Posted by A on February 20, 2003 at 10:28:52:
In Reply to: Re: Benfotiamine - will we be able to get this before it's too late? posted by A on February 20, 2003 at 06:16:46:
I was just wondering, what are the differences and what are the similarities of these two approaches to preventing blindness in diabetics, aside from one being on patent, of course?
LY333531
Doctor's Guide
June 18, 2002
By Jill Stein
Special to DG News
SAN FRANCISCO, CA -- June 18, 2002 -- New data released at the 62nd Scientific Sessions of the American Diabetes Association (ADA) suggest that treatment with LY333531 may improve diabetic peripheral neuropathy (DPN) diagnosed by abnormal vibration detection threshold.
The investigators say that LY333531 treatment may also address the underlying pathogenesis of diabetic microvascular complications.
Dr. William Litchy, with Health Partners Medical Group in Minneapolis, Minnesota, headed a study that evaluated the effect of LY333531 -- a protein kinase C beta inhibitor -- on neurological examinations, composite scores, and physician assessments in patients with DPN.
"There is increasing evidence for the role of protein kinase C beta hyperactivity in the biochemical pathway leading to microvascular damage and eventual neuronal degeneration in diabetes," Dr. Litchy noted. An increase in protein kinase C activity has been demonstrated in preclinical animal models of DPN.
LY333531 prevents and reverses the diabetes-induced alterations in endoneural blood flow and prevents and reverses the decrease in nerve conduction velocity in animal models, he continued. Given the possible importance of ischemic injury in the pathogenesis of DPN, normalization of blood flow may improve the electrophysiologic function of the peripheral nerve and sensory ability in persons with DPN.
In the one-year, double-blind, placebo-controlled, parallel trial, 205 type 1 or 2 diabetic patients with DPN were randomized to placebo or to 32 mg or 64 mg of LY333531. The treatment groups were well matched with respect to baseline scores, subscores and baseline composite scores on the Neuropathic Impairment Score (NIS), with reduction in score being indicative of clinical improvement.
Compared with placebo, 32 mg LY333531 resulted in significant improvements in change from baseline to end point in NIS of the lower limbs and NIS of the reflexes subscores. Improvement relative to placebo was also observed in NIS scores but this difference did not reach statistical significance.
Compared with placebo, 32 mg LY333531 resulted in significant improvements in change from baseline to endpoint in NIS of the lower limbs + 4.
The 64 mg LY333531 dose did not result in significant improvements in NIS score or subscores compared with placebo.
Improvement relative to placebo was also observed in the NIS of the lower limbs +4 + vibration detection threshold score but this difference did not reach statistical significance.
The 64 mg LY333531 dose did not result in significant differences in composite scores compared with placebo.
Compared with the placebo group, the 32 mg LY333531 group had significantly improved clinical global impression (GCI) ratings at end point.
The 64 mg LY333531 dose did not result in significant differences in GCI ratings at end point compared with placebo (p=0.044).
In patients with DPN diagnosed by abnormal vibration detection threshold, treatment with 32 mg LY333531 for one year resulted in improvements in neurological examination, composite scores of nerve function, and patient well being as evidenced by CGI, Dr. Litchy concluded. No significant improvement was demonstrated relative to placebo in patients receiving LY333531, 64 mg.
LY333531 is being developed by Eli Lilly
LY333531 June 2002
Breakthrough Diabetes Drug Tested
An experimental drug with the temporary name LY333531 shows promise in treating a condition associated with diabetes that often leads to amputation of legs, researchers reported .
Diabetic neuropathies belong to a family of nerve disorders that can lead to numbness and sometimes pain and weakness in the hands, arms, feet, and legs.
Although problems may also occur in every organ system -- including the digestive tract, heart, and sex organs -- the most common type is peripheral neuropathy, which affects the arms and legs and can lead to lower-limb amputation.
Over half of all diabetics suffer from peripheral neuropathy, the International Diabetes Federation reports, and there is no FDA-approved treatment for the condition.
LY333531 works by inhibiting the enzyme that causes small blood vessel damage and leads to peripheral neuropathy.
"Offering symptom relief has been about all we could for our (peripheral neuropathy) patients do up to this point," Dr. Aaron Vinik, professor of internal medicine at Eastern Virginia Medical Center in Norfolk, Va., told United Press International.
"We found that LY333531 gets to the root of the function of (the enzyme) activity. With LY333531, we believe that we are getting at the bottom of the disease process, and we can begin to modify that process rather than just treat its destructive and painful symptoms."
Vinik and his research team conducted a year-long trial of LY333531 among patients with type 1 and type 2 diabetic subjects who also suffered from peripheral neuropathy. The patients were split into two groups receiving difference doses of the drug, but both dosages resulted in improvements, Vinik said.
"This is a potential breakthrough in diabetes treatment," Dr. Anne Meyer, an endocrinologist and diabetes specialist practicing in San Francisco, told UPI. "We can really begin for the first time to talk about stopping and healing nerve damage caused by this terrible disease."
Based on results to date, Eli Lilly and Company, of Indianapolis, the manufacturer of the compound, will conduct three new global trials studying how LY333531 affects peripheral neuropathy. The trials will begin this year and Lilly plans to file with the Food and Drug Administration in 2004 for approval. Lilly also is investigating the drug as a possible treatment for diabetic complications that can lead to blindness.
The research was reported at the annual meeting of the American Diabetes Association
THIAMINE BENFOTIAMINE
Prevention of Diabetic Nephropathy by Thiamine
Paul Thornalley Ph.D.
University of Essex.
Objective: To evaluate therapy with thiamine (vitamin B1) and the synthetic thiamine analogue Benfotiamine for the prevention of diabetic nephropathy, and if this is associated with the expected biochemical changes in the kidney and other sites (retina, peripheral nerve) suggesting that retinopathy and neuropathy may also be alleviated.
Background/Rationale: Hyperglycaemia associated with insulin-dependent diabetes mellitus (IDDM) is a risk factor for the development of diabetic complications, including the development of impaired kidney function. Increased intracellular glucose concentration in cells of the small blood capillaries is an integral feature that leads to the development of kidney function impairment. As a consequence of this, the concentrations of key glucose-derived compounds inside cells called "triosephosphates" accumulate to abnormally high levels. This has been implicated as an initiating factor in two hypotheses proposed to explain the biochemical basis of development of kidney function impairment in diabetes that are currently under examination in research centres:
(i) The diacylglycerol/protein kinase C hypothesis. Increased levels of triosephosphates lead to increased formation of a molecule involved in cell function called "diacylglycerol". This activates the enzyme "protein kinase Cb" in blood capillary cells of the kidney, and leads to renal impairment.
(ii) Methylglyoxal glycation hypothesis - Increased levels of triosephosphates also lead to increased formation of a molecule called methylglyoxal. In IDDM, the concentration of methylglyoxal increased 5-6 fold and then reacts with proteins and nucleotides to form stable adducts called advanced glycation endproducts (AGEs). AGEs are implicated in protein crosslinking and activation of cells of the blood that leads to impairment of kidney function. These biochemical mechanisms also contribute to the development of retinopathy and neuropathy.
An idealised aim of the diabetic clinician would be to prescribe a medicine that normalises triosephosphates and prevents both activation of protein kinase Cb and increased formation of methylglyoxal. Such a therapeutic strategy is indeed practicable and, moreover, the therapeutic agent is readily available. The therapeutic strategy involves diverting triosephosphates to the pentosephosphate pathway of glucose metabolism; thereby accumulation of triosephosphates can be avoided. This is achieved by stimulating the activity of an enzyme called transketolase by thiamine supplementation, and this may prevent the development of diabetic nephropathy. It has been claimed that Benfotiamine, a synthetic derivative of thiamine that delivers thiamine into tissues more effectively than thiamine itself, suppresses neuropathy in experimental and clinical diabetes.
Description of Project: A study will be conducted with experimentally-induced diabetic rats with insulin therapy to investigate the effect of thiamine and Benfotiamine on the development of kidney function impairment. Physiological markers of the development of kidney impairment, and biochemical markers of thiamine metabolism and putative intervention into the biochemical mechanisms of kidney function impairment will be studied. Biochemical markers will be assessed in the retina and peripheral nerve of the same animals to see if there is evidence of similar reversal of mechanisms underlying the development of complications in these tissues (retinopathy and neuropathy) too. Some biochemical markers will also be determined in the liver, skeletal muscle, heart and brain to confirm no adverse effects and identify possible beneficial effects of thiamine supplementation at these sites (diabetic rats may be thiamine deficient in the liver, skeletal muscle and heart).
Anticipated Outcome: It is expected that thiamine and Benfotiamine will prevent the development of diabetic nephropathy. It is also expected that thiamine-induced biochemical changes will be found in the kidney and also retina and peripheral nerve, suggesting that delay of retinopathy and peripheral neuropathy by thiamine may be possible too.
Relevance to type 1 diabetes: This study has an outstanding chance of success. Thiamine supplementation is generally very safe - doses of up to 10,000 times the normal daily requirement (ca. 140 mg/kg) are without ill effect. If this study shows the expected benefits of thiamine/Benfotiamine therapy, the data should provide evidence to initiate therapeutic intervention in diabetic patients with thiamine and thiamine analogues to prevent kidney function impairment.