ALS-Management and Upcoming Clinical Trials.ppt

1、ALS-Management and Upcoming Clinical Trials,Abi Muthukumaran, MD Director of the ALS Program Cedars-Sinai Medical Center Los Angeles.,ALS Symptoms,Muscle weakness Atrophy StiffnessCramps Fasciculations,ALS Symptoms,Dysphagia Difficulty in swallowing Dysarthria Difficulty in speech Dysphonia Change i

2、n voice quality Respiratory Insufficiency Emotional Lability,ALS Symptoms,Weight loss Depression Anxiety Memory loss Fatigue Pain Drooling of saliva,ALS,Spontaneous motor activity Cramps Fasciculations,Wasting of hands & arms in ALS,ALS Management,A multidisciplinary approach Physical/Occupational T

3、herapy Speech Therapy Nutrition Assessment and Swallow evaluation Respiratory therapy/pulmonology Home Health Social Worker Palliative Care,Medical Management Riluzole,The only FDA approved drug for ALS treatment AAN Practice Advisory- Neurology 1997 Approved for use in the US, Europe- 1996 and Cana

4、da 2000 Safe, fairly well tolerated Moderate efficacy Expensive ($10,000/year !),Riluzole,Riluzole,Monitor LFTs at baseline and every month for first 3 months, followed by every 3 months long term Reduces damage to motor neurons by decreasing the release of glutamate Prolongs survival by 3-4 months,

5、 Cochran review 2005 Side effects include fatigue, nausea, diarrhoea and liver toxicity,Symptomatic Management,Important part of ALS treatment Several recent advances for symptom management Increase in survival and quality of life in patients seen in ALS centers,Symptomatic Management,Emotional labi

6、lity (Pseudobulbar affect) Associated frequently with bulbar dysfunction Amitriptyline (TCA) Forshew and Bromberg 2003Fluvoxamine (SSRI) Dextromethorphan/Quinidine Patient and caregiver education ( AAN Practice Parameter - Guidelines for symptomatic management of ALS ),ALS Management,Spasticity Bacl

7、ofen 10 mg po bid/tid and titrate up as tolerated Tizanidine- 4 mg po bid/tid Valium 20-40 mg po at bedtime Stretching of the muscles Baclofen pump for severe spasticity,ALS Management,Cramps and Fasciculations -Difficult to treat generally -Magnesium Slow Mag -Tonic water (quinine) -Chamomile tea ?

8、 -Low dose baclofen -Low dose benzodiazepines,ALS Management,Treatment of Pain Can occur at any stage in the disease Neuropathic, Musckulosketetal, immobility Combination of drugs NSAIDS, Gabapentin, Pregabalin, TCAs Severe Pain Narcotics,ALS Management,Treatment of Fatigue Amantidine dose 100 mg Po

9、 twice or three times daily Modafinil (Provigil)- 100 mg 1-2 times a day Treatment of other underlying causes ( thyroid dysfunction, anemia etc.),ALS Management,Insomnia Ambien Sedating antidepressants- Trazadone, Remeron Correcting underlying factors nocturnal hypoventilation, pain etc. Sleep hygei

10、ne,ALS Management,Bowel and Bladder Dysfunction-Bladder Urgencies - Oxybutinin (detrol), Catheters -Constipation increase fiber in diet, hydration, stool softners, laxatives, enema if severe,Sialorrhea Management,Glycopyrrolate (Robunil)- 1-2 mg every 4 hours Benztropine, Amitriptyline Transdermal h

11、yoscine patch Topical atropine drops - 1% every 4 hours Botox or Myobloc injection into the salivary glands Radiation therapy if very severe (AAN Practice Parameter- R. G Miller and Colleagues, revised Nov, 2006),Sialorrhea Management,ALS Management,Thick Mucus Production Increase Hydration Guiafene

12、sin (robitussin) liquid or pill form Propananol ? Suctioning and cough assist device,ALS Management,Goal of therapy Maximize function Establish safe exercises without overexertion Improvement of quality of life Prevention of contractures Patient transfers and assistive devices/aids Fall precautions,

13、ALS Management,Tremendous advances in technology Newer communication devices Sophisticated power wheel chairs Stair climbers Portable ramps Other durable medical equipments,Management of Dysphagia,Speech and swallow evaluation periodically in clinic Assessment of nutritional status High protein and

14、high calorie diet Barium swallow, video swallow studyEarly discussion about PEG tube Referral to GI specialist,G Tube,Management of Dysphagia,Indications for G-tube Moderate to severe dysphagia Significant weight loss Recurrent pneumonia Declining respiratory status,Management of Respiratory Failure

15、,FVC checks q 3 months in clinic by RT BIPAP if FCV 50 PPV Invasive ventilation/Tracheostomy when FVC 30 PPV Treating underlying infection Management of patient anxiety,Palliative Care,Palliative services involved early Hospice for patients with end stage ALS Comfort care and pain management Early D

16、ecision making Advanced Directives,Upcoming Clinical Trials,Arimoclomol,Oct 2005, Phase IIa study completed. 80 patients participated, 10 centers (NorthEast ALS Consortium) Study Goal- safety and tolerability profile for the drug Thought to work by upregulating the heat-shock proteins and“molecular

17、chaperones” in cells under oxidative stress Increased survival by 5 weeks in SOD-1 mouse model (by Univ of London),Nature Medicine, 2004,Arimoclomol,Results presented at the International ALS/MND meeting in Japan. Phase 2a study showed that the compound entered the BBB and CSF Phase 2b study with Ar

18、imoclomol planned, to begin in summer 2008 390 patients, 30-35 sites,Ceftriaxone,Ceftriaxone study Phase II Goal- tolerability and safety when given over long periods of time Shown in animal models to increase survival by few weeks. Mechanism- crosses the BBB and increases the level of glutamate tra

19、nsporter carrier protein to decrease the level of glutamate and cellular excitotoxicity,Ceftriaxone,60 patients initially, 10 US Centers First Stage- to study the level of drug in CSF Second stage to assess the safety profile when used over 16 weeks Third Stage Additional 540 patients will be enroll

20、ed to study efficacy (ongoing) Drug is given IV through a central venous catheter,Negative Drug Trials,Vitamin E TCH346 Celebrex Creatine Indinavir Topiramate(topamax) Neurontin Minocycline,Manganoporphyrin,a novel antioxidant (AEOLUS) 38 percent increase in survival in SOD mouse large study underwa

21、y. Small study with 30 patients showed safety. SC injection, 75 mg once a day.,Lithium for ALS Treatment,A small Italian study 44 pts Lithium and Riluzole vs Riluzole and placebo Slows progression of disease and 16 patients in lithium arm alive at 15 month follow up 29 % of patients died in placebo

22、arm,Lithium and ALS,Mechanism of action Increases autophagy Increase in number of mitochondria- spinal cord of SOD1 mouse model Increased motor neuron density,Fig. 5. Effects of lithium treatment on disease symptom progression and survival in patients with ALS Fornai, Francesco et al. (2008) Proc. N

23、atl. Acad. Sci. USA 105, 2052-2057,Lithium for ALS,A larger multicenter trial on the way 250 patients- NEALS, CALS NIH sponsored Expect to start this summer Double blinded placebo controlled randomized study Dosage- 150 mg po BID, upto 450 mg a day To maintain a serum drug level 0.4-0.8meq/litre,Lit

24、hium for ALS,Primary outcome- disease progression A 6 point drop in ALSFRS FVC decline If lithium is effective, then placebo patients will be switched to the drug,Lithium and ALS,Side EffectsNausea, vomiting, fatigue, diarrhea, dizziness, weight gain, weakness, tremor, drowsiness and seizure at toxi

25、c levels, irregular heart beat, renal failure, hypothyroidism,Other Studies,Diaphragm Pacing for respiratory muscle weakness to improve breathing (Cleveland)Larger clinical trial on the wayNutrition in ALS (phase 2 study, university of Kentucky),Exercise in ALS,There is emerging evidence that regula

26、r exercise helps the rate of decline Still some conflicting data SOD mouse in treadmill 10 weeks increase in survival Vs no exercise But high intensity exercise is badMahoney,2004,Conclusions,Unprecedented number of clinical trials in ALS in one time Marked diversity in technology and targeting diff

27、erent disease mechanisms. We need to improve patient access in multidisciplinary clinics and establish more clinical trials with the best study designs. Work with different organizations more closely ALSA, NIH, MDA and corporate sectors,Lou Gehrig,“Fans, for the past two weeks you have been reading about the bad break I got.Yet today I consider myself the luckiest man on the face of earth. I may have had a tough break, but I have an awful lot to live for”,Thank you for your patience,