Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this article the literature about didanosine, an antiretroviral drug, is reviewed. The mechanism of action, biochemical pharmacology, pharmacokinetics, and clinical results of phase-I trials are discussed. Serious adverse effects such as pancreatitis and peripheral neuropathy have occurred in these trials. An antiretroviral effect was observed in terms of an increase in CD4+ lymphocytes and a decrease in p24 antigen levels in HIV-infected individuals. Didanosine seems to be a promising drug against HIV infection, but knowledge about its clinical efficacy is scanty.
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PMID:Didanosine, a new antiretroviral drug. A review. 143 13

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

Twenty-one patients with AIDS or AIDS-related complex (ARC) received 2',3'-dideoxyinosine (didanosine; ddI) intravenously and then orally (initial dosages of 0.4 mg/kg and 0.8 mg/kg every 12 hours, respectively) for 6-44 weeks in an escalating-dose study. The major dose-limiting effects were peripheral neuropathy (three patients) and pancreatitis (two patients), which were observed at dosages greater than or equal to 20 mg/(kg.d). Hyperuricemia occurred at greater than or equal to 30 mg/(kg.d). No hematologic toxicity developed except for possible sporadic thrombocytopenia (two patients). Significant decreases in serum levels of p24 antigen and increases in CD4+ and CD8+ lymphocytes were noted at 2, 6, and 10-20 weeks and over a wide range of dosages, including the lowest given. Most patients had an increased feeling of well-being and/or a weight gain of greater than or equal to 2 kg at 6 weeks. For this population, ddI has promise as a therapeutic agent, thus warranting further study of this agent in controlled clinical trials.
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PMID:2',3'-Dideoxyinosine in patients with AIDS or AIDS-related complex. 197 26

In a phase I dosage-finding trial, 2',3'-dideoxyinosine (didanosine; ddI) was administered once daily to 36 patients with AIDS or AIDS-related complex for up to 65 weeks (mean, 32.1 weeks) at six dosage levels. Thirteen of 18 patients previously treated with zidovudine had developed hematologic intolerance. The maximal tolerated dosage of ddI was 12 mg/(kg.d); dose-limiting toxicities were pancreatitis and peripheral neuropathy. Other toxicities included elevation in hepatic transaminase levels, rash, cardiac conduction abnormality, and asymptomatic hyperuricemia. Eighty-six percent of patients who completed 6 weeks of treatment showed improvement in constitutional symptoms and significant weight gain. In patients treated with ddI, the mean number of CD4+ lymphocytes increased from 124/mm3 at baseline to 199/mm3 at 24 weeks (P = .0027) and the mean leukocyte count, total lymphocyte count, and hemoglobin level showed increases (all P less than .01) after 12 weeks. Serum levels of viral p24 antigen decreased greater than or equal to 50% in 14 of 19 assessable patients. No differences between the responses of patients previously treated with zidovudine and those of zidovudine-naive patients were observed. These results indicate that ddI has significant antiretroviral activity in vivo and a toxicity profile different from that of zidovudine.
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PMID:Treatment of AIDS and AIDS-related complex with 2',3'-dideoxyinosine given once daily. 197 27

To evaluate the long-term toxicity and activity profile of 2',3'-dideoxyinosine (ddI), a potent inhibitor of human immunodeficiency virus (HIV) replication, in vitro. 58 patients with AIDS or AIDS-related complex were studied with additional reference to the effect of previous treatment with zidovudine, and the effect of ddI on HIV-induced cognitive dysfunction. Doses above 9.6 mg/kg per day of ddI were frequently associated with toxicity (peripheral neuropathy, pancreatitis, or hepatitis). Doses of 9.6 mg/kg per day or below were well tolerated for up to 21 months. A subset of patients receiving 3.2-9.6 mg/kg per day of ddI had long-term immunological improvement and reduction of serum HIV p24 antigen. Immunological changes were especially seen in patients who had little previous zidovudine therapy. 5 patients with HIV-induced cognitive impairment improved with ddI. Thus, ddI may have anti-HIV activity at doses which are tolerated for long-term therapy, although pancreatitis could be a life-threatening complication.
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PMID:Long-term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS-related complex. 197 29

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

We conducted a Phase I open-label trial of 2',3'-dideoxyinosine (ddI) for the treatment of the acquired immunodeficiency syndrome (AIDS) and severe AIDS-related complex. A single daily dose of ddI was administered orally to 34 patients (17 with AIDS and 17 with AIDS-related complex) for a median of 12 weeks (range, 2 to 56). We studied six dose levels from 1.6 to 30.4 mg per kilogram of body weight per day. Of the 17 patients previously treated with zidovudine, 13 had had hematologic side effects. The maximal tolerated dose of oral ddI was estimated to be 20.4 mg per kilogram per day. Pancreatitis and peripheral neuropathy were the major dose-limiting toxic effects. Other toxic effects included elevations in hepatic transaminase levels, abnormalities in cardiac conduction, rash, and asymptomatic elevations in serum urate levels and the creatine kinase fraction from skeletal muscle. Treatment with ddI was associated with an increase in the mean number of CD4 lymphocytes from 125 per cubic millimeter at base line to 182 per cubic millimeter after 10 weeks (P = 0.005). There were also increases after 12 weeks in the mean total lymphocyte count (from 0.8 to 1.2 x 10(9) per liter) and the mean hemoglobin level (from 12.9 to 14.1 g per deciliter) (both P less than 0.01). The amount of human immunodeficiency virus p24 antigen decreased by more than 50 percent in 14 of 19 patients with detectable antigen. No differences in response were observed between patients previously treated with zidovudine and those never treated with the drug. We conclude that ddI has antiretroviral activity in patients with AIDS or AIDS-related complex and that the toxicity of ddI differs from that of zidovudine. However, controlled trials are necessary to evaluate the efficacy of ddI.
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PMID:Once-daily administration of 2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Results of a Phase I trial. 210 98

Ninety-two adult patients with AIDS or severe AIDS-related complex were treated with 2',3'-dideoxyinosine (didanosine; ddI) at dosages ranging from 0.8 to 66.0 mg/(kg.d) for at least 6 weeks in phase I trials. Potentially beneficial changes in weight (40% of patients), clinical signs or symptoms (40% of patients), CD4+ cell counts (25% of patients), and serum levels of HIV p24 antigen (50% of antigen-positive patients) were reported. Response rates tended to be higher among patients with AIDS-related complex and among those who had not received prior zidovudine therapy. A major response (improvement in at least one clinical parameter and in at least one laboratory marker) occurred in 29% of patients, and rates of major response tended to be higher in patients receiving higher dosages. The primary dose-limiting toxicity observed was peripheral neuropathy, which was observed with increasing frequency in patients receiving greater than 20 mg/(kg.d). Of the other adverse effects, pancreatitis was possibly dose-dependent and hyperuricemia (without clinical gout) occurred only at high doses. Dosages of 250 mg and 375 mg of ddI twice daily will be used in extended phase II/III studies.
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PMID:Overview of phase I trials of 2',3'-dideoxyinosine (ddI) conducted on adult patients. 216 65

Long-term follow-up of 44 patients with AIDS or AIDS-related complex (ARC) in a phase 1 trial of didanosine is reported. These patients were monitored for as long as 72 weeks (mean, 34 weeks) for toxicity and activity of didanosine. Pancreatitis and neuropathy, the major clinical toxicities, developed infrequently at the doses of didanosine (250-750 mg/d) employed during the latter part of the study. Consistent hematologic toxicity was not encountered; moreover, mean values for hematologic parameters such as hemoglobin concentration, white blood cell count, neutrophil count, lymphocyte count, and platelet count improved for up to 20-60 weeks. CD4 counts increased significantly through 10 weeks of therapy and in some patients remained at or above counts at enrollment for as long as 60 weeks. Serum concentrations of p24 antigen decreased significantly and remained at the decreased level for up to 48 weeks. An initial diagnosis of ARC (as opposed to AIDS), an initial CD4 count of > 100/mm3, and an increase in CD4 counts during the first 10 weeks of therapy were associated with a higher rate of survival and with lower rates of development of opportunistic infections and of other clinical manifestations of disease progression.
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PMID:Didanosine: long-term follow-up of patients in a phase 1 study. 809 46


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