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New therapy packs powerful one-two punch against HCV
Gastroenterology News John H. Walsh, Section Editor
Salmonella typhimurium Paves Its Own Road into Target Cells
cell invasion. This ruffling was similar to the changes produced by constituitively active Rac-1 and was accompaalmonella typhimurium enters nied by lamellopodia activity typiintestinal mucosal cells after adcally caused by activated CDC42. hering to their extracellular memInvolvement of these two substances brane. Entry is accomplished only in bacterial invasion was proven by after the adjacent cell membrane is finding that their inhibition by overaltered by a type of cytoskeletal rearexpression of dominant negative rangement known as membrane rufRac-1 or CDC42 prevented cytoskelfling. A mechanism used by Salmoetal changes and prevented bacterial nella to initiate membrane ruffling invasion. and bacterial penetration was deSopE also induced JNK-1 activscribed recently by Hardt et al. in ity by activating Rac-1 and the May 29 issue of Cell. SalmoCDC42, but did not activate the nella uses type III secretion to alternate Erk MAP kinase pathinject a toxin into its host cell way. Thus, type III secretion of that causes a series of biochemical SopE into cells by Salmonella changes that weaken cellular resisnot only causes changes that tance and ultimately lead to phagolead to bacterial internalization, cytosis of the bacterium. but also activates transcription Type III secretion is a recently factors that stimulate production described mechanism used by of TNF-a and other inflammatory bacteria to secrete proteins into cytokines. SopE was found to form cells to which they form attachspecific molecular interactions with ments. In the case of Salmonella, Rac-1 and with CDC-42 that led to cellular resistance to bacterial loss of GDP binding and to formaphagocytosis is diminished by a After S. typhimurium binds to the surface of an intestinal tion of the active GTP bound forms. process that also initiates inflamma- mucosal cell, it injects bacterial proteins through the host Once Salmonella enters the cell membrane by a type III secretory mechanism. One of tory reactions in the host cell. host cell, stimulation of inflammathese proteins, Sop E, causes a series of events leading An S. typhimurium protein to entry of the organism into the epithelial cell and tory products is enhanced and known as SopE has been identi- ultimately to inflammation and diarrhea. Sop E seletively ultimately causes tissue inflammaactivates two members of the rho family of small GTP fied as a key player in cellular binding proteins, CDC-42 and Rac-1, that cause rear- tion and diarrhea that are known infection. SopE is a GDP/GTP rangements of the actin cytoskeleton in the adjacent consequences of this infection. exchange factor that activates plasma membrane, leading to localized membrane ruf- This is another example of alterfling and enabling the bacterium to enter the cell. Activaseveral small-molecular-weight tion of CDC-42 and Rac-1 also leads to JNK-1 activation ation of specific intracellular GTPases in the Rho family, espe- which, along with other products of the internalized pathways by bacterial toxins that cially Rac-1 and CDC42. Activa- S. typhimurium, induces production of cytotoxic cyto- enable enteric pathogens to mulkines leading to inflammation and diarrhea tion of Rac-1 or of CDC42 causes tiply and survive.
S
New Therapy Packs Powerful One-Two Punch Against HCV leading hepatologist refers to the recently approved combination antiviral therapy for chronic hepatitis C (HCV) as a significant breakthrough. Rebetron, manufactured by Schering-Plough Corp., (Kenilworth, NJ) consists of a 6-month course of interferon injections combined with ribavirin capsules. It was approved by
A
changes in cellular morphology and motility including membrane ruffling formation of filopodia, and their activation by SopE appears to be a principal step leading to Salmonella invasion and pathogenesis. SopE, either microinjected or artificially expressed in cultured cells, caused membrane ruffling and led to internalization of a strain of S. typhimurium that lacks SopE, does not induce ruffling, and is incapable of
the FDA in June for adult hepatitis C patients who initially respond to and later relapse with standard treatment (interferon alone). An estimated 4 million Americans are believed to be infected with HCV. The virus is responsible for about 10,000 deaths a year in this country, and is the leading indication for liver transplantation. Interferon alone eliminates the virus in only 10%–20% of patients, but another 25%–40% respond and subse-
quently relapse. In patients for whom the FDA approved the therapy, nearly half experienced a sustained remission (6 months or more) when administered the interferon/ribavirin combination in trials held in both the United States and Europe, roughly 10-fold better than the patients who received interferon alone. Although the FDA approved the therapy specifically for the subgroup of patients who relapse after responding to interferon alone, physicians GASTROENTEROLOGY 1998;115:255–256
Gastroenterology News continued
will be able to prescribe the treatment for patients as a first course. While the FDA has not yet reviewed the data, Willis C. Maddrey of the University of Texas Southwestern Medical Center in Dallas notes that published results out of Europe suggest that naive patients respond better to the combination. From 20% to 40% of HCV patients develop cirrhosis, but the clinical complications often take as many as 20 years to present. Maddrey points out that patients who are not cirrhotic have shown a substantially higher response rate to the treatment than those who are in a later stage of the disease. ‘‘I cannot see a patient right now and accurately predict that he will or won’t develop cirrhosis in
20 years,’’ Maddrey says. ‘‘But I can say that if you take your chances and don’t get treated, and you develop cirrhosis, you’re going to be much more resistant to treatment.’’ Of course, the new treatment won’t be for everyone. The side effects of the combination therapy are potentially serious, because ribavirin causes a nonimmune hemolytic anemia, with an average drop in hemoglobin of about 2 g. ‘‘It’s important for physicians to plan for that, to test patients’ hemoglobin levels before treatment and at 2 and 4 weeks, and not to use this drug in anyone who couldn’t stand a moderate drop in hemoglobin,’’ says Maddrey. The combination therapy is also expensive, estimated at $6400–$8600 for
the 6-month course. But Maddrey suspects that cost-efficacy studies will ultimately support the new therapy’s use. As for the slight majority of HCV patients who don’t respond to the Rebetron, Maddrey predicts that the next breakthrough will come with the addition, not substitution, of another antiviral drug, possibly a protease inhibitor, to the combination treatment. ‘‘It’s similar to what occurred in AIDS, where we did well with AZT for awhile, but the real breakthrough came when we added a protease inhibitor to the AZT,’’ he says. ‘‘We feel that multidrug therapy is the wave of the future, and that hitting this virus in two or three sites gives us a much better chance of eradication.’’
First Crohn’s Disease Drug on Approval Track
Approximately 100,000 Americans currently suffer from Crohn’s disease, which is characterized by inflammation of the gastrointestinal tract. Infliximab blocks activity of TNF-a, a key proinflammatory mediator. The FDA committee reviewed data from two clinical trials of patients suffering from active and fistulizing Crohn’s disease. In the first study, 65% of patients treated with Infliximab achieved a clinical response and 33% went into remission within 4 weeks of treatment. A second study found that approximately two thirds of participants experienced closure of at least 50% of their enterocutaneous fistulae.
At the same time that it recommended approval, the committee called on Centocor Inc. to continue testing the drug to determine its long-term safety and effectiveness. ‘‘The intravenous infusion of Infliximab shows a lot of promise for patients with active Crohn’s disease despite ongoing therapy with steroids and immunosuppressants,’’ says Dr. Stephen Hanauer of the University of Chicago. ‘‘The infusions have also been very effective for Crohn’s disease fistulae. Additional data are needed to assess the value of repeated infusions on an ongoing basis to prevent relapse.’’
Among the questions: Will one drug-company merger touch off other industry deals by competitors seeking to keep pace, and what will the resulting mega-companies mean for new drug development? Given the increasingly large capital required to translate basic research into new and improved pharmaceuticals, many analysts believe such mergers will become increas-
ingly common, and that, unlike consolidations of the past, which often had the effect of stifling competition, these larger companies will help ensure the global approach increasingly necessary to achieve major scientific advances.
n FDA advisory committee has unanimously recommended approval of a tumor necrosis factor (TNF)-a antibody, the first drug specifically aimed at Crohn’s disease. Infliximab, manufactured by Centocor Inc. (Leiden, The Netherlands), is a monoclonal antibody that relieves symptoms of patients with moderate to severe Crohn’s disease for whom conventional therapy is inadequate. The drug has also been found to be effective in healing draining fistulae, the painful channels that open between the bowel and the skin, mostly in the perianal area, causing drainage of mucous and/or fecal material.
A
American Home/Monsanto Pairing: Start of a Trend? he announcement in June that American Home Products was buying Monsanto in the largest-ever pharmaceutical industry transaction has revived speculation last heard in February, when the planned marriage of Glaxo Wellcome and SmithKline Beecham was abruptly called off.
T
256
Stories by Dan Gordon The section editor can be sent suggestions for articles at [email protected]
Salmonella typhimurium Paves Its Own Road into Target Cells
cell invasion. This ruffling was similar to the changes produced by constituitively active Rac-1 and was accompaalmonella typhimurium enters nied by lamellopodia activity typiintestinal mucosal cells after adcally caused by activated CDC42. hering to their extracellular memInvolvement of these two substances brane. Entry is accomplished only in bacterial invasion was proven by after the adjacent cell membrane is finding that their inhibition by overaltered by a type of cytoskeletal rearexpression of dominant negative rangement known as membrane rufRac-1 or CDC42 prevented cytoskelfling. A mechanism used by Salmoetal changes and prevented bacterial nella to initiate membrane ruffling invasion. and bacterial penetration was deSopE also induced JNK-1 activscribed recently by Hardt et al. in ity by activating Rac-1 and the May 29 issue of Cell. SalmoCDC42, but did not activate the nella uses type III secretion to alternate Erk MAP kinase pathinject a toxin into its host cell way. Thus, type III secretion of that causes a series of biochemical SopE into cells by Salmonella changes that weaken cellular resisnot only causes changes that tance and ultimately lead to phagolead to bacterial internalization, cytosis of the bacterium. but also activates transcription Type III secretion is a recently factors that stimulate production described mechanism used by of TNF-a and other inflammatory bacteria to secrete proteins into cytokines. SopE was found to form cells to which they form attachspecific molecular interactions with ments. In the case of Salmonella, Rac-1 and with CDC-42 that led to cellular resistance to bacterial loss of GDP binding and to formaphagocytosis is diminished by a After S. typhimurium binds to the surface of an intestinal tion of the active GTP bound forms. process that also initiates inflamma- mucosal cell, it injects bacterial proteins through the host Once Salmonella enters the cell membrane by a type III secretory mechanism. One of tory reactions in the host cell. host cell, stimulation of inflammathese proteins, Sop E, causes a series of events leading An S. typhimurium protein to entry of the organism into the epithelial cell and tory products is enhanced and known as SopE has been identi- ultimately to inflammation and diarrhea. Sop E seletively ultimately causes tissue inflammaactivates two members of the rho family of small GTP fied as a key player in cellular binding proteins, CDC-42 and Rac-1, that cause rear- tion and diarrhea that are known infection. SopE is a GDP/GTP rangements of the actin cytoskeleton in the adjacent consequences of this infection. exchange factor that activates plasma membrane, leading to localized membrane ruf- This is another example of alterfling and enabling the bacterium to enter the cell. Activaseveral small-molecular-weight tion of CDC-42 and Rac-1 also leads to JNK-1 activation ation of specific intracellular GTPases in the Rho family, espe- which, along with other products of the internalized pathways by bacterial toxins that cially Rac-1 and CDC42. Activa- S. typhimurium, induces production of cytotoxic cyto- enable enteric pathogens to mulkines leading to inflammation and diarrhea tion of Rac-1 or of CDC42 causes tiply and survive.
S
New Therapy Packs Powerful One-Two Punch Against HCV leading hepatologist refers to the recently approved combination antiviral therapy for chronic hepatitis C (HCV) as a significant breakthrough. Rebetron, manufactured by Schering-Plough Corp., (Kenilworth, NJ) consists of a 6-month course of interferon injections combined with ribavirin capsules. It was approved by
A
changes in cellular morphology and motility including membrane ruffling formation of filopodia, and their activation by SopE appears to be a principal step leading to Salmonella invasion and pathogenesis. SopE, either microinjected or artificially expressed in cultured cells, caused membrane ruffling and led to internalization of a strain of S. typhimurium that lacks SopE, does not induce ruffling, and is incapable of
the FDA in June for adult hepatitis C patients who initially respond to and later relapse with standard treatment (interferon alone). An estimated 4 million Americans are believed to be infected with HCV. The virus is responsible for about 10,000 deaths a year in this country, and is the leading indication for liver transplantation. Interferon alone eliminates the virus in only 10%–20% of patients, but another 25%–40% respond and subse-
quently relapse. In patients for whom the FDA approved the therapy, nearly half experienced a sustained remission (6 months or more) when administered the interferon/ribavirin combination in trials held in both the United States and Europe, roughly 10-fold better than the patients who received interferon alone. Although the FDA approved the therapy specifically for the subgroup of patients who relapse after responding to interferon alone, physicians GASTROENTEROLOGY 1998;115:255–256
Gastroenterology News continued
will be able to prescribe the treatment for patients as a first course. While the FDA has not yet reviewed the data, Willis C. Maddrey of the University of Texas Southwestern Medical Center in Dallas notes that published results out of Europe suggest that naive patients respond better to the combination. From 20% to 40% of HCV patients develop cirrhosis, but the clinical complications often take as many as 20 years to present. Maddrey points out that patients who are not cirrhotic have shown a substantially higher response rate to the treatment than those who are in a later stage of the disease. ‘‘I cannot see a patient right now and accurately predict that he will or won’t develop cirrhosis in
20 years,’’ Maddrey says. ‘‘But I can say that if you take your chances and don’t get treated, and you develop cirrhosis, you’re going to be much more resistant to treatment.’’ Of course, the new treatment won’t be for everyone. The side effects of the combination therapy are potentially serious, because ribavirin causes a nonimmune hemolytic anemia, with an average drop in hemoglobin of about 2 g. ‘‘It’s important for physicians to plan for that, to test patients’ hemoglobin levels before treatment and at 2 and 4 weeks, and not to use this drug in anyone who couldn’t stand a moderate drop in hemoglobin,’’ says Maddrey. The combination therapy is also expensive, estimated at $6400–$8600 for
the 6-month course. But Maddrey suspects that cost-efficacy studies will ultimately support the new therapy’s use. As for the slight majority of HCV patients who don’t respond to the Rebetron, Maddrey predicts that the next breakthrough will come with the addition, not substitution, of another antiviral drug, possibly a protease inhibitor, to the combination treatment. ‘‘It’s similar to what occurred in AIDS, where we did well with AZT for awhile, but the real breakthrough came when we added a protease inhibitor to the AZT,’’ he says. ‘‘We feel that multidrug therapy is the wave of the future, and that hitting this virus in two or three sites gives us a much better chance of eradication.’’
First Crohn’s Disease Drug on Approval Track
Approximately 100,000 Americans currently suffer from Crohn’s disease, which is characterized by inflammation of the gastrointestinal tract. Infliximab blocks activity of TNF-a, a key proinflammatory mediator. The FDA committee reviewed data from two clinical trials of patients suffering from active and fistulizing Crohn’s disease. In the first study, 65% of patients treated with Infliximab achieved a clinical response and 33% went into remission within 4 weeks of treatment. A second study found that approximately two thirds of participants experienced closure of at least 50% of their enterocutaneous fistulae.
At the same time that it recommended approval, the committee called on Centocor Inc. to continue testing the drug to determine its long-term safety and effectiveness. ‘‘The intravenous infusion of Infliximab shows a lot of promise for patients with active Crohn’s disease despite ongoing therapy with steroids and immunosuppressants,’’ says Dr. Stephen Hanauer of the University of Chicago. ‘‘The infusions have also been very effective for Crohn’s disease fistulae. Additional data are needed to assess the value of repeated infusions on an ongoing basis to prevent relapse.’’
Among the questions: Will one drug-company merger touch off other industry deals by competitors seeking to keep pace, and what will the resulting mega-companies mean for new drug development? Given the increasingly large capital required to translate basic research into new and improved pharmaceuticals, many analysts believe such mergers will become increas-
ingly common, and that, unlike consolidations of the past, which often had the effect of stifling competition, these larger companies will help ensure the global approach increasingly necessary to achieve major scientific advances.
n FDA advisory committee has unanimously recommended approval of a tumor necrosis factor (TNF)-a antibody, the first drug specifically aimed at Crohn’s disease. Infliximab, manufactured by Centocor Inc. (Leiden, The Netherlands), is a monoclonal antibody that relieves symptoms of patients with moderate to severe Crohn’s disease for whom conventional therapy is inadequate. The drug has also been found to be effective in healing draining fistulae, the painful channels that open between the bowel and the skin, mostly in the perianal area, causing drainage of mucous and/or fecal material.
A
American Home/Monsanto Pairing: Start of a Trend? he announcement in June that American Home Products was buying Monsanto in the largest-ever pharmaceutical industry transaction has revived speculation last heard in February, when the planned marriage of Glaxo Wellcome and SmithKline Beecham was abruptly called off.
T
256
Stories by Dan Gordon The section editor can be sent suggestions for articles at [email protected]