Predicting injection site muscle damage. III: Evaluation of intramuscular formulations in the L6 cell model.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
L A Evans
Publications and source records attributed to L A Evans.
Predicting injection site muscle damage. II: Evaluation of extended release parenteral formulations in animal models.
PURPOSE: The goal of this study was to find a resource sparing alternative to the rabbit lesion model (RbLV) for assessing injection site toleration in extended release (ER) intramuscular (IM) formulation screening. METHODS: ER formulations (danofloxacin oily and aqueous suspensions) were evaluated in RbLV, rat and rabbit plasma creatine phosphokinase (CK), and rat foot edema (RFE) models as described in the companion article. RESULTS: None of the short term models could consistently predict acute and chronic effects of the. For example, RFE predicted little muscle damage from aqueous vehicle (0.03 +/- 0.03 g) and 60 mg/ml (0.08 +/- 0.03 g) formulation; while RbLVdays1-3 was marked and greater (p < 0.05) for 60 mg/ml (6.0 +/- 3.1) than vehicle (2.2 +/- 2.9) formulations. Furthermore, RbLVdays 1-3) for vehicle (6.5 +/- 7.5) and 60 mg/ml (4.9 +/- 4.6) danofloxacin oily formulations were worse (p < 0.05) than oil alone (1.4 +/- 2.2); an observation not predicted by CK models, since they apparently reflected only the acute muscle damage of formulation components immediately available to surrounding tissue at the time of injection. CONCLUSIONS: The CK models may be useful to screen those ER formulations with unacceptable acute damage due to immediately available components. However, to evaluate potential delayed effects from ER formulations, the long-term model RbLV was still recommended.
Animals↗
Predicting injection site muscle damage. I: Evaluation of immediate release parenteral formulations in animal models.
PURPOSE: The current animal model generally accepted by the pharmaceutical industry and the FDA for assessment of muscle damage following intramuscular injection (IM) is the rabbit lesion volume model (RbLV). However, this model is resource intensive. The goal of this study was to find a resource sparing alternative to the rabbit lesion model for assessing injection site toleration in IM formulation screening. METHODS: Short term animal model alternatives to RbLV for evaluating IM formulations were examined. In addition to RbLV, myeloperoxidase (MPO), p-nitrophenyl N-acetyl-beta-glucosaminide (NA beta G) and/or plasma creatine phosphokinase (CK) activities were determined in rabbits (Rb) and rats (Rt) after injection of formulations (digoxin, azithromycin and danofloxacin). The edema from these formulations 24 hr after subcutaneous injection into the rat footpad (RFE) was also determined. RESULTS: MPO and NA beta G were not considered very useful as biochemical predictors of muscle damage for these formulations. Histology generally correlated with RbLV values. Compared to saline, RbLV was marked for all formulations within 1-3 days of injection. After day 3, lesions quickly resolved, and no significant differences were found. For these formulations, all CK animal models and RFE were generally predictive of RbLV. A formulation with RtCK > 1000 U/L or RbCK > 3000 U/L, was predicted to be poorly, tolerated. CONCLUSIONS: Due to ease, number of animals, time and intrinsic mechanism, we concluded that for most formulations, 2 and 4 hr RtCK data alone should be reasonably predictive of muscle damage.
Acetylglucosaminidase↗
Changes in biologic phenotype of human immunodeficiency virus during treatment of patients with didanosine.
Progression to AIDS in patients harboring human immunodeficiency virus type-1 (HIV-1) isolates expressing a syncytium-inducing (SI) phenotype is faster than in those in whom the virus expresses a non-SI (NSI) phenotype. Zidovudine monotherapy does not appear to alter this outcome. To examine the role of didanosine (ddI) monotherapy in phenotype expression, HIV-1 isolates from 73 patients receiving ddI for up to 72 weeks were analyzed. After 12 weeks, the number of isolates expressing an NSI phenotype was 29% higher than at the start of treatment. Patients receiving high-dose ddI (375 mg twice daily) were significantly more likely to express the NSI phenotype at 12 weeks than patients who received low-dose ddI (100 mg twice daily), even after adjustment for phenotype and CD4 cell count at baseline, suggesting that ddI may be selective against the faster-replicating virus. ddI at 375 mg twice daily significantly increases the probability of an NSI phenotype over the short term in patients with advanced HIV disease.
Antiviral Agents↗
Stingray hickey.
A large number of injuries from stingrays are reported each year in the United States. Usually these injuries are inflicted by the stingray's tail, after the resting stingray is stepped on. The tail has a stinger that can cause puncture wounds with envenomation. We report a case in which an injury from a stingray was due to its bite.
Adult↗
Productive in vitro infection of human umbilical vein endothelial cells and three colon carcinoma cell lines with HIV-1.
The objective of this study was to assess the ability of HIV-1 to establish an in vitro infection of primary human umbilical vein endothelial cells (HUVEC). The HUVEC and colon carcinoma cell lines were inoculated with different isolates of HIV-1 (HIV-1SF2, HIV-1Mck and HIV-1LAI) and productive viral infection was assessed by both the detection of p24 core antigen in the culture supernatants and the presence of specific spliced HIV mRNA. The infection which was detected in the inoculated HUVEC and all the colon carcinoma cell lines could not be blocked using an antibody targeted against the CD4 receptor. Furthermore, the HIV-inoculated HUVEC secreted elevated levels of IL-6 and this increase was found to be proportional to the size of the viral inoculum. No changes in the production of IL-1 beta, TNF-alpha, IFN-alpha and IFN-gamma were detected following HIV infection. The colon carcinoma cells, however, did not secrete increased levels of these cytokines following HIV-1 inoculation. These results confirm that non-CD4 expressing cells, such as endothelial cells and certain colon epithelial cells, serve as targets and reservoirs for HIV. Moreover, the production of IL-6 by HIV-infected endothelial cells may be a contributing factor to the aberrant immunoregulation associated with HIV infection in vivo.
Base Sequence↗
Primary structure of the V3 region of gp120 from sequential human immunodeficiency virus type 1 isolates obtained from patients from the time of seroconversion.
V3 loop sequences were compared from 5 human immunodeficiency virus type 1 (HIV-1)-infected patients over time. Three patients remained asymptomatic and 2 became symptomatic with large decrease in CD4 cell counts. The patient isolates were previously evaluated for phenotypic and antigenic properties and had different sensitivities to serum neutralization and changes in phenotype. This study showed a number of amino acid changes for the 2 symptomatic patients, each of whom progressed to AIDS during the study. The only amino acid substitution consistently associated with reduced CD4 cell counts, cytopathic effect, and progression to AIDS was Arg at position 11. Specific amino acid changes could not be correlated with increasing serum neutralization resistance or cytotropism changes. Increased loop charge was associated with a switch from macrophage to T cell tropism and a decrease in the number of CD4 cells. The study shows the importance of naturally occurring mutations in the V3 loop in controlling the biologic properties of HIV-1.
Acquired Immunodeficiency Syndrome↗
Neutralizing antibodies against sequential autologous human immunodeficiency virus type 1 isolates after seroconversion.
The emergence of human immunodeficiency virus type 1 (HIV-1) variants with different sensitivities to serum neutralization and biologic phenotype was studied for 2-5 years after primary HIV-1 infection in 5 subjects. In 3 subjects, the initial virus isolate from seroconversion could be neutralized by autologous serum, but isolates obtained at two subsequent times exhibited reduced sensitivity to serum neutralization, decreased replication in primary macrophages, and increased ability to induce syncytia. Two of these 3 subjects progressed to AIDS and died. Sequential virus isolates from the other 2 subjects showed variability in sensitivity to serum neutralization or biologic features. These patients remained relatively stable in clinical status. Thus, viruses isolated at seroconversion appear to be either non-syncytium-inducing, strong macrophage-tropic, serum neutralization-sensitive phenotypes with stable clinical status or to have escaped neutralization by autologous sera over time, have reduced macrophage tropism and increased syncytia formation, and be associated with disease progression.
Acquired Immunodeficiency Syndrome↗
Incorporating computer-based learning in a medical school environment.
A systematic multifaceted approach is effective in integrating computer-based learning in a medical school environment. The need to educate medical students in computer use, the growing economic constraints facing many medical schools, and the permeation of computer technology in the medical profession encourage collaboration across academic disciplines and services to meet well identified instructional needs through computer-based learning.
Attitude↗
Pseudofolliculitis barbae associated with an unusual hair whorl.
Descriptions of hair direction in the literature have emphasized unusual patterns of the scalp and associated developmental brain defects. We present the case of a white patient with unilateral pseudofolliculitis barbae associated with a hair whorl in the inframandibular region. To our knowledge, this is the first reported case of pseudofolliculitis barbae associated with a hair whorl.
Adult↗
Calcium biomineralization in the radular teeth of the chiton, Acanthopleura hirtosa.
A method has been devised for isolating the calcium biomineral from the iron biominerals and organic components present in the major lateral teeth of the chiton Acanthopleura hirtosa. Fourier-transform infrared spectroscopy of the calcium biomineral indicated that it was an apatite material containing carbonate and fluoride ions. Carbonate was not found to be present as a separate phase. The apatite was further separated into low and high density fractions, both of which showed crystallinity intermediate between that of bovine tibia cortical bone and human tooth enamel, as indicated by powder X-ray diffraction analysis. The calcified region of the major lateral teeth was also studied in situ using transmission electron microscopy and electron diffraction analysis, revealing a close spatial relationship between the mineral apatite phase and underlying organic matrix. It is suggested that the architectural arrangement of apatite biomineral and fibrous organic constituents imparts specialized mechanical properties to the tooth making it ideally suited for the task of obtaining food from hard surfaces.
Animals↗
Culture and properties of cells derived from Kaposi sarcoma.
We describe the establishment of four continuous cell cultures isolated from pleural or peritoneal fluid of patients with Kaposi sarcoma (KS) and show evidence that these cells are derived from vascular endothelium. Although provision of an extracellular matrix (fibronectin, laminin, or matrigel) was essential, the cell cultures were not dependent on exogenously added growth factors (platelet-derived growth factor, epidermal growth factor with or without heparin) for continuous culture. Specific staining for endothelial cell (EC) markers (factor VIII, Ulex europaeus type 1 lectin) and the secretion of endothelin, a vascular EC product, were demonstrated. The KS cells secreted large amounts of cytokines (granulocyte-macrophage-CSF, TNF-alpha, IL-1 beta, and especially IL-6). Conditioned media from the KS cells caused normal capillary EC to proliferate. The KS cells synthesized fibroblast growth activity in amounts sufficient to induce the proliferation of normal EC and fibroblasts. These data support the existence of a paracrine pathway of EC proliferation in KS and suggest that KS cells could sustain their own growth via an autocrine mechanism.
Acquired Immunodeficiency Syndrome↗
Several CD4 domains can play a role in human immunodeficiency virus infection in cells.
The human immunodefiency virus (HIV) uses the human CD4 glycoprotein as a receptor for infection of susceptible cells. Cells expressing a series of mutated forms of the CD4 gene have shown a variability in their ability to support replication of three HIV type 1 (HIV-1) and three HIV-2 strains. Moreover, when different stages of virus production were examined by a variety of assays, a consistent delay was observed in all cell lines containing CD4 mutants compared with those with intact full-length CD4. Cells expressing the CD4.415 mutant (modified at the serine 415 corresponding to a phosphorylation site of the cytoplasmic domain) showed only a minimal effect on virus replication. Cells expressing CD4.403 and CD4.401 mutants (lacking the whole cytoplasmic domain) manifested a moderate delay in production of virus progeny. The most substantial effect on HIV replication was observed in cells expressing a chimeric hybrid containing sequences corresponding to the first 177 residues of the N-terminal CD4 fused to CD8 sequences encoding the hinge, transmembrane, and cytoplasmic domains of the human CD8. Furthermore, in a cell-to-cell contact assay, fusion was absent when the CD4 proximal membrane domain was replaced by the CD8 counterpart. In addition, a strong correlation between the down-modulation of the surface CD4 and HIV expression was observed. These observations suggest that in addition to the known binding region, other domains of CD4 could play an important role in regulating HIV entry of cells.
CD4 Antigens↗
Biologic heterogeneity of human immunodeficiency virus type 2 (HIV-2) strains.
Seven HIV-2 isolates recovered from peripheral blood mononuclear cells (PBMC) of patients from the Ivory Coast have been biologically characterized. All seven strains replicated well in primary human lymphocyte and macrophage cultures and in established human T cell lines. They showed differences in infectivity and replicating ability in primary PBMC cultures from chimpanzees, rhesus macaques, and baboons. Moreover, variations in levels of virus replication in PBMC from 13 seronegative donors were observed. Four strains (UC2, UC3, UC7, and UC8) were highly cytopathic and caused extensive surface CD4 antigen depletion in acutely infected PBMC and SupT1 cells. Two strains (UC1 and UC6) showed minimal or no cytopathology, no CD4 down-modulation, and much lower levels of virus protein expression in SupT1 cells. These findings reflect the heterogeneity of HIV-2 strains and suggest that these biological properties could influence pathogenesis in the host.
Animals↗
Characteristics of HIV infection and pathogenesis.
Explore the source record for details and available documents.
Brain↗
Antibody-dependent cellular cytotoxicity is directed against both the gp120 and gp41 envelope proteins of HIV.
To define the target antigens for antibody-dependent cellular cytotoxicity (ADCC), assays were performed using affinity-purified human immunoglobulin (Ig) or polyclonal rabbit sera directed against specific proteins of HIV. ADCC was not found using affinity-purified anti-core (p25) human Ig or sera obtained from rabbits hyper-immunized with recombinant p25. However, when affinity-purified human Ig or rabbit antisera specific for the envelope glycoproteins, gp120 or gp41, were used in ADCC assays, killing of HIV-infected cells was observed. These results indicate that antibodies in the infected individual that mediate ADCC are directed against both the gp120 and gp41 HIV envelope proteins and not against the viral core protein.
Antibody-Dependent Cell Cytotoxicity↗
Simultaneous isolation of HIV-1 and HIV-2 from an AIDS patient.
Two distinct human immunodeficiency viruses, HIV-1SF480 and HIV-2UC2 were isolated simultaneously from the blood of an Ivory Coast patient with AIDS. The HIV subtypes were segregated by their differential ability to infect established human cell lines and by the cell surface expression of type-specific viral antigens. The viruses could be distinguished by both immunoblot and Southern blot analyses. The results indicate that an individual can be infected by both HIV subtypes.
Acquired Immunodeficiency Syndrome↗
Characterization of a noncytopathic HIV-2 strain with unusual effects on CD4 expression.
A new isolate of the human immunodeficiency virus type 2, designated HIV-2UC1, was recovered from an Ivory Coast patient with normal lymphocyte numbers who died with neurologic symptoms. Like some HIV-1 isolates, HIV-2UC1 grows rapidly to high titers in human peripheral blood lymphocytes and macrophages and has a differential ability to productively infect established human cell lines of lymphocytic and monocytic origin. Moreover, infection with this isolate also appears to involve the CD4 antigen. However, unlike other HIV isolates, HIV-2UC1 does not cause cytopathic effects in susceptible T cells nor does it lead to loss of CD4 antigen expression on the cell surface. These results indicate that HIV-2 may be found in individuals with neurologic symptoms and that the biological characteristics of this heterogeneous subgroup can differ from those typical of HIV-1.
Acquired Immunodeficiency Syndrome↗