Pharmacokinetics of hyperimmune anti-human immunodeficiency virus immunoglobulin in persons with AIDS

Hyperimmune anti-human immunodeficiency virus immunoglobulin (HIVIG) is an intravenous immunoglobulin prepared from HIV-infected asymptomatic donors with a CD4 cell count greater than 400 cells/microl and a high titer of antibody to HIV-1 p24 protein. Twelve persons with AIDS received four doses of HMG (two at 50 mg/kg of body weight and then two at 200 mg/kg) every 28 days. Pharmacokinetics were evaluated by measurement of anti-p24 antibody. HIVIG was well tolerated, and all participants completed the study. Three subjects who were not receiving Pneumocystis carinii pneumonia (PCP) prophylaxis developed PCP. The mean value for HIVIG clearance was 3.02 ml/kg/day at 50 mg/kg and 3.65 ml/kg/day at 200 mg/kg (P = 0.027); the mean trough antibody titers (reciprocal units) were 1,442 and 4,428, respectively. This study indicates that high titers of anti-p24 antibody can be maintained with a monthly administration schedule of HIVIG and that short-term safety is acceptable. Comparisons to evaluate the therapeutic potential of HIVIG are justified.     

A comparative study of human immunodeficiency virus culture, polymerase chain reaction and anti-human immunodeficiency virus immunoglobulin A antibody detection in the diagnosis during early infancy of vertically acquired human immunodeficiency virus infection

Asynchrony of delivered and spontaneous breaths in mechanically ventilated infants may impair gas exchange and prolong the need for assisted ventilation. We conducted a randomized, controlled trial of a patient-triggered, flow-synchronized ventilator on 30 preterm infants with respiratory distress syndrome who weighed between 1100 and 1500 gm at birth. Entry criteria included radiographic evidence of respiratory distress syndrome and the need for mechanical ventilation and surfactant replacement therapy. Patients were assigned to either conventional time-cycled, pressure-limited ventilation or patient-triggered, flow-synchronized ventilation in an assist/control mode. Otherwise clinical management was identical. Time to extubation was the primary outcome measure. Patients treated with flow-synchronized ventilation were weaned more rapidly and had a significantly shorter mean time to extubation than those treated with time-cycled, pressure-limited ventilation, 119 versus 271 hours, p = 0.0152. In addition, there was no difference in the rate of complications between the two groups. There were, however, considerable reductions in patient charges of $4344 per patient in the flow-synchronized ventilation group.     

Synthesis of N-acetylglucosaminyl- and N-acetylgalactosaminylceramides as cerebroside analogs and their anti-human immunodeficiency virus type 1 activities

Monoglycosylceramide derivatives containing mimicks of ceramide were synthesized as cerebroside analogs from D-glucosamine or D-galactosamine derivatives and N-benzyloxycarbonyl-L-serine myristylamide by using trimethylsilyl trifluoromethanesulfonate (TMSOTf) as a promoter. The synthesized sulfate glycolipids show moderate anti-HIV-1 activities.     

Imidazo[1,5-b]pyridazine-d4T conjugates: synthesis and anti-human immunodeficiency virus evaluation

Various techniques for generation of peptide and peptidomimetic libraries are summarized in this article. Multipin, tea bag, and split-couple-mix techniques represent the major methods used to make peptides and peptidomimetics libraries. The synthesis of these libraries were made in either discrete or mixture format. Peptides and peptidomimetics combinatorial libraries were screened to discover leads against a variety of targets. These targets, including bacteria, fungus, virus, receptors, and enzymes were used in the screening of the libraries. Discovered leads can be further optimized by combinatorial approaches.     

ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease

The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 microM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, 50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.     

In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine

Transition state mimetic tripeptide human immunodeficiency virus (HIV) protease inhibitors containing allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] were synthesized and tested for activity against HIV in vitro. Two compounds, KNI-227 and KNI-272, which were highly potent against HIV protease with little inhibition of other aspartic proteases, showed the most potent activity against the infectivity and cytopathic effect of a wide spectrum of HIV strains. As tested in target CD4+ ATH8 cells, the 50% inhibitory concentrations of KNI-227 against HIV type 1 LAI (HIV-1LAI), HIV-1RF, HIV-1MN, and HIV-2ROD were 0.1, 0.02, 0.03, and 0.1 microM, respectively, while those of KNI-272 were 0.1, 0.02, 0.04, and 0.1 microM, respectively. Both agents completely blocked the replication of 3'-azido-2',3'-dideoxythymidine-sensitive and -insensitive clinical HIV-1 isolates at 0.08 microM as tested in target phytohemagglutinin-activated peripheral blood mononuclear cells. The ratios of 50% cytotoxic concentrations to 50% inhibitory concentrations for KNI-227 and KNI-272 were approximately 2,500 and > 4,000, respectively, as assessed in peripheral blood mononuclear cells. Both compounds blocked the posttranslational cleavage of the p55 precursor protein to generate the mature p24 Gag protein in stably HIV-1-infected cells. The n-octanol-water partition coefficients of KNI-227 and KNI-272 were high, with log Po/w values of 3.79 and 3.56, respectively. Degradation of KNI-227 and KNI-272 in the presence of pepsin (1 mg/ml, pH 2.2) at 37 degrees C for 24 h was negligible. Current data warrant further careful investigations toward possible clinical application of these two novel compounds.     

Ketoconazole and other imidazole derivatives are potent inhibitors of peroxisomal phytanic acid alpha-oxidation

Twelve young adults were treated with either melatonin, 3 mg or 6 mg, or placebo, at two different times before an early evening nap (18.00-20.00 h) according to a balanced double-blind Latin square design. Polysomnographic monitoring revealed that both dosages of melatonin significantly shortened sleep latency and increased total sleep time in comparison to placebo, irrespective of the time of administration. Subjects also tended to assess their sleep as 'deeper' after melatonin treatment. Based on previous data and the present results, it was concluded that exogenous melatonin exerts hypnotic effects only when circulating levels of endogenous melatonin are low.     

Identification of potent P2Y-purinoceptor agonists that are derivatives of adenosine 5'-monophosphate

1. A series of chain-extended 2-thioether derivatives of adenosine monophosphate were synthesized and tested as agonists for activation of the phospholipase C-linked P2Y-purinoceptor of turkey erythrocyte membranes, the adenylyl cyclase-linked P2Y-purinoceptor of C6 rat glioma cells, and the cloned human P2U-receptor stably expressed in 1321N1 human astrocytoma cells. 2. Although adenosine monophosphate itself was not an agonist in the two P2Y-purinoceptor test systems, eleven different 2-thioether-substituted adenosine monophosphate analogues were full agonists. The most potent of these agonists, 2-hexylthio AMP, exhibited an EC50 value of 0.2 nM for activation of the C6 cell receptor. This potency was 16,000 fold greater than that of ATP and was only 10 fold less than the potency of 2-hexylthio ATP in the same system. 2-hexylthio adenosine was inactive. 3. Monophosphate analogues that were the most potent activators of the C6 cell P2Y-purinoceptor were also the most potent activators of the turkey erythrocyte P2Y-purinoceptor. However, agonists were in general more potent at the C6 cell receptor, and potency differences varied between 10 fold and 300 fold between the two receptors. 4. Although 2-thioether derivatives of adenosine monophosphate were potent P2Y-purinoceptor agonists no effect of these analogues on the human P2U-purinoceptor were observed. 5. These results support the view that a single monophosphate is sufficient and necessary for full agonist activity at P2Y-purinoceptors, and provide insight for strategies for development of novel P2Y-purinoceptor agonists of high potency and selectivity.     

The dual-function hamster receptor for amphotropic murine leukemia virus (MuLV), 10A1 MuLV, and gibbon ape leukemia virus is a phosphate symporter

Previously, we showed that the amphotropic receptor homolog in hamster cells functions as a receptor not only for amphotropic murine leukemia viruses and 10A1 murine leukemia virus but also for gibbon ape leukemia virus (C.A. Wilson, K. B. Farrell, and M. V. Eiden, J. Virol. 68:7697-7703, 1994). Here, we demonstrate that this receptor functions as a sodium-dependent Pi transporter and that Na-Pi uptake can be specifically blocked following infection with either amphotropic murine leukemia virus, 10A1 murine leukemia virus, or gibbon ape leukemia virus.     

Dynamics study on the anti-human immunodeficiency virus chemokine viral macrophage-inflammatory protein-II (VMIP-II) reveals a fully monomeric protein

Encoded by Kaposi's sarcoma-associated herpesvirus, viral macrophage-inflammatory protein-II (VMIP-II) is unique among CC chemokines in that it has been shown to bind to the CXC chemokine receptor CXCR4 as well as to a variety of CC chemokine receptors. This unique binding ability allows vMIP-II to block infection by a wide range of human immunodeficiency virus type I (HIV-1) strains, but the structural and dynamic basis for this broad range of binding is not known. 15N T1, T2 and 15N[-HN] nuclear Overhauser effect (NOE) values of vMIP-II, determined through a series of heteronuclear multidimensional nuclear magnetic resonance (NMR) experiments, were used to obtain information about the backbone dynamics of the protein. Whereas almost all chemokine structures reveal a dimer or multimer, vMIP-II has a rotational correlation time (tauc) of 4.7 +/- 0.3 ns, which is consistent with a monomeric chemokine. The rotational diffusion anisotropy, D parallel/D perpendicular, is approximately 1.5 +/- 0.1. The conformation of vMIP-II is quite similar to other known chemokines, containing an unstructured N-terminus followed by an ordered turn, three beta-strands arranged in an antiparallel fashion, and one C-terminal alpha-helix that lies across the beta-strands. Most of the protein is well-ordered on a picosecond time scale, with an average order parameter S2 (excluding the N-terminal 13 amino acids) of 0.83 +/- 0. 09, and with even greater order in regions of secondary structure. The NMR data reveal that the N-terminus, which in other chemokines has been implicated in receptor binding, extends like a flexible tail in solution and possesses no secondary structure. The region of the ordered turn, including residues 25-28, experiences conformational exchange dynamics. The implications of these NMR data to the broad receptor binding capability of vMIP-II are discussed.     

Chronic varicella-zoster virus skin lesions in patients with human immunodeficiency virus are related to decreased expression of gE and gB

The pathogenesis of chronic, verrucous varicella-zoster virus (VZV) cutaneous lesions in human immunodeficiency virus (HIV)-infected persons is unknown. It has been hypothesized that these lesions are due to an altered pattern of virus gene expression. Immediate early and late (L) gene expression in five chronic verrucous VZV lesions, four full-blown herpes zoster vesicular lesions in HIV-infected persons, and eight vesicular herpes zoster lesions in immunocompetent individuals was semiquantitatively assessed immunohistochemically using specific antibodies to the IE63, gE (L), and gB (L) proteins. All patients had evidence of IE63 expression in keratinocytes; however, gE expression was either weak or absent in keratinocytes of three verrucous lesions, and gB was either weak or absent in two. These results suggest that chronic VZV skin lesions are associated with diminished gE and gB expression. It is inferred that the VZV behavior in keratinocytes may vary from a latency-like state to a fully developed, productive infection.     

Association of non-acquired immunodeficiency syndrome-defining cancers with human immunodeficiency virus infection

Kaposi's sarcoma and non-Hodgkin's lymphoma were among the earliest recognized manifestations of the acquired immunodeficiency syndrome (AIDS) epidemic. Excluding these two tumors, the overall risk of all other cancers in human immunodeficiency virus (HIV)-infected individuals is similar to that of the general population. However, varying levels of evidence link several additional neoplasms to HIV infection. The evidence is strongest for an association with Hodgkin's disease, with lower relative and absolute risks than for non-Hodgkin's lymphoma. Anogenital intraepithelial neoplasia also appears to be HIV associated, but increases of invasive disease are still uncertain for both cervical and anal cancers. Various studies have suggested associations with testicular seminoma, multiple myeloma, oral cancer, and melanoma, but the data are inconsistent. Leiomyosarcoma and benign leiomyomas have increased in incidence in HIV-infected children but are unusual in HIV-infected adults. Conjunctival carcinoma is seen in HIV-infected individuals in sub-Saharan Africa but it is uncommon in Western countries. Most other cancers do not seem to have increased incidences in HIV infection. The etiologic mechanisms of HIV-related cancer likely differ among these diverse cancers and do not globally increase cancer risk.     

New phthalimide derivatives with potent analgesic activity: II

Seven new phthalimide derivatives (9a-g) with 1,2,4-oxadiazol-5-yl methyl group attached to nitrogen have been synthesized from N-phthaloylglycine 6 and arylamidoximes 7a-g. All of these showed potent analgesic effect with acetic acid induced "writhing" test in mice. One of the better compounds (ID50 = 2.2 mg/Kg i.p.) has been found to be 9a which also demonstrates analgesic activity against inflammatory pain.