Summary
Synopsis
Zalcitabine is a dideoxynucleoside antiretroviral agent that is phosphorylated to the active metabolite 2′,3′-dideoxycytidine 5′-triphosphate (ddCTP) within both uninfected and HIV-infected cells. At therapeutic concentrations, ddCTP inhibits HIV replication by inhibiting the enzynie reverse transcriptase and terminating elongation of the proviral DNA chain.
The results of 3 large pivotal trials comparing zidovudine monotherapy with combination therapy have now clearly established that zalcitabine plus zidovudine combination therapy improves survival, delays disease progression and is associated with an improvement in viral load and CD4+ cell count compared with zidovudine monotherapy. More recently, clinical end-point and surrogate marker data have established the efficacy of zalcitabine in combination with the protease inhibitor saquinavir in zidovudine-experienced patients. Other studies have demonstrated the utility of zalcitabine in combination with ritonavir and the nucleoside analogue lamivudine. Importantly, early use of zalcitabine in the treatment sequence does not appear to limit the therapeutic efficacy of subsequent therapy with other nucleoside analogues such as lamivudine.
Peripheral neuropathy is the most frequent dose-limiting adverse effect associated with zalcitabine therapy and is generally reversible on discontinuation of treatment. Stomatitis and mouth ulcers may occur frequently with zalcitabine therapy but tend to resolve with continuing treatment. Haematological toxicity, which is a common adverse effect associated with zidovudine, is reported infrequently with zalcitabine. Overall, combination therapy with zalcitabine plus zidovudine or saquinavir has been shown to have a tolerability profile comparable to that of either agent alone, although treatment with zidovudine plus zalcitabine was associated with a significant increase in the incidence of haematological toxicity compared with zidovudine monotherapy in one study.
Therefore, current data suggest that zalcitabine is a useful antiretroviral agent for inclusion as a component of initial double combination therapy with zidovudine or as part of triple combination therapy including zidovudine plus a protease inhibitor in the management of patients with HIV infection.
Pharmacodynamic Properties
Zalcitabine is phosphorylated to the active antiviral compound 2′,3′-dideoxy-cytidine 5′-triphosphate (ddCTP) within both uninfected and HIV-infected cells. ddCTP inhibits HIV replication by inhibition of the enzyme reverse transcriptase and termination of viral DNA chain elongation. In both these roles ddCTP competes with endogenous deoxycytidine triphosphate. Zalcitabine has demonstrated significant antiretroviral activity against HIV-1 in vitro. In addition, synergistic antiretroviral activity has been reported for zalcitabine in combination with several other antiretroviral agents including zidovudine, stavudine and saquinavir.
Resistance to zalcitabine usually arises from a series of mutations within the HIV pol gene and develops less frequently than resistance to zidovudine. Cross-resistance between zidovudine and zalcitabine has been described. The activation state of the target cell, whether the cell under investigation is acutely or chronically infected with HIV, and/or the levels of intracellular phosphorylating enzymes may also contribute to variation in the antiviral activity of zalcitabine between cell lines.
In vitro investigations suggest that zalcitabine-induced inhibition of an enzyme responsible for the synthesis of mitochondrial DNA (DNA polymerase γ) may be responsible for the development of peripheral neuropathy in clinical practice.
Pharmacokinetic Properties
Following oral administration, zalcitabine is rapidly absorbed, with peak plasma concentrations typically achieved in 1 to 2 hours. The oral bioavailability of zalcitabine exceeded 80% in some studies. Zalcitabine partially crosses the blood-brain barrier; drug concentrations in the CSF represented a mean of 14 to 20% of simultaneously measured plasma concentrations. Placental transfer of zalcitabine has been reported in vitro and in vivo.
Zalcitabine has a short plasma elimination half-life of 1.1 to 1.8 hours and is predominantly excreted unchanged in the urine. Hepatic metabolism of the drug is minimal and only about 10% of an orally administered dose is excreted in the faeces.
Clinical Efficacy
The results of 3 large pivotal studies, ACTG 175, CPCRA 007 and Delta, have clearly demonstrated that combination therapy with zidovudine plus zalcitabine or zidovudine plus didanosine improves survival and delays disease progression compared with zidovudine monotherapy. Although not exclusively limited to zidovudine-naive patients, the benefits of zalcitabine plus zidovudine therapy appear to be greater in this patient population than in zidovudine-experienced patients. Improvements in surrogate marker and clinical end-points have also been reported in zidovudine-experienced patient populations with advanced HIV infection (CD4+ cell count 50 to 300 cells/μl) treated with 2- or 3-drug combination regimens comprising zalcitabine plus the protease inhibitor saquinavir ± zidovudine. Zalcitabine has also demonstrated utility in combination with the protease inhibitor ritonavir as first-line treatment in a pilot study. Impressive surrogate marker data have also been reported in zidovudine-experienced patients receiving a 3-drug regimen comprising lamivudine, zalcitabine and zidovudine. Furthermore, the addition of lamivudine ± loviride to ongoing therapy with zidovudine plus zalcitabine in patients with advanced HIV infection was associated with a greater reduction in disease progression compared with the addition of lamivudine ± loviride to zidovudine alone. This therefore suggests that prior use of zalcitabine does not limit the subsequent utility of other nucleoside analogues such as lamivudine.
Tolerability
Peripheral neuropathy is the major dose-limiting adverse effect associated with zalcitabine therapy and has been reported to occur in 12 to 46% of patients in clinical studies; risk factors for the development of zalcitabine-induced peripheral neuropathy include a baseline CD4+ count ≤50 cells/μl, diabetes mellitus and a low serum cobalamin level. Mouth ulcers and stomatitis occurred with an incidence of 3 to 4% in 3 large studies and 29% in a fourth study; these effects may resolve with continuing administration of the drug. Pancreatitis is an infrequent adverse effect associated with zalcitabine therapy, generally developing in <1% of patients. Other adverse effects associated with zalcitabine include hepatotoxicity and cutaneous/hypersensitivity reactions.
The tolerability profile of combination therapy with zalcitabine plus zidovudine or saquinavir generally reflects that of the individual drugs and has not been associated with the development of any unexpected adverse effects. However, the incidence of haematological adverse effects with zidovudine plus zalcitabine therapy was significantly greater than that reported for zidovudine alone in one study.
Although tolerability data in children are limited, rash, stomatitis and peripheral neuropathy have been reported after administration of the drug to this patient group.
Drug Interactions
Several important drug interactions have been reported between zalcitabine and other drugs used in the management of patients with HIV infection. Potentially nephrotoxic agents, notably the aminoglycosides, amphotericin and foscarnet, may reduce the renal clearance of zalcitabine and potentially increase the incidence of zalcitabine-associated adverse effects. Importantly, the concomitant use of zalcitabine with pentamidine should be avoided because of an increased risk of the development of severe pancreatitis. Furthermore, zalcitabine should be coadministered with caution with other drugs that may cause peripheral neuropathy (for example, didanosine, dapsone, metronidazole, stavudine, isoniazid and pentamidine) should be avoided where possible. A reduction in the bioavailability of zalcitabine has been reported with the concomitant administration of aluminium hydroxide/magnesium hydroxide antacid mixture.
To date, clinically significant pharmacokinetic interactions have not been reported between zalcitabine and other antiretroviral agents including zidovudine, saquinavir and nevirapine. However, inhibition of zalcitabine phosphorylation by lamivudine has been reported in vitro.
Dosage and Administration
The recommended dosage of zalcitabine for use in combination with zidovudine in adults and adolescents (age >13 years) is 0.75mg administered orally every 8 hours. The same dosage is recommended for use in combination with the protease inhibitor saquinavir. The optimal dosage of zalcitabine as part of triple combination therapy has yet to be determined, although 0.75mg every 8 hours has been widely used in clinical studies.
Zalcitabine dosage should be reduced in patients with renal insufficiency; 0.75mg twice daily is recommended in patients with a creatinine clearance (CLCR) of 0.6 to 2.4 L/h (10 to 40 ml/min) decreasing to 0.75mg once daily in patients with a CLCR<0.6 L/h (<10 ml/min). Zalcitabine should be discontinued if peripheral neuropathy develops and reinstituted (at a dose of 0.375mg every 8 hours) only if symptoms become no more than mild in nature. Caution is also recommended when the drug is administered to patients with a history of poor bone marrow reserve, elevated amylase levels, pancreatitis or alcohol abuse and in patients receiving parenteral nutrition.
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References
Whittinglon R, Brogden RN. Zalcitabine: a review of its pharmacology and clinical potential in acquired immunodeficiency syndrome (AIDS). Drugs 1992 Oct; 44: 656–83
Cooney DA, Dalai M, Mitsuyu H, et al. Initial studies on the cellular pharmacology of 2′,3′-dideoxycytidine, an inhibitor of HTLV-III infectivity. Biochem Pharmacol 1986; 35: 2065–8
De Jong MD, Boucher CAB, Galasso GJ, et al. Consensus symposium on combined antiviral therapy. Antiviral Res 1996 Jan; 29: 5–29
Mitsuya H, Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2′,3′-dideoxynucleosides. Proc Natl Acad Sci USA 1986 Mar; 83: 1911–5
Brennan TM, Taylor DL, Bridges CG. The inhibition of human immunodeficiency virus type 1 in vitro by a non-nucleoside reverse transcriptase inhibitor MKC-442, alone and in combination with other anti-HIV compounds. Antiviral Res 1995 Mar; 26: 173–87
Bridges EG, Dutschman GE, Gullen EA, et al. Favorable interaction of β-L(−) nucleoside analogues with clinically approved anti-HIV nucleoside analogues for the treatment of human immunodeficiency virus. Biochem Pharmacol 1996 Mar 22; 51: 731–6
Chong K-T, Pagano PJ, Hinshaw RR. Bisheteroarylpiperazine reverse transcriptase inhibitor in combination with 3′-azido-3′-deoxythymidine or 2′,3′-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 replication in vitro. Antimicrob Agents Chemother 1994 Feb; 38: 288–93
Connell EV, Hsu M-C, Richman DD. Combinative interactions of a human immunodeficiency virus (HIV) Tat antagonist with HIV reverse transcriptase inhibitors and an HIV protease inhibitor. Antimicrob Agents Chemother 1994 Feb; 38: 348–52
Craig JC, Whittaker L, Duncan IB. In vitro anti-HIV and cytotoxicological evaluation of the triple combination: AZT and ddC with HIV proteinase inhibitor saquinavir (Ro 31-8959). Antiviral Chem Chemother 1994 Nov; 5: 380–6
Craig JC, Duncan IB, Whittaker L, et al. Antiviral synergy between inhibitors of HIV proteinase and reverse transcriptase. Antiviral Chem Chemother 1993; 4(3): 161–6
Degré M, Beck S. Anti-HIV activity of dideoxynucleosides, foscarnet and fusidic acid is potentiated by human leukocyte interferon in blood-derived macrophages. Chemotherapy 1994 May–Jun; 40: 201–8
Demine CA, Bechtold CM, Stock D, et al. Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication. Antimicrob Agents Chemother 1996 Jun; 40: 1346–51
Eron Jr JJ, Johnson VA, Merrill DP, et al. Synergistic inhibition of replication of human immunodeficiency virus type 1, including that of a zidovudine-resistant isolate, by zidovudine and 2′,3′-dideoxycytidine in vitro. Antimicrob Agents Chemother 1992 Jul; 36: 1559–62
Johnson VA, Merrill DP, Chou T-C, et al. Human immunodeficiency virus type 1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2′,3′-dideoxy-cytidine, or recombinant interferon-α-A against zidovudine-sensitive or -resistant HIV-1 in vitro. J Infect Dis 1992 Nov; 166: 1143–6
Mathez D, Schinazi RF, Liotta DC, et al. Infectious amplification of wild-type human immunodeficiency virus from patients’ lymphocytes and modulation by reverse transcriptase inhibitors in vitro. Antimicrob Agents Chemother 1993 Oct; 37: 2206–11
Palmer S, Harmenberg J, Cox S. Synergistic inhibition of human immunodeficiency virus isolates (including 3′-azido-3′-deoxythymidine-resistant isolates) by foscarnet in combination with 2′,3′-dideoxyinosine or 2′,3′-dideoxycytidine. Antimicrob Agents Chemother 1996 May; 40: 1285–8
Perno C-F, Cooney DA, Gao W-Y, et al. Effects of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/macrophages. Blood 1992 Aug 15; 80: 995–1003
Taylor DL, Brennan TM, Bridges CG, et al. Synergistic inhibition of human immunodeficiency virus type 1 in vitro by 6-0-butanoylcastanospermine (MDL 28 574) in combination with inhibitors of the virus-encoded reverse transcriptase and proteinase. Antiviral Chem Chemother 1995 May; 6: 143–52
Mazzulli T, Rusconi S, Merrill DP, et al. Alternating versus continuous drug regimens in combination chemotherapy of human immunodeficiency virus type 1 infection in vitro. Antimicrob Agents Chemother 1994 Apr; 38: 656–61
Veal GJ, Barry MG, Back DJ. Zalcitabine (ddC) phosphorylation and drug interactions. Antiviral Chem Chemother 1995 Nov; 6: 379–84
Veal GJ, Wild MJ, Barry MG, et al. Effects of dideoxyinosine and dideoxycytidine on the intracellular phosphorylation of zidovudine in human mononuclear cells. Br J Clin Pharmacol 1994 Oct; 38: 323–8
Veal GJ, Hoggard PG, Barry MG, et al. Interaction between lamivudine (3TC) and other nucleoside analogues for intracellular phosphorylation. AIDS 1996 May; 10: 546–8
Baba M, Pauwels R, Balzarini J, et al. Ribavirin antagonizes inhibitory effects of pyrimidine 2′,3′-dideoxynucleosides on replication of human immunodeficiency virus in vitro. Antimicrob Agents Chemother 1987 Oct; 31(10): 1613–7
Faraj A, Fowler DA, Bridges EG, et al. Effects of 2′,3′-dideoxynucleosides on proliferation and differentiation of human pluripotent progenitors in liquid culture and their effects on mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994 May; 38: 924–30
Johnson M, Caiazzo T, Molina J-M, et al. Inhibition of bone marrow myelopoiesis and erythropoiesis in vitro by anti-retroviral nucleoside derivatives. Br J Haematol 1988 Oct; 70: 137–41
Steinberg HN, Zekdis JB. The effect of the antiviral dideoxycytidine (DDC) on the growth of human bone marrow progenitor cells in vitro. Proc Am Soc Clin Oncol 1988 Mar; 7: abstr. 14
Nusbaum NJ, Abraham T. Combination antiretroviral chemotherapy: a potential strategy in AIDS-related malignancy. Anticancer Drugs 1996 Jan; 7: 109–13
Zhang H, Cooney DA, Sreenath A, et al. Quantitation of mito-chondrial DNA in human lymphoblasts by a competitive polymerase chain reaction method: application to the study of inhibitors of mitochondrial DNA content. Mol Pharmacol 1994 Dec; 46: 1063–9
Lewis LD, Hamezeh FM, Lietman PS. Ultrastructural changes associated with reduced mitochondrial DNA and impaired mitochondrial function in the prescence of 2′3′-dideoxycytidine. Antimicrob Agents Chemother 1992 Sep; 36: 2061–5
Medina DJ, Tsai C-H, Hsiung GD, et al. Comparison of mitochondrial morphology, mitochondrial DNA content, and cell viability in cultured cells treated with three anti-human immunodeficiency virus dideoxynucleosides. Antimicrob Agents Chemother 1994 Aug; 38: 1824–8
Magnani M, Casabianca A, Rossi L, et al. Inhibition of HIV-1 and LP-BM5 replication in macrophages by dideoxycytidine and dideoxycytidine 5′-triphosphate. Antiviral Chem Chemother 1995 Sep; 6: 312–9
Keilbaugh SA, Hobbs GA, Simpson MV. Anti-human immunodeficiency virus type 1 therapy and peripheral neuropathy: prevention of 2′,3′-dideoxycytidine toxicity in PC12 cells, a neuronal model, by uridine and pyruvate. Mol Pharmacol 1993 Oct; 44: 702–6
Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995 May; 1: 417–22
Sommadossi J-P. Nucleoside analogs: similarities and differences. Clin Infect Dis 1993 Feb; 16 Suppl. 1: S7–15
Chen C-H, Cheng Y-C. Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2′,3′-dideoxycytidine. J Biol Chem 1989 Jul 15; 264: 11934–7
Anderson TD, Davidovich A, Feldman D, et al. Mitochondrial schwannopathy and peripheral myelinopathy in a rabbit model of dideoxycytidine neurotoxicity. Lab Invest 1994 May; 70: 724–39
Toltzis P, Mourton T, Magnuson T. Comparative embryonic cytotoxicity of antiretroviral nucleosides. J Infect Dis 1994 May; 169: 1100–2
Luster MI, Rosenthal GJ, Cao W, et al. Experimental studies of the hematologic and immune system toxicity of nucleoside derivatives used against HIV infection. Int J Immunopharmacol 1991; 13 Suppl 1: 99–107
Brandi G, Casabianca A, Schiavano GF, et al. Efficacy and toxicity of long-term administration of 2′,3′-dideoxycytidine in the LP-BM5 murine-induced immunodeficiency model. Antiviral Chem Chemother 1995 May; 6: 153–61
Coffin JM. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 1995; 267: 483–9
Moyle GJ. Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences. Drugs 1996 Aug; 52: 168–85
Arts EJ, Wainberg MA. Mechanisms of nucleoside analog antiviral activity and resistance during human immunodeficiency virus reverse transcription. Antimicrob Agents Chemother 1996; 40: 527–40
Craig C, Moyle G. The development of resistance of HIV-1 to zalcitabine. AIDS 1997; 11: 271–9
Smith M, Salomon W, Wainberg MA. Development and significance of nucleoside drug resistance in infection caused by the human immunodeficiency virus type 1. Clin Invest Med 1994 Jun; 17: 226–43
Larder BA. Viral resistance and the selection of antiretroviral combinations. J Acquir Immune Defic Syndrom Hum Retrovirol 1995; 10 Suppl. 1: 28–33
Tantillo C, Ding JP, Jacobo-Molina A, et al. Locations of antiAIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase: implications for mechanisms of drug inhibition and resistance. J Mol Biol 1994 Oct 28; 243: 369–87
Shirasaka T, Yarchoan R, O’Brien MC, et al. Changes in drug sensitivity of human immunodeficiency virus type 1 during therapy with azidothymidine, dideoxycytidine, and dideoxy-inosine: an in vitro comparative study. Proc Natl Acad Sci USA 1993 Jan 15; 90: 562–6
Sylvester S, Caliendo A, Sepkowitz K, et al. HIV-1 resistance mutations and plasma RNA levels during ZDV + ddC combination therapy [abstract]. 3rd Conference on Retroviruses and Opportunistic Infections 1996 Jan 28: 107
Harrigan PR, Kemp SD, Kinghorn I, et al. A placebo controlled trial of AZT alone or in combination with DDI or DDC: viral load and drug resistance [abstract]. AIDS 1994 Nov; 8 Suppl. 4: S20
Richman DD, Meng T-C, Spector SA, et al. Resistance to AZT and ddC during long-term combination therapy in patients with advanced infection with human immunodeficiency virus. J Acquir Immune Defic Syndr 1994 Feb; 7: 135–8
Fitzgibbon JE, Howell RM, Haberzettl CA, et al. Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2′,3′-dideoxycytidine. Antimicrob Agents Chemother 1992 Jan; 36: 153–7
Zhang D, Caliendo AM, Eron JJ, et al. Resistance to 2′,3′-dideoxycytidine conferred by a mutation in codon 65 of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1994 Feb; 38: 282–7
Gu Z, Gao Q, Fang H, et al. Identification of a mutation at codon 65 in the IKKK motif of reverse transcriptase that encodes human immunodeficiency virus resistance to 2′,3′-dideoxy-cytidine and 2′,3′-dideoxy-3′-thiacytidine. Antimicrob Agents Chemother 1994 Feb; 38: 275–81
Gu Z, Arts EJ, Parniak MA, et al. Mutated K65R recombinant reverse transcriptase of human immunodeficiency virus type 1 shows diminished chain termination in the presence of 2′,3′-dideoxycytidine 5′-triphosphate and other drugs. Proc Natl Acad Sci USA 1995 Mar 28; 92: 2760–4
Gu Z, Salomon H, Cherrington JM, et al. K65R mutation of human immunodeficiency virus type 1 reverse transcriptase encodes cross-resistance to 9-(2-phosphonylmethoxy-ethyl) adenine. Antimicrob Agents Chemother 1995 Aug; 39: 1888–91
Gu ZX, Gao Q, Li XG, et al. Novel mutation in the human immunodeficiency virus type-1 reverse transcriptase gene that encodes cross-resistance to 2′,3′-dideoxyinosine and 2′,3′-dideoxycytidine. J Virol 1992 Dec; 66: 7128–35
Gao Q, Gu Z, Parniak MA, et al. The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2′,3′-dideoxyinosine and 2′,3′-dideoxycytidine confers high-level resistance to the (−) enantiomer of 2′,3′-dideoxy-3′-thiacytidine. Antimicrob Agents Chemother 1993 Jun; 37: 1390–2
Fitzgibbon JE, Farnham AE, Sperber SJ, et al. Human immunodeficiency virus type-1 pol gene mutations in an AIDS patient treated with multiple antiretroviral drugs. J Virol 1993 Dec; 67: 7271–5
Loveday C. HIV-1 genotypic and phenotypic resistance in Delta patients [abstract no. Th.B4354]. 11th International Conference on AIDS, Vancouver July 1996
Larder BA, Kohli A, Bloor S, et al. Human immunodeficiency virus type I drug susceptibility during zidovudine (AZT) monotherapy compared with AZT plus 2′,3′-dideoxyinosine or AZT plus 2′,3′-dideoxycytidine combination therapy. J Virol 1996; 70: 5922–9
Lacey SF, Larder BA. Novel mutation (V75T) in human immunodeficiency virus type 1 reverse transcriptase confers resistance to 2′,3′-didehydro-2′,3′-dideoxythymidine in cell culture. Antimicrob Agents Chemother 1994 Jun; 38: 1428–32
Shirasaka T, Kavlick MF, Ueno T, et al. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proc Natl Acad Sci USA 1995 Mar 14; 92: 2398–402
Schmit JC, Cogniaux J, Hermans P, et al. Multiple drug resistance to nucleotide analogues and nonnucleoside reverse transcriptase inhibitors in an efficiently replicating human immunodeficiency virus type 1 patient strain. J Infect Dis 1996; 174: 962–8
Nájera I, Richman DD, Olivares I, et al. Natural occurrence of drug resistance mutations in the reverse transcriptase of human immunodeficiency virus type 1 isolates. AIDS Res Hum Retroviruses 1994 Nov; 10: 1479–88
Cinatl Jr J, Cinatl J, Weber B, et al. Decreased anti-human immunodeficiency virus type-1 activities of 2′,3′-dideoxy-nucleoside analogs in MOLT-4 cell sublines resistant to 2′,3′-dideoxynucleoside analogs. Acta Virol 1993 Oct; 37: 360–8
Cinatl Jr J, Cinatl J, Rabenau H, et al. Failure of antiretroviral therapy: role of viral and cellular factors. Intervirology 1994 Nov–Dec; 37: 307–14
Perno CF, Yarchoan R, Bulzarini J, et al. Different pattern of activity of inhibitors of the human immunodeficiency virus in lymphocytes and monocyte/macrophages. Antiviral Res 1992 Apr; 17: 289–304
Perno CF, Yarchoan R, Cooney DA, et al. Inhibition of human immunodeficiency virus (HIV-1/HTLV-IIIBa-L) replication in fresh and cultured human peripheral blood monocytes/ macrophages by azidothymidine and related 2′,3′-dideoxy-nucleosides. J Exp Med 1988 Sep 1; 168: 1111–25
Perno CF, Cooney D, Yarchona R, et al. Inhibition of human immunodeficiency virus (HIV) infections of fresh peripheral blood monocyte/macrophages (M/M) by dideoxynucleosides and phosphonoformate. Antiviral Res 1988; 9: 157
Hengstschläger M, Denk C, Wawra E. Cell cycle regulation of deoxycytidine kinase. Evidence for post-transcriptional control. FEBS Lett 1993; 321: 237–40 7.
Arnér ESJ, Eriksson S. Mammalian deoxyribonucleoside kinases. Pharmacol Ther 1995; 67: 155–86
Gao W-Y, Agbaria R, Driscoll JS, et al. Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2′,3′-dideoxynucleoside analogs in resting and activated human cells. J Biol Chem 1994 Apr 29; 269: 12633–8
Gao W-Y, Shirasaka T, Johns DG, et al. Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells. J Clin Invest 1993 May; 91: 2326–33
Watson AJ, Wilburn LM. Inhibition of HIV infection of resting peripheral blood lymphocytes by nucleosides. AIDS Res Hum Retroviruses 1992 Jul; 8: 1221–7
Perno CF, Aquaro S, Rosenwirth B, et al. In vitro activity of inhibitors of late stages of the replication of HIV in chronically infected macrophages. J Leukoc Biol 1994 Sep; 56: 381–6
Magnani M, Gazzanelli G, Brandi G, et al. 2′,3′-Dideoxycytidine induced drug resistance in human cells. Life Sci 1995 Jul 21; 57: 881–7
Magnani M, Brandi G, Casablanca A, et al. 2′,3′-Dideoxycytidine metabolism in a new drug-resistant cell line. Biochem J 1995 Nov 15; 312 (Pt 1): 115–23
Gustavson LE, Fukuda EK, Rubio FA, et al. A pilot study of the bioavailability and pharmacokinetics of 2′,3′-dideoxycytidine in patients with AIDS or AIDS-related complex. J Acquir Immune Defic Syndr 1990; 3: 28–31
Klecker Jr RW, Collins JM, Yarchoan RC, et al. Pharmacokinetics of 2′,3′-dideoxycytidine in patients with AIDS and related disorders. J Clin Pharmacol 1988 Sep; 28: 837–42
Gould Chadwick E, Nazareno LA, Nieuwenhuis TJ, et al. Phase I evaluation of zalcitabine administered to human immunodeficiency virus-infected children. J Infect Dis 1995 Dec; 172: 1475–9
Pizzo PA, Butler K, Balis F, et al. Dideoxycytidine alone and in an alternating schedule with zidovudine in children with symptomatic human immunodeficiency virus infection. J Pediatr 1990 Nov; 117: 799–808
Dudley MN. Clinical pharmacokinetics of nucleoside antiretroviral agents. J Infect Dis 1995 Mar; 171 Suppl. 2: S99–112
Morse GD, Shelton MJ, O’Donnell AM. Comparative pharmacokinetics of antiviral nucleoside analogues. Clin Pharmacokinel 1993 Feb; 24: 101–23
Devineni D, Gallo JM. Zalcilabine: clinical pharmacokinetics and efficacy. Clin Pharmacokinet 1995 May; 28: 351–60
Shelton MJ, O’Donnell AM, Morse GD. Zalcilabine. Ann Pharmacother 1993 Apr; 27: 480–9
Kaslrissios H, Nakano M, Burton P, et al. Improved combined solid-phase extraction-RIA method for quantifying zalcitabine in plasma. Clin Chem 1996 Mar; 42: 465–6
Burger DM, Rosing H, ten Napel CHH, el al. Application of a radioimmunoassay for determination of levels of zalcitabine (ddC) in human plasma, urine, and cerebrospinal fluid. Anli-microb Agents Chemother 1994 Dec; 38: 2763–7
Roberts WL, Buckley TJ, Rainey PM, et al. Solid-phase extraction combined with radioimmunoassay for measurement of zalcitabine (2′,3′-dideoxycytidine) in plasma and serum. Clin Chem 1994 Feb; 40: 211–5
Nazareno LA, Holazo AA, Limjuco R, et al. The effect of food on pharmacokinetics of zalcitabine in HIV-positive patients. Pharm Res 1995 Oct; 12: 1462–5
Yarchoan R, Perno CF, Thomas RV, el al. Phase I studies of 2′,3′-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1988 Jan 16; I: 76–81
Bazunga M, Tran HT, Kertland H, et al. The effects of renal impairment on the pharmacokinetics of Zalcitabine (ddC) [abstract]. J Clin Pharmacol 1996 Sep; 36: 851
Roche. HIVID tablets; product descripion. June 1996
Aiuti F, Boucher C, Dianzani F, et al. Consensus conference on laboratory markers in HIV infection. J Biol Regul Homeost Agents l995 Jul–Sep; 9: 119–20
Goldman AI, Carlin BP, Crane LR, et al. Response of CD4 lymphocytes and clinical consequences of treatment using ddI or ddC in patients with advanced HIV infection. J Acquir Immune Defic Syndrom Hum Retrovirol 1996 Feb 1; 11: 161–9
Choi S, Lagakos SW, Schooley RT, et al. CD4+ lymphocytes are an incomplete surrogate marker for clinical progression in persons with asymptomatic HIV infection taking zidovudine. Ann Intern Med 1993; 118: 674–80
Williams IG, De Cock KM. The XI International Conference on AIDS Vancouver 7–12 July 1996. Areview of Clinical Science Track B. Genitourin Med 1996; 72: 365–9
Harrigan R. Measuring viral load in the clinical setting. J Acquir Immune Defic Syndrom Hum Retrovirol 1995; 10 Suppl. 1: S34–40
Katzenstein DA, Hammer SM, Hughes MD, et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infecled adults with 200 to 500 CD4 cells per cubic millimeter. N Engl J Med 1996 Oct 10; 335: 1091–8
Deyton L. Importance of surrogate markers in evaluation of antiviral therapy in HIV infection. JAMA 1996; 276: 159–60
Levy JA. Surrogate markers in AIDS research. Is there truth in numbers? JAMA 1996; 276: 161–2
Forsyth BWC. Primary care of children with HIV infection. Curr Opin Pediatr 1995 Oct; 7: 502–12
Pizzo PA, Wilfert C. Antiretroviral therapy for infection due to human immunodeficiency virus in children. Clin Infect Dis 1994 Jul; 19: 177–96
Mofenson L, Balsley J, Simonds RJ, et al. Recommendations of the U.S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. MMWR 1994 Aug 5; 43: 1–20
Mildvan D, Bergé P. Prophylactic zalcilabine and interferon-α for a large-bore needlestick exposure to human immunodeficiency virus. J Acquir Immune Defic Syndr 1994 Apr; 7: 416–7
Update: Provisional Public Health Service recommendations for chemoprophyIaxis after occupational exposure to HIV. MMWR 1996 Jun 7; 45: 468–72
Portegies P. HIV-1, the brain, and combination therapy. Lancet 1995 Nov 11; 346: 1244–5
Everall IP. Neuropsychiatric aspects of HIV infection. J Neurol Neurosurg Psychiatry 1995 Apr; 58: 399–402
Goebel FD. Combination therapy from a clinician’s perspective. J Acquir Immune Defic Syndrom Hum Retrovirol 1995; 10 Suppl. 1: S62–68
McIntyre K, Torres R, Luck D, et al. Pilot study of zidovudine (AZT) and zalcitabine (ddC) combination in HIV-associated dementia [abstract]. 10th International Conference on AIDS 1994; 1: 201
Follansbee S, Drew L, Olson R, et al. The efficacy of zalcitabine (ddC, HIVID) versus zidovudine (ZDV) as monotherapy in ZDV naive patients with advanced HIV disease: a randomized, double-blind, comparative trial (ACTG 114: N3300) [abstract]. 9th Int Conf Aids 1993; 1: 487
Bozzette SA, Kanouse DE, Berry S, et al. Health status and function with zidovudine or zalcitabine as initial therapy for AIDS: a randomized controlled trial. JAMA 1995 Jan 25; 273: 295–301
Torres RA, Barr MR, Mclntyre KI, et al. A comparison of zidovudine, didanosine, zalcitabine and no antiretroviral therapy in patients with advanced HIV disease. Int J STD AIDS 1995 Jan–Feb; 6: 19–26
Abrams DI, Goldman AI, Launer C, et al. A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. N Engl J Med 1994 Mar 10; 330: 657–62
Fischl MA, Olson RM, Follansbee SE, et al. Zalcitabine compared with zidovudine in patients with advanced HI V-1 infection who received previous zidovudine therapy. Ann Intern Med 1993 May 15; 118: 762–9
Fischl MA, Stanley K, Collier AC. Combination and monotherapy with zidovudine and zalcitabine in patients with advanced HIV disease. Ann Intern Med 1995 Jan 1; 122: 24–32
Hammer SM, Katzenstein DA, Hughes MD, et al. A trial comparing nucleoside monotherapy with combination therapy in HI V-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996 Oct 10; 335: 1081–90
Collier AC, Coombs RW, Schoenfeld DA, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. N Engl J Med 1996 Apr 18; 334: 1011–7
Schooley RT, Ramirez-Ronda C, Lange JMA, et al. Virologic and immunologic benefits of initial combination therapy with zidovudine and zalcitabine or didanosine compared with zidovudine monotherapy. J Infect Dis 1996 Jun; 173: 1354–66
Katlama C. Clinical and survival benefit of 3TC™ in combination with zidovudine-containing regimens in HIV-1 infection: interim results of the CAESAR study [abstract no. SS2.1]. AIDS 1996; 10 Suppl.: S9
Saravolatz LD, Winslow DL, Collins G, et al. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-inlected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. N Engl J Med 1996 Oct 10; 335: 1099–106
Delta Coordinating Committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996 Aug 3; 348: 283–91
Moyle GJ, Walker M, Harris R, el al. Early versus delayed zalcitabine (ddC)/zidovudine (ZDV) combination in HIV-positive persons with CD4 cell counts 300-500/mm3: a double-blind placebo controlled trial (Roche study M50003) [abslract no. P49]. AIDS 1996; 10 Suppl. 2: S31
Bartlett JA, Benoit SL, Johnson VA. Lamivudine plus zidovudine compared with zalcilabine plus zidovudine in patients with HIV infection: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996 Aug 1; 125: 161–72
Hoffman-La Roche. HIVID®: combination therapy in HIV disease. Clinical expert report
Meng T-C, Fischl MA, Boota AM, et al. Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. Ann Med 1992; 116(1): 13–20
Henry K, Tierney C, Kahn J, et al. A randomized, double-blind, placebo-controlled study comparing combination nucleoside and triple therapy for the treatment of advanced HIV disease (CD4 < = 50/mm3) [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington, DC
Thompson M, Creagh T, Harmon M, et al. Impact on survival of combination or sequential antiretroviral therapy compared with AZT monotherapy [abstract]. 3rd Conference on Retroviruses and Opportunistic Infections 1996 Jan 28: 106
Graham NMH, Hoover DR, Park LP, et al. Survival in HIV-infected patients who have received zidovudine: comparison of combination therapy with sequential monotherapy and continued zidovudine monotherapy. Ann Intern Med 1996 Jun 15; 124: 10310–1038
Lange JMA. Triple combinations: present and future. J Acquir Immune Defic Syndrom Hum Retrovirol 1995; 10 Suppl. 1: 77–82
Testa MA, Lenderking WR, Fischer L, et al. Effects of combination therapy with saquinavir, zidovudine and zalcitabine on quality of life [abstract]. 11th International Conference on AIDS 1996 Jul 7; 1: 239
Ruiz L, Romeu J, Martinez-Picado J, et al. Efficacy of triple combination therapy with zidovudine (ZDV) plus zalcitabine (ddC) plus lamivudine (3TC) versus double (ZDV + 3TC) combination therapy in patients previously treated with ZDV + ddC. AIDS 1996; 10: F61–6
Mathez D, Bagnarelli P, De Truehis P, et al. A triple combination of ritonavir+AZT+DDC as a first line treatment of patients with AIDS: update [abstract]. 11th International Conference on AIDS 1996 Jul 7; 1: 19
Conde-Mercado JM, Feregrino GM, Eid Lidt G, et al. Antiviral combined and thymostimulin in patients with HIV stages III and IV. Effects on the CD4 cells counts [abstract]. 10th International Conference on AIDS 1994; 1: 211
Lavelle J, Haas D, HIV/Wellferon® Clinical Trial Team. Long-term safety and efficacy of initial triple combination therapy with ZDV, ddC and interferon alpha-n1 vs ZDV and ddC in patients with CD4+ cell counts 300–500 cells/mm3. 3rd Conference on Retroviruses and Opportunistic Infections 1996 Jan 28: 107
Freimuth W, Wang Y, Docsa S, et al. Surrogate marker responses from an open-label, extended use delavirdine mesylate (DLV) treatment in triple combination (ZDV+DLV +DDI or ZDV+DLV+DDC) for HIV-1+ patients [abstiact]. 11th International Conference on AIDS 1996 Jul 7; 1: 78
Scheibel SF, Saget B, Elbeik T, et al. Extreme suppression of HIV-1 plasma RNA using a combination of zidovudine, didanosine, zalcitabine, epivir, saquinavir, and interferon-α in patients with HIV-I infection [abstract]. 11th International Conference on AIDS 1996 Jul 7; 2: 78
Spector SA, Blanchard S, Connor EM, et al. Results of a clinical trial comparing two doses of 2′3′-dideoxycytidine (ddC) in the treatment of children with symptomatic human immunodeficiency virus (HIV) infection who were intolerant or had failed zidovudine (ZDV) therapy (ACTG 138) [abstract]. Pediatr Res 1994 Apr; 35 (Pt 2): 197A
Dankner WM, Rice M, Nyhan WL, et al. Effect of salvage dideoxycytidine on growth, nutritional parameters and metabolic rates of children with advanced HIV disease [abstract]. 2nd National Conference on Human Retroviruses 1995 Jan 29: 104
Husson R, Shirasaka T, Butler K, et al. High level resistance to AZT, but not to ddC or ddI in HIV from children receiving long-term antiretroviral therapy [abslract no. 571]. 32nd Inl Conf Antimicro Ag Chemother 1992: 206
Simpson K, Hatziandreu EJ, Andersson F, et al. Cost effectiveness of antiviral treatment with zalcitabine plus zidovudine for AIDS patients with CD4+ counts less than 33/μl in 5 European countries. PharmacoEconomics 1994 Dec; 6: 553–62
Merigan TC. Treatment of AIDS with combinations of anti-retroviralagents. Am J Med 1991; 90 Suppl. 4A: 8S–17S
Moyle G, Goll A, Snape S, et al. Safety and tolerability of zalcitabine (ddC) in patients with AIDS or advanced AIDS-related complex in the European Expanded Access Programme. Int J Antimicrob Agents 1996; 7(1): 41–8
Moore RD, Fortgang I, Keruly J, et al. Adverse events from drug therapy for human immunodeficiency virus disease. Am J Med 1996 Jul; 101: 34–40
Simpson DM, Tagliati M. Nucleoside analogue-associated peripheral neuropathy in human immunodeficiency virus infection. J Acquir Immune Defic Syndrom Hum Retrovirol 1995 Jun 1; 9: 153–61
Blum AS, Dal PGJ, Feinberg J, et al. Low-dose zalcitabine-related toxic neuropathy: frequency, natural history, and risk factors. Neurology 1996 Apr; 46: 999–1003
Fichtenbaum CJ, Clifford DB, Powderly WG. Risk factors for dideoxynucleoside-induced toxic neuropathy in patients with the human immunodeficiency virus infection. J Acquir Immune Defic Syndrom Hum Retrovirol 1995 Oct 1; 10: 169–74
Berger AR, Arezzo JC, Schaumburg HH, et al. 2′,3′-dideoxy-cytidine (ddC) toxic neuropathy: a study of 52 patients. Neurology 1993 Feb; 43: 358–62
Dubinsky RM, Yarchoan R, Dalakas M, et al. Reversible axonal neuropathy from the treatment of AIDS and related disorders with 2′,3′-dideoxycytidine (ddC). Muscle Nerve 1989; 12: 856–60
Lipsky JJ. Zalcitabine and didanosine. Lancet 1993 Jan 2; 341: 30–2
Powderly WG, Klebert MK, Clifford DB. Ototoxicity associated with dideoxycytidine [letter]. Lancet 1990 May 5; 335: 1106
Martinez OP, French MAH. Acoustic neuropathy associated with zalcitabine-induced peripheral neuropathy. AIDS 1993 Jun; 7: 901–2
Faller JP, Ziegler F, Balblanc JC, et al. Acute paralysis of the serratus muscle in an HIV positive patient treated by DDC [abstract]. 10th International Conference on AIDS 1994; 1: 191
Jay C, Ropka M, Dalakas MC. The drugs 2′,3′-dideoxyinosine (ddI) and 2′,3′-dideoxycytidine (ddC) are safe alternatives in people with AIDS with zidovudine-induced myopathy. J Acquir Immune Defic Syndr 1994 Jun; 7: 630–1
Greenspan D, Hilton JF, Canchola AJ, et al. Association between oral ulcers and zalcitabine [abstract]. 10th International Conference on AIDS 1994; 1: 62
Ramirez-Ronda CH, Santana J, Rivera-Vazquez C, et al. Oral ulcers in HIV infected persons taking zalcitabine plus zidovudine: initial results [abstract]. 2nd National Conference on Human Retroviruses 1995 Jan 29: 153
Indorf AS, Pegram PS. Esophageal ulceration related to zalcitabine (ddC). Ann Intern Med 1992 Jul 15; 117: 133–4
Merigan TC, Skowron G, Bozzette SA, et al. Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections. A phase I and II study. Ann Intern Med 1989 Feb 1; 110: 189–94
McNeely MC, Yarchoan R, Broder S, et al. Dermatologic complications associated with administration of 2′,3′-dideoxy-cytidine in patients with human immunodeficiency virus infection. J Am Acad Dermatol 1989 Dec; 21: 1213–7
Wardropper AG, Ong ELC. Erythema multiforme secondary to dideoxycytidine (DDC). Int J STD AIDS 1995 Nov–Dec; 6: 450
Tancrede-Bohlin E, Grange F, Bournerias I. Hypersensitivity syndrome associated with zalcitabine therapy. Lancet 1996 Apr 6; 347: 971
Henry K, Acosta EP. Hepatotoxicity and rash associated with zidovudine and zalcitabine chemoprophylaxis. Ann Intern Med 1996 May 1; 124: 855
Brivet FG, Naveau SH, Lemaigre GF, et al. Pancreatic lesions in HIV-infected patients. Baillieres Clin Endocrinol Metab 1994 Oct; 8: 859–77
Aponte-Cipriani SL, Teplitz C, Yancovitz S. Pancreatitis possibly related to 2′-3′-dideoxycytidine. Ann Intern Med 1993 Sep 15; 119: 539–40
Moyle GJ. Occurrence of lymphomas during ddC or ddC/ zidovudine combination therapy in persons infected with HIV type I [letter]. J Acquir Immune Defic Syndrom Hum Retrovirol 1996; 13(5): 464–5
Moyle GJ, Walker M, Harris R, et al. Safety and activity of zalcitabine and zidovudine combination in HIV-positive people with CD4 cell counts ≤300 cells/mm3. Antiviral Ther 1996 Aug; 1(3): 180–8
Acosta EP, Fletcher CV. Antiretroviral drug interactions. Int J Antimicrob Agents 1995 Apr; 5: 73–83
Taburet A-M, Singlas E. Drug interactions with antiviral drugs. Clin Pharmacokinet 1996 May; 30: 385–401
Heylen R, Miller R. Interactions with antiretroviral drugs. Pharm J 1993 Feb 13; 250: 214–6
Massarella JW, Holazo AA, Koss-Twardy S, et al. The effects of cimetidine and Maalox(Rm) on the pharmacokinetics of zalcitabine in HIV-positive patients [abstract]. Pharm Res 1994 Oct; 11 Suppl.: S-415
Massarella JW, Nazareno LA, Passe S, et al. The effect of probenecid on the pharmacokinetics of zalcitabine in HIV-positive patients. Pharm Res 1996 Mar; 13: 449–52
Lee BL, Tauber MG, Chambers HF, et al. The effect of trimethoprim on the pharmacokinetics of zalcitabine in HIV-infected patients [abstract]. 35th Int Conf Antimicro Ag Chemother 1995 Sep 17: 6
LeLacheur SF, Simon GL. Exacerbation of dideoxycytidine-induced neuropathy with dideoxyinosine. J Acquir Immune Defic Syndr 1991; 4: 538–9
Herskowitz A, Willoughby SB, Baughman KL, et al. Cardiomyopathy associated with antiretroviral therapy in patients with HIV infection: a report of six cases. Ann Intern Med 1992 Feb 15; 116: 311–3
MacGregor TR, Lamson MJ, Cort S, et al. Steady state pharmacokinetics of nevirapine, didanosine, zalcitabine, and zidovudine combination therapy in HIV-1 positive patients [abstract]. Pharm Res 1995 Sep; 12 Suppl.: S101
Lee BL, Tauber MG, Chambers HF, et al. Zalcitabine and dapsone pharmacokinetic interaction in HIV-infected patients [abstract]. Clin Pharmacol Ther 1995 Feb; 57: 186
Lee BL, Täuber MG, Chambers HF, et al. The effect of zalcitabine on the pharmacokinetics of isoniazid in HIV-infected patients [abstract no. A4]. 34th Int Conf Antimicro Ag Chemother 1994: 3
Hoffman La Roche. Zalcitabine prescribing information. Basel, Switzerland, 1997
Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1996: recommendations of an international panel. JAMA 1996 Jul 10; 276: 146–54
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Various sections of the manuscript reviewed by: B.G. Gazzard, Chelsea and Westminster Hospital, London, England; C. Hooper, Center for AIDS and Sexually Transmitted Diseases, University of Washington, Seattle, Washington, USA; D. Johns, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; M. Magnani, Istituto di Chimica Biologica ‘G Fornaini’, University of Urbino, Urbino, Italy; G. Moyle, Chelsea and Westminster Hospital, London, England; S. Palmer, Department of Virology, Swedish Institute for Infectious Disease Control, Stockholm, Sweden; A.J. Pinching, Department of Immunology, The Medical College of Saint Bartholomew’s Hospital, London, England; P. Volberding, Department of Medicine, San Francisco General Hospital, San Francisco, California, USA.
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Adkins, J.C., Peters, D.H. & Faulds, D. Zalcitabine. Drugs 53, 1054–1080 (1997). https://doi.org/10.2165/00003495-199753060-00009
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DOI: https://doi.org/10.2165/00003495-199753060-00009