Thalidomide Clinical Trial for PSC at Mayo Clinic

[Guest guest]

Have any of you signed up for the PSC thalidomide clinical trial Dr.

Lindor is beginning at the Mayo Clinic in Rochester, MN?

Fred and I received information about it and are going to be asking

some questions of the nurse coordinator. Here's what we got:

Hello ,

Your email message was sent to me as I am one of the coordinators for

trials in PSC. The minocycline study has been closed but we have

another trial in PSC evaluating a drug called thalidomide. Your

husband would need to be seen at Mayo Rochester by Dr. Lindor

prior to entering a study. You can schedule an appointment for him by

calling Sara Epperson at (507)284-4313. You can contact me with any

questions you may have.

a

a nsen, MS, RN

Research Coordinator

Department of Gastroenterology & Hepatology

Mayo Clinic

(507)284-2698 Pager 284-6423

(507)266-4531 (fax)

jorgensen.roberta@...

Wife of Fred, PSC 03/04, UC 03/06, Pancreatitis 10/07

P.S. Fred started eating REAL (albeit bland) food

yesterday. Feels much better. NO diarrhea at ALL today. Nothing, in

fact. So now he thinks he's constipated. (Welcome to my world.)

[Guest guest]

Hi ;

If you are looking for questions to ask of the nurse coordinator

about thalidomide, please ask about adverse effects of thalidomide

over the long-term:

Aliment Pharmacol Ther. 2007 Mar 1;25(5):557-67.

Thalidomide in luminal and fistulizing Crohn's disease resistant to

standard therapies.

Plamondon S, Ng SC, Kamm MA

St Mark's Hospital, Harrow, UK.

BACKGROUND: Thalidomide has been shown to be an effective treatment

in Crohn's disease. AIM: To assess the efficacy and tolerability of

thalidomide in refractory Crohn's disease patients. METHODS: Twenty-

five patients were treated. Retrospective 'estimated' Crohn's Disease

Activity Indices were assessed at baseline and at the end of follow-

up. Clinical response was defined as symptomatic improvement and a

reduction in the 'estimated' Crohn's Disease Activity Index of >100

points, > or =50% reduction in draining fistulas or clinical

improvement in perianal ulcers. Clinical remission was defined as

symptom resolution and an 'estimated' Crohn's Disease Activity Index

<150, complete fistula closure or complete ulcer healing. RESULTS:

Six of eight patients treated for luminal disease responded to

thalidomide at a median follow-up of 12 months (three clinical

responses, three clinical remissions). The median reduction

in 'estimated' Crohn's Disease Activity Index was 212 points (P =

0.005). Nine of 11 patients with active fistulizing disease responded

to thalidomide (six responses; three remissions). The four patients

treated for both luminal and fistulizing disease had fistula

response. Three of them had a response in luminal disease activity.

One of two patients with ulcerating perianal disease responded.

Twelve patients discontinued treatment because of adverse effects

(three sedation; two abdominal pain; one leucopoenia; six

neuropathy). CONCLUSION: Thalidomide is an effective short- to medium-

term treatment in selected patients with refractory luminal and

fistulizing Crohn's disease. Its long-term use is limited by toxicity.

PMID: 17305756.

I understand that thalidomide is a tumor necrosis factor blocker, and

so could act like Remicade to block inflammation, but the high

percentage of adverse effects reported above, suggests that it use

could be risky?

I have also read that thalidomide can activate platelets, and can

preciptate deep vein thrombosis unless taken with aspirin or warfarin:

Am J Hematol. 2006 Jun;81(6):420-2.

Efficacy of prophylactic warfarin for prevention of thalidomide-

related deep venous thrombosis.

Ikhlaque N, Seshadri V, Kathula S, Baumann MA

Division of Hematology/Oncology, State University School of

Medicine, Dayton, Ohio 45428, USA.

BACKGROUND: Deep venous thrombosis (DVT) is a common complication of

thalidomide treatment. There is little information to guide

clinicians in selecting effective preventive treatments and physician

practice varies. We sought to determine whether prophylactic

anticoagulation with warfarin prevents DVT related to thalidomide

treatment. METHODS: We reviewed the records of 131 patients receiving

thalidomide for a variety of indications. Fifty-five patients were

prescribed warfarin with the intent of preventing DVT. Thirty-seven

patients received warfarin at a dose of 1-2 mg per day (low dose) and

18 received a dose intended to raise the INR to 2-3 (high dose).

RESULTS: Twenty-one of the 131 patients developed venous thrombosis

during thalidomide treatment. Eighteen of the 76 patients (23.7%) who

were not prescribed prophylactic anticoagulation developed DVT

compared to 3 of the 55 patients (5.5%) who were prescribed any dose

of prophylactic warfarin (P = 0.010). Only 1 of the 37 patients who

received low-dose warfarin developed DVT (P = 0.011). Bleeding

complications occurred in 4 patients, all of whom were receiving high-

dose warfarin. CONCLUSION: Prophylactic anticoagulation with warfarin

reduces the risk of thrombosis during thalidomide treatment. Low-dose

warfarin may be as effective as higher dose treatment and may result

in fewer bleeding complications. PMID: 16680743.

IBD patients are already at risk for DVT, and I worry that

thalidomide might make this risk much higher? From what I have read

about thalidomide, I would not let my son take it.

Best regards,

Dave R.

[Guest guest]

Dave,Thanks so much for posting this.It doesn't sound like anything I would want Bill to try.He already has had enough problems with platelets being too high and with blood clots.Where or where is a safe drug, where is the nor-urso ?Let's hope we can spark something new soon.LeeHi ;If you are looking for questions to ask of the nurse coordinator about thalidomide, please ask about adverse effects of thalidomide over the long-term:Aliment Pharmacol Ther. 2007 Mar 1;25(5):557-67. Thalidomide in luminal and fistulizing Crohn's disease resistant to standard therapies.. 

[Guest guest]

Dave-

Appreciate the articles and your comments. If it's mainly to treat

retractable UC and Crohns, we're not interested anyway. (Fred's been

responding well to steroids and Asacal with his latest flare up.) Will

call the nurse in any event, just to get more info, as I'm curious as

to just what they hope to accomplish, but if you wouldn't let your son

take it, I wouldn't let Fred take it.

Wife of Fred, PSC, 03/04, UC 03/06, Pancreatitis 10/07

>

> Hi ;

>

> If you are looking for questions to ask of the nurse coordinator

> about thalidomide, please ask about adverse effects of thalidomide

> over the long-term:

>

>

[Guest guest]

Only

playing devils advocate here – (edited for

length.)

“In 1964, an Israeli physician gave the man

two tablets of thalidomide.  The result

was soon followed by more favorable experiences, followed by a clinical trial. Dr. Sheskin's drug of last resort revolutionized the care of leprosy, and led to the

closing of most leprosy hospitals.â€

“Serious infections including sepsis

and tuberculosis

cause the level of tumor

necrosis factor α (TNFα) to rise. TNFα

is a chemical mediator in the body, and it may enhance the wasting process in

cancer patients as well. Thalidomide may reduce the levels of TNFα, and it

is possible that the drug's effect on ENL is caused by this mechanism.â€

Thalidomide also has potent

anti-inflammatory effects  - Thalomid, in conjunction with dexamethasone,

is now standard therapy for multiple myeloma.

Thalidomide also inhibits the

growth of new blood vessels (angiogenesis),

which may be useful in treating macular

degeneration and other diseases; this effect also helps AIDS

patients with Kaposi's

sarcoma.

The FDA

formed a Thalidomide Working Group in 1994 to provide consistency between its

divisions, with particular emphasis

on safety monitoring. The agency also

imposed severe restrictions on the distribution of Thalomid through the System

for Thalidomide Education and Prescribing Safety (STEPS) program.

Thalidomide is also being investigated for

treating symptoms of prostate

cancer, glioblastoma,

lymphoma,

arachnoiditis,

Behçet's

disease, and Crohn's disease. In a

small trial, Australian researchers found thalidomide

sparked a doubling of the number of T cells in patients, allowing the patients' own immune

system to attack cancer cells.â€Â 

On a personal note – my neighbor who had a

nasty blood cancer (too long & hard to spell) was given 6 months to

live.  MD in Houston put him in a clinical trial using Thalidomide.  He did so well, MD sought and was

given approval to use it for him beyond their clinical trial.  He lived for an additional 6 years on

Thalidomide!

Dr Lindor is no slouch when it comes to PSC, he

(and Mayo Clinic) must really think it “might†help or he wouldn’t be wasting

his time and money pursuing it.  I’d at

least listen to what they have to say about the trial.  My totally uneducated thinking is, he’s probably looking at the T cells doubling (in the

right place) and going Mmmmm.  The side effects

don’t sound good, but like chemo, if it works and cures PSC……….. I’d take it in a heart beat.  Again, I’m only playing devils advocate.  I know we’ll all be watching the results of

this study.  Barb in Texas     

Disoriented T Cells Cause Liver Disease

T cells activated in the gut during

inflammatory bowel disease can be re-routed to the liver and cause chronic

liver disease, according to Eksteen and colleagues in the December 1, 2004 issue of The Journal

of Experimental Medicine.  A chronic

liver disease known as primary sclerosing cholangitis (PSC) has been linked

to inflammatory bowel disease (IBD) in the past. But

the connection between the two disorders has been unclear, especially as the

liver condition often develops years after IBD has resolved or the colon has

been surgically removed. Eksteen and colleagues now

show that T cells that

were activated in the gut – probably during IBD - are found in the livers of

patients with PSC, but not in those of patients with other

inflammatory liver diseases.

The

authors explain this detour by

showing that an attractant protein that normally directs T cells into the gut

is aberrantly produced in the liver during PSC. T

cells expressing the receptor for the protein are thus re-routed to the liver,

although the authors do not know what triggers liver cells to make the

attractant in the first place. T cells can survive as memory cells for many years after they are

activated, and the authors believe this may explain how the liver disease can

crop up years after IBD has resolved. Adapted from materials provided by Journal Of

Experimental Medicine.

-----Original Message----- From

what I have read about thalidomide, I would not let my son take it.

 

[Guest guest]

Barb,

Thanks for playing the devil's advocate. You brought up some very important

points in the articles you posted as did Dave. It is crucial to see both sides.

If one were to read the side effects of the immunosuppresants after tranplant,

you may opt out of translant also...but you can't do that when you reach that

point. All drugs have side effects, some worse than others...and when it comes

to research it makes it harder to decide whether to take the chance. I bet if

this drug were to cure PSC we would all (or the majority) have ourselves or

loved ones in line to take it. I wish Dr. Lindor the best of luck with this and

hopefully one day he will find us the cure we all are praying for.

Joanne (mom of Todd)

Sent from my Verizon Wireless BlackBerry

[Guest guest]

Hi Barb and Joanne;

I agree that we have to hear both sides of the story ... it would be

nice to see both the rationale for why thalidomide is being tested in

PSC, and what the expected benefits and risks might be. Once both

sides of the story are presented then we can each make our own

decisions.

I was simply trying to point out that this drug has some adverse

effects, and that these would be worth discussing before entering

into a thalidomide trial. I confess that my opinion of this drug is

somewhat tainted by the fact that when I was growing up in the early

1960's in the U.K. I saw many kids living with birth defects

resulting from the mother's use of this drug. This had a BIG

impression on me!

I would like to point out that thalidomide did not lead to the

closure of leprosy clinics. Rather it was multidrug antibiotic

therapies that did so. WHO does not recommend use of thalidomide in

treatment of leprosy, nor in the treatment of erythema nodosum

leprosum (ENL) that can sometimes accompany leprosy:

___________________________

Pediatrics 111: 712 (2003)

The schizophrenic career of a " monster drug " .

Crawford CL

Comment on: Pediatrics. 2002 Aug;110(2 Pt 1):404-6.

To the Editor;

The events surrounding Sheskin's discovery showing the effect of

thalidomide in treating leprosy patients with erythema nodosum

leprosum (ENL) are vividly described in Dark Remedy. The

Impact of Thalidomide and Its Revival as a Vital Medicine1 and

recounted in Silverman's review of the book. Silverman2 quotes

s's and Brynner's statement that " because of Dr Sheskin's

discovery, 90% of leprosy hospitals around the world were shut down. "

Leprosy hospitals, it is true, have been shut down, but this is

attributable to the widespread use of dapsone and multidrug

therapy, rather than thalidomide, which has no antibacterial effect.

For example, in Benin, a country of 6 million people, 20 leprosaria

have been closed or turned into health centers since the World Health

Organization (WHO) decided to eliminate the disease.3 Moreover, WHO

no longer recommends the use of thalidomide for treating ENL.4

Brynner, in beginning treatment with thalidomide for pyoderma

gangrenosum, was so concerned about developing nerve damage that he

wrote, " I had read all about that [nerve damage], and the fact that

it could be permanent terrified me more than anything else. " Yet he

makes no attempt to explain why thalidomide neuropathy has not been

reported in leprosy patients given the drug. In patients with

nonleprous disorders the frequency is at least 21%.5

C.L. Crawford, MRCP

Imperial College School of Medicine

Chaning Cross Hospital

London W6 8RF, United Kingdom

REFERENCES

1. s T, Brynner R. Dark Remedy. The Impact of Thalidomide and

Its Revival as a Vital Medicine. Cambridge, MA: Perseus Publishing;

2001

2. Silverman WA. The schizophrenic career of a " monster drug. "

Pediatrics. 2002;110:404-406

3. Benin: phasing out the leprosaria. In: Leprosy. Learning from

success. Geneva, Switzerland: World Health Organization, 2001:30-33.

WHO/CDS/CPE/CEE/2001.20

4. World Health Organization. The final push strategy to eliminate

leprosy as a public health problem - questions and answers. 1st ed.

Geneva, Switzerland: World Health Organization; 2002

5. Ochonisky S, Verroust J, Bastuji-Garin S, Gheradi R, Revuz J.

Thalidomide neuropathy incidence and clinicoelectrophysiologic

findings in 42 patients. Arch Dermatol. 1994;130:66-69

http://pediatrics.aappublications.org/cgi/reprint/111/3/712

PMID: 12612270

___________________

Use of thalidomide in leprosy

http://www.who.int/lep/research/thalidomide/en/index.html

Thalidomide or alpha-(N-phthalimido) glutarimide was first marketed

in 1957 for morning sickness and nausea and soon became the `drug of

choice to help pregnant women'.

By the early 1960s the drug was found to be associated with a

congenital abnormality causing severe birth defects in children born

of women who had been prescribed this drug during pregnancy. More

than 10,000 cases of birth defects were reported in over 46 nations

following exposure to the drug. Children were born with missing or

abnormal legs, arms, feet and hands; spinal cord defects; cleft lip

or palate; absent or abnormal external ears; heart, kidney, and

genital abnormalities; and abnormal formation of the digestive system.

A few years later, however, thalidomide was reintroduced as the

treatment for a complication of leprosy called erythema nodosum

leprosum (ENL). Although the evidence was not fully established, very

soon the drug was heralded as the drug of choice for the management

of ENL reactions in leprosy and regulatory authorities granted

exemption from licensing requirements to enable doctors to obtain

limited supplies of thalidomide under strictly controlled

circumstances for use in named patients. Thalidomide's effectiveness

in minimizing symptoms of ENL was mainly due to its antipyretic

action. Its effectiveness in controlling neuritis, the major cause of

permanent disabilities in leprosy, was limited.

Several controlled studies done in the 1970s have demonstrated that

prednisolone is more effective in controlling ENL and associated

neuritis. In addition, it was demonstrated that clofazimine, an anti-

leprosy drug introduced on a small scale in the early 1960s had anti-

inflammatory action. Studies showed that clofazimine is the drug of

choice for the management of chronic, recurrent ENL reactions, as it

had both anti-reaction and anti-leprosy effects.

The drug clofazimine is now a component of the multidrug therapy

(MDT), introduced by WHO in 1981 as the standard treatment for

leprosy and now supplied free of charge to all patients worldwide.

The presence of clofazimine in the combination has significantly

reduced the frequency and severity of ENL reactions.

Because of its known teratogenic effects, WHO does not recommend the

use of thalidomide in leprosy. Experience has shown that it is

virtually impossible to develop and implement a fool-proof

surveillance mechanism to combat misuse of the drug. Today, a number

of thalidomide babies continue to be born each year reflecting

regulatory insufficiency and widespread use under inadequate

supervision.

____________________

Best regards,

Dave R.

>

> Only playing devils advocate here †" (edited for length.)

> “In 1964, an Israeli physician gave the man two tablets of

thalidomide. The result was soon followed by more favorable

experiences, followed by a clinical trial. Dr. Sheskin's drug of last

resort revolutionized the care of leprosy, and led to the closing of

most leprosy hospitals.

[Guest guest]

Barb,

Thanks for enlighting the group regarding the possible

very potent uses of Thalidomide.

Also for posting that very interesting article

" Disoriented T Cells " from the journal of Experimental

Medicine.

PSC/UC

--- Barb Henshaw wrote:

> Only playing devils advocate here – (edited for

> length.)

> “In 1964, an Israeli physician gave the man two

> tablets of thalidomide. The result was soon

> followed by more favorable experiences, followed by

> a clinical trial.

>

Disoriented T Cells Cause Liver Disease

>

> T cells activated in the gut during inflammatory

> bowel disease can be re-routed to the liver and

> cause chronic liver disease, according to Eksteen

> and colleagues in the December 1, 2004 issue of The

> Journal of Experimental Medicine.

__________________________________________________

[Guest guest]

Hi Everyone, Is there a central location on our website were all the on going clinical trials related to PSC is located? I'd be interested in participating. I don't know if they'd want me since I haven't had any symptoms since Jan 2006, but I'd like to help if possible. Washington, DC __________________________________________________