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Biomedical subjects

E Roth

Publications and source records attributed to E Roth.

At least 37 records · Page 2Linked to original sources
PubMed1996

Vertical strabismus after cataract surgery.

PURPOSE: To compare anesthesia methods with resultant strabismus patterns in patients with vertical diplopia after cataract surgery. METHODS: The authors analyzed 28 consecutive patients with acquired vertical diplopia after cataract surgery to identify the strabismus pattern. The method of anesthesia administration was available in 21 patients. Three orbital dissections with simulated retrobulbar blocks were performed on cadavers to ascertain the possibility of injuring the vertical rectus muscles at the time of injection. RESULTS: Fifty percent of the involved muscles were overactive, 39 percent were restricted, and 11 percent were paretic. Eleven patients received retrobulbar, and ten received peribulbar anesthesia. The inferior rectus in 17 patients and the superior rectus muscle in 11 were involved. The odds of damaging the inferior rectus, as opposed to the superior rectus muscle, with peribulbar anesthesia was 4.8 times higher than with retrobulbar blocks. Cadaveric dissections showed the likelihood of direct needle injury to either vertical recti with retrobulbar blocks. CONCLUSIONS: In this patient population, permanent vertical strabismus after cataract surgery results more often from overacting or restricted muscles than from primary muscle paresis. Both the superior and inferior recti can be injured with retrobulbar anesthesia, but peribulbar injections affect the inferior rectus muscle more frequently.

Anesthesia, Local↗
PubMed1996

Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor.

Indinavir (IDV) (also called CRIXIVAN, MK-639, or L-735,524) is a potent and selective inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease. During early clinical trials, in which patients initiated therapy with suboptimal dosages of IDV, we monitored the emergence of viral resistance to the inhibitor by genotypic and phenotypic characterization of primary HIV-1 isolates. Development of resistance coincided with variable patterns of multiple substitutions among at least 11 protease amino acid residues. No single substitution was present in all resistant isolates, indicating that resistance evolves through multiple genetic pathways. Despite this complexity, all of 29 resistant isolates tested exhibited alteration of residues M-46 (to I or L) and/or V-82 (to A, F, or T), suggesting that screening of these residues may be useful in predicting the emergence of resistance. We also extended our previous finding that IDV-resistant viral variants exhibit various patterns of cross-resistance to a diverse panel of HIV-1 protease inhibitors. Finally, we noted an association between the number of protease amino acid substitutions and the observed level of IDV resistance. No single substitution or pair of substitutions tested gave rise to measurable viral resistance to IDV. The evolution of this resistance was found to be cumulative, indicating the need for ongoing viral replication in this process. These observations strongly suggest that therapy should be initiated with the most efficacious regimen available, both to suppress viral spread and to inhibit the replication that is required for the evolution of resistance.

Base Sequence↗
PubMed1996

Human growth hormone kinetics in critically ill patients.

Several studies have shown that exogenous human growth hormone (HGH) exerts an anabolic effect on protein metabolism in surgical patients with mild or moderate catabolism. However, contradictory results have been demonstrated in polytrauma patients where HGH did not improve protein metabolism. Aim of this study was to evaluate whether the pharmacokinetics of recombinant biosynthetic human GH (r-HGH) are altered in critically ill patients. After an overnight fast, r-HGH was infused at a rate of 460 micrograms/h/kg/bw during 120 min to five intensive care unit (ICU) patients. The patients were catabolic (nitrogen balance -11 +/- 0.5), showed normal liver function, and only one patient had a slightly impaired kidney function (creatinine > 1.5 mg/dl). Endogenous GH secretion was suppressed by continuous infusion of 50 micrograms/m2/h somatostatin. From plasma GH curves, elimination half life (t1/2kle), whole body clearance (Cltot) and steady state distribution space (DS) were calculated in an open two compartment model. Additionally, the effects of r-HGH infusion on plasma insulin, glucagon and amino acid concentrations were evaluated. T1/2kle was 19.6 +/- 2.3 min, Cltot 2.9 +/- 0.4 ml/kg/bw/min and DS 76.4 +/- 3.8 ml/kg/bw for 90 min. The plasma levels of total amino acids including the branched chain amino acids valine, leucine and isoleucine and of glutamine were significantly higher during r-HGH infusion than during the basal and somatostatin periods. In conclusion, the elimination of r-HGH in catabolic ICU patients is not different from that of healthy volunteers.

Adult↗
PubMed1996

Safety and efficacy of increasing dosages of glycyl-glutamine for total parenteral nutrition in polytrauma patients.

Supplementation of parenteral nutrition with glutamine (GLN) has been suggested to improve the efficacy of nutritional support by stimulating protein synthesis and improving immunocompetence. In the present study we investigated the impact of infusing the dipeptide glycyl-glutamine (GLY-GLN) at increasing dosages on plasma amino acid concentrations in patients with polytrauma. Nine polytraumatized patients were randomly assigned according their age and their trauma score to three experimental groups. Group 1 received 280, group II 450, and group III 570 mg GLY-GLN per kg body weight/day for a period of four days (3rd to 7th posttraumatic day), resulting in a maximum daily GLN administration (calculated for a 70 kg patient) of 14 g, 21 g and 28 g, respectively. Seven polytraumatized patients receiving the nutrition solution without GLY-GLN supplementation served as controls. All patients received total parenteral nutrition with an average amino acid administration of 1.1 g/kg/day and a total energy intake of 30 kcal/kg/day. GLY-GLN infusion did not evoke any side effects. In comparison with the control group, arterial plasma GLN concentrations increased significantly on day I after start of infusion in groups II and III, but remained raised throughout the study period only in group III (p < 0.003). Similarly, plasma GLY concentrations were also significantly raised in group III (p < 0.04). The maximum increase of plasma GLY was found on the second infusion day, after which plasma concentrations of GLY fell to concentrations even below those observed in the control group at the end of the study period. Excretion of GLY-GLN, GLN or GLY in the urine during the GLY-GLN infusions was negligible. We conclude from this first available dose finding study on glutamine-containing dipeptides that in polytraumatized patients infusion of 570 mg/kg/day of GLY-GLN (corresponding to 28 g glutamine or 40 g dipeptide/70 kg, respectively) is necessary to induce a sustained effect on plasma glutamine concentrations. No pathological accumulation of free glycine or of the dipeptide was seen with any of the three dosage steps of GLY-GLN. Thus, the administration of even high doses of GLY-GLN is feasible and safe in patients with polytrauma and is not associated with any relevant renal substrate loss.

Adult↗
PubMed1996

[Glutamine: effects on the immune system, protein balance and intestinal functions].

Glutamine is the most abundant free amino acid of the human body. In catabolic stress situations such as after operations, trauma and during sepsis the enhanced transport of glutamine to splanchnic organs and to blood cells results in an intracellular depletion of glutamine in skeletal muscle. Glutamine is an important metabolic substrate for cells cultivated under in vitro conditions and is a precursor for purines, pyrimidines and phospholipids. Increasing evidence suggests that glutamine is a crucial substrate for immunocompetent cells. Glutamine depletion in the cultivation medium decreases the mitogen-inducible proliferation of lymphocytes, possibly by arresting the cells in the G0-G1 phase of the cell cycle. Glutamine depletion in lymphocytes prevents the formation of signals necessary for late activation. In monocytes glutamine deprivation downregulates surface antigens responsible for antigen preservation and phagocytosis. Glutamine is a precursor for the synthesis of glutathionine and stimulates the formation of heat-shock proteins. Moreover, there are suggestions that glutamine plays a crucial role in osmotic regulation of cell volume and causes phosphorylation of proteins, both of which may stimulate intracellular protein synthesis. Experimental studies revealed that glutamine deficiency causes a necrotising enterocolitis and increases the mortality of animals subjected to bacterial stress. First clinical studies have demonstrated a decrease in the incidence of infections and a shortening of the hospital stay in patients after bone marrow transplantation by supplementation with glutamine. In critically ill patients parenteral glutamine reduced nitrogen loss and caused a reduction of the mortality rate. In surgical patients glutamine evoked an improvement of several immunological parameters. Moreover, glutamine exerted a trophic effect on the intestinal mucosa, decreased the intestinal permeability and thus may prevent the translocation of bacteria. In conclusion, glutamine is an important metabolic substrate of rapidly proliferating cells, influences the cellular hydration state and has multiple effects on the immune system, on intestinal function and on protein metabolism. In several disease states glutamine may consequently, become an indispensable nutrient, which should be provided exogenously during artificial nutrition.

Animals↗
PubMed1995

Influence of glutamine on the phenotype and function of human monocytes.

Reduced concentrations of glutamine (GLN) in plasma and skeletal muscle, defective host defense systems, and a diminished expression of the HLA-DR antigen on monocytes are important diagnostic parameters for late post-injury sepsis. In this in vitro study, we investigated whether blood monocyte-derived macrophage antigen expression and function from healthy donors is influenced by GLN. Lowering the GLN concentration in culture medium from 2 mmol/L to 200 mumol/L reduced the expression of HLA-DR by 40% (P < .001) on monocyte-derived macrophages, and decreased tetanus toxoid-induced antigen presentation. In addition, low GLN levels downregulated the expression of intercellular adhesion molecule-1 (ICAM-1/CD54), Fc receptor for IgG (Fc gamma RI/CD64), and complement receptors type 3 (CR3; CD11b/CD18) and type 4 (CR4; CD11c/CD18). A correlation was found between the phagocytosis of IgG-sensitized ox erythrocytes or opsonized Escherichia coli and the decreased expression of Fc gamma RI and CR3. Monocyte expression of CD14, CD71, and Fc gamma RIII/CD16 and capacity to phagocytose latex beads were not affected by altering the level of GLN. Depletion of GLN was associated with a significant reduction in cellular adenosine triphosphate (ATP), which may have influenced cell surface marker expression and phagocytosis. It remains to be seen whether these in vitro findings are of clinical significance in the treatment of sepsis.

Adenosine Triphosphate↗
PubMed1995

Arginase release following liver reperfusion. Evidence of hemodynamic action of arginase infusions.

Immediately after hepatic reperfusion in human orthotopic liver transplantation, high amounts of arginase are released from the graft, thereby influencing nitric oxide metabolism. This metabolic alteration may be one component of the ischemia-reperfusion syndrome in OLT with its hemodynamic disturbances (e.g., systemic hypotension, pulmonary hypertension). The aim of this study was to compare hemodynamic and metabolic changes following OLT in the pigs with those obtained under arginase infusions in catheterized, anesthetized pigs. Following liver revascularization in the pigs, plasma arginase concentrations increased from 48 +/- 19 IU/L to 2613 +/- 944 IU/L, resulting in a drop in plasma levels of L-arginine (-87%) and in a drop in nitrite (-82%) and nitrate (-53%) concentrations. Of the measured organ-specific hemodynamic alterations, the mean pulmonary arterial pressure increased from 17 +/- 2 mmHg to 30 +/- 5 mmHg, whereas the flow/pressure index of the portal vein decreased about 60%. A primed continuous infusion of arginase (25,000 IU) increased plasma arginase levels to a maximum of 3,690 +/- 962 IU and evoked a decrease of L-arginine, but did not alter plasma nitrite or nitrate levels. The administration of arginase in healthy pigs did not influence cardiac output, mean arterial pressure, heart rate, or total peripheral resistance, but led to an increase of mean pulmonary arterial pressure from 19 +/- 3 to 48 +/- 5 mmHg and to a reduction of arterial hepatic blood flow from 229 +/- 65 ml/min to 154 +/- 41 ml/min. From this we conclude that high levels of liver arginase cause hemodynamic alterations in the lung and the liver. We hypothesize that the pulmonary hypertension and the reduced hepatic blood flow found during the immediate reperfusion period after OLT are possibly related to the increased arginase release due to the hepatic damage of the graft.

Animals↗
PubMed1995

In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors.

Inhibitors of the human immunodeficiency virus type 1 (HIV-1) protease have entered clinical study as potential therapeutic agents for HIV-1 infection. The clinical efficacy of HIV-1 reverse transcriptase inhibitors has been limited by the emergence of resistant viral variants. Similarly, variants expressing resistance to protease inhibitors have been derived in cell culture. We now report the characterization of resistant variants isolated from patients undergoing therapy with the protease inhibitor MK-639 (formerly designated L-735,524). Five of these variants, isolated from four patients, exhibited cross-resistance to all members of a panel of six structurally diverse protease inhibitors. This suggests that combination therapy with multiple protease inhibitors may not prevent loss of antiviral activity resulting from resistance selection. In addition, previous therapy with one compound may abrogate the benefit of subsequent treatment with a second inhibitor.

Base Sequence↗
PubMed1995

Acute effects of insulin-like growth factor I on interorgan glucose and lactate flux in protein-catabolic dogs.

Insulin-like growth factor-I (IGF-I) is a potent protein-anabolic hormone with a glucose-lowering effect and is therefore a possible agent for treating catabolic patients. In this study we investigated the effect of recombinant human (rh) IGF-I on the interorgan flux of glucose under hypo- and normoglycemic conditions in catabolic, anaesthetized, and catheterized dogs. We administered a primed (40 micrograms/kg) continuous (1.5 micrograms.kg-1.min-1) infusion of rhIGF-I (Kabi Biopharma, Stockholm, Sweden) for 180 min together with either a saline (0.9% NaCl) or an amino acid solution (2.2 mg AA.kg-1.min-1 solution of Vamin, Kabi Nutrition, Stockholm, Sweden). RhIGF-I administration lowered plasma glucose levels for approximately 50% of the baseline (P < 0.001) and stimulated glucose uptake from skeletal muscle about twofold (P < 0.01), but did not modify glucose balances across the gut and liver. The same effects were found when infusing rhIGF-I together with AA. A co-infusion of rhIGF-I and glucose to maintain normoglycemic conditions stimulated glucose uptake from skeletal muscle by about fivefold (P < 0.001) and glucose uptake across the gut by about 50%, but reduced the hepatic glucose liberation (-65%; P < 0.01). The rhIGF-I infusion did not alter arterial lactate levels, but stimulated lactate release from skeletal muscle (P < 0.05) and lactate uptake across the liver (P < 0.05). We conclude that rhIGF-I reduces plasma glucose levels mainly by stimulating glucose uptake across skeletal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Resistance of nitrogen metabolism to growth hormone treatment in the early phase after injury of patients with multiple injuries.

OBJECTIVES AND DESIGN: Several studies have shown an anticatabolic effect of recombinant human growth hormone (rhGH) in surgical patients. We investigated, in a prospective, randomized, double blind, and placebo-controlled study, the effect of r-hGH on hormone and nitrogen metabolism in 14 patients with multiple injuries in the early phase of injury. MATERIALS AND METHODS: All patients were treated in the intensive care unit, had mechanical ventilation, and were highly catabolic, with a mean daily nitrogen loss of 13.2 +/- 1.8 g. r-hGH was given subcutaneously (once a day, at 8 PM) in a dosage of 0.2 IU/kg.d for seven days, starting on the second day after injury. RESULTS: Administration of r-hGH evoked a significant increase in plasma concentrations of GH, insulin-like growth factor-I (IGF-I), and insulin-like growth factor binding-protein-3 (IGFBP-3). No significant differences were found for either daily or cumulative nitrogen balances (-103.1 +/- 14 g for patients receiving r-hGH and -92.1 +/- 18.1 for those with placebo). r-hGH therapy did not affect skeletal muscle extracellular water, nor did it affect plasma or muscle concentrations of total free amino acids or glutamine. Plasma albumin, prealbumin, and retinol-binding protein concentrations were also unchanged by r-hGH therapy, as were the urinary excretion of potassium and urea. CONCLUSIONS: We conclude that elevated plasma levels of GH, insulin, and IGF-I are unable to effect a protein anabolic drive in patients with multiple injuries during the early postinjury phase and assume that this r-hGH resistance to nitrogen metabolism takes place at the level distal to IGF-I.

Adult↗
PubMed1995

Utilization of tyrosine-containing dipeptides and N-acetyl-tyrosine in hepatic failure.

The impact of hepatic dysfunction on the elimination and hydrolysis of three potential tyrosine sources for total parenteral nutrition, the dipeptides L-alanyl-L-tyrosine (Ala-Tyr) and glycyl-L-tyrosine (Gly-Tyr), and N-acetyl-L-tyrosine (Nac-Tyr) were evaluated in six patients with hepatic failure (five chronic, one acute) and seven healthy subjects. In controls, whole-body clearance (Cltot) of Ala-Tyr was higher than of Gly-Tyr (3,169 +/- 214 vs. 1,780 +/- 199 mL/kg/min, P < .01), and both exceeded clearance of Nac-Tyr (309 +/- 29 mL/kg/min, P > .01). Both dipeptides were hydrolyzed and released tyrosine immediately. In hepatic failure, elimination and hydrolysis of Ala-Tyr and Gly-Tyr were comparable to controls, but Cltot of Nac-Tyr was reduced (236 +/- 26 mL/kg/min). Neither in controls nor in patients an increase in plasma tyrosine concentration was seen after Nac-Tyr, and the major part of Nac-Tyr infused was lost in urine. The Cltot of tyrosine as evaluated after Ala-Tyr infusion (with the immediate release of tyrosine) was severely reduced in hepatic failure (152.7 +/- 38.4 vs. 484.4 +/- 41.4 mL/kg/min, P < .001) and half-life (kle) was retarded from 14.4 +/- 1.4 to 90.2 +/- 32.2 minutes (P < .03). The authors conclude that acute and chronic hepatic dysfunction does not affect elimination and hydrolysis of the dipeptides Ala-Tyr and Gly-Tyr and the constituent amino acids are released immediately. Nac-Tyr elimination was not grossly affected by hepatic failure, but neither in healthy subjects nor in hepatic failure patients was an increase of tyrosine seen. Both dipeptides but not Nac-Tyr may serve as a tyrosine source in parenteral nutrition. Moreover, by its rapid hydrolysis, the use of Ala-Tyr, for the first time, enables a simple rapid nonisotope evaluation of tyrosine kinetics for assessment of liver function.

Adult↗
PubMed1995

Tumour necrosis factor-alpha and interleukin-6: early indicators of bacterial infection after human orthotopic liver transplantation.

OBJECTIVE: To see if it was possible to predict the development of infection after liver transplantation from concentrations of endotoxin, tumour necrosis factor-alpha (TNF-alpha), or interleukin-6 (IL-6) in plasma. DESIGN: Prospective open study. SETTING: University hospital, Austria. SUBJECTS: 46 Consecutive patients who underwent liver transplantation for end stage liver disease, 1989-90. INTERVENTIONS: Samples of 4 ml blood were taken in endotoxin free tubes, and of 10 ml into heparinised tubes at the beginning of the operation, during hepatectomy, at the beginning and end of the anhepatic phase, 10 minutes after reperfusion, and at the end of the operation. MAIN OUTCOME MEASURES: Correlation between development of infections postoperatively and operative release of endotoxin, TNF-alpha, and IL-6. RESULTS: There was no correlation between development of postoperative infections and operative concentrations of endotoxin, and of TNF-alpha and IL-6 up to the end of the anhepatic phase. There was, however, a sixfold increase in TNF-alpha and IL-6 concentrations between the end of the anhepatic phase and the end of the operation in patients who subsequently developed infections (p = 0.01). CONCLUSION: The increase in the concentrations of these two cytokines in the blood after reperfusion of the transplanted liver seems to predict the development of subsequent bacterial infection.

Adult↗
PubMed1995

[A new mode of expression for the assessment of capacities of DNA repair by flow cytometry].

Flow cytometry technic was used to study DNA synthesis of Hep G2 cells following mitomycin C and adriblastine treatments during 24 hours. DNA synthesis was expressed by 2 methods: the new expression global DNA synthesis (S+G2)/G1 that considered the cells during scheduled and unscheduled DNA syntheses of S and G2 phases and the cell cycle (Fox program) that evaluated the cells during scheduled DNA synthesis by the terms G1 = 2n, S = 2n+x and G2 = 4n which excluded unscheduled DNA synthesis. The experimental data treated with this new expression led to the determination of threshold concentrations for the two tested compounds where the DNA repair mechanisms were overloaded, leading to cell death. This term was shown to be more accurate to describe the genotoxic action of compounds. Furthermore, these threshold concentrations of DNA damages was found to be linked with significant increase of micronuclei in the micronucleus test.

Antibiotics, Antineoplastic↗
PubMed1994

Transhepatic metabolism of TNF-alpha, IL-6, and endotoxin in the early hepatic reperfusion period after human liver transplantation.

Several studies have shown that the postoperative course of cytokines such as TNF-alpha or IL-6 is predictive of rejection and infection after human orthotopic liver transplantation (OLT). The aim of this prospective clinical trial was to evaluate the impact of transhepatic metabolism of endotoxin (ET), tumor necrosis-factor-alpha (TNF-alpha), and interleukin-6 (IL-6) after hepatic ischemia/reperfusion on the postoperative graft function. In 13 consecutive elective adult OLT patients with primary grafts, we determined concentrations of ET, TNF-alpha, and IL-6 in the radial artery, portal vein, and right hepatic vein at 1, 4, 7, 10, and 13 min after reperfusion. Of the 13 patients, four had ET levels below the detection limit (< 10 ng/L), and one patient had extremely high ET concentrations (151 ng/L in the hepatic vein). In the remaining patients the mean ET levels were 26 +/- 14, 26 +/- 15, and 24 +/- 14 ng/L in the portal vein, hepatic vein, and in the radial artery, respectively. These values indicate that in patients with a moderately elevated ET level, no transhepatic concentration differences of ET exist. However, in the patient with severe endotoxemia, the liver was apparently an ET-producing organ (HV-P: 29 +/- 13 ng/L). TNF-alpha levels were not measurable in four patients, and varied between 15 and 72 pg/ml (portal vein) in the remaining patients. The transhepatic concentration differences (HV-P and HV-A, respectively) of patients with PNF or dysfunction were higher than in those with "good" or "excellent" graft function (HV-P: 160 +/- 122 pg/ml vs. 7.3 +/- 9.7 pg/ml; P < 0.01 and HV-A: 137 +/- 101 pg/ml vs. 3.9 +/- 12 pg/ml; P < 0.01, respectively). Arterial IL-6 levels were below 88 pg/ml (mean value: 31 +/- 20 pg/ml) at the beginning of the operation, and increased considerably in three patients during the anhepatic phase and after reperfusion. No clinical correlation was found with the transhepatic concentration differences of IL-6. We conclude that in OLT patients without infection no transhepatic ET exchange was documented. However, a stimulated hepatic TNF-alpha release seems to be predictive of the beginning of liver dysfunction.

Adolescent↗
PubMed1994

Ca2+ release and Ca2+ entry induced by rapid cytosolic alkalinization in Jurkat T-lymphocytes.

4-Aminopyridine (4-AP), a compound usually known as a K(+)-channel inhibitor, induced rapid cytosolic alkalinization from pH 7.15 to pH 7.4, and subsequently Ca2+ mobilization in the T-lymphocyte cell line Jurkat. Other weak bases, such as NH4Cl or triethanolamine, induced a smaller and/or slower increase in cytosolic pH, resulting in a lower or no detectable Ca2+ signal. In the presence of extracellular Ca2+, 4-AP mediated a rapid and sustained increase in the free cytosolic Ca2+ concentration similar to that obtained by T-cell receptor-mediated stimulation. In the absence of extracellular Ca2+, 4-AP transiently released Ca2+ from an intracellular store that is most likely identical with the agonist- and Ins(1,4,5)P3-sensitive Ca2+ pool of Jurkat T-cells. As possible mechanisms for Ca2+ release from this particular pool as induced by 4-AP we examined (i) formation of Ins(1,4,5)P3 and (ii) sensitization of the Ins(1,4,5)P3-receptor/Ca(2+)release system by increasing intracellular pH. Although 4-AP did not induce formation of inositol polyphosphates, as demonstrated by h.p.l.c. analysis, in permeabilized cells the dose-response curve for Ins(1,4,5)P3 was shifted to the left by changing the intracellular pH from 7.2 to 7.4. This indicated that sensitization of the Ins(1,4,5)P3-receptor/Ca(2+)-release system was responsible for the effects of 4-AP seen in intact cells. In conclusion, 4-AP appears a novel tool for depletion of the agonist-sensitive Ca2+ pool of T-cells without simultaneous formation of Ins(1,4,5)P3, thereby inducing capacitative Ca2+ entry in these cells.

4-Aminopyridine↗
PubMed1994

L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor.

To date, numerous inhibitors of the human immunodeficiency virus type 1 protease have been reported, but few have been studied extensively in humans, primarily as a consequence of poor oral bioavailability in animal models. L-735,524 represents a class of human immunodeficiency virus type 1 protease inhibitors, termed hydroxyaminopentane amides, that incorporate a basic amine into the hydroxyethylene inhibitor backbone. L-735,524 is a potent inhibitor of virus replication in cell culture and inhibits the protease-mediated cleavage of the viral precursor polyproteins that results in the production of noninfectious progeny viral particles. The compound is effective against viruses resistant to reverse transcriptase inhibitors and is synergistically active when used in combination with reverse transcriptase inhibitors. Most importantly, L-735,524 exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals by using clinically acceptable formulations. Accordingly, the compound was selected for evaluation of safety and pharmacokinetic studies in humans.

Administration, Oral↗