Upload
stuart-farmer
View
237
Download
1
Embed Size (px)
Citation preview
Damiano Gullo
UO Endocrinologia
Ospedale Garibaldi-Nesima
Catania
Damiano Gullo
UO Endocrinologia
Ospedale Garibaldi-Nesima
Catania
Efficacia dell’acido lipoico
nel dolore neuropatico
diabetico
Incontro Nazionale Neurofisiologia: Nuove Strategie
“Controversie sulla diagnosi e terapia del
dolore neuropatico”
Opinioni a confronto
Palermo, 29-30 novembre 2012
• Neuropathy is a microvascular complication of diabetes
mellitus that leads to considerable morbidity and a
decreased quality of life.
• DN is a term indicating all signs and symptoms of peripheral
nerve dysfunction in diabetic patients in whom other causes
of neuropathy have been excluded.
• DN is a major public health problem, affecting approximately
13–26% of diabetic patients.
• Neuropathy is a microvascular complication of diabetes
mellitus that leads to considerable morbidity and a
decreased quality of life.
• DN is a term indicating all signs and symptoms of peripheral
nerve dysfunction in diabetic patients in whom other causes
of neuropathy have been excluded.
• DN is a major public health problem, affecting approximately
13–26% of diabetic patients.
Diabetic neuropathy (DN)Diabetic neuropathy (DN)
NeuropathiesClinical ClassificationNeuropathiesClinical Classification
Focal
Diffuse
Proximal
Distal
large-fiber
small-fiber
Focal
Diffuse
Proximal
Distal
large-fiber
small-fiber
• Neuropathic pain is difficult to treat, and standard analgesics
are usually not effective enough.
• The medications which are currently used to treat diabetic
neuropathic pain include mainly antidepressants,
antiepileptics, and opioids.
• These medications are limited in their effectiveness, they
have considerable side effects, and they have no effect on
the processes by which hyperglycaemia leads to cell
damage.
• Neuropathic pain is difficult to treat, and standard analgesics
are usually not effective enough.
• The medications which are currently used to treat diabetic
neuropathic pain include mainly antidepressants,
antiepileptics, and opioids.
• These medications are limited in their effectiveness, they
have considerable side effects, and they have no effect on
the processes by which hyperglycaemia leads to cell
damage.
Neuropathic painNeuropathic pain
2011
EVIDENCE-BASED GUIDELINE: TREATMENT OF PAINFUL DIABETIC NEUROPATHY—REPORT OF THE AMERICAN ASSOCIATION OF NEUROMUSCULAR AND ELECTRODIAGNOSTIC MEDICINE, THE AMERICAN ACADEMY OF NEUROLOGY, AND THE AMERICAN ACADEMY OF PHYSICAL MEDICINE & REHABILITATIONBril et al. 2011
Other Pharmacological Agents.
Recommendations:1. Capsaicin and isosorbide dinitrate spray should be considered for the
treatment of PDN (Level B).2. Clonidine, pentoxifylline, and mexiletine should probably not be
considered for the treatment of PDN (Level B).3. The lidoderm patch may be considered for the treatment of PDN (Level
C).
4. There is insufficient evidence to support or refute the usefulness of vitamins and alpha-lipoic acid in the treatment of PDN (Level U).
Other Pharmacological Agents.
Recommendations:1. Capsaicin and isosorbide dinitrate spray should be considered for the
treatment of PDN (Level B).2. Clonidine, pentoxifylline, and mexiletine should probably not be
considered for the treatment of PDN (Level B).3. The lidoderm patch may be considered for the treatment of PDN (Level
C).
4. There is insufficient evidence to support or refute the usefulness of vitamins and alpha-lipoic acid in the treatment of PDN (Level U).
What about lipoic acid..anyone?What about lipoic acid..anyone?
• Discovered in 1937 by Snell et al., who found that certain bacteria
needed a compound from potato extract for growth.
• In 1951, the so-called potato-growth factor was isolated by Reed and
colleagues, and lipoic acid was discovered as a molecule that assists in
acyl-group transfer and as a co-enzyme in the Krebs cycle.
• In the 1980s, alpha-lipoic acid was recognized as a powerful antioxidant.
It is produced by animals and humans, and can be found in liver, skeletal
muscle, potatoes, and broccoli.
• Intravenous and oral LA are approved for the treatment of diabetic
neuropathy in Germany.
• Discovered in 1937 by Snell et al., who found that certain bacteria
needed a compound from potato extract for growth.
• In 1951, the so-called potato-growth factor was isolated by Reed and
colleagues, and lipoic acid was discovered as a molecule that assists in
acyl-group transfer and as a co-enzyme in the Krebs cycle.
• In the 1980s, alpha-lipoic acid was recognized as a powerful antioxidant.
It is produced by animals and humans, and can be found in liver, skeletal
muscle, potatoes, and broccoli.
• Intravenous and oral LA are approved for the treatment of diabetic
neuropathy in Germany.
History of lipoic acidHistory of lipoic acid
• R-LA occurs naturally in foods covalently bound to lysine in proteins (lipoyl lysine). Animal tissues rich in lipoyllysine (~1-3 mcg/g dry wt) include kidney, heart, and liver, while vegetables rich in lipoyllysine include spinach and broccoli.
• LA in supplements is not bound to proteins.
The amounts of LA available in dietary supplements (200-600 mg) are as much as 1,000 times greater than the amounts obtained in the diet.
• Most LA supplements contain a (50/50) mixture of R-LA and S-LA.
• Since taking LA with a meal decreases its bioavailability, it is generally recommended that LA be taken on an empty stomach (one hour before or two hours after eating).
• R-LA occurs naturally in foods covalently bound to lysine in proteins (lipoyl lysine). Animal tissues rich in lipoyllysine (~1-3 mcg/g dry wt) include kidney, heart, and liver, while vegetables rich in lipoyllysine include spinach and broccoli.
• LA in supplements is not bound to proteins.
The amounts of LA available in dietary supplements (200-600 mg) are as much as 1,000 times greater than the amounts obtained in the diet.
• Most LA supplements contain a (50/50) mixture of R-LA and S-LA.
• Since taking LA with a meal decreases its bioavailability, it is generally recommended that LA be taken on an empty stomach (one hour before or two hours after eating).
Food Sources of LA Supplements
• R-LA is the isomer that is synthesized by plants and animals and
functions as a cofactor for mithocondrial enzymes.
• After oral dosing with LA, peak plasma concentrations of R-LA were
found to be 40%-50% higher than S-LA, suggesting R-LA is better
absorbed than S-LA.
• In rats, R-LA was more effective than S-LA in enhancing insulin-
stimulated glucose transport and metabolism in skeletal muscle, and R-
LA was more effective than LA and S-LA in preventing cataracts.
• However, virtually all of the published studies of LA supplementation in
humans have used LA. At present, it is not clear whether R-LA
supplements are more effective than LA supplements in humans.
• R-LA is the isomer that is synthesized by plants and animals and
functions as a cofactor for mithocondrial enzymes.
• After oral dosing with LA, peak plasma concentrations of R-LA were
found to be 40%-50% higher than S-LA, suggesting R-LA is better
absorbed than S-LA.
• In rats, R-LA was more effective than S-LA in enhancing insulin-
stimulated glucose transport and metabolism in skeletal muscle, and R-
LA was more effective than LA and S-LA in preventing cataracts.
• However, virtually all of the published studies of LA supplementation in
humans have used LA. At present, it is not clear whether R-LA
supplements are more effective than LA supplements in humans.
Racemic vs. R-LA Supplements
Mean TSS levels on a weekly basis during the placebo run-in and the randomized double-blind period of the trial. *P < 0.05 for ALA600, ALA 1200, and ALA1800 vs. placebo; **P < 0.05
for ALA1800 vs. placebo.
Ziegler D et al. Diabetes Care 2006;29:2365-2370
Copyright © 2011 American Diabetes Association, Inc.
• Ziegler et al 1995 Diabetologia. Treatment of symptomatic diabetic peripheral
neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre
randomized controlled trial (ALADIN Study).
• Ruhnau KJ at al. 1999. Diabetes. Effects of 3-week oral treatment with the
antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic
polyneuropathy.
• Ametov Aset al. Diabetes Care 2003. The sensory symptoms of diabetic
polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial.
• Ziegler D et al. Diabetes Care 2006. Oral treatment with alpha-lipoic acid
improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial.
• Ziegler et al 1995 Diabetologia. Treatment of symptomatic diabetic peripheral
neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre
randomized controlled trial (ALADIN Study).
• Ruhnau KJ at al. 1999. Diabetes. Effects of 3-week oral treatment with the
antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic
polyneuropathy.
• Ametov Aset al. Diabetes Care 2003. The sensory symptoms of diabetic
polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial.
• Ziegler D et al. Diabetes Care 2006. Oral treatment with alpha-lipoic acid
improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial.
Randomized, placebo-controlled studies with alpha lipoic acid in persons with symptomatic peripheral diabetic neuropathy.Randomized, placebo-controlled studies with alpha lipoic acid in persons with symptomatic peripheral diabetic neuropathy.
Int J Endocrinol. 2012;
Meta-Analysis. pooled standardized mean difference -all trials Meta-Analysis. pooled standardized mean difference -all trials
Meta-Analysis. Overall, the pooled standardized mean difference estimated from
all trials revealed a reduction in TSS scores of −2.26 (CI: −3.12 to −1.41; P =
0.00001) in favour of alpha lipoic acid administration (Table 4)
Int J Endocrinol. 2012; 2012: 456279.
• Based on the four level 1b randomized, placebo-controlled
studies, there is evidence to support that alpha lipoic acid
causes a significant and clinically relevant decrease in
neuropathic pain when administered for a period of three weeks
at a dosage of 600 mg per day (grade of recommendation A)
• Intravenous administration of alpha lipoic acid leads to
significant and clinically relevant improvements of symptomatic
peripheral diabetic neuropathy in the short term.
• Based on the four level 1b randomized, placebo-controlled
studies, there is evidence to support that alpha lipoic acid
causes a significant and clinically relevant decrease in
neuropathic pain when administered for a period of three weeks
at a dosage of 600 mg per day (grade of recommendation A)
• Intravenous administration of alpha lipoic acid leads to
significant and clinically relevant improvements of symptomatic
peripheral diabetic neuropathy in the short term.
ConclusionsConclusions
Int J Endocrinol. 2012; 2012: 456279.Published online 2012 January 26. doi: 10.1155/2012/456279
In general, alpha lipoic acid (ALA) is considered a safe supplement.
• Anaphylactoid reactions, including laryngospasm, were reported after intravenous LA administration. The most frequently reported side effects of oral LA supplementation are allergic reactions affecting the skin, including rashes, and itching.
• Abdominal pain, nausea, vomiting, diarrhea, and vertigo have also been reported, and one trial found that the incidence of nausea, vomiting, and vertigo was dose-dependent.
• Malodorous urine has been noted by people taking 1,200 mg/day of LA orally.
• In rare circumstances, alpha lipoic acid may cause insulin autoimmune syndrome; also known as Hirata disease, a condition characterized by hypoglycemia and very high levels of insulin.
In general, alpha lipoic acid (ALA) is considered a safe supplement.
• Anaphylactoid reactions, including laryngospasm, were reported after intravenous LA administration. The most frequently reported side effects of oral LA supplementation are allergic reactions affecting the skin, including rashes, and itching.
• Abdominal pain, nausea, vomiting, diarrhea, and vertigo have also been reported, and one trial found that the incidence of nausea, vomiting, and vertigo was dose-dependent.
• Malodorous urine has been noted by people taking 1,200 mg/day of LA orally.
• In rare circumstances, alpha lipoic acid may cause insulin autoimmune syndrome; also known as Hirata disease, a condition characterized by hypoglycemia and very high levels of insulin.
Safety & Dangers of Alpha Lipoic AcidSafety & Dangers of Alpha Lipoic Acid
Fine