In vitro and in vivo influenza virus-inhibitory effects of viramidine.

Viramidine, the 3-carboxamidine derivative of ribavirin, was effective against a spectrum of influenza A (H1N1, H3N2 and H5N1) and B viruses in vitro, with the 50% effective concentration (EC50) ranging from 2 to 32 microg/ml. The mean 50% cytotoxic concentration (CC50) in the MDCK cells used in these experiments was 760 microg/ml. Ribavirin, run in parallel, had a similar antiviral spectrum, with EC50 values ranging from 0.6 to 5.5 microg/ml; the mean CC50 for ribavirin was 560 microg/ml. Oral gavage administrations of viramidine or ribavirin to mice infected with influenza A/NWS/33 (H1N1), A/Victoria/3/75 (H3N2), B/Hong Kong/5/72 or B/Sichuan/379/99 viruses were highly effective in preventing death, lessening decline in arterial oxygen saturation, inhibition of lung consolidation and reducing lung virus titers. The minimum effective dose of viramidine in these studies ranged from 15 to 31 mg/kg/day, depending upon the virus infection, when administered twice daily for 5 days beginning 4 h pre-virus exposure. The LD50 of the compound was 610 mg/kg/day. Ribavirin's minimum effective dose varied between 18 and 37.5 mg/kg/day with the LD50 determined to be 220 mg/kg/day. Viramidine's efficacy was also seen against an influenza A/NWS/33 (H1N1) virus infection in mice, when the compound was administered in the drinking water, the minimum effective dose being 100 mg/kg/day. Delay of the initiation of either viramidine or ribavirin therapy, using the approximate 1/3 LD50 dose of each, was protective as late as 48 h after exposure to the A/NWS/33 virus. While both compounds appear to have similar efficacy against influenza virus infections, when one considers the lesser toxicity, viramidine may warrant further evaluation as a possible therapy for influenza.

In vitro activity of expanded-spectrum pyridazinyl oxime ethers related to pirodavir: novel capsid-binding inhibitors with potent antipicornavirus activity.

Picornaviruses (PV) include human rhinovirus (HRV), the primary cause of the common cold, and the enteroviruses (EV), which cause serious diseases such as poliomyelitis, meningoencephalitis, and systemic neonatal disease. Although no compounds for PV infections have been approved in the United States, pirodavir was one of the most promising capsid-binding compounds to show efficacy in human clinical trials for chemoprophylaxis of the common cold. Susceptibility to hydrolysis precluded its use as an oral agent. We have developed orally bioavailable pyridazinyl oxime ethers that are as potent as pirodavir. Compounds BTA39 and BTA188 inhibited a total of 56 HRV laboratory strains and three clinical isolates as determined by neutral red uptake assay. At concentrations of <100 nM, BTA39 inhibited 69% of the HRV serotypes and isolates evaluated, BTA188 inhibited 75%, and pirodavir inhibited 59% of the serotypes and isolates. The 50% inhibitory concentrations (IC(50)s) for the two compounds ranged from 0.5 nM to 6,701 nM. The compounds also inhibited EV, including coxsackie A and B viruses (IC(50) = 773 to 3,608 nM) and echoviruses (IC(50) = 193 to 5,155 nM). BTA39 only inhibited poliovirus strain WM-1 at 204 nM, and BTA188 only inhibited poliovirus strain Chat at 82 nM. EV 71 was inhibited by BTA39 and BTA188, with IC(50)s of 1 and 82 nM, respectively. Both compounds were relatively nontoxic in actively growing cells (50% cytotoxic doses, >/=4,588 nM). These data suggest that these oxime ethers warrant further investigation as potential agents for treating selected PV infections.

Fulminant Crohn's colitis after allogeneic stem cell transplantation.

We report a case of fulminant Crohn's colitis that occurred following non-myeloablative allogeneic stem cell transplantation for Hodgkin's lymphoma. Adoptive transfer of inflammatory bowel disease by haematopoietic cells is recognised in several animal models of inflammatory bowel disease and remission of Crohn's disease has been reported in patients who have received a bone marrow transplant. However, adoptive transfer of Crohn's disease susceptibility leading to phenotypic manifestation of the disease after transplantation has not been previously reported. Having ruled out an infective cause of a colitis in this case, we speculated that adoptive transfer of Crohn's disease may have occurred and performed a genetic analysis of known susceptibility loci for significant donor-recipient mismatches. The donor and recipient had several haplotype mismatches in HLA class III genes at the IBD3 locus. In addition, the donor (but not the recipient) had a polymorphism of the 5' UTR of NOD2/CARD15 that may be associated with Crohn's disease. This case highlights the question of whether adoptive transfer of Crohn's disease can occur between allogeneic stem cell transplant donor and recipient, in a similar fashion to that reported for other autoimmune diseases. This report should also stimulate debate regarding the need for stem cell transplant donor screening for inflammatory bowel disease.

Pulmonary complications following bone marrow transplantation.

Pulmonary complications account for significant morbidity and mortality in patients following bone marrow transplants (BMT). They are distinct from other immunosuppressed patients in that there is a predictable course of immunosuppresion and therefore of likely pulmonary complications. This is important when interpreting abnormal radiology as the predictable time course will enable narrowing the differential diagnoses to certain pulmonary complications that characteristically occur at a particular time following BMT. Early recognition and correct treatment of the pulmonary complications should minimize the significant mortality and morbidity. This review aims to discuss the role of radiology in the diagnosis and management of pulmonary complications following BMT.

Interaction of the human adenovirus proteinase with its 11-amino acid cofactor pVIc.

The interaction of the human adenovirus proteinase (AVP) and AVP-DNA complexes with the 11-amino acid cofactor pVIc was characterized. The equilibrium dissociation constant for the binding of pVIc to AVP was 4.4 microM. The binding of AVP to 12-mer single-stranded DNA decreased the K(d) for the binding of pVIc to AVP to 0.09 microM. The pVIc-AVP complex hydrolyzed the substrate with a Michaelis constant (K(m)) of 3.7 microM and a catalytic rate constant (k(cat)) of 1.1 s(-1). In the presence of DNA, the K(m) increased less than 2-fold, and the k(cat) increased 3-fold. Alanine-scanning mutagenesis was performed to determine the contribution of individual pVIc side chains in the binding and stimulation of AVP. Two amino acid residues, Gly1' and Phe11', were the major determinants in the binding of pVIc to AVP, while Val2' and Phe11' were the major determinants in stimulating enzyme activity. Binding of AVP to DNA greatly suppressed the effects of the alanine substitutions on the binding of mutant pVIcs to AVP. Binding of either or both of the cofactors, pVIc or the viral DNA, to AVP did not dramatically alter its secondary structure as determined by vacuum ultraviolet circular dichroism. pVIc, when added to Hep-2 cells infected with adenovirus serotype 5, inhibited the synthesis of infectious virus, presumably by prematurely activating the proteinase so that it cleaved virion precursor proteins before virion assembly, thereby aborting the infection.

Genvir (Flamel Technologies).

Flamel Technologies is developing Genvir (formerly known as Viropump), a twice-daily controlled-release formulation of aciclovir, for potential use in the treatment of herpes simplex virus and varicella zoster virus infections. Genvir utilizes Flamel's proprietary Micropump technology, a microparticle-based drug delivery system designed to extend the time of absorption of drugs in the small intestine. The drug shows a comparable therapeutic efficacy to valaciclovir and famciclovir (both GlaxoSmithKline) [313393]. Phase III trials have been completed [302829]. In August 2000, Flamel filed for regulatory approval for the treatment of herpes in France, as a prelude to a pan-European approval [378641] and is preparing an IND application to begin clinical trials for genital herpes in the US [245970].

Influence of virus strain, challenge dose, and time of therapy initiation on the in vivo influenza inhibitory effects of RWJ-270201.

The influenza virus neuraminidase inhibitor RWJ-270201 (cyclopentane carboxylic acid, 3-[cis-1-(acetylamino)-2-ethylbutyl]-4[(aminoiminomethyl)amino]-2-hydroxy-[cis, 2S, 3R, 4R]) was significantly inhibitory to an infection in mice induced by influenza A/NWS/33 (H1N1) virus when oral gavage (p.o.) treatment with 10 mg/kg per day was delayed at least 60 h after virus exposure. Treatment was 5 mg/kg twice daily for 5 days. Viral challenge doses of influenza A/Shangdong/09/93 (H3N2) virus ranging from the LD(70) to the LD(100) did not affect the marked antiviral efficacy of 12.5 mg/kg of RWJ-270201 administered p.o. twice daily for 5 days beginning 4 h pre-virus exposure; infection by an approximate 2 LD(100) dose (10(8) cell culture infectious doses/ml) was only weakly inhibited by the same treatment as seen by significant increase in mean day to death. Murine infections induced by influenza A/Bayern/57/93 (H1N1) and B/Lee/40 viruses were significantly inhibited by 100, 10, and 1 mg/kg per day of RWJ-270201 using the above treatment regimen; influenza A/PR/8/34 (H1N1) virus infections in mice were only moderately inhibited, the antiviral effects using this virus being lessening of arterial oxygen decline, reduced lung consolidation, and inhibition of lung virus titers primarily at the higher dosages.

A new form of antiviral combination therapy predicted to prevent resistance from arising, and a model system to test it.

Combination therapy in the treatment of viral infections in which, for example, three different drugs against three different targets on three independent proteins are administered, has been highly successful clinically. However, it is only a matter of time before a virus will arise resistant to all three drugs, because the mutations leading to drug resistance are independent of each other. But, what if the mutations leading to drug resistance are not independent of each other, but confer some cost to the virus? If the cost is too great, than resistance may not arise. To impose such a cost in the clinical treatment of viral infections, we propose a new form of combination therapy. Here, three different drugs against three different targets on the same virus-coded protein are administered. If the physiological functions of the three different target sites are not independent of each other, then, a mutation at one site may alter the physiological functions at the other sites. We present a model system in which to test the efficacy of this new form of triple combination therapy. Human adenovirus has a virus-coded proteinase that is essential for the synthesis of infectious virus. It contains an active site and two cofactor binding sites; the functions of the active site are dependent upon the cofactors interacting with their binding sites. We describe how to obtain drugs against the three different sites.

Cyclopentane neuraminidase inhibitors with potent in vitro anti-influenza virus activities.

A novel series of cyclopentane derivatives have been found to exhibit potent and selective inhibitory effects on influenza virus neuraminidase. These compounds, designated RWJ-270201, BCX-1827, BCX-1898, and BCX-1923, were tested in parallel with zanamivir and oseltamivir carboxylate against a spectrum of influenza A (H1N1, H3N2, and H5N1) and influenza B viruses in MDCK cells. Inhibition of viral cytopathic effect ascertained visually and by neutral red dye uptake was used, with 50% effective (virus-inhibitory) concentrations (EC(50)) determined. Against the H1N1 viruses A/Bayern/07/95, A/Beijing/262/95, A/PR/8/34, and A/Texas/36/91, EC(50)s (determined by neutral red assay) of the novel compounds were < or =1.5 microM. Twelve strains of H3N2 and two strains of avian H5N1 viruses were inhibited at <0.3 microM. Influenza B/Beijing/184/93 and B/Harbin/07/94 viruses were inhibited at <0.2 microM, with three other B virus strains inhibited at 0.8 to 8 microM. The novel inhibitors were comparable in potency to (or slightly more potent than) zanamivir and oseltamivir carboxylate. No cytotoxicity was seen with the compounds at concentrations of < or =1 mM in cell proliferation assays. The antiviral activity of RWJ-270201, chosen for clinical development, was studied in greater detail. Its potency and that of oseltamivir carboxylate decreased with increasing multiplicity of virus infection. Time-of-addition studies indicated that treatment with either compound needed to begin 0 to 12 h after virus exposure for optimal activity. Exposure of cells to RWJ-270201 caused most of the virus to remain cell associated, with extracellular virus decreasing in a concentration-dependent manner. This is consistent with its effect as a neuraminidase inhibitor. RWJ-270201 shows promise in the treatment of human influenza virus infections.

In vivo influenza virus-inhibitory effects of the cyclopentane neuraminidase inhibitor RJW-270201.

The cyclopentane influenza virus neuraminidase inhibitor RWJ-270201 was evaluated against influenza A/NWS/33 (H1N1), A/Shangdong/09/93 (H3N2), A/Victoria/3/75 (H3N2), and B/Hong Kong/05/72 virus infections in mice. Treatment was by oral gavage twice daily for 5 days beginning 4 h pre-virus exposure. The influenza virus inhibitor oseltamivir was run in parallel, and ribavirin was included in studies with the A/Shangdong and B/Hong Kong viruses. RWJ-270201 was inhibitory to all infections using doses as low as 1 mg/kg/day. Oseltamivir was generally up to 10-fold less effective than RWJ-270201. Ribavirin was also inhibitory but was less tolerated by the mice at the 75-mg/kg/day dose used. Disease-inhibitory effects included prevention of death, lessening of decline of arterial oxygen saturation, inhibition of lung consolidation, and reduction in lung virus titers. RWJ-270201 and oseltamivir, at doses of 10 and 1 mg/kg/day each, were compared with regard to their effects on daily lung parameters in influenza A/Shangdong/09/93 virus-infected mice. Maximum virus titer inhibition was seen on day 1, with RWJ-270201 exhibiting the greater inhibitory effect, a titer reduction of >10(4) cell culture 50% infective doses (CCID(50))/g. By day 8, the lung virus titers in mice treated with RWJ-270201 had declined to 10(1.2) CCID(50)/g, whereas titers from oseltamivir-treated animals were >10(3) CCID(50)/g. Mean lung consolidation was also higher in the oseltamivir-treated animals on day 8. Both neuraminidase inhibitors were well tolerated by the mice. RWJ-270201 was nontoxic at doses as high as 1,000 mg/kg/day. These data indicate potential for the oral use of RWJ-270201 in the treatment of influenza virus infections in humans.

Utilization of alpha-1-acid glycoprotein levels in the serum as a parameter for in vivo assay of influenza virus inhibitors.

Alpha-1-acid glycoprotein (AGP), an acute phase protein in serum assayed by single radial immunodiffusion using a commercially available kit, was found to significantly increase in mice infected with influenza A and B viruses. Experiments were run to determine the rate of increase of serum AGP and its relation to other influenza disease parameters, including lung consolidation, development of lung virus titres, decline in arterial oxygen saturation (SaO2), histopathological changes in the lung, and death of the animal. Maximal AGP levels occurred by day 3 in the animals, at about the same time lung virus titres reached their peak and inflammatory effects were evident in the lung. Serum levels of AGP were then compared with other disease parameters in the evaluation of the anti-influenza A and B virus efficacy of oseltamivir and ribavirin in mice. Treatment was by oral gavage twice daily for 5 days, beginning 4 h before virus exposure using doses of 100, 10, and 1 mg/kg per day of oseltamivir and 75 mg/kg per day of ribavirin. Against the influenza A infection, significant inhibition of death, SaO2 decline, and lung consolidation was seen at all doses of each compound; day-6 AGP levels were reduced in a dose-responsive manner. Lung virus titres were lessened at this time, but to a significant degree only at the high dose of oseltamivir and by ribavirin. The influenza B virus infection, which appeared more severe than the influenza A infection, was also significantly inhibited by both compounds, but to a lesser extent. The serum AGP levels were again lessened by therapy with both compounds. The influence of challenge dose of influenza A virus on AGP level and on the antiviral activity of 20 mg/kg per day of oseltamivir, administered by oral gavage, was determined in mice. The AGP level was in proportion to the viral challenge dose; oseltamivir significantly inhibited AGP levels and all other disease parameters regardless of size of viral inoculum. These data indicate murine AGP levels to be markedly stimulated by infection with influenza A and B viruses, and the level of the protein to be an additional measure of antiviral efficacy.

Pegasys (Hoffmann-La Roche).

Hoffmann-La Roche has developed a PEGylated interferon alpha-2a, Pegasys, for the potential treatment of chronic hepatitis C and hepatitis B virus infection. It was first approved in Switzerland in August 2001 [418260] and was expected to be launched in September/October 2001 [419333]. In May 2000, Roche submitted a BLA to the US FDA, for approval to market Pegasys for the treatment of chronic HCV infection in non-cirrhotic and cirrhotic patients with compensated liver disease [329872], [348368], [367781]. Approval was still pending in December 2000 [387363], [392481]. Roche expects the US launch to take place in the second half of 2001 [400857]. In April 2001, Roche received a complete response letter from the FDA for Pegasys and was working with the FDA to address the questions raised in the letter [407595], [418310]. In August 2001, Roche expected approval for HCV in the US in 2002 and for HBV in 2004 [419333]. At this time, Roche planned to file an sNDA for combination with ribavirin [421285]. By March 2001, EU and Canadian filings had been made [401793]. Roche also planned to launch the product for chronic HBV infection and various malignancies in 2004 and 2005, respectively [400857]. Pegasys was filed for registration in Brazil in the first part of 2000 [418310]. As of December 1999, the drug was in phase II for HCV infection in Japan. It is being developed by Nippon Roche, which intended to extrapolate foreign phase III data for use in an NDA application in Japan [351804]. As a result of a meeting of Japan's PMSB in March 2001, Pegasys may be given priority in the review of its NDA, if submitted [403782]. In August 2001, Schering-Plough entered into a licensing agreement with F Hoffman-La Roche Ltd and Hoffmann-La Roche Inc that settles all patent disputes regarding the two companies' PEGinterferon products. Under the terms of the agreement, Schering-Plough and Roche will cross license to each other all patents applicable to Peg-Intron and Pegasys. The settlement agreement also includes a Schering-Plough sublicense of Enzon's branched PEG patents to Roche [418935], [418956]. Roche is collaborating with Maxim Pharmceuticals to develop PEG-IFN alpha-2a in conjunction with Maxim's Maxamine [378609]. In July 1998, Hoffmann-La Roche and Weston Medical signed a global agreement to license INTRAJECT (Weston's single-use, disposable, prefilled, needle-free injector for subcutaneous delivery of injectable liquid pharmaceuticals) for delivery of Pegasys [292119]. In April 1999, ABN Amro predicted annual sales of SFr 25 million in 2000, rising to SFr 75 million in 2002 [328676]. In September 2000, Merrill Lynch predicted sales of SFr 70 million in 2001, rising to SFr 700 million in 2004 [383742]. In March 2001, Deutsche Bank estimated that the product has sales potential of SFr 1600 million [421009].

Inhibition of measles virus replication by 5'-nor carbocyclic adenosine analogues.

Despite intense efforts to increase vaccine coverage, measles virus (MV) still causes significant morbidity and mortality in the world, sometimes as the result of severe, chronic, lethal disease. In an effort to develop therapies to supplement immunization strategies, a number of 5'-nor carbocyclic adenosine analogues were evaluated for anti-MV activity in CV-1 monkey kidney cells. Of those compounds tested, those either unsubstituted at C4 or possessing a hydroxyl, azido or amino substituent at that position were the most active, with particularly significant inhibition of MV, strain Chicago-1. The EC50 values against this strain ranged from <0.1 to 1 mg/ml, as determined by cytopathic effect reduction assay, and confirmed by neutral red uptake. By virus yield reduction assay (+)-(1S,25,3R,4S)-4-(6'-amino-9'H-purin-9'-yl)cyclopentane-1,2,3-triol (2) (-)-(1R,2S,3R)-1-(6'-amino-9'H-purin-9'-yl)-2,3-dihydoxycyclopent-4-ene (3) (-)-(1R,2S,3R)-1-(6'-amino-9'H-purin-9'-yl)cyclopentane-2,3-dihydoxycyclopentane (5) and (-)-(1R,2R,3R,4S)-4-amino-1-(6'-amino-9'H-purin-9'-yl)cyclopentane-2,3-diol (8) were the most potent compounds tested, all with EC90 values of < or =0.4 mg/ml. Compounds 3 and 5 were also tested against other MV strains, and similarly inhibited those strains except for four designated as Bil, Edmonston, SA and X-1108. Compound 8 did not potently inhibit these other MV strains. In addition, 3, 5 and 8 demonstrated synergistic (additive) inhibition of MV replication in combination with ribavirin at several concentrations. Compounds 3, 5 and 8 were also potent MV inhibitors even when added to infected cells 24 h after virus exposure. None of these three compounds was virucidal at concentrations that inhibited viral replication as determined by virus yield reduction assay. Most compounds tested were also not toxic at concentrations >100 mg/ml in actively growing and stationary-phase cells. Results suggest that these compounds may be clinically useful anti-MV virus agents.

RWJ-270201 BioCryst Pharmaceuticals/Johnson & Johnson.

RWJ-270201, the lead compound in a series of influenza neuraminidase inhibitors, is under development by BioCryst for the potential treatment of influenza [214908], [337716]. Phase III trials commenced in North America and Europe in February 2000 [355053]. Phase II studies were performed to test the effectiveness of RWJ-270201 at reducing viral titers in infected patients. Data showed that the compound was well tolerated and produced statistically significant reductions in viral titers [337716]. Under a worldwide influenza collaboration formed in September 1998, two subsidiaries of Johnson & Johnson, the RW Johnson Pharmaceutical Research Institute and Ortho McNeil, have received exclusive worldwide rights to RWJ-270201 [298487].

Technology evaluation: Sch-58500, Canji.

Sch-58500 is a gene therapy utilizing the p53 gene and is under development by Canji and Schering-Plough for the potential treatment of various types of cancer. It is in phase II/III clinical trials in the US for stage III ovarian cancer [328228,328893], phase II clinical trials for hepatocellular and colorectal cancer metastatic to the liver [273331,324279], and phase I clinical trials for several other types of cancer [282801,284932,328228].

2-5A-DNA conjugate inhibition of respiratory syncytial virus replication: effects of oligonucleotide structure modifications and RNA target site selection.

To define more fully the conditions for 2-5A-antisense inhibition of respiratory syncytial virus (RSV), relationships between 2-5A antisense oligonucleotide structure and the choice of RNA target sites to inhibition of RSV replication have been explored. The lead 2-5A-antisense chimera for this study was the previously reported NIH8281 that targets the RSV M2 RNA. We have confirmed and extended the earlier study by showing that NIH8281 inhibited RSV strain A2 replication in a variety of antiviral assays, including virus yield reduction assays performed in monkey (EC90 = 0.02 microM) and human cells (EC90 = microM). This 2-5A-antisense chimera also inhibited other A strains, B strains and bovine RSV in cytopathic effect inhibition and Neutral Red Assays (EC50 values = 0.1-1.6 microM). The 2'-O-methylation modification of NIH8281 to increase affinity for the complementary RNA and provide nuclease resistance, the introduction of phosphothioate groups in the antisense backbone to enhance resistance to exo- and endonucleases, and the addition of cholesterol to the 3'-terminus of the antisense oligonucleotide to increase cellular uptake, all resulted in loss of activity. Of the antisense chimeras targeting other RSV mRNAs (NS1, NS2, P, M. G, F, and L), only those complementary to L mRNA were inhibitory. These results suggest that lower abundance mRNAs may be the best targets for 2-5A-antisense; moreover, the active 2-5A antisense chimeras in this study may serve as useful guides for the development of compounds with improved stability, uptake and anti-RSV activity.

Antiviral activities of biflavonoids.

Biflavonoids such as amentoflavone (1), agathisflavone (2), robustaflavone (3), hinokiflavone (4), volkensiflavone (5), rhusflavanone (7), succedaneflavanone (9), all isolated from Rhus succedanea and Garcinia multiflora, as well as their methyl ethers and acetates, volkensiflavone hexamethyl ether (6), rhusflavanone hexaacetate (8), and succedaneflavanone hexaacetate (10) were evaluated for their antiviral activities. The inhibitory activities against a number of viruses including respiratory viruses (influenza A, influenza B, respiratory syncytial, parainfluenza type 3, adenovirus type 5, and measles) and herpes viruses (HSV-1, HSV-2, HCMV, and VZV) were investigated. The results indicated that robustaflavone exhibited strong inhibitory effects against influenza A and influenza B viruses with EC50 values of 2.0 micrograms/ml and 0.2 microgram/ml, respectively, and selectivity index values (SI) of 16 and 454, respectively. Amentoflavone and agathisflavone also demonstrated significant activity against influenza A and B viruses. Amentoflavone and robustaflavone exhibited moderate anti-HSV-1 anti-HSV-2 activities with EC50 values of 17.9 micrograms/ml (HSV-1) and 48.0 micrograms/ml (HSV-2) and SI values of > 5.6 (HSV-1) and > 2.1 (HSV-2) for amentoflavone; EC50 values of 8.6 micrograms/ml (HSV-1) and 8.5 micrograms/ml (HSV-2), and SI values of > 11.6 (HSV-1) and > 11.8 (HSV-2) for robustaflavone. Rhusflavanone demonstrated inhibitory activities against influenza B, measles, and HSV-2 viruses with SI values of 9.3, 8 and > 6.4, respectively. Succedaneaflavanone exhibited inhibitory activities against influenza B virus and VZV with SI values of 15 and < 3.0, respectively.

Five-year follow-up of a prospective randomised multi-centre trial of weekly chemotherapy (CAPOMEt) versus cyclical chemotherapy (CHOP-Mtx) in the treatment of aggressive non-Hodgkin's lymphoma. Central Lymphoma Group.

BACKGROUND: Weekly alternating regimen known as CAPOMEt is compared to standard cyclical chemotherapy (CHOP-Mtx) in aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Three hundred and eighty-one patients with aggressive NHL were randomised to receive either cyclophosphamide, doxorubicin, vincristine, prednisone and methotrexate (CHOP-Mtx) on a cyclical basis or a weekly regimen incorporating the same drugs with the addition of etoposide (CAPOMEt). RESULTS: After pathological review, 281 patients were deemed eligible. At the census date of 31 March 1994, 158 patients were alive with a median follow up of 5.9 years (minimum 3.0 years). Analysis of all patients and eligible patients showed no significant treatment differences in the rates of complete remission (CR), failure free survival (FFS) or overall survival (OS) between the two arms. The actuarial median OS was 24 months for CAPOMEt compared with 31 months for CHOP-Mtx, with five-year actuarial survival rates of 37% and 43%, respectively. Myelosuppression was significantly more severe with CHOP-Mtx and neurotoxicity was much more common with CAPOMEt. CONCLUSION: Weekly CAPOMEt is equally effective as standard cyclical CHOP-Mtx treatment in aggressive NHL.