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J Mordenti

Publications and source records attributed to J Mordenti.

At least 19 recordsLinked to original sources
PubMed2002

Treatment of mildly to moderately active ulcerative colitis with a tryptase inhibitor (APC 2059): an open-label pilot study.

BACKGROUND: Mast cells isolated from the colonic mucosa in active ulcerative colitis appear to be partially degranulated, suggesting the release of tryptase. AIM: To investigate the safety and activity of APC 2059, a highly specific tryptase inhibitor, in the treatment of ulcerative colitis. METHODS: This was an open-label, Phase 2, multicentre pilot study in patients with mildly to moderately active ulcerative colitis, with a disease activity index of 6-9 on a 12-point scale. Fifty-six adults received 20 mg APC 2059 subcutaneously twice daily and 53 completed 28 days of treatment. The primary end-point was response, defined as a final disease activity index of < or = 3. Supplementary analyses were also performed. RESULTS: Sixteen (29%) of 56 patients responded. Five (9%) showed complete remission (disease activity index=0). Twenty-seven (49%) improved, with a final disease activity index of < or = 3 or a four-point reduction. Improvement or normalization in each category of the disease activity index was as follows: stool frequency, 64%; bleeding, 64%; endoscopy, 50%; physicians' rating, 63%. There were no significant relationships between outcome and pharmacokinetics. The most common adverse events were related to the injection site (32.1%). CONCLUSIONS: In this pilot study, the tryptase inhibitor APC 2059 was safe and there was evidence of activity in the treatment of ulcerative colitis.

Adult↗
PubMed1999

Intraocular pharmacokinetics and safety of a humanized monoclonal antibody in rabbits after intravitreal administration of a solution or a PLGA microsphere formulation.

Poly(lactic-co-glycolic) acid (PLGA) bioresorbable microspheres are used for controlled-release drug delivery and are particularly promising for ocular indications. The objective of the current study was to evaluate the pharmacokinetics and safety of a recombinant human monoclonal antibody (rhuMAb HER2) in rabbits after bolus intravitreal administration of a solution or a PLGA-microsphere formulation. On Day 0, forty-eight male New Zealand white rabbits (2.3-2.6 kg) were immobilized with intramuscular ketamine/xylazine, and the test materials were injected directly into the vitreous compartment. Group 1 animals received rhuMAb HER2 in 50:50 lactide: glycolide PLGA microspheres; Group 2 animals received rhuMAb HER2 in solution (n = 24/group). The dose for each eye was 25 microg (50 microl). After dosing, animals were sacrificed at 2 min, and on 1, 2, 4, 7, 14, 23, 29, 37, 44, 50, and 56 days (n = 2/timepoint/group). Safety assessment included direct ophthalmoscopy, clinical observations, body weight, and hematology and clinical chemistry panels. At necropsy, vitreous and plasma were collected for pharmacokinetics and analysis for antibodies to rhuMAb HER2, and the vitreal pellet (Group 1) was prepared for histologic evaluation. All animals completed the study per protocol-both treatments were well tolerated, and no suppurative or mixed inflammatory cell reaction was observed in the vitreal samples (Group 1) at any of the time points examined. Antibodies to rhuMAb HER2 were detected in plasma samples by Day 7 in both treatment groups, but infrequently in vitreous samples. There were no safety implications associated with this immune response. The in vitro characterization of the PLGA microspheres provided reasonable projections of the in vivo rhuMAb HER2 release kinetics (Group 1). The total amount of antibody that was released was similar in vitro (25.9%) and in vivo (32.4%). RhuMAb HER2 (Group 2) was cleared slowly from the vitreous compartment, with initial and terminal half-lives of 0.9 and 5.6 days, respectively. The volume of distribution approximated the vitreous volume in a rabbit eye.

Animals↗
PubMed1996

Pharmacokinetics and interspecies scaling of recombinant human factor VIII.

Recombinant human (rh) factor VIII is a glycoprotein consisting of multiple polypeptides with relative mobilities (M(r)) ranging from 80,000 to 210,000. It is produced in mammalian cells. Single-dose intravenous pharmacokinetic studies were conducted with rh factor VIII (Kogenate rh Antihemophilic Factor, Miles, Inc.) in male mice (21.0-25.8 g) and rats (252.0-254.2 g). Each species received 400 IU/kg, and blood was collected up to 12 hr (mice) or 32.5 hr (rats) post-dose. Immunoreactive factor VIII concentrations in plasma were quantified by a sensitive and specific ELISA. In both species, the disposition profiles were described by the sum of two exponentials. The pharmacokinetics of rh factor VIII in mouse were as follows: clearance, 27.7 ml/hr/kg; initial volume of distribution, 72 ml/kg; steady-state volume of distribution, 148 ml/kg; and terminal half-life, 4.1 hr. In rat, the mean estimates were as follows: clearance, 16.0 ml/hr/kg; initial volume of distribution, 41 ml/kg; steady-state volume of distribution, 125 ml/kg; and terminal half-life, 5.5 hr. These pharmacokinetic parameters for rh factor VIII in animals and human rh factor VIII pharmacokinetic parameters from the literature were evaluated to determine if the parameters can be represented by the allometric relationship, Y = aWb, where Y is the pharmacokinetic parameter, and W is body weight. The following allometric relations were obtained for rh factor VIII: clearance (ml/hr) = 10.4W0.69, half-life (hr) = 7.5 W0.18, initial volume of distribution (ml) = 43.6 W1.04, and steady-state volume of distribution (ml) = 99.1 W0.84. The allometric exponents for each parameter conformed to theory and were within the range of values commonly observed for xenobiotics and therapeutic proteins. These studies suggest that the pharmacokinetics of rh factor VIII in laboratory animals are predictive of the disposition in humans despite the complex nature of its biological interactions and the chemical diversity of the purified material.

Animals↗
PubMed1996

Pharmacokinetics, tissue distribution, and expression efficiency of plasmid [33P]DNA following intravenous administration of DNA/cationic lipid complexes in mice: use of a novel radionuclide approach.

The pharmacokinetics, tissue distribution, and efficacy of a systemic gene transfer method were examined in male BALB/c mice (6-8 weeks old) using 33P-labeled plasmid DNA for luciferase. The DNA was delivered via tail vein injection in saline ([33P]DNA) or in a cationic lipid formulation ([33P]DNA/lipid). One group of mice received approximately equal to 1-3 microCi (45 micrograms of DNA) of either formulation, and mice were euthanized at 2 and 20 min, and 1 and 24 h postdose (2 mice/time point). Blood and plasma radioactivity were quantified, and whole body autoradiographic (WBAR) images were obtained from 20-microns whole body sections. A tissue distribution (TD) study was conducted in a second group of mice, which received approximately equal to 4-6 microCi (45-60 micrograms of DNA) of [33P]DNA/lipid. Mice were euthanized at 1.5 h (1 mouse; [33P]DNA/lipid) or 24 h (2 mice/ group), and organ radioactivity and luciferase expression were measured in lung, liver, kidney, spleen thymus, and parotid salivary gland by direct quantitation methods. Microautoradiography (MAR) was performed on a third group of mice (n = 2), which received 3 microCi (45 micrograms of DNA) of [33P]DNA/lipid and were euthanized at 24 h postdose. For WBAR, the [33P]DNA/lipid tissue distribution (% dose equiv/g) at 2 min was lung >> liver > spleen (red pulp) > kidney (cortex); at 24 h the ranking was spleen (red pulp) > liver > lung, kidney (cortex). The [33P]DNA organ distribution observed at 2 min was liver >> spleen (red pulp) > lung, blood > kidney (cortex); at 24 h the ranking was liver, spleen (red pulp) > kidney (cortex) > lung, blood. High levels of radioactivity in bone (cortical, marrow, growth plate) in both groups may represent uptake of the 33P-labeled test articles by the cellular component of the bone marrow, particularly macrophages, as well as deposition of [33P]phosphate in the bone matrix following metabolism of the [33P]DNA. In the luciferase component of the study, no expression was observed in the [33P]DNA group at 24 h. The [33P]- DNA/lip group exhibited expression as early as 1.5 h in the lung; at 24 h, expression was seen in all the organs examined. Microautoradiography of 24-h tissue samples revealed radioactivity in hepatic Kupffer cells, reticuloendothelial system cells in the marginal zone of the spleen, and diffusely along alveolar septae with scattered accumulations in alveolar macrophages. The results of the WBAR, TD, MAR, and luciferase assay show that the use of cationic lipids significantly altered the biodistribution and resulting expression of the DNA plasmid. Further, 33P (0.25 MeV beta, half-life = 25 days) was shown to be an excellent radionuclide for quantitative WBA and MAR, providing sharp images with less personal hazard and greater ease of handling than 32P (1.71 MeV beta, half-life = 14.3 days).

Animals↗
PubMed1996

Design of biological equivalence programs for therapeutic biotechnology products in clinical development: a perspective.

The determination of biological equivalence requires that studies are conducted to establish that two molecules, two formulations, of two dosing regimens, for example, are indistinguishable with respect to safety and efficacy profiles that have been previously established. The criteria that are used to establish biological equivalence will depend on the nature of the change (e.g., molecular, process, formulation), the stage of the development program, the duration of treatment, and the intended clinical indications. Key components of an equivalence program include chemical characterization, in vitro and in vivo bioactivity against reference material, pharmacokinetics, and safety. Special considerations for patient populations, endogenous concentrations, environmental factors, immunogenicity, assay methodology, biochemical identity, pharmacodynamic equivalence, and statistical methodology are discussed. In addition, the role of preclinical in vivo assessments is addressed. Specific case studies provide insight into the varied nature of approaches that are currently employed.

Biotechnology↗
PubMed1995

Safety, pharmacokinetics, and antiviral response of CD4-immunoglobulin G by intravenous bolus in AIDS and AIDS-related complex.

To assess the safety, pharmacokinetics, and antiviral effects of intravenous recombinant CD4 immunoglobulin G (CD4-IgG), a 12-week Phase One study with an optional maintenance phase was performed. Twenty-two subjects with advanced human immunodeficiency virus (HIV) infection were enrolled; 15 subjects completed the initial 12 weeks. CD4-IgG doses were 30, 100, or 300 micrograms/kg weekly; 1,000 micrograms/kg once, twice, or three times per week; or 3,000 micrograms/kg twice weekly. Serum concentrations of CD4-IgG increased linearly with dose, with average peak serum concentrations of 22 micrograms/ml with 1,000 micrograms/kg. CD4-IgG was well tolerated; one patient had self-limited tachycardia and flushing associated with CD4-IgG therapy. No changes were seen in CD4 cell counts, hematologic or coagulation studies, serum chemistries, HIV p24 antigen titers, or plasma HIV titers. No subject developed anti-CD4 antibodies. HIV isolates from five patients had IC90 values that were higher than the peak concentrations of CD4-IgG achieved in those patients. Additional studies that achieve higher CD4-IgG concentrations are necessary to evaluate the antiviral activity of this compound.

AIDS-Related Complex↗
PubMed1995

Development of a humanized disulfide-stabilized anti-p185HER2 Fv-beta-lactamase fusion protein for activation of a cephalosporin doxorubicin prodrug.

The humanized anti-p185HER2 antibody, humAb4D5-8, has completed Phase II clinical trials for p185HER2-overexpressing breast cancer. Here, this antibody is used as a building block to engineer a disulfide-linked Fv (dsFv) beta-lactamase fusion protein for use in antibody-dependent enzyme-mediated prodrug therapy using cephalosporin-based prodrugs. Three Fv variants were designed with an interchain disulfide bond buried at the VL/VH interface and secreted from Escherichia coli. One variant, dsFv3 (VL L46C VH D101C0, has similar affinity for antigen (Kd = 0.7 nM) as the wild-type Fv and was used to construct a fusion protein in which beta-lactamase, RTEM-1, is joined to the carboxy terminus of VH. The dsFv3-beta-lactamase fusion protein secreted from E. coli efficiently activates a cephalothin doxorubicin prodrug (PRODOX, kcat/km = 1.5 x 10(5) s-1 M-1). PRODOX is approximately 20-fold less toxic than free doxorubicin against breast tumor cell lines SK-BR-3 and MCF7, which express p185HER2 at elevated and normal levels, respectively. Prebinding the dsFv3-beta-lactamase fusion protein specifically enhances the toxicity level of PRODOX to that of doxorubicin against SK-BR-3 but not MCF7 cells. The fusion protein retains both antigen-binding plus kinetic activity in murine serum and is cleared rapidly as judged by pharmacokinetic analysis in nude mice (initial and terminal half-lives of 0.23 and 1.27 h, respectively). Development and characterization of the dsFv3-beta-lactamase fusion protein is an important step toward targeted prodrug therapy of p185HER2-overexpressing tumors.

Animals↗
PubMed1995

Characterization of the MN gp120 HIV-1 vaccine: antigen binding to alum.

PURPOSE: The characterization of recombinant MN gp120/alum vaccine requires the study of the gp120-alum interaction for the successful formulation of an alum-based HIV-1 vaccine. METHODS: Several observations suggest that the gp120-alum interaction is weak, wherein buffer counterions such as phosphate, sulfate, bicarbonate may cause the desorption of gp120 from alum. Comparison of gp120 with other proteins using particle mobility measurements shows that the weak binding of gp120 to alum is not an anomaly. Serum and plasma also cause desorption of gp120 from alum with a half-life of only a few minutes, wherein this half-life may be faster than the in-vivo recruitment of antigen presenting cells to the site of immunization. RESULTS: Immunization of guinea pigs, rabbits and baboons with gp120 formulated in alum or saline demonstrated that alum provides adjuvant activity for gp120, particularly after early immunizations, but the adjuvant effect is attenuated after several boosts. CONCLUSIONS: These observations indicate that both the antigen and the adjuvant require optimization together.

AIDS Vaccines↗
PubMed1995

Engineering linear F(ab')2 fragments for efficient production in Escherichia coli and enhanced antiproliferative activity.

We developed a novel bivalent antibody fragment, the linear (L-) F(ab')2, comprising tandem repeats of a heavy chain fragment VH-CH1-VH-CH1 cosecreted with a light chain. Functional humanized L-F(ab')2 directed against p185HER2 was secreted from Escherichia coli at high titer (> or = 100 mg/l) and purified to homogeneity. The L-F(ab')2 binds two equivalents of antigen with an apparent affinity (Kd = 0.46 nM) that is within 3-fold of the corresponding thioether-linked F(ab')2 fragment. The N-terminal site binds antigen with an affinity (Kd = 1.2 nM) that is approximately 4-fold greater than that for the C-terminal site, as shown by the comparison of L-F(ab')2 variants containing a single functional binding site. L-F(ab')2 has greater antiproliferative activity than the thioether-linked F(ab')2 against the p185HER2-overexpressing tumor cell line BT474. Linear and thioether-linked F(ab')2 have very similar pharmacokinetic properties in normal mice, and their serum permanence times are respectively 7- and 8-fold longer than the corresponding Fab fragment. L-F(ab')2 offers a facile route to bivalent antibody fragments that are potentially suitable for clinical applications, and that may have improved biological activity compared with thioether-linked F(ab')2 fragments.

Animals↗
PubMed1995

Transport of recombinant human CD4-immunoglobulin G across the human placenta: pharmacokinetics and safety in six mother-infant pairs in AIDS clinical trial group protocol 146.

Recombinant CD4-immunoglobulin G (rCD4-IgG) is a 98-kDa human immunoglobulin-like protein that is produced by fusing the gp120 binding domain of CD4 to the Fc portion of the human IgG1 heavy chain. This hybrid molecule was given to human immunodeficiency virus (HIV)-infected pregnant women at the onset of labor by intravenous bolus at 1 mg/kg of body weight (group A; n = 3) and 1 week prior to and at the onset of labor by the same route and at the same dose (group B; n = 3). In addition to pharmacokinetic studies, safety in the mothers and infants was determined through routine chemistries, hematology, and urinalysis; immunologic and HIV infection statuses in the infants were assessed through lymphocyte cultures, p24 antigen level determination, culture of HIV from plasma, PCR, lymphocyte subset enumeration, quantitative immunoglobulin analysis, and lymphocyte proliferation. Thirty minutes after the rCD4-IgG injection, concentrations in maternal serum were 12 to 23 micrograms/ml. These concentrations declined slowly, with initial and terminal half-lives (mean +/- standard deviation) of 9.95 +/- 3.23 and 47.6 +/- 22.3 h, respectively. Infants were born 2.6 to 46.5 h after rCD4-IgG administration; concentrations of rCD4-IgG in cord blood ranged from 28 to 107 ng/ml. The half-life of rCD4-IgG in infants ranged from 5 to 29 h. These data demonstrate that the transfer of rCD4-IgG from the mother to the fetus is rapid and that newborns do not appear to have any difficulty eliminating rCD4-IgG. No safety concerns in mothers or infants were encountered. Although the study did not address the question of efficacy, none of the infants was HIV type 1 infected 36 months later. In summary, these findings document that bifunctional immune molecules can be transported across the placenta, and this general approach may be used in the future to block vertical transmission of HIV type 1.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Inhibition of TNF by a TNF receptor immunoadhesin. Comparison to an anti-TNF monoclonal antibody.

TNF is an important mediator of inflammation, which can have deleterious effects when produced inappropriately. We have described a recombinant inhibitor of TNF, termed TNFR-IgG, or TNFR immunoadhesin, composed of the extracellular portion of the type 1 (p55) TNF receptor (TNFR) linked to the hinge and Fc regions of IgG heavy chain. This bivalent, Ab-like molecule is a potent inhibitor of TNF, exhibiting significantly higher affinity for the cytokine than soluble TNFR. Here, we compare the TNF-neutralizing capacity of TNFR-IgG to that of an anti-TNF mAb. In vitro, TNFR-IgG was 10- to 50-fold more potent than anti-TNF mAb at blocking the cytotoxic effect of exogenous TNF on actinomycin D-treated murine L-M cells. In vivo, the plasma half-life of TNFR-IgG in mice was approximately 6 days, similar to that reported for the anti-TNF mAb. However, the immunoadhesin was approximately 10-fold more effective than the Ab at neutralizing the activity of endogenous TNF, as assessed in a model for murine listeriosis. These results demonstrate a markedly greater potency of the TNFR immunoadhesin compared with the anti-TNF mAb at inhibiting TNF activity in vitro and in vivo.

Animals↗
PubMed1994

Molecular and biological properties of an interleukin-1 receptor immunoadhesin.

Overproduction of the cytokine interleukin 1 (IL-1) is an important factor in the pathogenesis of several autoimmune and inflammatory disease. To develop a recombinant inhibitor of IL-1 with an extended pharmacologic half-life, we constructed an IL-1 receptor immunoadhesin (IL-1R-IgG), by fusing the extracellular domain of the type IL-1 receptor with the hinge and Fc regions of human IgG1 heavy chain. Transfected human 293 cells express IL-1R-IgG as a secreted, disulfide-bonded homodimer. The secreted protein contains an intact antibody Fc region, as indicated by immunoblotting, and a functional IL-1 receptor region, as indicated by ligand-blotting. Saturation binding analysis indicates an equilibrium dissociation constant (KD) of 350 pM for the binding of IL-1R-IgG to its ligand, IL-1 beta. Kinetic analysis of the binding reveals an off rate of 0.1 min-1 and an on rate of 1.5 x 10(8) min-1 M-1, yielding a calculated KD of 770 pM. These binding properties are similar to those of cell-surface type I IL-1 receptor. IL-1R-IgG is capable of inhibiting the biological activity of IL-1 beta in vitro, as evidenced in a thymocyte proliferation assay. Pharmacokinetic analysis in mice indicates that IL-1R-IgG has a terminal half-life of 91 hr in the blood circulation. This half-life is markedly longer than the values reported for other recombinant inhibitors of IL-1 such as the IL-1 receptor antagonist or soluble IL-1 receptor. Thus, IL-1R-IgG may be useful for investigating the interaction of IL-1 with its receptor and the role of IL-1 in disease, as well as for potential intervention in pathological situations involving overproduction of IL-1.

Animals↗
PubMed1994

Pharmacokinetics and tissue distribution of recombinant human transforming growth factor beta 1 after topical and intravenous administration in male rats.

Recombinant human transforming growth factor beta (rhTGF-beta 1) enhances the healing process after topical application to various animal wound models. A detailed pharmacokinetic and tissue distribution study was performed to support the clinical development of rhTGF-beta 1 for wound healing indications. Rats received radioiodinated or unlabeled rhTGF-beta 1 as an intravenous (iv) bolus or as a topical formulation applied to a full thickness wound. Plasma concentrations of TGF-beta 1 were estimated from TCA-precipitable radioactivity or were measured by ELISA. Following iv administration, the initial half-life was rapid (< 11 min), regardless of whether radiolabeled or unlabeled rhTGF-beta 1 was used. The terminal half-life was long (163 min) when the test material was radioiodinated and administered as a trace dose and relatively short (< or = 61 min) when given at high doses and assayed by ELISA. Analysis of plasma radioactivity by SDS-PAGE revealed a time-dependent clearance of the 25-kDa parent molecule without a significant appearance of lower molecular weight radiolabeled metabolites. The majority of the radioactivity was associated with highly perfused organs, known iodide elimination pathways, and the thyroid at 1 and 8 hr after iv injection. After topical administration of a high dose (0.8 mg/kg), no immunoreactive TGF-beta 1 was detectable in plasma samples taken over a 48-hr period. However, trace amounts (< or = 0.05 ng/mL) of acid-precipitable radioactivity were detected in plasma after topical application of [125I]rhTGF-beta 1 (1 microgram/kg, 126 microCi/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1993

The pharmacokinetics and absorption of recombinant human relaxin in nonpregnant rabbits and rhesus monkeys after intravenous and intravaginal administration.

Recombinant human relaxin (rhRlx) is being developed as a potential cervical ripening agent to be applied intravaginally or intracervically prior to parturition. The pharmacokinetics and absorption of rhRlx were determined in nonpregnant female rabbits and rhesus monkeys after intravenous bolus (iv) and intravaginal administration of 0.1 mg/kg; additionally, rabbits were dosed with 0.5 mg/kg intravaginally. In rabbits (n = 6), mean (+/- SD) peak concentrations following iv bolus administration were 1554 +/- 296 ng/mL. The weight-normalized clearance (CL/W) was 5.9 +/- 0.4 mL/min/kg, initial volume of distribution (V1/W) was 57 +/- 9 mL/kg, and volume of distribution at steady state (Vss/W), assuming central compartment elimination, was 240 +/- 20 mL/kg. Vss/W could be as large as 2000 +/- 400 mL/kg without this assumption. The estimated amounts of rhRlx absorbed in rabbits following intravaginal administration of 0.1 and 0.5 mg/kg (n = 5/dose) were 3.1 +/- 1.4 and 0.7 +/- 0.3%, respectively; peak concentrations were 600 +/- 297 and 1066 +/- 584 pg/mL, respectively. In rhesus monkeys (n = 5) after iv administration, peak concentrations were 971 +/- 277 ng/mL; CL/W was 4.1 +/- 0.6 mL/min/kg, V1/W was 78 +/- 25 mL/kg, and Vss/W, assuming central compartment elimination, was 690 +/- 220 mL/kg. The upper limit for Vss/W was 1600 +/- 200 mL/kg when no assumptions were made regarding site (compartment) of elimination. After intravaginal administration (n = 6), two monkeys had undetectable rhRlx concentrations throughout the 48-hr sampling interval; one monkey had only one sample containing measurable rhRlx (51 pg/mL) at 24 hr; and three monkeys absorbed < 2% of the 0.1 mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1992

Phase I study of continuous-infusion soluble CD4 as a single agent and in combination with oral dideoxyinosine therapy in children with symptomatic human immunodeficiency virus infection.

To determine the safety and pharmacokinetics of recombinant soluble CD4 (sCD4) administered by continuous intravenous infusion to children with symptomatic human immunodeficiency virus type 1 infection, we conducted a phase I study at the National Cancer Institute. Three dose levels of sCD4 were evaluated: 100, 300, and 1000 micrograms/kg per day. After an initial 12 weeks of treatment with sCD4 alone, dideoxyinosine at a dose of 90 mg/m2 every 8 hours was added and subjects were observed for an additional 12 weeks. Combination therapy was continued in patients in whom it was well tolerated. In addition to toxicity and pharmacokinetic monitoring, surrogate markers of antiviral activity were evaluated. Eleven children were enrolled in the study. During the 12 weeks of treatment with sCD4 alone, and during subsequent sCD4 plus dideoxyinosine combination therapy, no significant toxic reaction attributable to sCD4 or dideoxyinosine was encountered. Low-level anti-CD4 antibodies developed in two patients. Steady-state sCD4 levels increased proportionately at higher doses. The CD4 cell counts and serum p24 antigen levels did not provide evidence of antiviral activity. We conclude that sCD4 was well tolerated at doses up to 1000 micrograms/kg per day when administered by continuous intravenous infusion; however, evidence of in vivo antiviral activity was not observed in this study.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Estimation of permanence time, exit time, dilution factor, and steady-state volume of distribution.

General solutions for exist time, permanence time, dilution factor, and volume of distribution at steady state are derived for compartmental and noncompartmental systems. These derivations require that the systems are linear and state-determined. Unique values for these parameters cannot be determined when the site of elimination is not known; in this case the parameters can be defined by a range. Interpretation of this range and its significance and use in clinical situations are illustrated with two examples.

Mathematics↗