Role of in Diabetic Neuropathy

DefinisiNeuropathy is a medical term describing disorders of the nerves of the peripheral nervous system (specifically excluding encephalopathy and myelopathy, which refer to the central nervous system.)

Dorland’s Medical Dictionary

DefinisiPeripheral neuropathy is defined as deranged function and structure of peripheral motor, sensory, and autonomic neurons, involving either the entire neuron or selected levels

Dyck PJ (1982). "Current concepts in neurology. The causes, classification, and treatment of peripheral neuropathy". N. Engl. J. Med. 307

Trauma atau tekanan pada saraf. Diabetes.Vitamin deficiencies. Alcoholism. Autoimmune diseases. Other diseases ( penyakit ginjal, penyakit

hati,hypothiroid)Penyakit keturunan. Terpapar racun. (obat-obat untuk

kanker)

Etiology

Gejala- Gejala 1.Sensasi menusuk.

2.Sensasi geli.

3.Sensasi terbakar.

4.Sensasi gatal.

5.Nyeri tusuk.

Neuropathic pain

neuropathic pain is "initiated or caused by a primary lesion or

dysfunction in the nervous system”.

Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms (2nd edition ed.)

JENIS – JENIS NYERI / PAINJENIS – JENIS NYERI / PAIN

Neuropathic Pain Nociceptive Pain

Nyeri disebabkan karena kerusakan pada sistem saraf (susunan saraf perifer ataupun pusat)

Nyeri disebabkan karena adanya luka pada jaringan tubuh

(otot, tulang, kulit, viseral)

Mixed PainNyeri dengan

komponen Neuropathic

dan Nociceptive

Contoh :

Contoh : Contoh :Perifer :- Diabetic Neuropathy- Post Herpetic Neuralgia- Trigeminal Neuralgia- Post Surgical Neuropathy- Post Traumatic NeuropathyCentral :- Post Stroke Pain

- Low back pain with radiculopathy - Cervical radiculopathy- Cancer pain - Carpal Tunnel Syndrome

- Nyeri karena inflamasi- Nyeri karena patah tulang- Nyeri sendi krn Osteoarthritis- Post Operative Visceral Pain

Neuropathic Pain Nociceptive Pain

Nyeri kronik (bulan/tahunan) Nyeri akut (bbrp jam/hari)

Disebabkan krn kerusakan atau penyakit pada saraf

Disebabkan karena kerusakan atau inflamasi yang mengenai

otot atau persendian

Nyeri ringan sampai menyiksa dan berlangsung terus-menerus

Nyeri sedang sampai berat yang akan hilang jika luka sembuh

Menyebabkan ‘extreme sensitivity’ pada sentuhan – memakai baju menyebabkan

nyeri

Menyebabkan gatal, pada sekitar luka

Penderita menjadi depresi karena merasa nyeri tidak dapat hilang

dan dapat menyebabkan gangguan tidur

Penderita mearasa cemas dan stress, tetapi optimis bahwa akan

bebas dari rasa nyeri

Wall PD. Textbook of Pain. 4th ed; 1999; Jude EB. Clin in Pod Med and Surg.1999;16:81-97; Price SA. Pathophysiology: Clinical Concepts of Disease Processes. 5th ed; 1997: Goldman L. Cecil Textbook of Medicine. 21st ed; 2000

Perbandingan Perbandingan Neuropathic Pain dan Neuropathic Pain dan

Nociceptive PainNociceptive Pain

Woolf CJ, Mannion RJ. Neuropathic Pain: Etiology, symptoms, mechanisms, and management. Lancet, 1999;353:1959-64.

Syndrome

Symptoms

Patophysiology

Etiology

Neuropathic pain

Stimulus-independent pain

Stimulusdependent pain

Mechanisms

Nerve damage

Traumatic

Toxic

Infectious

Metabolic

Hereditary Compression

Ischaemic

Th/ Pain killer, eg : gabapentin,

pregabalin

Th/ Based on etiology

Ex : Oral Anti Diabetic, Steroid, Anti biotics, etc.

Immune - mediated

Th/ nerve repaired

Methycobal – active cobalamin

Proses Patologi Pada NeuropathySegmental demyelinationExamples:Diabetic neuropathyAlcoholic neuropathyUremic neuropathyGuillain-Barre syndrome

Wallerian degenerationExamples:Spondylosis deformansHernia of intervartebral discCarpal tunnel syndromeFacial palsyGlaucomatous optic atrophy

Axonal degenerationExamples:Drug-induced neuropathies[Vincristine, isonicotinicacid hydrazide (INH), etc.]Herpes zoster

Direction of degeneration

Direction of degeneration

Nerve cell

Myelin sheathAxon

Muscle

Klasifikasi Neuropathy

Apakah kedua sisi tubuh terkena ? satu sisi asimetris

dua sisi simetris

Tipe dari saraf yang terkena; apakah saraf motorik, sensorik, atau autonom.

Berapa banyak saraf yang terkena?

bila satu saraf mononeuropathy,

bila lebih dari satu polyneuropathy

Klasifikasi Neuropathy

Bagian tubuh mana yang terkena? mendekati batang tubuh/menjahui batang tubuh.

Neuropathy pada tangan dan kaki disebut distal neuropathy, otot paha disebut proximal neuropathy

Diagnosa1. Ditemukan gejala, seperti kelemahan

otot; nyeri.

2. Pemeriksaan neurology.

3. EMG.

4. Standarized test ; seperti mengukur kekuatan otot, kemampuan saraf otonom.

5. X-ray.

Diabetic Neuropathy

Impact of Diabetic Impact of Diabetic NeuropathyNeuropathy

15% of Diabetics will develop an ulcer

85,000 amputations per year

27% direct medical cost of Diabetes

Diabetes Care 26:1790-1795, 2003

Diabetic Peripheral Neuropathy Symptoms

Asymptomatic

Painful

Sensory Loss

39%

11%

50%

Boulton AJM. Clin. Diab. 23, 2005Argoff C, Cole BE, Fishbain DE, Irving G. Mayo Clin. Proc. 2006:81 (S4)Boulton AJM et al. Diab. Care 27, 2004

Diabetic Neuropathy: SymptomsDiabetic Neuropathy: Symptoms

Hyperglycemia

Microvascular Insufficiency

Nerve Degeneration

Neuronal Dysfunction

Endothelial Dysfunction

Proposed Mechanisms in the Pathogenesis of Diabetic Neuropathy

Etiology of Diabetic NeuropathyEtiology of Diabetic Neuropathy

Vinik Aaron. Diabetic Neuropathy: Pathogenesis and Therapy. The Amer. Journal of Med. August 1999;107 (2B):17S-26S.

Painful Diabetic Neuropathy (PDN)

Neuropathy atau kerusakan saraf yang disebabkan oleh diabetes dan dapat timbul sebagai “insensate neuropathy” (hilangnya fungsi sensoris) atau painful neuropathy .

Painful Diabetic Neuropathy (PDN)

1.Pengontrolan gula darah yang kurang baik pada penderita DM.

2.Bisa berlangsung selama 12 bulan

Gejala-gejala PDN

Pencegahan & Terapi Neuropathy

1. Mengontrol berat badan, gula darah.

2. Medikamentosa.

3. Terpenting menghilangkan nyeri

Methycobal

An active form of cobalamin

Participates in transmethylation

Improves synthesis of proteins, nucleic acids and phospholipids which are needed in the repair of damaged nerves.

Difference between Methycobal and other types of Cobalamins

Structures of other types of CobalaminsStructure of Methycobal

CyanocobalaminHydroxocobalamin DBCC

Bagaimana beda preparat MBL dari preparat OH – B 12 dan

CN- B 12?

Preparat hidrokso dan ciano B 12 merupakan bentuk tidak aktif dan diindikasikan hanya untuk anemia dan neuropati akibat defisensi vit.B12. MBL mengandung CH3-B12, adalah bentuk aktif vitamin B 12 dan diindikasikan untuk pengobatan neuropati perifer.

Objective: Evaluate Methycobal transport to human C.S.F.Method : CH3-B12 - 1,000ug

:CN -B12 - 1,000ugOne I.M. inj.

Methycobal R

Nabuo Tanaka, et al.: Hakone Symp.”Nervous Sys. & Vit. B12”, p5, 1981

MethycobalSerum and C.S.F. with high levels of CH3-B12

Haruto Uchino et al,.:Kyoto Symp. Periph. Neuropathy and Methyobal,” p(1):1978

91.2%

73.2%

25.9%

0.9%

8.1%

0.7%

Human Health Care Company

Nucleic Acid and Protein Synthesis

Methycobal activates the synthesisof DNA in nerve cells and promotes

protein synthesis

①

Phospholipid synthesisMethycobal synthesizes lecithin,a major component of myelin sheath

②

Deoxyuridinemonophosphate

(d-UMP)

Thiamidinemonophosp

hate(d-TMP)

5 methyltetrahydrofolic acid(5-methyl THF)

5,10 methylenetetrahydrofolicacid

di-hydrofolic acid

tetra-hydrofolic acid

S-adenosylhomocysteine

Homocystine

Methyionine synthetase

Methionine

(SAM)S-adenosylmethionine

EthanolamineTransmethylationCholine

AcetylcholineLecithin

DNA

Kerja biokimia dari

John M. Scott et al : Lancet,337 （ 1981 ） Tashiro.S ： Hakone Symposium“The nervous system and Methyl B12”,30 （ 1981 ）

meningkatkan sintesa asam nukleat dan protein di dalam sel-sel saraf

CH3-

TransmethylationTransmethylation

5 methyltetrahydrofolic acid5 methyltetrahydrofolic acid Tetrahydrofolic acidTetrahydrofolic acid

MethionineMethionine

Methionine synthaseMethionine synthase

HomocysteineHomocysteine

S-adenosylhomocysteineS-adenosylhomocysteine S-adenosylmethionineS-adenosylmethionine

Methycobal

DNA

CH3

Methycobal 500µg®

Scot JM, et al.: Lancet 1981, 337

Thymine

meningkatkan sintesa lesitin, komp utama selubung myelin

Homocysteine Methionine

S-adenosylhomocysteine S-adenosylmethionine

Lechitin Cephalin

Tashiro S, et al.: Hakkone Symposium,”The Nervous System and Methyl B12,” 1981, p-30

Methycobal 500µg®

MethycobalCH3

Homocysteine Metabolism

Homocysteine and Diabetes

• Hyperhomocysteinemia ( 15 umol/l) significantly increases risk of DN (p=0.01)

• Logistic regression model shows homocysteine was the only significant variable associated with prevalence of DN, OR: 2.6 (95% CI 1.07-6.33)

0

2

4

6

8

10

12

14

16

18

Hom

ocys

tein

e (u

mol

/l)

Normal WCDM* PCDM*

WCDM – well-controlled DMPCDM – poorly controlled DM

Drzewoski et.al. Diabetes Nutr Metab 2000 Dec; 13(6): 319-24Ambrosch et.al. Diabet Med 2001 Mar;18(3):185-92

p <0.001

Improves subjective symptoms in diabeticneuropathy patients

0

0.5

1.0

1.5

2.0

2.3

42cases

Pacebo group:

Methycobal group:CH3 B12 1500μg/day 12 ｗ eeks

12 ｗ eeks

Numbness Pain Weakness Cramps Impotence NS 　 NS 　 P<0.005 NS 　　 P<0.02 NS P<0.002 NS P<0.03 NS

NS: Non significant Methycobal 　 Placebo

Devathasan G. et al.: Clinical Trials Journal.23 (2), p.130, 1986

Mea

n S

co

re

Methycobal injection for acute cases in-patients:

1To study the effect of Methycobal inj. in diabetic neuropathy (treatment period: 12 weeks)

Method

Aim

Shiga Medical College Yasuda et al ： , 25 （ 11 ） ,109（ 1988 ）

Patients with diabetic neuropathy８ casesSeverity: Moderate to Severe

12 weeks500μg×3A/weeks, intravenous

Methycobal injection for acute cases in-

patients: 2●Overall Improvement

●Improvement in subjective symptoms (%) (After 12 weeks)Lower limbs spontaneous painLower limbs spontaneous pain

Numbness

Loss of perception

Moderate improvement37.5

Slight improvement50.0

No change12.5

500 100(%)

4weeks

Remarkable Improvement

25.0 37.5 25.0 12.5

37.5 37.525.0

85.7

80.0

75.0

71.4

Result

8weeks

Shiga Medical College Yasuda et al ： , 25 （ 11 ） ,109 （ 1988 ）

12weeks

Drug InformationCompositionEach tablet contains 500 μg of mecobalamin.Each 1 ml ampule contains 500 μg of mecobalamin.

IndicationPeripheral neuropathiesMegaloblastic anemia dus to vitamin B12 deficiency(inj. only)

Usually for adults, orally administer 1 tablet 3 times a day (1,500 μg of mecobalamin).The dosage should be adjusted according to the age of patient and the severity ofsymptoms.

InjecitonPeripheral NeuropathiesThe usual abult dosage is 1 amplule, equivalent to 500μg of mecobalamin,administered intramuscularly or intravenously three times a week.The dosage should be adjusted according to the age of patient and the severity ofsymptoms.

Megaloblastic AnemiaThe usual abult dosage is 1 ampule,equivalent to 500μg of mecobalamin, administeredintramuscularly or intravenously three times a week.After about 2 months of administration one ampule should be administered every one tothree months as maintenance therapy.

AvailabilityTablet: Box of 30's & 100's Injection: Box of 10's

Dosage and AdministrationTablet

Efek Samping

Dilaporkan terjadi pada 146 penderita dari total 15.180 penderita (0.96%). Efek samping utama adalah anoreksia pada 52 penderita (0.34%), kelainan GI pada 38 penderita (0.25%), nausea/vomiting pada 18 penderita (0.12%, diare pada 17 penderita (0.11%) dan erupsi kulit pada 14 penderita (0.09%).