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Idun Pharmaceuticals Initiates Phase 2 Clinical Trial
In Liver Transplantation
Wednesday October 8, 8:05 am ET
SAN DIEGO, Oct. 8 /PRNewswire/ -- Idun Pharmaceuticals, Inc. today
announced that it has initiated a Phase 2 clinical trial of IDN-6556 in
patients undergoing liver transplantation. IDN-6556 is designed to protect
liver cells from excessive programmed cell death, also known as apoptosis.
The study will evaluate if IDN-6556 can decrease the cellular liver damage
that can occur during the transport and transplant periods. In the study,
the drug will be administered to the donor liver during transport to the
transplant center, as well as to the liver recipient. The study was
initiated at Mayo Clinic in Rochester, MN, which is the first of twelve
leading transplant hospitals that are expected to participate in the
approximately 100 patient clinical trial.
"While there are approximately 5,000 liver transplants performed each
year in the United States, there are over 17,000 patients on the waiting
list for a transplant," according to Gregory Gores, M.D., Professor of
Medicine at the Mayo Clinic and Research Foundation and a principal
investigator in the study. "There is an enormous need for additional
therapies that may allow an increased number of organs to be transplanted.
I have conducted several pre-clinical studies in models of liver
transplantation with IDN-6556 and it has exhibited very beneficial
effects. We hope to see the same sort of benefits in this patient group."
"We are excited to initiate this very important study," said David
Shapiro, M.D., Idun's Chief Medical Officer. "We believe that the drug has
considerable potential in treating several hepatic diseases and feel that
liver transplantation offers the fastest route to clinical proof of
efficacy and ultimately, regulatory approval."
IDN-6556, given orally, is currently being studied in a Phase 2 human
clinical trial in several groups of patients, initially those with
hepatitis C virus who have failed to respond to existing drugs. Idun
recently announced that the Food and Drug Administration granted orphan
drug designation for the use of the drug in liver and other solid organ
transplant patients.
Idun Pharmaceuticals, Inc. is a biopharmaceutical company located in
San Diego, CA, creating innovative human therapeutics with a primary focus
on controlling apoptosis, or programmed cell death. Apoptosis is a
normally occurring biological process mediated by a cascade of
intra-cellular enzymes. Too much or too little apoptosis is believed to
play a role in many important human diseases. Idun believes that its drugs
will have utility in treating liver disease, inflammation, cancer, and
cardiovascular disease. Idun has an extensive patent portfolio covering
the fundamental and core technologies involved in the regulation of cell
death.
Some of the statements in this press release are forward-looking
statements and do not guarantee future performance and involve risks and
uncertainties. Actual results may differ substantially from the results
that the forward-looking statements suggest for various reasons. These
forward-looking statements are made only as of the date of this press
release.
Source: Idun Pharmaceuticals, Inc.
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Branched-Chain Amino Acids Effective Treatment for
Cirrhosis
By Darin Ingels, ND
People with cirrhosis of the liver may live longer,
improve their liver function, have fewer hospital
admissions and days in the hospital, and have an
increased quality of life by taking supplemental
branched-chain amino acids (BCAAs), according to a new
study in Gastroenterology (2003;124:1792ˆ801). This is
encouraging for the thousands of people suffering from
this devastating disease.
Cirrhosis is a chronic condition of the liver in which
the cells become damaged and scar tissue forms. As
more scar tissue forms, the functioning of the liver
becomes impaired to the point that transplantation is
often necessary for survival. Cirrhosis is the third
leading cause of death in the United States in adults
aged between 45 and 65 years. It is most often caused
by excessive alcohol consumption, but may also be
caused by chronic hepatitis (such as hepatitis B or
hepatitis C viruses), autoimmune disease, diabetes,
gallbladder disease, or trauma. There is currently no
cure for cirrhosis; treatment is aimed primarily at
treating symptoms and preventing or managing
complications.
In the new study, 174 older adults with advanced
cirrhosis were randomly assigned to receive one of
three treatments for one year. The active-treatment
group received 14.4 grams per day of BCAA (providing
7.2 grams of L-leucine, 3.6 grams of L-isoleucine, and
3.6 grams of L-valine per day), while the other groups
received either a similar amount of lactalbumin (a
milk protein) or maltodextrin (a carbohydrate).
Lactalbumin and maltodextrin are commonly used to help
treat malnutrition associated with cirrhosis. The
number of participants who died or had disease
progression, the number of hospital admissions, and
the duration of hospital stay during the study were
recorded. Other measurements, including nutritional
status, liver function, anorexia, and quality of life,
were taken periodically throughout the study.
The number of people with disease progression or who
died was 57% lower in participants taking BCAAs than
in those taking lactalbumin and 49% lower than in
those taking maltodextrin. Those taking BCAAs were
admitted to the hospital less than half as often and
also spent fewer days in the hospital than those in
the lactalbumin or maltodextrin groups. Liver
function, nutritional status, and quality of life were
all significantly improved after BCAA supplementation.
Scientists do not completely understand how BCAAs help
cirrhosis, although improvements in nutrition probably
account for some of the benefits. Some participants
had an aversion to the taste of the BCAAs, which was
provided in powder form; this led to lower compliance
than was expected. BCAAs are available in capsule
form, but a large number of capsules would have to be
taken to achieve a dose of 14.4 grams per day. Some
physicians recommend taking BCAAs on an empty stomach,
because food proteins can inhibit the absorption of
BCAAs or inhibit their uptake into cells.
Darin Ingels, ND, MT (ASCP), received his bachelor‚s
degree from Purdue University and his Doctorate of
Naturopathic Medicine from Bastyr University in
Kenmore, WA. Dr. Ingels is the author of The Natural
Pharmacist: Lowering Cholesterol (Prima, 1999) and
Natural Treatments for High Cholesterol (Prima, 2000).
He currently is in private practice at New England
Family Health Associates located in Southport, CT,
where he specializes in environmental medicine and
allergies. Dr. Ingels is a regular contributor to
Healthnotes and Healthnotes Newswire. |
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Poor survival after liver retransplantation:
Is hepatitis C to blame?
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: Liver Transpl. 2003 Oct;9(10):1019-24. Links
Poor survival after liver retransplantation: Is hepatitis C to blame?
Watt KD, Lyden ER, McCashland TM.
Internal Medicine/Hepatology, University of Nebraska Medical Center,
Omaha, NE.
Data from 1990 to 1996 suggest that the prevalence of hepatitis C
virus (HCV) infection in repeated orthotopic liver transplantation
(re-OLT) is increasing, and patient survival may be worse.
Aims of the study are to: (1) assess the prevalence of HCV in re-
OLT, (2) compare survival between primary OLT and re-OLT for HCV
versus non-HCV diseases, and (3) evaluate Model for End-Stage Liver
Disease (MELD) scores in re-OLT.
The United Network for Organ Sharing database for adult patients
undergoing primary OLT or re-OLT from January 1996 to June 2002 was
analyzed.
Patients with malignancy or those who underwent re-OLT within 30
days of primary OLT were excluded. A total of 22,120 primary OLTs
and 2,129 re-OLTs were performed. HCV was noted in 9,564 primary
OLTs (43.2%) and 899 re-OLTs (42.2%). Overall 1, 3, and 5-year
patient survival rates were 86%, 79%, and 73% for primary OLT, but
67%, 56%, and 52% for re-OLT (P <.001).
Survival rates of patients with HCV at 1, 3, and 5 years were 86%,
76%, and 68% for primary OLT and 61%, 50%, and 45% for re-OLT (P
<.001). Survival was less for patients with HCV compared with those
with autoimmune hepatitis (AIH) and hepatitis B for re-OLT (P <.01).
However, survival after re-OLT was no different for those with HCV
than for those with all other causes. MELD scores between 11 and 20
were the most common for re-OLT.
A marked decreased in survival was noted in all patients who
underwent re-OLT with MELD scores greater than 25. HCV prevalence in
OLT has reached a plateau in recent years. Survival after re-OLT is
inferior to that for primary OLT, but re-OLT survival appears to
have improved.
Survival after re-OLT is lower in patients with HCV compared with
those with AIH and hepatitis B, but no different than for those with
most other liver diseases. Survival appeared worse in patients who
underwent re-OLT with a MELD score greater than 25.
PMID: 14526394 [PubMed - in process]
www.hcvadvocate.com |
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Adult-to-Adult
Living Donor Liver Transplantation Cohort Study
Hepatology, October 2003, Volume 38, Number 4
Liver transplantation is now the standard of care for patients with
end-stage liver disease. In 2002, more than 4,500 liver
transplantations were performed in the United States. At the same
time, more than 18,000 patients were awaiting liver transplantation,
and in recent years, the waiting list has continued to grow. As a
consequence, the numbers of patients dying on the transplant
waiting list has grown. The introduction of the MELD system was
designed to assign livers to patients in greatest need and thus
decrease waiting list mortality. This approach may be partially
successful, but the continued shortage of cadaveric livers will mean
that the mortality rate on the waiting list will remain high.
Among remedies to the shortage of livers for transplantation, living
donor liver transplantation (LDLT) is perhaps the most immediately
practicable, but is also quite controversial. LDLT has become widely
accepted for pediatric patients. For children, the left lobe of an
adult liver is adequate for transplantation, and this procedure
(particularly from parent to child) has been done successfully for
more than a decade. For adults, transplantation of a left lobe
of the liver (~20% to 30% of the liver mass) is usually inadequate
to support life, particularly in patients with end-stage liver
disease. Transplantation of the right lobe (~50% to 60% of the liver
mass) can be successful in adults, but the donor operation is more
extensive and accordingly more life threatening. Adult-to-adult,
right-lobe LDLT was introduced in the United States in 1997
and now accounts for almost 5% of adult liver transplantations.
Nevertheless, the donor operation is challenging and potentially
dangerous. Indeed, between 1998 to 2003, at least 2 healthy, adult
donors died shortly after right-lobe liver donation.
To address these issues and set an agenda for future research, the
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) and the American Association for the Study of Liver Diseases
cosponsored a 2-day workshop entitled "Living Donor Liver
Transplantation" in December 2000, a summary of which has been
published (Liver Transplantation 2002;8:174-88). A major conclusion
from the meeting was the immediate and critical need for a
prospective study of LDLT focusing on the relative risks and
benefits of the use of living versus cadaveric livers and on the
short- and long-term complications of the donor operation.
Accordingly, NIDDK has established a multicenter clinical study
entitled the "Adult-to-Adult Living Donor Liver Transplantation
Cohort Study" (A2ALL), which consists of 9 transplant centers
experienced in performing LDLT and a data coordinating center
responsible for directing and maintaining a clinical database. The
primary goal of A2ALL will be to provide objective and reliable
information on the outcomes of LDLT for both donors and recipients.
Outcomes will be compared between recicients of living donation and
potential living donor recipients who had a living donor evaluated
but did not go through with the living donor transplantation, which
is a common occurrence.
Both a prospective and a retrospective database of LDLTs will be
established. Special areas of focus will include graft and patient
survival, acute rejection, biliary complications, hepatitis C and
its recurrence after transplantation, and quality of life. Major
emphasis will also be placed on evaluation and follow-up of liver
donors including careful analyses of the adequacy of informed
consent, short- and long-term complications of the donor surgery,
and long-term follow-up of donors assessing general health, quality
of life, and personal and psychological effects of liver donation.
PRINCIPAL INVESTIGATORS and A2ALL LIVER TRANSPLANT CENTERS
--Michael Abecassis, M.D., Northwestern University, Chicago, IL;
--Carl Berg, M.D., University of Virginia, Charlottesville, VA;
--Mark Ghobrial, M.D., Ph.D., University of California, Los Angeles,
CA;
--Jean Emond, M.D., Columbia University, New York , NY;
--Robert A. Fisher, M.D., Virginia Commonwealth University,
Richmond, VA;
------Chris E. Freise, M.D., University of California, San
Francisco, CA;
--Abraham Shaked, M.D., University of Pennsylvania, Philadelphia,
PA;
--Roshan Shrestha, M.D., University of North Carolina, Chapel Hill,
NC;
--James Trotter, M.D., University of Colorado Health Sciences
Center, Denver,
CO.
PRINCIPAL INVESTIGATOR
Robert Merion, M.D., University of Michigan, Ann Arbor, MI.
PROGRAM OFFICER FOR A2ALL STUDY
James Everhart, M.D., M.P.H., NIDDK, Bethesda, MD.
Additional support for A2ALL is provided by the American Society of
Transplant Surgeons (ASTS) and the Health Resources Services
Administration (HRSA) of the Department of Health and Human
Services.
A2ALL was initiated in September 2002 and patient data accrual will
begin in autumn of 2003
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From American Journal of Transplantation
Hepatitis C Positive Grafts may Be Used in Orthotopic
Liver Transplantation:
A Matched Analysis
Posted 09/15/2003
Sammy Saab, Rafik M. Ghobrial, Ayman B. Ibrahim, Gregg Kunder, Francisco
Durazo, Steven Han, Douglas G. Farmer, Hasan Yersiz, Leonard I. Goldstein,
Ronald W. Busuttil
Abstract and Introduction
Abstract
Hepatitis C (HCV)-positive liver grafts have been increasingly used in
patients with decompensated liver disease from HCV because of critical
shortage of available organs. Fifty-nine recipients of HCV-positive grafts
were matched to patients who received HCV-negative grafts. All recipients
were transplanted for HCV liver disease. Matching variables were (1) status,
(2) pre-transplant creatinine, (3) recipient age, (4) donor age, (5) warm
ischemia time, and (6) year of transplantation. Both unmatched and matched
analyses were performed on patient survival, graft survival, and time to HCV
recurrence. There was no significant statistical difference in patient,
graft, or HCV recurrence-free survival between recipients of HCV-positive
and HCV-negative grafts with matched and unmatched analyses (p>0.05). The
3-year estimates of HCV disease-free survival were 12% ( ± 9%) and 19% ( ±
7%) using HCV-positive and -negative grafts, respectively. The use of
HCV-positive grafts in recipients with HCV does not appear to affect patient
survival, graft survival, or HCV recurrence when compared with the use of
HCV-negative grafts. Our results suggest that HCV-positive grafts can be
used in a HCV liver transplant recipient.
Introduction
We describe 59 patients who were recipients of hepatitis C (HCV)-positive
grafts. Eight patients are studied in addition to 51 patients previously
described by our group who received HCV-positive grafts.[1] Longer follow-up
is available for the 51 patients, and the outcomes of all 59 patients is
studied using a matched analysis.
Orthotopic liver transplantation (OLT) is a definitive treatment for
decompensated liver disease. Whereas the 1-year survival for patients with
decompensated cirrhosis is less than 60%, orthotopic liver transplantation
achieves overall 5-year survival rates of greater than 60-70%.[2-5]
Currently, the leading indication for liver transplantation is hepatitis C
infection (HCV).
The number of available donor organs limits OLT. Since 1988, the number of
individuals on the waiting list for liver transplantation has grown from 616
to just over 16 000.[2] Although innovations such as split-liver transplants
and living related donations will likely expand the donor pool, the donor
shortage will likely remain critical for the foreseeable future. A number of
studies have suggested that the use of an infected HCV graft does not impact
on clinical outcome (Table 1).[6-11] Vargas et al. found no statistical
difference in the HCV recurrence rate, graft survival, and patient survival
in 23 patients with HCV who were transplanted using HCV-positive grafts
compared with 169 patients who received HCV-negative grafts..[7] Similar
results were found by Testa et al. who compared the clinical outcome of 22
patients who received HCV-positive grafts with 115 patients who received
HCV-negative grafts.[9] Although there was a trend towards greater
recurrence in patients who received HCV-positive grafts, the results were
not statistically significant. Using the United Network for Organ Sharing
(UNOS) Scientific Registry, Marroquin et al. compared outcomes of 96
recipients who received HCV-positive grafts to 2827 recipients who received
HCV-negative grafts.[10] Patient survival was significantly higher in
recipients of HCV-positive grafts than in recipients of HCV-negative
grafts.[10] In a separate analysis using the UNOS Scientific Registry, graft
survival was similar in recipients of HCV-positive and -negative grafts.[11]
In a database of over 500 patients transplanted for HCV from a single
institution, Ghobrial et al. also demonstrated no effect on patient and
graft survival by the use of HCV-positive grafts.[1]
Because of the existing shortage of organs and the increased demand by
HCV-infected patients for liver transplantation, it is essential to study
whether HCV-infected grafts can be safely used. The potential use of
HCV-positive grafts would have public policy implications, as it will likely
increase the donor pool for OLT. Using our existing institutional database,
we used pair-wise matched analysis to test the hypothesis that patient and
graft survival was similar between recipients of HCV-positive grafts and
HCV-negative grafts.
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