Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2',3'-Dideoxyinosine (ddI) has shown activity against human immunodeficiency virus in phase I clinical trials. The drug is rapidly degraded by acid, however, thus raising questions as to the efficiency and reproducibility of its absorption after oral administration. This investigation studies the bioavailability of several oral dosage forms of ddI. When ddI was given to fasting patients as an oral solution with antacid, the bioavailability was 41% +/- 7% (mean +/- SEM). However, when given as buffered tablets, the bioavailability was considerably less (25% +/- 5%). The bioavailability increased slightly when the tablets were given with supplemental antacid (36% +/- 6%). Two enteric-coated preparations had reasonable bioavailability (36% +/- 5% and 26% +/- 5%), but the peak plasma level was much lower and occurred at a much later time than with the oral solution. When ddI was given as a premeasured powder containing sucrose and buffer to be reconstituted by the patient (the "sachet" preparation), the bioavailability was 29% +/- 6%. This was similar to that of the oral solution for this particular group of patients (30% +/- 7%). However, the bioavailability of the sachet was only 17% +/- 4% when administered with food. When the sachet was given to patients receiving ranitidine, no consistent change in bioavailability was noted. Also, no change in ddI pharmacokinetics was noted in patients receiving ganciclovir.
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PMID:Pharmacokinetics of 2',3'-dideoxyinosine in patients with severe human immunodeficiency infection. II. The effects of different oral formulations and the presence of other medications. 191 62

2',3'-Dideoxyinosine (didanosine; ddI) was administered to 37 adults with AIDS or AIDS-related complex in an escalating-dose phase I study. Groups of three or four patients received intravenous dosages of 0.4 mg/(kg.d) to 25.6 mg/(kg.d) divided into two or three daily doses for 2 weeks, followed by oral ddI at twice the intravenous dosages. When given with antacids, ddI was well absorbed by the oral route and penetrated into the cerebrospinal fluid. The patients had an increase in mean number of CD4+ cells from 114/mm3 at entry to 161/mm3 at week 6 (P = .00004). They also had an increase in the CD4+/CD8+ ratio and in total number of lymphocytes. Sixteen of 18 evaluable patients had a decrease in levels of human immunodeficiency virus p24 antigen by week 6 (P = .0034). Many patients reported increased energy and appetite and gained weight. Dose-limiting toxicities at high dosages were painful peripheral neuropathy and sporadic pancreatitis. However, dosages up to 9.6 mg/(kg.d) have been tolerated in patients for 11-14 months. Thus, ddI has activity against human immunodeficiency virus at dosages that can be tolerated for approximately 1 year. However, life-threatening pancreatitis is a possible complication even at low dosages, and the best ways to manage and avoid adverse effects are still under study.
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PMID:The National Cancer Institute phase I study of 2',3'-dideoxyinosine administration in adults with AIDS or AIDS-related complex: analysis of activity and toxicity profiles. 197 24

We performed a phase I study of escalating dosages of 2',3'-dideoxyinosine (didanosine; ddI) in 19 patients with AIDS or AIDS-related complex in order (1) to establish the maximal tolerated dosage, (2) to determine the nature of toxic adverse effects, (3) to measure changes in levels of circulating human immunodeficiency virus p24 antigen and in CD4+ cell counts, and (4) to evaluate the pharmacokinetics of ddI. Almost all patients had received zidovudine therapy previously. The maximal tolerated dosage of ddI was found to be approximately 12 mg/(kg.d) when it was administered orally for 28 weeks. The major dosage-limiting adverse effects encountered were neuropathy, pancreatitis, and hepatitis. These occurred at dosages higher than those associated with decreases in levels of p24 antigen. The major toxic effects of ddI are different from those associated with zidovudine. At the proper dosage, ddI may prove to be an effective agent for the chronic treatment of infection with human immunodeficiency virus and should be especially useful in the treatment of patients who cannot tolerate zidovudine.
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PMID:Phase I study of 2',3'-dideoxyinosine: experience with 19 patients at New York University Medical Center. 197 25

AIDS has remained a significant and worsening medical problem since its first description as a new clinical entity in 1981. In the past 6 years, substantial progress has been made in the chemotherapy for this disease; such progress is likely to exert a major effect on the epidemic of human immunodeficiency virus infection in the coming decade. In this article, we overview the preclinical development of an antiretroviral drug, 2',3'-dideoxyinosine (didanosine; ddI), which has recently been shown in early phase I studies to have activity against human immunodeficiency virus in patients with AIDS or AIDS-related complex. Although we will not know the full clinical potential of ddI until we have the results of ongoing controlled clinical trials, this drug appears to possess desirable features for clinical use.
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PMID:Overview of the preclinical development of an antiretroviral drug, 2',3'-dideoxyinosine. 211 2

2',3'-Dideoxyinosine (DDI) and 2',3'-dideoxy-2,6-diaminopurine riboside (ddDAPR) are potent and selective inhibitors of human immunodeficiency virus (HIV) replication in MT-4 cells. They are also inhibitory to the transformation of C3H/3T3 cells by Moloney murine sarcoma virus (MSV). In vivo, they are only marginally effective in delaying MSV-induced tumor formation, and mortality associated therewith in newborn NMRI mice. When combined with ribavirin, DDI and ddDAPR become much more effective in inhibiting MSV and HIV replication in vitro and MSV-induced tumor formation in vivo. These observations point to the potential role of ribavirin in potentiating the anti-HIV activity of DDI in AIDS patients.
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PMID:Potentiating effect of ribavirin on the in vitro and in vivo antiretrovirus activities of 2',3'-dideoxyinosine and 2',3'-dideoxy-2,6-diaminopurine riboside. 212 3

2',3'-Dideoxyinosine (ddI) is a purine analogue that after intracellular metabolic conversion suppresses the replication of the human immunodeficiency virus (HIV). We conducted a Phase I dose-escalation study of ddI in 17 patients with the acquired immunodeficiency syndrome (AIDS) and 20 patients with AIDS-related complex. The drug was administered twice daily over a dose range of 0.4 to 66 mg per kilogram of body weight per day for 2 to 44 weeks. The maximal tolerated oral dose of ddI was estimated to be 12 mg per kilogram per day. The major dose-limiting toxic effects were a painful peripheral neuropathy (in eight patients) and pancreatitis (in five). Asymptomatic elevations of the serum aminotransferase levels (in 13 patients) and the serum urate level (in 10) were also noted, but there was no dose-related hematologic toxicity. At the maximal tolerated dose, the peak plasma levels of ddI were 6.3 to 9.6 mumol per liter 0.6 to 1 hour after oral administration; the mean plasma half-life was 1.5 hours. The administration of ddI was associated with statistically significant decreases in serum level of p24 antigen and increases in the numbers of CD4 cells at 2, 6, 10, and 20 weeks. These changes were seen at all dose levels studied. Either a clinical improvement or a weight gain of greater than or equal to 2 kg was observed in 25 of 34 patients at six weeks. We conclude that ddI is a promising therapeutic agent in patients with AIDS or AIDS-related complex. Its efficacy is currently being evaluated in large-scale, controlled clinical trials.
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PMID:2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial. 210 98

The safety and activity of several antiretroviral agents are being evaluated for treatment of acquired immunodeficiency syndrome (AIDS) in infants and children. Intermittent oral and intravenous regimens and continuous intravenous infusion of the dideoxynucleoside, 3'-azido-3'-deoxythymidine (zidovudine, AZT), have been shown to be beneficial in improving neuro-developmental function and growth velocity in pediatric patients with AIDS. AZT, however, is limited by the associated development of neutropenia and anemia, which frequently necessitates transfusions. Another dideoxynucleoside, 2',3'-dideoxycytidine (ddC), also shows theoretical promise in the treatment of the pediatric AIDS population. This agent is not associated with the hematologic toxicity induced by AZT but does produce a painful sensory peripheral neuropathy. Sequential therapy with AZT and ddC may limit the toxic effects associated with the use of these drugs individually. Dideoxyinosine and soluble recombinant CD4 are two newer antiretroviral agents that are under investigation for the management of AIDS in infants and children. The activity of recombinant CD4 in preventing the transplacental transmission of human immunodeficiency virus is also being evaluated.
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PMID:Treatment of human immunodeficiency virus-infected infants and young children with dideoxynucleosides. 215 4

Several 2'-fluoroarabino-2',3'-dideoxy- and 2'-fluoro-2',3'-unsaturated 2',3'-dideoxy pyrimidine nucleoside analogues are reported. The saturated analogues 1-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)thymine (2'-threo-FddT, 33), 1-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)uracil (2'-threo-FddU, 22) were readily prepared from the corresponding 2'-deoxy-2'-fluoroarabinosyl nucleoside analogue by radical deoxygenation of the 3'-OH. The unsaturated compounds 1-(2,3-dideoxy-2-fluoro-beta-D-glycero-pent-2-enofuranosyl)thymine (2'-Fd4T, 40) and 1-[5-O-(mono-methoxytrityl)-2-fluoro-2,3-dideoxy-beta-D-glycero-pen t-2- enofuranosyl]uracil (39) were synthesized by an elimination reaction of the O-2,3'-anhydro-2'-fluoro-lyxo derivatives under basic conditions. The cytidine analogues 28 and 41 were prepared by amination of the corresponding uridine derivatives; compounds 28 and 41 were deprotected to give 1-(2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)cytidine (2'-threo-FddC, 29) and 1-(2,3-dideoxy-2-fluoro-beta-D-glycero-pent-2- enofuranosyl)cytosine (2'-Fd4C, 42), respectively. All of these novel compounds were evaluated in vitro against human immunodeficiency virus (HIV) (LAV isolate). 2'-threo-FddC (29) was the most active of the newly synthesized substances against HIV with an ID50 of 0.8 microgram/mL; ddC had an ID50 of 0.007 micrograms/mL. Because of its potency in the initial tests, 29 was further evaluated in both T cells and macrophage/monocyte cell lines, with several different isolates of HIV. Although 2'-threo-FddC (29) exhibited good antiviral activity in these systems it was less active than AZT in these assays. At 1 microM the inhibition of CFU-GM by 29 was found to be 35-40%; this is slightly higher than seen with AZT.
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PMID:Synthesis and anti-HIV activity of several 2'-fluoro-containing pyrimidine nucleosides. 216 62

Dideoxynucleosides (zidovudine[AZT], dideoxycytidine[ddC], and dideoxyinosine[ddI]) are promising new agents for the management of human immunodeficiency virus type 1 (HIV-1) infections. In light of recent data demonstrating defects in the polymorphonuclear leukocyte (PMN) bactericidal activity of HIV-1-infected patients and since many chemotherapeutic agents affect PMN function, we examined their effects on the function of PMNs from both healthy and HIV-1-infected individuals in vitro. AZT (0.1 to 25 microM), ddC (0.01 to 1 microM), and ddI (0.2 to 50 microM) had no effect on viability, chemotaxis to N-fromylmethionyl leucyl phenylalanine, phagocytosis of Candida albicans or Staphylococcus aureus, or superoxide production following stimulation by N-formylmethionyl leucyl phenylalanine. Killing of C. albicans was not affected by AZT but was enhanced by 0.1 and 1 microM ddc (a 1 microM, killing was 26.0 +/- 2.02% compared with 17.0 +/- 0.73% for controls: P = 0.006) and 0.2 to 50 microM ddI (at 10 microM, killing was 25.0 +/- 0.68% compared with 17.8 +/- 0.91% for controls; P = 0.002). Killing of S. aureus was unchanged by AZT and ddC but was significantly enhanced by ddI at 0.2 to 20 microM (at 2 microM, killing was 71.2 +/- 5.57% compared with 51.4 +/- 6.29% for controls; P = 0.0045). In addition, the preexisting defective bactericidal capacity of PMNs from HIV-1-infected patients was enhanced by ddI (P less than 0.025). Potential enhancement by these dideoxynucleosides of certain PMN functions of HIV-1-infected patients deserves further study.
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PMID:Effects of antiretroviral dideoxynucleosides on polymorphonuclear leukocyte function. 217 34

The symptomatic HIV-infection is characterized by the involvement of multiple organs with a predominance of infectious complications. Treatment of these complications usually follows established therapeutic regimens for the resulting diseases of affected organs. Successful reconstitution of the immunodeficiency resulting from HIV-infection has been unsuccessful so far. Recently, promising results have been obtained by the treatment of patients with antiviral substances which inhibit viral replication. The prototype substance, Zidovudine (AZT) has been proven to be beneficial for patients in advanced stages of the disease and more recently has been shown to delay the occurrence of full-blown AIDS in patients with AIDS-related complex. In consequence, substances with less side effects such as Dideoxycytidine or Dideoxyinosine are currently under investigation.
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PMID:[Symptomatic HIV infection. Approaches to rational therapy]. 219 60


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