patient, weighing 44kg, with renal failure, was treated by amikacin for 52 days. Her individual pharmacokinetic parameters were assessed 12 times in the course of therapy. The intraindividual variability of key parameters was quantified and compared with published interindividual variability. RESULTS: Intraindividual volume and clearance variability was measured at about one fourth to one third of the value observed for interindividual variability. Half-life intraindividual variability was almost equivalent to the interindividual variability: 24.5% versus 32%. CONCLUSIONS: The high pharmacokinetic variability observed has important potential clinical consequences. This case illustrates the need to ensure the effectiveness of treatment, to re-evaluate periodically the patient's status in order to take into account the intraindividual variability of pharmacokinetics parameters.

Human immunodeficiency virus infection and AIDS in a person with negative serology.

A 38-year-old woman resident of Ivory Coast died of AIDS, while remaining human immunodeficiency virus (HIV)-seronegative. She had been regularly tested because her husband was HIV-seropositive. The subject's lack of specific antibodies was assessed using commercial tests and confirmed by a radioimmunoprecipitation assay of the patient's virus. She was unquestionably HIV-1-infected, with a high plasma virus load, and her virus could be isolated. Molecular analyses indicated this retrovirus was clade A, which is common in Africa, and it was highly homologous to the virus isolated from her husband. The subject's seronegative status was thought to be due to rapid depletion of specific CD4+ helper T cells, resulting from accelerated disease progression, and was host-related rather than due to a specific HIV strain.

The bactericidal capacity of peripheral blood monocytes from HIV positive patients may collapse very soon after the infection.

The activity of peripheral blood monocytes from HIV positive patients was measured by the intensity of the chemoluminescence those cells emit when they ingest a foreign particle. In most patients (84%) that value was impaired. Such an alteration may occur very early in the course of the disease. The anti-p24 antibody titer was correlated with monocyte phagocytic potential as measured by the chemoluminescent value thus indicating the need for adequate monocyte activity in order to obtain antibody formation. The severity of opportunistic infections that HIV positive subjects may develop is a clear indication that their immune systems are abnormal. The most frequently affected cells are those which bear the viral receptor, the CD4 antigen. Those cells are mainly the helper T cells and monocytes. The monocytes are the immune system phagocytic cells which actively control infections, in part by the release oxidative radicals. Those radicals can easily be measured by the chemoluminescence (CL) the cells emit when they ingest a foreign particle. This study examines the CL emitted by peripheral blood monocytes from HIV-positive and control subjects while they phagocytose opsonized zymosan in vitro and correlates these values with other laboratory parameters.

Pharmacokinetics of R 82913 in patients with AIDS or AIDS-related complex.

R 82913, a tetrahydroimidazobenzodiazepinthione (TIBO) derivative with potent activity against human immunodeficiency virus 1 (HIV-1) in vitro, was given to 22 patients with AIDS or AIDS-related complex in a dose-escalating pilot study. Doses of 10 to 300 mg administered daily by intravenous infusion were well tolerated for up to 50 weeks, with no haematological or biochemical evidence of toxicity. Mean OKT4 cell count rose slightly during the second month of treatment when higher steady-state plasma concentrations of the drug were achieved. Median p24 antigen concentration fell by 41% during the first month of therapy. When the rise in p24 antigen before therapy was compared to the fall during treatment, end-point analysis showed a significant difference (p less than 0.03). The combination of potent antiretroviral activity in vitro and the observed effect on HIV p24 antigen and absence of toxicity in vivo indicate that R 82913 and related TIBO derivatives merit further study in the treatment of retroviral infections.

Serum levels of IL-2, IL-1 alpha, TNF-alpha, and soluble receptor of IL-2 in HIV-1-infected patients.

Serum levels of the interleukins (IL-1 alpha, IL-2), tumor necrosis factor-alpha (TNF-alpha), and soluble receptor of IL-2 (sIL-2R) were studied by enzyme-linked immunosorbent assay (ELISA) in 12 normal healthy controls and 52 HIV-1 seropositive patients. Results indicated that: (1) sIL-2R levels were significantly increased in most HIV-1 seropositive patients. This increase appeared to be correlated with low CD4 cell counts and with the presence of detectable levels of p25 antigen. Furthermore, initially high levels of sIL-2R appeared to be correlated with progression of disease. (2) IL-2 levels were found to be increased in about 43% of asymptomatic carriers (ASY) and subjects with lymphoadenopathy-associated syndrome (LAS) compared with 12% in the case of AIDS-related complex (ARC) and AIDS patients. (3) There was a positive correlation between serum levels of TNF-alpha and IL-1 alpha in nearly all patients. Detectable levels of both cytokines were found in 34% of ASY and LAS patients and only rarely were detectable in ARC and AIDS patients. (4) Sixteen patients in whom progression of disease was observed were studied initially and at the moment they upstaged. No significant modification of serum levels of the three cytokines and sIL-2R studied could be evidenced. It was concluded that sIL-2R could be a useful marker of disease activity and progression, though a prospective study is necessary. For IL-2, IL-1 alpha, and TNF-alpha, this study indicated the presence of variable alterations in serum levels in HIV-1-infected patients.

Detection of anti-Epstein-Barr virus trans-activator (ZEBRA) antibodies in sera from patients with human immunodeficiency virus.

Patients with AIDS and AIDS-related complex often show symptoms of Epstein-Barr virus (EBV) reactivation. Several EBV-encoded trans-acting factors activate the EBV lytic cycle, and one, ZEBRA (BamHI Z EBV replication activator; also called EB1), switches EBV from its latent to productive cycle. Indirect immunofluorescence studies were done using human cells transfected with a recombinant DNA-harboring cDNA sequence spanning BZLF1 (BamHI Z left frame 1) that was inserted downstream of the adenovirus major late promoter. IgG anti-ZEBRA antibodies were detected in a high proportion of asymptomatic HIV carriers and in AIDS patients but were absent in healthy control individuals. The presence of anti-ZEBRA antibodies in the sera of HIV-positive patients favors the hypothesis that EBV reactivates in such subjects. This finding may be of practical importance in the prognostication of AIDS development.

Platelet antibodies in serum of patients with human immunodeficiency virus (HIV) infection.

Between 10 and 15% of human immunodeficiency virus (HIV) seropositive individuals develop an immune thrombocytopenic purpura; however, the mechanism involved in platelet destruction is not yet established. In the present work, we have analyzed 208 sera from HIV seropositive individuals, including 85 thrombocytopenic patients, for the presence of autoantibodies against platelet proteins by using the Western blot technique. Our results indicate that: (1) antibodies against platelet proteins were found in 8 of 123 (6.5%) nonthrombocytopenic patients, as compared with 17 of 85 (20%) of thrombocytopenic patients (p less than 0.03); (2) these antibodies appeared to be more frequently found in advanced stages of disease (p less than 0.02); (3) the reactivity of positive sera with antigenic determinants implicated several distinct platelet proteins; (4) antigens thus recognized are unrelated to the major membrane glycoproteins IIb and IIIa, as well as absent in vero cells and trypsin-sensitive cells. Such results underscore the difficulties in establishing the mechanisms involved in platelet destruction during HIV infection.

[Sero-epidemiological study in Mauritania (1985-1986): incidence of treponematosis, hepatitis B virus, HIV virus and viral hemorrhagic fevers]. / Etude séro-épidémiologique en Mauritanie (1985-1986): fréquence des tréponématoses, du virus de l'hépatite B, du virus VIH et des fièvres hémorragiques virales.

A serological serosurvey was made in different ethnic groups of Mauritania in 1985. A very high prevalence of hepatitis B markers was found with more than 20% of HBs antigen carriers. Treponema specific antibodies in low-age classes observed is a reflect of endemic syphilis. The seroprevalence of antibody against HIV and viral haemorrhagic fever viruses (Rift Valley fever, Crimean-Congo haemorrhagic fever and haemorrhagic fever with renal syndrome) was very low.

PIP: A serological survey in Mauritania in 1985-86 provided data on certain viral and bacterial markers whose frequency has been well established in countries neighboring this gateway between North Africa and subSaharan Africa. Blood samples from 1230 male blood donors and 983 pregnant women at the hospital in Nouakchott were analyzed for treponema infection, hepatitis B, HIV, and for antibodies to certain viruses causing hemorrhagic fever. Positive results for treponema specific antibodies using the Kline reaction were obtained in 76 of 2213 serums examined. High positive rates in young age groups reflect endemic nonvenereal treponematosis. 16 of 218 persons aged 10-19 tested positive compared to 10 of 593 aged 30-39 and 2 of 133 aged over 40. Observed differences between ethnic groups were highly significant. Infection rates were higher among males except among the Poulars. A very high prevalence of hepatitis B markers was found with more than 20% of hepatitis B surface antigen carriers among the 766 samples studied. 88.68% of the 813 subjects studied had been infected with the hepatitis B virus. The results suggest that nomadism, or the hygienic conditions of nomadism, favor contamination by the hepatitis B virus. 3 of the 510 samples examined were positive for HIV. Only 1 of the positive samples was from a Mauritanian, a 28-year-old male Poular. The other 2 positive results were obtained from foreigners temporarily residing at Nouakchott. The prevalence of antibodies against the viruses responsible for hemorrhagic fever was very low: 1/965 for the Crimee-Congo, 2/965 for the Rift Valley fever virus, and 3/965 for the Hantaan virus.

Detection of anti-mitochondrial antibodies by ELISA and Western-blot techniques and identification by one and two-dimensional gel electrophoresis of M2 target antigens.

Seven hundred and eleven sera were simultaneously studied by immunofluorescence (IF), complement fixation test (CFT) and ELISA for the detection of anti-mitochondrial antibodies (AMA). One hundred and nineteen of these sera were also studied by Western-blot techniques, while some of them were examined by two-dimensional gel electrophoresis so as to identify the polypeptides recognized by M2 antibodies. The results indicated that: (1) ELISA is a more sensitive technique for detecting type M2 AMA (27 scored positive in 27 primary biliary cirrhosis (PBC), as compared to 21/27 by IF and 16/27 by CFT). (2) Although ELISA appeared to be a promising screening method, some false positive results were observed that necessitated a double confirmation of positive sera by another technique. (3) Western-blot experiments with rat mitochondrial purified preparation indicated that sera from AMA type 2 could recognize eight different polypeptides and that most of them identified 63-60, 48, 44, and 35-33 kD polypeptides, whereas the 54 and 27 kD were less frequently recognized. A trypsin treatment of antigens confirmed the enzyme sensitivity of most of these antigens. These results suggested some heterogeneity among M2 AMA, though this series of PBC was not large enough to relate the heterogeneous pattern noticed in Western-blot to the clinical and histological patterns observed in PBC.

[Anti-tetanus immunization. Complexity and polymorphism of humoral and cellular manifestations]. / Immunisation anti-tétanique. Complexité et polymorphisme des manifestations humorales et cellulaires.

In general, anti-tetanus vaccination is well tolerated by the recipients, but the repeated inoculations of the vaccine might result in immediate or delayed type of hypersensitivity. The more recent knowledge of the epitopic construction of the toxin defined by tools offered by molecular biology, has helped understand the complexity of humoral and cellular responses as a consequence to vaccination. We have analyzed in this work major antitetanus post-vaccinal manifestations in normal subjects, as well as in patients suffering from different pathological disorders, with regard to immunoglobulin class expression, idiotypic profile, HLA-susceptibility and in vitro cellular responses.

Idiotypic specificity of a human monoclonal anti-Rhesus(D) antibody.

A human monoclonal IgG anti-Rhesus(D) (H2D5D2) obtained after transformation of lymphoid cells by Epstein-Barr virus was purified from culture supernatant by affinity chromatography. Rabbits were immunized with the monoclonal anti-D. The rabbit antisera, after appropriate absorption, reacted only against the immunizing monoclonal anti-D. The antiidiotypic antibodies (anti-id ab) were purified and gave a complete inhibition of the monoclonal anti-D, whereas no inhibition was observed with monoclonal or polyclonal IgG or with sera containing high titres of anti-D. Polyclonal anti-D obtained from 118 immunized blood donors were coated on Rh-positive red cells. Agglutination by anti-id ab was observed in 4 cases (3.4%), indicating a cross-reactivity between the monoclonal anti-D and the polyclonal anti-D present in the sera of some immunized donors.

Idiotypy of anti-Rh antibodies.

Anti-id sera to Rh antibodies were produced by injecting rabbits with purified Rh antibodies. These sera were shown to agglutinate O Rh+ RBC coated by the immunizing antibody and--in some cases--by other anti-D antibodies. Id and cross-reactive id were shown to be located in the antigen-binding and in the non-antigen binding regions of Rh antibodies. An unique example of evolution of idiotypic specificities on human antibodies has been reported. Lastly, we have demonstrated by rosette assay, presence on some PBL of receptors for Fab'2 anti-Rh coating O Rh+ red cells. Rosettes could not be obtained with lymphocytes of a donor and Fab'2 anti-Rh of another individual. Rosettes appeared at a period of time in which the amount of antibody was decreasing.

Idiotypic and anti-idiotypic determinants on lymphocytes during anti-Rh immunization.

Evolution of idiotypic determinants on lymphocytes membrane and presence of other lymphocytes carrying anti-idiotypic determinants, were studied in Rh negative human volunteer blood donors during immunization towards Rh factor. For this purpose E-Rh Rosettes, direct immunofluorescence, inhibition of E-Rh Rosettes by anti-idiotypic sera as well as EA-Rh Rosettes--induced with Fab'2 fragments from anti-Rh antibodies and lymphocytes from the same subject--were examined and compared to the evolution of circulating antibodies. E-Rh Rosettes preceded or accompanied production of anti-Rh antibodies; their frequency decreased after the fifth month following immunization, meanwhile EA-Rh Rosettes increased in parallel with antibody decrease. The direct immunofluorescence and the inhibition of E-Rh Rosettes, by anti-idiotypic sera, show the presence of idiotypic determinants on lymphocyte membranes; the presence of EA-Rh Rosettes, coinciding with the decrease in antibodies demonstrate the existence of lymphocytes bearing auto-anti-idiotypic determinants.