Anti tubercular drugs

1. ANTI-TUBERCULAR DRUGS Presented by – Dr.Sushrut Varun Satpathy 3 rd year PG Deptt.of Pharmacology,SMIMS Moderator – Dr.Supratim Datta Assoc.Prof . Deptt . Of pharmacology

2. CHRONIC GRANULOMATOUS DISEASE MAJOR HEALTH PROBLEM ( DEVELOPING COUNTRIES) 1/3 RD OF WORLD’S POPULATION INFECTED WITH MYCO. TUBERCULOSIS 9.4 MILLION ACTIVE TB CASES GLOBALLY ( 2.3 MILLION CASES – INDIA – HIGHEST CONTRIBUTOR)-WHO-2010 G.O.I 2012 DECLARED TB – NOTIFIABLE DISEASE

3. EVERY DAY IN INDIA , More than 900 people die of TB ( ~ 2 deaths every 3 minutes )

4. CONTROL AND TREATMENT OF TB –COVERED UNDER NATIONAL PROGRAMME (RNTCP) Goal of RNTCP – Decrease mortality and morbidity due to TB Cut transmission of infection until TB cases ceases to be major public health problem – detecting and curing sputum smear positive patients Achieve and maintain a cure rate of atleast 85% among new sputum smear (+) and maintain detection of atleast 70% Only effective means to achieve the goal of RNTCP is the application of DOTS strategy

5. Components of DOTS – systematic strategy having 5 components Political and administrative commitment Good quality diagnosis, primarily by sputum smear microscopy Uninterrupted supply of good quality drugs Directly observed treatment (DOT) Systematic monitoring and accountability

6. Diagnosis of tuberculosis Identification of TB suspects – m/c symptom – Persistent cough , usually with expectoration Others – weight loss , tiredness , fever with evening rise , night sweats , chest pain , shortness of breath , anorexia and haemoptysis

7. Sites of extra-pulmonary tuberculosis

8. A pulmonary TB suspect is defined as : An individual having a cough of 2 weeks or more Contacts of smear positive TB pts having cough of any duration Suspected/confirmed extra-pulmonary TB having cough of any duration HIV pts having cough of any duration

9. 1specimen (+) out of 2 - smear positive TB Smear (+) TB is further classified as new or re-treatment cases based on their previous treatment history Both specimens are smear (-) - prescribed symptomatic treatment and broad spectrum anti- biotics as Co- trimoxazole for 10-14 days Antibiotics such as FQs ( ciprofloxacin, ofloxacin , levofloxacin etc), rifampicin or streptomycin, which are active against TB , should never be used

10. According to clinical utility – Anti-TB drugs can be divided into first line and second line First line drugs – ISONIAZID (H) RIFAMPIN (R) PYRAZINAMIDE (Z) ETHAMBUTOL (E) STREPTOMYCIN (S) Second line drugs – Ethionamide ( Eto ) Prothionamide ( Pto ) Cycloserine (Cs) Terizidone ( Trd ) Para-Amino salicylic acid (PAS) Rifabutin Thiacetazone ( Thz ) FLUOROQUINOLONES Ofloxacin ( Ofx ) Levofloxacin ( Lvx ) Moxifloxacin ( Mfx ) Ciprofloxacin ( Cfx ) INJECTABLE DRUGS – Kanamycin (Km) Amikacin (Am) Capreomycin (Cm)

11. Alternative grouping of Anti-tubercular drugs GROUP 1 First line oral anti-TB drugs Isoniazid,Rifampin,Pyrazinamide,Ethambutol GROUP 2 Injectable anti-TB drugs Streptomycin , Kanamycin , Amikacin,Capreomycin GROUP 3 Fluoroquinolones Ofloxacin,Levofloxacin,Moxifloxacin,Ciprofloxacin GROUP 4 Second line oral anti-TB drugs Ethionamide , Prothionamide,Cycloserine,Terizidone,PAS GROUP 5 Drugs with unclear efficacy Thiacetazone , Clarithromycin , Clofazimine,Linezolid,Amoxicillin / clavulanate,Imipenem / cilastatin

12. Adopted from : treatment of tuberculosis guidelines ; WHO, Fourth edition(2010) and RNTCP, DOTS-plus Guidelines 2010 Not recommended by WHO for routine use in MDR-TB patients Group 1 – are the most potent and best tolerated oral drugs used routinely Group 2 – potent and bactericidal , but injectable drugs Group 3 – include FQs which are well tolerated bactericidal oral drugs ; all patients with drug resistant TB should receive one FQ Group 4 – less effective, bacteriostatic /more toxic oral drugs for resistant TB Group 5 – drugs with uncertain efficacy; not recommended for MDR-TB; may be used in XDR-TB

13. Isoniazid ( Isonicotinic acid hydrazide , H) Primarily tuberculocidal Fast multiplying are rapidly killed , but quiescent ones are only inhibited Acts on extracellular as well as on intracellular TB Equally active in acidic or alkaline pH One of the cheapest anti-tubercular drugs

14. Mechanism of Action - Inhibition of synthesis of mycolic acids Two gene products labelled ‘ InhA ’ and ‘ KasA ’ , which function in mycolic acid synthesis are targets of INH action INH enters sensitive mycobacteria which convert it by a catalase-peroxidase enzyme into a reactive metabolite then forms adduct with NAD that inhibits InhA and KasA

15. INH enters bacilli by passive diffusion Drug is not directly toxic to the bacillus but must be activated to its toxic form within the bacillus by KatG ( multifunctionary , catalase – peroxidase ) KatG catalyzes the production from INH of an isoNicotinoyl radical that subsequently interacts with mycobacterial NAD and NADP to produce a dozen adducts

16. A nicotinoyl -NAD isomer, inhibits the activities of enoyl acyl carrier protein reductase ( InhA ) and β - ketoacyl acyl carrier protein synthase ( KasA ) Inhibition of these enzymes inhibits synthesis of mycolic acid -- bacterial cell death Another Adduct, a nicotinoyl -NADP isomer , potently inhibits mycobacterial DHFRase ,thereby interfering with nucleic acid synthesis

17. Other products of KatG activation of INH include superoxide,H 2 O 2 , alkyl hydroperoxides and NO radical may also contribute to INH bactericidal effect

18. Resistance of INH About 1 in 10 6 tubercle bacilli is inherently resistant to clinically attained INH concentration If INH given alone , such bacteria will proliferate selectively and after 2-3 months , an apparently resistant infection appears M/C mechanism which confers HIGH level resistance – mutation of KatG (single point mutations in heme binding catalytic domain of KatG , serine to asparagine change at position 315) INH resistance may also involve mutation in InhA and KasA genes Resistance due to efflux is also possible

19. Combined with other drugs ,INH has good resistance preventing action . No cross resistance with other anti-tubercular drugs occurs ???? (KD tripathi 7 th edition ;767) Overexpression of of the genes for InhA – confers low level resistance to INH and some cross-resistance to ethionamide KatG 315 mutants have a high probablity of co-occurrence with ethambutol resistance Mutation in KatG , ahpC , and inhA have also been associated with rpoB mutations

20. Absorption , Distribution and Excretion Bioavailability of oral isoniazid is ~ 100% for 300 mg dose INH is completely absorbed orally and penetrates all body tissues , tubercular cavities, placenta and meninges Extensively metabolized in liver Most important pathway being N- acetylation by NAT2 Acetylated pathway is excreted in urine Rate of acetylation shows genetic variation

21. Fast acetylators (30 – 40% of indians ) T1/2 of INH 1 Hr Slow acetylators (60 – 70% of indians ) T1/2 of INH 3 Hr Acetylator status does not matter if INH is taken daily,but biweekly regimes are less effective in fast acetylators INH induced peripheral neuritis > common in slow acetylators A hepatotoxic minor metabolite is produced by CYP2E1 from acetylhydrazine

22. Interactions Aluminium hydroxide inhibits INH absorption INH retards phenytoin , carbamazepine , diazepam, theophylline and warfarin metabolism by inhibiting CYP2C19 and CYP3A4 Since rifampin is an enzyme inducer, its concurrent use counteracts the inhibitory effect of INH PAS inhibits INH metabolism and prolongs its T1/2

23. Drug Daily dose Mg/kg maximum 3 times per week dose Mg/kg Daily Max ISONIAZID (H) 5 (4-6) 300 10(8-12) 900 mg

24. Adverse effects Well tolerated Peripheral neuritis and a variety of neurological manifestations ( paresthesias , numbness , mental disturbances , mental disturbances , rarely convulsions ) – dose dependent toxic effects Interference with the production of the active co-enzyme pyridoxal phosphate from pyridoxine -- increased excretion in urine – pyridoxine given prophylactically (10 mg/dl) INH neurotoxicity is treated by pyridoxine 100 mg/day Hepatotoxicity ( rare in children ), but more common in older people and in alcoholics ( chronic alcoholism induces CYP2E1 – generates the hepatotoxic metabolite ) Others – lethargy , rashes , fever , acne and arthralgia

25. Rifampin ( Rifampicin , R) Semisynthetic derivative of Rifamycin B obtained from streptomyces mediterranei Bactericidal to M. Tuberculosis and many other gram(+) and gram (-) bacteria like staph.aureus , N.meningitidis , H.influenza , E.coli,Kleibsella , Pseudomonas,Proteus and legionella Against TB bacilli , it is as efficacious as INH and better than all other drugs Bactericidal actions covers all subpopulations of TB bacilli , but acts best on slowly or intermittenly dividing ones ( spurters ) Both extra and intracellular organisms are affected Good sterilizing and resistance preventing actions

26. Mechanism of action - Interrupts RNA synthesis by binding to β subunit of mycobacterial DNA dependent RNA polymerase (encoded by rpoB gene )

27. RESISTANCE – Prevalence of rifampin -resistant isolates are 1 in every 10 7 to 10 8 bacilli Rifampin resistance is nearly always due to mutation in the rpoB gene reducing its affinity for the drug ( In 86% cases due to mutations at codons 526 and 531 of rpoB gene) No cross resistance with any other anti-tubercular drug, except rifampin congeners Rifampin monoresistance occurs at a higher rates when pts with AIDS and multi- cavitary TB are treated with either rifapentine or rifabutine

28. Pharmacokinetics - Well absorbed orally Bioavailability ~ 70% , food decreases absorption Rifampin is to be taken in empty stomach Widely distributed in the body; penetrates intracellularly , enters tubercular cavities, caseous masses and placenta It crosses meninges , largely pumped out of CNS by P– glycoprotein Metabolized in liver – active deacetylated metabolite – excreted mainly in Bile , some in urine Rifampin and its deacetylated metabolite undergoes enterohepatic circulation T1/2 – 2-5 hrs

29. Interactions Rifampicin is a microsomal enzyme inducer – increases several CYP450 isoenzymes – CYP3A4 , CYP2D6, CYP1A2 , CYP2C subfamily Enhances its own metabolism ( area under the plasma concentration-time curve is reduced by ~ 35%) as well as that of many drugs including warfarin , oral contraceptives, corticosteroids, sulfonylureas , corticosteroids, HIV protease inhibitors, NNRTIs , theophylline , metoprolol , fluconazole,ketoconazole , clarithromycin , phenytoin etc Contraceptives failure have occurred – advisable to switch over to an OCP containing higher dose ( 50 µg ) of estrogen or alternative method of contraception

30. Adverse effects - Incidence of adverse effects is similar to INH Hepatitis , a major adverse effect, generally occurs in pts with pre-existing liver disease and is dose related Jaundice – discontinuation of drug – reversible Minors reactions , not requiring drug withdrawal and more common with intermittent regimes Cutaneous syndrome : Flu syndrome : Abdominal syndrome : Urine and secretions may become orange-red but this is harmless

31. Other uses of rifampin Leprosy Prophylaxis of Meningococcal and H.influenza meningitis and carrier state Second/third choice drug for MRSA, Diptheroids and legionella infections Combination of doxycycline and rifampin is first line therapy of brucellosis

32. Pyrazinamide (Z) Chemically similar to INH – Pyrazinamide was developed parallel to it (1952) Weakly tuberculocidal more active in acidic medium and slowly replicating bacteria More lethal to intracellular bacilli and at sites showing inflammatory response Highly effective during the first 2 months of therapy when inflammatory changes are present Inclusion enabled duration of treatment to be shortened and risk of relapse to be reduced

33. M.O.A – not well established Similar to INH – converted inside mycobacterial into active metabolite pyrazinoic acid by pyrazinamidase encoded by pncA gene Gets accumulated in acidic medium and probably inhibits mycolic acid synthesis, but by interacting with a different fatty acid synthase Pyrazinoic acid also appears to disrupt mycobacterial cell membrane and its transport function Resistance to Z develops rapidly if it is used alone, and is mostly due to mutation in the pncA gene

34. Absorbed orally Widely distributed , good penetration in CSF Extensively metabolized in liver and excreted in urine Plasma T1/2 ~ 6 hrs Adverse effects – Hepatotoxicity Hyperuricaemia Others – abdominal distress non-gouty arthralgia fever

35. Ethambutol (E) Selectively Tuberculo static Active against MAC as well as some other mycobacteria Fast multiplying bacilli – more susceptible Added to triple regime of RHZ – hastens the rate of sputum conversion and prevents development of resistance M.O.A – Inhibits arabinosyl transferases (encoded by embAB genes) involved in arbinogalactan synthesis interfering mycolic acid incorporation in mycobacterial cell wall

36. Resistance to E develops slowly Most commonly associated with mutation in embB gene , About 3/4 th of oral dose is absorbed Distributed widely , but penetrates meninges incompletely and is temporarily stored in RBCs Excreted in urine by GFR and tubular secretion Plasma T1/2 ~ 4 hrs

37. ADVERSE EFFECTS - Dose dependent and reversible visual disturbances like Optic Neuritis - reduced visual acuity , central scotoma and loss of ability to see Green, less commonly Red - ? Due to its effect on Amacrine and bipolar cells of retina ^ Hyperuricemia Peripheral neuritis

38. Streptomycin First clinically useful anti-TB drug Tuberculocidal but less effective than INH or rifampin Acts only on extracellular bacilli – poor penetration Penterates tubercular cavities , but does not cross to CSF Poor action in acidic medium Not absorbed orally , must be administerd by IM inj. T1/2 is prolonged in renal failure NOT HEPATOTOXIC Use restricted to max. of 2 months- labelled as ‘supplemental’ 1 st line drug !

39. Other drugs - Thiacetazone – tuberculostatic drug. Major A/E – hepatitis , bone marrow suppression and steven johnson syndrome ( not used in HIV pys due to risk of severe hypersensitivity reactions including exfoliative dermatitis) PAS related to sulfonamides , acts by similar mechanism – bacteriostatic Ethionamide / prothionamide – tuberculostatic –hepatitis , optic neuritis and hypothyroidism , can also be used in leprosy ^ Cycloserine is a cell wall synthesis inhibiting drug and can cause neuropsychiatric adverse effects

40. Kanamycin and Amikacin are injectable aminoglycosides – used in treatment of MDR TB Capreomycin – injectable polypeptide – ototoxicity , nephrotoxicity , hypokalemia and hypomagnesemia FQs – Ofloxacin , Moxifloxacin and Levofloxacin - effective against MAC in AIDS patients Newer macrolides like Azithromycin and Clarithromycin against non-tubercular atypical mycobacteria

41. Rifabutin more effective than Rifampicin against MAC , longer T1/2 ~ 45 hrs , less potential than rifampicin to induce microsomal enzymes and thus , prefered in pts on anti-HIV drugs ( protease inhibitors or NNRTIs mainly nevirapine ) commonly causes – GI discomfort Anterior Uveitis , Hepatitis, clostridium associated diarrhoea , diffuse polymyalgia syndrome , yellow skin discoloration Rifapentine – similar to rifampicin but more lipophillic and longer acting . Not approved for adm . to HIV pts because of higher rate of relapse

42. Treatment of Tuberculosis - Combination chemotherapy ( short course chemotherapy) – to prevent the emergence of resistance to any 1drug For treatment purpose , previously treated patients were divided into three categories . Under RNTCP 2010 guidelines , only two categories are distinguished Category 1 – new pts who have not been exposed to anti-tubercular agents earlier ( previous category 1 as well as 3 cases) Category 2 – old cases who have been exposed to anti-tubercular drugs earlier ( treatment defaulters and relapse cases)

43. First line agents

44. New patient ( category 1) Initial treatment with 4 drugs (HRZE) including 3 bactericidal drugs reduces the risk of selecting resistant bacilli ^ After intensive phase – few bacilli left – only 2 highly effective cidal drugs in the continuation phase Extension of intensive phase beyond 2 months is not recommended now . However , In such cases , authorities recommend 9 month treatment instead of 6 month ?? ( KD Tripathi 7 th ed. ;2013: 774-775 )

45. RNTCP guideline - If the sputum smear is positive after 2 months of treatment , the intensive phase of four drugs (HRZE) are continued for another 1 month sputum examined after completion of extension of intensive phase irrespective of the results – 4 months of continuation phase is started If sputum smear postitve after 5 or more months of treatment – “ failure ”- placed on “ previously treated ” and sputum sent ( C & DST)

46. While treating TB meningitis( NEW pts) , Streptomycin is used in place of ethambutol during the intensive phase ( H 3 R 3 Z 3 S 3 instead of H 3 R 3 Z 3 E 3 ) Continuation phase of treatment with TBM or spinal TB is for 7 months – total duration is for 9 months In areas with high level of primary (H) resistance – WHO suggests inclusion of (E) along with (H+R) in continuation phase

47. Previously treated ( Category 2) For TB pts who have had more than one month anti-TB treatment previously Higher risk of having drug resistance 5 drugs are prescribed in the intensive phase and total duration of treatment is 8 months Relapses , Treatment after default , Failures and others are treated with this regime Regimen is 2 S 3 H 3 R 3 Z 3 E 3 /1 H 3 R 3 Z 3 E 3 /5 H 3 R 3 E 3

48. Intensive phase consists of 2 months of HRZES followed by 1 month of HRZE, all given under direct observation thrice a week on alternate days Pts subjected for follow up sputum examination at the end of 3 months If sputum smear (+) at the end of 3 months of treatment , intensive phase drugs (HRZE) are extended for another Irrespective of sputum results at the end extended intensive phase , 5 months of continuation phase is started If the sputum remains positive at the end of extended intensive phase, sputum is sent to accredited C & DST

49. MultiDrug -Resistant (MDR) TB Defined as resistance to both H and R , and may be any number of other (1 st line) drug MDR –TB has a more rapid course with worse outcomes IDENTIFICATION OF MDR – TB SUSPECTS – Following are the criteria to label a patient as MDR-TB suspect – A new smear (+) pt. remaining smear (+) at end of 5 th month A new smear (-) pt. becoming smear (+) at the end of 5 th month A pt. treated with regimen for previously treated remaining (+) at fourth month Smear-positive contacts of an established / confirmed MDR-TB case

50. Diagnosis of MDR-TB Diagnosis of MDR-TB should be done through C & DST from a quality assured lab On being diagnosed as MDR-TB case- Pt. referred to a designated state level DOTS-plus site Specialized centers limited in number , atleast one such center is expected to be in each state with ready access to an C & DST DOTS-plus site- supported by qualified staff available to manage pts. using second line RNTCP MDR-TB regimen

51. RNTCP MDR-TB treatment regimen - RNTCP is using a standardised treatment regimen (STR) , comprising of 6 drugs ( kanamycin (Km), levofloxacin ( lvx ), ethionamide ( Eto ), pyrazinamide (Z), ethambutol (E) and cycloserine (Cs) Dosages of drugs are based upon 3 weight bands

52. Drug 16-25 kg 26-45 kg > 45 kg Km 500 mg 500 mg 750 mg LVX 200 mg 500 mg 750 mg Eto 375 mg 500 mg 750 mg E 400 mg 800 mg 1000 mg Z 500 mg 1250 mg 1500 mg Cs 250 mg 500 mg 750 mg PAS 5 g 10 g 12 g Pyridoxine 50 mg 100 mg 100 mg

53. All drug given in a single daily dosage under DOT by a DOT provider All pts. will receive drugs under direct supervision on 6 days of the week On the 7 th day (Sunday) , oral drugs will be administered unsupervised and kanamycin will be omitted If intolerance occurs to drugs , ethionamide , cycloserine and PAS may be split into two dosages and the morning dose adm . under DOT and evening subsequently self-administered Empty blister packs of self-administered doses will be checked the next morning during DOT

54. 100 mg of pyridoxine is adm . to all pts under RNTCP MDR-TB regimen If pts gain atleast 5 kgs of weight during treatment and crosses the weight band range , DTS-plus site committee may consider moving the patient to the higher weight band drug dosages ^ DURATION OF TREATMENT - IP – atleast 6 months Extended up to 7/8/9 th months in pts who have (+) culture result taken in 4/5/6 th months of treatment correspondingly Continuation phase is given for 18 months following IP

55. Follow up schedule - Smear examination should be conducted monthly during IP and atleast quaterly during the CP Culture examinations should be done atleast 4, 6,12, 18 and 24 months of treatment

56. Guidelines fro treatment of MDR + XDR TB Use minimum 4 drugs ( 6 drugs in extensive phase ) Follow the hierarchy of drugs from class 1 through class 5 as follows : Use any first line oral agent that may be effective Use injectable agent to which strain is susceptible Use a later generation FQ Use second line oral drugs to which the patient is not exposed previously Use drugs with unclear efficacy

57. Class 1 First line oral drugs H,R,Z,E Class 2 Injectable agents Streptomycin, Kanamycin , Amikacin , Capreomycin Class 3 Fluoroquinolones Levofloxacin , Moxifloxacin Class 4 Oral Bacteriostatic PAS, Cycloserine , Ethionamide Class 5 Drugs with uncertain efficacy Linezolide , Clofazimine , Amoxicillin + clavulanate , Clarithromycin , Imipenem / cilastatin , Thiacetazone , high dose Isoniazid

58. For example if bacteria is resistant to H and R only, the treatment will be 6 ZE + FQ + One injectable + PAS + Cycloserine in the extensive phase 18E + FQ + PAS + Cycloserine in the continuation phase Injectable drugs and Z is removed and rest 4 drugs are continued for minimum 18 months in continuation phase

59. Extensively drug resistant TB MDR-TB cases that are also resistant to FQs as well one of the injectable 2 nd line drugs and may be any number of other drugs Bacilli are resistant to atleast 4 most effective cidal drugs viz. H,R,FQ and one of Km/Am/Cm XDR-TB- very difficult to treat - rapid course and high mortality To prevent further amplification of resistance – standardized MDR regimen ( category 4 treatment) must be immediately stopped Expert panel may decide on instituting category 5 treatment , including group 5 drugs – uncertain efficacy and expensive New drugs like PA-824 and TMC-207 is also being evaluated

60. Tuberculosis in Pregnant Women - H,R,E and Z safe to the foetus and recommends the standard 6 month (2HRZE + 4 HR)- WHO and British Thoracic Society S is C/I - ototoxic Z not recommended in US – lack of adequate teratogenecity data In India – advisable to avoid Z and to treat pregnant TB pts in India – 2 HRE + 7 HR ( total 9 months) All pregnant women treated with INH should receive Pyridoxine 10-25 mg/day

61. Role of Corticosteroids - Tb is a relative C/I for use of glucocorticoids . However in certain situations , Glucocorticoids may be used under the cover of effective Anti-TB therapy – Tuberculosis of serous membranes like pleura , pericardium , meninges etc. to prevent fibrous tissue formation and its sequelae To treat hypersensitvity reactions to antitubercular drugs Tuberculosis of the eye , larynx , genitourinary tract to prevent fibrosis and scar tissue formation Prednisolone is a preferred agent except in meningitis ( dexamethasone is preferred) Steroids C/I in intestinal TB – risk of perforation

62. Atypical Mycobacterial Infections - Clarithromycin or Azithromycin is recommended for prophylaxis of Mycobacterium Avium Complex (MAC) in pts with CD4 count < 50 µl Treatment of MAC requires REC regimen ( Rifabutin + Ethambutol + Clarithromycin / Azithromycin Due to its long T1/2 , Azithromycin can be used as once weekly dose in place of one daily dose of Clarithromycin for prophylaxis of MAC Other drugs effective against atypical mycobacteria are quinolones ( ciprofloxacin , levofloxacin , moxifloxacin and gatifloxacin ) and Amikacin

63. Treatment regimen of MAC infection - Intensive phase Clarithromycin 500 mg BD or Azithromycin 500 mg OD Ethambutol 1000 mg/day (15 mg/kg) depends on Rifabutin 300 mg/day the response ± till CD4 >100 Ciprofloxacin 500 mg BD and sympt.relief or Levofloxacin 500 mg OD ( 2- 6 months) or Moxifloxacin 400 mg OD Maintenance phase Clarithromycin / azithromycin Ethambutol / Rifabutin / 1 FQ doses – same min 12 mths

64. THANK YOU FOR YOUR PATIENCE !! HAVE A GREAT DAY !