ΑΡΙΣΤΟΤΕΛΗΣ. Έκδοση του Συλλόγου Αποφοίτων Φαρμακοποιών του Αριστοτελείου Πανεπιστημίου Θεσσαλονίκης. Συντακτική Επιτροπή Περιοδικού

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1 ΑΡΙΣΤΟΤΕΛΗΣ Έκδοση του Συλλόγου Αποφοίτων Φαρμακοποιών του Αριστοτελείου Πανεπιστημίου Θεσσαλονίκης Συντακτική Επιτροπή Περιοδικού Παλαιές φαρμακευτικές μπουκάλες Λένια Ιωαννίδου Βέρα Μίου Γιάννης Κουής Γιαννούλα Αγγελοπούλου Τάκης Αγγελόπουλος Η Συντακτική Επιτροπή του ΑΡΙΣΤΟΤΕΛΗ διατηρεί το δικαίωμα να μη δημοσιεύει ή να περικόβει κατά την κρίση της οποιοδήποτε χειρόγραφο. Ενυπόγραφα άρθρα δεν απηχούν απαραίτητα και τη γνώμη της Συντακτικής Επιτροπής και δημοσιεύονται χωρίς γλωσσική επιμέλεια. Ανυπόγραφες παρουσιάσεις είναι προϊόν συλλογικής δουλειάς. Το Copyright των ενυπογράφων άρθρων ανήκει στους συγγραφείς. Διοικητικό Συμβούλιο ΑΡΙΣΤΟΤΕΛΗ Γιαννούλα Αγγελοπούλου: Πρόεδρος Γιάννης Κουής: Αντιπρόεδρος Χρύσω Πετρίδου: Γραμματέας Χαράλαμπος Κέκκος: Ταμίας Λευτέρης Γεωργίου: Μέλος Κλεόπας Χατζηχαραλάμπους-μέλος Γιώργος Γεωργίου-μέλος Ταχ. Θυρ , 1307 Λευκωσία Τηλ: ή Τηλεομοιότυπο: , Διανέμεται δωρεάν σε όλους τους φαρμακοποιούς της Κύπρου Διεκπεραίωση γραφικών & στοιχειοθεσία: Microtype Designs, Καστοριάς 12, 1055 Λευκωσία - Κύπρος. Τηλ , alecs@spidernet.com.cy Εκτύπωση: Tυπογραφεία ΧΡ. ΝΙΚΟΛΑΟΥ ΚΑΙ ΥΙΟΙ ΛΤΔ nicolaouprinters@cytanet.com.cy ΙOYNIOΣ ΤΕΥΧΟΣ 24 1

2 ΠΕΡΙΕΧΟΜΕΝΑ TA EN OIKΩ... 3 Χρονικό του Αριστοτέλη... 3 Δραστηριότητες των Φαρμακοποιών... 6 ΕΠΙΣΤΗΜΟΝΙΚΗ ΕΠΙΣΚΟΠΗΣΗ... 9 Tuberculosis-Continues to Challenge and Deceive... 9 Lysosome Function and the Chediak-Higashi syndrome...21 ΕYPΩΠAΪKA ΔPΩMENA O εκσυγχρονισμός του ευρωπαϊκού κοινωνικού μοντέλου σε ένα ενεργητικό και δυναμικό κράτος πρόνοιας - Στρατηγική της Λισσαβόνας ΕΠΙΣΤΗΜΟΝΙΚΗ ΕΝΗΜΕΡΩΣΗ Μείωση της μνήμης σχετιζόμενη με την ηλικία Ανεμευλογιά στα παιδιά Οι Ογκολογικοί Αιματολογικοί Δείχτες και η χρησιμότητα τους Νέα γρίπη Α (Η1Ν1) KΛINIKH ΔIAITOΛOΓIA Kαρκίνος και Δίαιτα ΦYΣIKEΣ EΠIΛOΓEΣ Αρωματοθεραπεία KOΣMETOΛOΓIA Aυξητικοί παράγοντες: Tο μέλλον της κοσμετολογίας και των αισθητικών επεμβάσεων ΦAPMAKEYTIKH ENHMEPΩΣH Δελτίο Tύπου XΟΡΗΓΟΙ ΙOYNIOΣ ΤΕΥΧΟΣ 24

3 ΤΑ ΕΝ ΟΙΚΩ Χρονικό του Αριστοτέλη Βέρα Μίου Φαρμακοποιός, Α.Π.Θ. Αγαπητοί συνάδελφοι, κάπως αργοπορημένα σας μεταφέρω τα δρώμενα του Συλλόγου ΑΡΙΣΤΟΤΕΛΗΣ. Κανονικά το ραντεβού μας ήταν πριν από τις διακοπές μας, για να μπορεί το περιοδικό μας να σας κρατά συντροφιά στις διακοπές σας, αλλά λόγω τεχνικών προβλημάτων αυτό δεν κατέστει δυνατόν. Δεν πειράζει όμως, να μας και πάλι, φορτωμένους νέα. Η ετήσια γενική συνέλευση του ΑΡΙΣ- ΤΟΤΕΛΗ πραγματοποιήθηκε στις 7 Φεβρουαρίου στο ξενοδοχείο ALDIANA στον Μαζωτό. Συνδυάστηκε με ένα όμορφο και ξεκούραστο Σαββατοκυρίακο των μελών του συλλόγου, μαζί με τις οικογένειές τους στο ήσυχο αυτό παραλιακό ξενοδοχείο. Περάσαμε όλοι, μικροί και μεγάλοι πολύ ωραία. Τα παιδιά είχαν την ευκαιρία να ασχοληθούν με τα διάφορα αθλήματα και δραστηριότητες που διέθετε το ξενοδοχείο, για να κάνει τη διαμονή και αυτών αλλά και των γονιών τους πιο άνετη. Στο τεράστιο εστιατόριο του ALDIANA είχαμε την ευκαιρία να ικανοποιήσουμε οποιαδήποτε γευστική μας επιθυμία. Ακόμη και τους πιο ιδιότροπους ή εκλεκτικούς από μας κατάφεραν να ικανοποιήσουν, με τις τόσες διαφορετικές κουζίνες (γαλλική, ιταλική, κυπριακή, κινέζικη) που διέθετε το ξενοδοχείο. Και το πιο πρωτότυπο, όλα ή σχεδόν όλα μαγειρεύονταν μπροστά μας. Σαββατόβραδο όμως χωρίς μουσική και χορό γίνεται; Όχι φυσικά. Ο γερμανός dj του club με την ελληνική και ξένη μουσική του παρέσυρε τους φαρμακοποιούς στη πίστα, ενώ απολάμβαναν τα κοκτέιλ του μπάρμαν- show man. Την Κυριακή 8 Φεβρουαρίου πραγματοποιήθηκε στο ίδιο ξενοδοχείο, η ετήσια γενική συνέλευση. Κατά την ημερήσια διάταξη, η πρόεδρος του συλλόγου κα Γιαννούλα Αγγελοπούλου παρέθεσε την έκθεση των πεπραγμένων του απερχόμενου Δ.Σ και ο ταμίας κος Πάμπος Κέκκος παρέθεσε την ταμιακή έκθεση. Ακολούθησαν οι αρχαιρεσίες για την εκλογή του νέου Δ.Σ το οποίο έχει την πιο κάτω σύνθεση: Γιαννούλα Αγγελοπούλου-πρόεδρος Γιάννης Κουής-αντιπρόεδρος Χρύσω Πετρίδου-γραμματέας Πάμπος Κέκκος-ταμίας Λευτέρης Γεωργίου-μέλος Κλεόπας Χατζηχαραλάμπους-μέλος Γιώργος Γεωργίου-μέλος Και την ελεγκτική επιτροπή την απαρτίζουν τα μέλη: Τάκης Αγγελόπουλος Άριστος Πετρίδης και Σταύρος Ιακωβίδης Το νέο Δ.Σ με την ανάληψη των καθηκόντων του και πιστό στους στόχους του συλλόγου, αποφάσισε την διοργάνωση της 12ης Επιστημονικής Ημερίδας, η οποία πραγματοποιήθηκε την Κυριακή 31 Μαίου 2009 με μεγάλη επιτυχία στο ξενοδοχείο KANIKA PANTHEON στη Λεμεσό. Ομιλητής της ημερίδας ήταν ο διακεκριμένος αναπληρωτής καθηγητής της Μοριακής Φαρμακολογίας του Τμήματος Φαρμακευτικής 3

4 ΤΑ ΕΝ ΟΙΚΩ 4 του Πανεπιστημίου Πατρών Δρ Αντρέας Παπαπετρόπουλος με θέμα «Καρκίνος και αντινεοπλασματικά φάρμακα». Το ενδιαφέρον των φαρμακοποιών κρατήθηκε αμείωτο σε όλη τη διάρκεια της διάλεξης του κύριου καθηγητή για τις νέες επιτεύξεις της επιστήμης μας στην καταπολέμηση του καρκίνου. Χορηγός της εκδήλωσης ήταν όπως και στις προηγούμενες ημερίδες του ΑΡΙΣΤΟΤΕΛΗ, η εταιρεία MUNDIPHARMA PHARMACEUTICAL LTD, πιστός αρωγός στις προσπάθειες του συλλόγου μας στην δια βίου μάθηση των Κυπρίων φαρμακοποιών. Μέσα από τις στήλες και του περιοδικού αυτού θα θέλαμε να εκφράσουμε τις ευχαριστίες μας στην εταιρεία και ιδιαίτερα στο διευθυντή της κον Μένοικο Πέτρου. Όπως σας είχα αναφέρει στο προηγούμενο τεύχος ο ΑΡΙΣΤΟΤΕΛΗΣ θα ταξιδέψει στην Κωνσταντινούπολη, στην έδρα της Ορθοδοξίας και πρωτεύουσα της Βυζαντινής Αυτοκρατορίας με το τουριστικό γραφείο SEASONS TRAVEL. Τότε δεν είχα τις λεπτομέρειες του ταξιδιού, όμως τώρα θα σας περιγράψω τι θα επισκεφθούμε σ αυτή την πολυσυζητημένη πόλη. Το ταξίδι θα πραγματοποιηθεί την Τετάρτη 30 Σεπτεμβρίου μέχρι την Κυριακή 4 Οκτωβρίου. Η αναχώρηση είναι προγραμματισμένη στις μ.μ το απόγευμα της Τετάρτης για την Αθήνα και θα διανυκτερεύσουμε στο ξενοδοχείο Astor. Την Πέμπτη το πρωί στις π.μ θα αναχωρήσουμε για την Κωνσταντινούπολη όπου θα μας υποδεχθεί ελληνόφωνος ξεναγός και θα καταλύσουμε στο ξενοδοχείο Holiday Inn Old City. Το μεσημέρι της ίδιας μέρας θα ταξιδέψουμε με ιδιωτικό πλοιάριο για τα Πριγκηπονήσια όπου θα επισκεφθούμε τη Θεολογική Σχολή της Χάλκης, και το φημισμένο θέρετρο των Βυζαντινών με τα πεύκα και τις αμμώδεις παραλίες. Την Παρασκευή θα γίνει η ξενάγησή μας στην Πόλη για να δούμε την Αγία Σοφία ένα από τα σημαντικότερα μνημεία της παγκόσμιας κληρονομιάς, την Αγία Ειρήνη, το Γαλάζιο Τζαμί, τον Ιππόδρομο, την Μονή Αγίου Σεργίου του Βάκχου, το φημισμένο παλάτι Τοπ Καπί, την επίσημη κατοικία των Σουλτάνων και την ανατολίτικη αγορά Grand Bazaar με τα 4000 καταστήματα. Το Σάββατο θα επισκεφθούμε το Πατριαρχείο, τη Μονή Χώρα, την Πύλη του Ρωμανού, τη Ζωοδόχο Πηγή, την Παναγία των Βλαχερνών και το παλάτι Dolmabahce. Την Κυριακή το πρωί, το ταξίδι στην πόλη που ενώνει τις δύο ηπείρους Ευρώπη και Ασία, το ταξίδι στην πόλη που για πάνω από χίλια χρόνια απετέλεσε κέντρο του ελληνισμού τελειώνει. Θα αναχωρήσουμε με την Ολυμπιακή για την Αθήνα και λίγο μετά το μεσημέρι θα φτάσουμε στην Λάρνακα. Με ανυπομονησία περιμένουμε την εκδρομή αυτή του συλλόγου μας. Κλείνοντας θέλω να σας υπενθυμίσω το 6ον Παγκύπριο Φαρμακευτικό Συνέδριο που θα πραγματοποιηθεί στις Οκτωβρίου 2009 με πολλά ενδιαφέροντα θέματα. Ο ΑΡΙΣΤΟΤΕ- ΛΗΣ θα βρίσκεται εκεί γιατί πιστεύουμε στη δια βίου μάθηση.

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6 ΤΑ ΕΝ ΟΙΚΩ Δραστηριότητες Φαρμακοποιών Γιάννα Aγγελοπούλου Φαρμακοποιός A.Π.Θ. Αγαπητοί συνάδερφοι σας χαιρετώ, Οι εκδηλώσεις που πραγματοποιήθηκαν για μας τους φαρμακοποιούς αυτό το διάστημα είναι οι ακόλουθες: α)στις 18 Μαρτίου σ ένα ωραιότατο παραδοσιακό περιβάλλον στην κάβα Agrovino στο χωριό της Λόφου της επαρχίας Λεμεσού, η εταιρία ΔΡΟΓΟΦΑΡΜΑ και η εταιρεία φυσικών καλλυντικών APIVITA σ ένα άψογα οργανωμένο συμπόσιο, παρουσίασαν την σειρά περιποίησης προσώπου Wine elixir, καθώς επίσης τα καινούργια προϊόντα και τις δραστηριότητες της APIVITA για το Την εκδήλωση που να σημειώσουμε έγινε σε μια κάβα κρασιών χαιρέτησε και τίμησε με την παρουσία του ο πρόεδρος του Π.Φ.Σ κ. Νίκος Νουρής καθώς και φαρμακοποιοί απ όλη την Κύπρο. Ακολούθησε δείπνο στην παραδοσιακή ταβέρνα Λόφου. β) Στις 16 Απριλίου, η εταιρεία Health and Diet Food Center LTD παρουσίασε, στο ξενοδοχείο Κλεοπάτρα στη Λευκωσία τα νέα προϊόντα της εταιρείας Uriage-Γαλλίας με ομιλητή τον πολύ αξιόλογο Dr. Toni MariusA. Lonesco MD, PhD Dermotologist, Dermatology polyclinic, Saint Louis Hospital-Paris France με θέμα : Hyseac- A multi-target approach in acne-prone skins! Sunblockers-The philosophy of Sunburn Μετά το πέρας της επιστημονικής παρουσίασης ακολούθησε κοκτέιλ. γ) Η εταιρεία Παπαέλληνας στις 29 Απριλίου διοργάνωσε στο ξενοδοχείο Curium Palace στη Λεμεσό, ενημερωτικό σεμινάριο όπου παρουσιάστηκαν τα νέα προϊόντα της Roc. Ομιλήτρια η κ. Άντρη Χαραλάμπους, Brand Development Manager. Το ίδιο σεμινάριο πραγματοποιήθηκε και στην Πάφο στο ξενοδοχείο Alexander. δ) Στις 31 Μαΐου στο ξενοδοχείο ΚΑΝΙΚΑ PANTHEON στη Λεμεσό, ο σύλλογός μας ΑΡΙΣΤΟΤΕΛΗΣ πραγματοποίησε την 12 η επιστημονική Ημερίδα του με μεγάλη επιτυχία. Θέμα: Καρκίνος και Αντινεοπλασματικά Φάρμακα. Ομιλητής ο διακεκριμένος Αναπληρωτής καθηγητής Μοριακής Φαρμακολογίας του Τμήματος Φαρμακευτικής του Πανεπιστημίου Πατρών Dr Αντρέας Π Πετρόπουλος. Κατά γενική ομολογία τόσο το θέμα της διάλεξης όσο και η παρουσίαση του συγκεκριμένου καθηγητή ικανοποίησε και ενθουσίασε όλους τους παρευρισκομένους. Την εκδήλωση προλόγισε και 6

7 ΤΑ ΕΝ ΟΙΚΩ λάμπρυνε με την παρουσία της, η συνάδελφος και βουλευτής Αθηνά Κυριακίδου, την οποία ευχαριστούμε ιδιαίτερα για την συμπαράστασή της. στ)η εταιρεία Glaxo SmithKline σε επιστημονική ενημέρωση που έκανε στις 24 Ιουνίου στο Atlantica Bay Hotel στη Λεμεσό με ομιλήτρια την αγαπητή σ όλους μας pharmacy Representative Άντρη Παντελή παρουσίασε το θέμα Καλοκαιρινές Δερματικές Προκλήσεις. Μετά το τέλος του επιστημονικού μέρους ακολούθησε ε)η σχετικά καινούργια στον κυπριακό χώρο εταιρεία καλλυντικών Dermaglow, πραγματοποίησε cocktail party στο Columbia Plaza στην Λεμεσό στις 3 Ιουνίου. Κάνοντας το ξεκίνημα μιας νέας εποχής για την ομορφιά, παρουσιάστηκαν εν συντομία τα προϊόντα της εταιρείας Dermaglow, ενώ την όλη εκδήλωση κόσμησε με την παρουσία της η ωραιότατη και διάσημη στον κόσμο του modeling Εύη Αδάμ. δείπνο και έτσι είχαμε την ευκαιρία εμείς οι φαρμακοποιοί να πούμε τα δικά μας. Αυτά για τώρα. Γιάννα Αγγελοπούλου Η ΣΥΝΤΑΚΤΙΚΗ ΕΠΙΤΡΟΠΗ ΚΑΙ ΤΟ ΔΙΟΙΚΗΤΙΚΟ ΣΥΜΒΟΥΛΙΟ ΤΟΥ ΑΡΙΣΤΟΤΕΛΗ ΕΚΦΡΑΖΟΥΝ ΤΙΣ ΕΥΧΑΡΙΣΤΙΕΣ ΤΟΥΣ ΠΡΟΣ ΤΟΥΣ ΦΙΛΟΥΣ ΚΑΙ ΧΟΡΗΓΟΥΣ ΤΟΥ ΠΕΡΙΟΔΙΚΟΥ 7

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9 EΠIΣTHMONIKH EΠIΣKOΠHΣH Tuberculosis Continues to Challenge and Deceive Dr Anna-Maria Shiarli ABSTRACT Tuberculosis is the second most infectious cause of death, after HIV, and a health hazard not only in developing but also in developed countries like the UK. This case report outlines the case of a 38-year old man from Somalia who presented with a rather unusual form of isolated extrapulmonary peritoneal tuberculosis. The delay in the diagnosis caused a serious deterioration in the patient s condition which was made even worse by the hepatitis that he developed due to his antituberculous therapy. Through this case, the report gives an account of the pathology of tuberculosis explaining its rather systemic nature and the variability in its clinical presentation which can delay diagnosis. It also outlines its management and its main challenges as well as its prevention in the population. Next, the report concentrates on several issues underlined by the specific case discussed. It gives an account on peritoneal tuberculosis and its diagnostic challenges emphasising the need for accurate and possibly less invasive and less time-consuming investigations. Moreover, the issue of antituberculous therapy-induced hepatitis is discussed, the need for its immediate diagnosis and possible alternatives in antituberculous treatment in such cases. Fluoroquinolones, and in particular levofloxacin, seem to be good candidates for the treatment of tuberculosis when the first-line antituberculous drugs cause hepatotoxicity. 1.1 Introduction After HIV, tuberculosis is the second most common infectious cause of death in the world. It is particularly prevalent in less developed countries like India and Africa where malnutrition and overcrowding create favourable conditions for the transmission of the disease. However, even in countries like UK and the United States the burden of Tuberculosis is still quite high with around 7000 and new cases each year respectively. The bacterium, Mycobacterium Tuberculosis, has the ability to induce a cell-mediated hypersensitivity reaction within the host, with the formation of the characteristic granulomata. The reaction causes serious tissue destruction so that the disease may be disseminated to many parts of the body apart from the lungs (where it usually starts), making tuberculosis a rather systemic disease. Moreover, the bacterium has been proven particularly difficult to manage as resistance to medication develops rapidly. The multi-drug regime used, because of its duration and the associated side effect,s may prove to be a real burden to the patient. This report outlines the case history of a 38 year old young man from Somalia who presented with extrapulmonary tuberculosis. The unusual presentation delayed his diagnosis and treatment. When treatment was finally started the toxicity and side effects caused by the medication caused the change of the type and duration of his regime, with consequent impact on the patient s health and quality of life. This report then continues to give an account of tuberculosis, its pathology and its management. In the discussion, several issues brought out by the case history are analysed in more detail. These include peritoneal tuberculosis, hepatotoxicity induced anti-tuberculous drugs and the use of fluoroquinolones, and in particular levofloxacin, in the treatment of tuberculosis. 9

10 EΠIΣTHMONIKH EΠIΣKOΠHΣH The Case History The patient initially presented in May 2006 to his GP with central abdominal pain increasing in frequency and severity over some days, followed by flu-like symptoms and fever and gradual loss of his appetite. Investigations which included blood count and biochemistry, U&E s, LFT s, glucose, inflammatory markers, HIV and Hepatitis serology and chest X-ray showed no abnormality, so the patient was prescribed omeprazole for his abdominal pain. Indeed the pain responded to the medication for the two following months. The following July his symptoms got worse with episodes of watery diarrhoea (10-20/day) associated with crampy abdominal pain, sweating and fever with rigors. Initially the patient thought that this was due to the hot weather and as he has a history of hay fever he assumed that this was just part of his allergy. However, over several days his stools became normal and the pain became more constant and permanent and especially associated with eating, causing loss of appetite and consequent loss in his weight. Also, his medication did not seem to ease of the pain and his abdomen became gradually swollen. He also experienced episodes of morning vomiting increasing in frequency. On examination, at his GP, he had a tense distended abdomen with rebound tenderness but no guarding or shifting dullness. Investigations were repeated and although stool cultures and white blood cell count were normal, his CRP was increased at 163. At this point he was advised to attend at the Accident and Emergency but he did not until the following day, when his condition got worse to the point that he was so weak he could not get out of bed or walk. He was admitted therefore in mid-july Investigations and examination showed only an increased CRP but no other evidence of infection or source of infection and a CT of the abdomen was ordered. This showed areas of thickening on the peritoneum and therefore the patient underwent a diagnostic laparoscopy with peritoneal biopsy. At laparoscopy, turbid fluid was found within the abdomen which was sent for microscopy and cultures and several nodules were found on the peritoneum and some on the small bowel. On macroscopic examination of the biopsy tissue, irregular pieces of brown tissue were found and on microscopic examination the tissue contained a large number of epithelioid granulomata including Langerhans giant cells and occasional foci of central necrosis. However, these were negative for Ziehl-Nielsen stain for acid and alcohol fast bacilli. The diagnosis of peritoneal TB was made and the patient was prescribed the standard regimen of anti-tuberculous medication: rifampicin, isoniazid, pyrazinamide, and ethambutol, and he was discharged. Two days later the patient started vomiting and he stopped eating and even drinking because of abdominal pain. His abdomen became swollen again. He was therefore admitted again, this time with abnormal liver biochemistry: raised ALP of around 68 mmol/l (normal: 5-10 mmol/l) as well as his raised CRP. His creatinine and urea were also marginally low at around 52 mmol/l (normal creatinine: mmol/l) and 2mmol/l (normal urea: mmol/l). A diagnosis of drug-induced hepatitis was made and his condition continued deteriorating whilst in hospital with the ALP levels reaching 183mmol/l and his bilirubin going abnormal at around 43 μmol/l (normal 0-22 μmol/l). He was therefore challenged with one medication at a time to discover the cause of his hepatitis. It was found that Isoniazid was causing his hepatitis, but when this was eliminated from the regime, the patient proved to be still intolerant of the medication. This intolerance was caused by pyrazinamide which had to be eliminated as well. A new management plan was therefore made with ethambutol and rifampicin taken for seven months and Streptomycin and Levofloxacin taken for the next two months. The patient was discharged about 6 weeks after his last admission Two months later the patient develops new crampy central abdominal pain associated with eating and he is prescribed Lanzoprazol which did not fully relieve the pain. The pain was due to intra-abdominal inflammatory swelling related to his TB and he was prescribed prednisolone at

11 EΠIΣTHMONIKH EΠIΣKOΠHΣH 30mg for 2 weeks and then at 15mg for the next month. He was also advised, due to the complexity of his condition, to extend the duration of his TB medication. During his steroid medication the patient developed an itchy rash on his chest and face and had episodes of chest infections which, as he described, only he in his household was experiencing. Since stopping his medication in February 2007 the patient has been experiencing pain and weakness in his muscles and, as he described at his most recent review at the clinic, his arms feel too weak sometimes even to bring a cup to his mouth. He has now gained most of his weight back, about 10 kg since his diagnosis. The duration and severity of the tuberculosis infection had a great impact on his social and personal life. The patient is a student at the University studying Business and Marketing and his studies were disrupted in the final year by his disease. He now has to repeat the year. Moreover, the patient has a family with 2 children, one and six years old and he is also the carer of his nephews who are living with him. His inability to fullifill his duties during the time of his illness, as well as his bad psychological condition during the infection caused conflict with subsequent separation with his partner, which is fortunately now resolved. 3.1 Tuberculosis Epidemiology Tuberculosis is one of the commonest infectious causes of death in the world (2nd after HIV) causing about 1.7 million deaths each year1. In the UK there are about 7000 new cases each year 2 and there is increased incidence in countries like India and Africa due to the effects if poor nutrition, overcrowding and inefficient treatment, and amongst immigrant populations from these countries (about 2 million new cases each year). The incidence of TB is particularly increasing among HIV patients with about 50 million people co-infected, whilst other disease states like diabetes mellitus, Hodgkin s lymphoma, chronic lung disease (especially silicosis), chronic renal failure and alcoholism show increased risk for acquisition or reactivation of the disease The pathology of the infection Initially the infection with the bacilli causes inflammatory infiltration of neutrophils and macrophages causing the phagocytosis of the organism. The bacilli however are not eliminated since, once inside the macrophage, the bacterium replicates blocking the action of the phagosomelysosome system3 and therefore manages to proliferate in the alveolar macrophages and alveolar parenchyma for the first 3 weeks of infection. After these 3 weeks Th1 cells recruited from lung lymph nodes induce a hypersenstitivity reaction. When presented to the antigen, the Th1 cells differentiate and produce INF-γ. This critical factor is what causes the macrophages to become bactericidal4as it stimulates the formation of the phagolysosome and the production of nitric oxide which in turn causes oxidative destruction of the bacterium. Simultaneously, the activated macrophages produce Tumour Necrosis Factor (TNF) which induces a granulomatous reaction: Monocytes are recruited, differentiate into epithelioid histiocytes and the secretion of lytic enzymes causes tissue necrosis and the formation granulomata which contain the bacteria. The granulomata consist of a central area of necrotic tissue, caesation, surrounded by epithelioid cells which fuse to form Langerhans cells with multiple nuclei. The destruction of the surrounding tissue due to lytic enzymes causes fibrosis and therefore a Granulomatous lesions: caesation surrounded by epithelioid and multinucleated giant cells 11

12 EΠIΣTHMONIKH EΠIΣKOΠHΣH 12 fibrin wall surrounds the lesions. There is evidence to suggest that genetic factors may also play a part in the course of the disease in individual hosts. Polymorhisms in the NRAMP1 gene have been found to produce a disease without the delayed hypersensitivity response. NRAMP1 is a protein found in endosomes and lysosomes that causes cationic influx in lysosomes which may produce oxygen free radicals that kill the bacterium within the macrophage, without the need for the Th1-induced activation The patterns of infection The infection with the bacilli of Mycobacterium tuberculosis occurs in two pathologic patterns: primary and secondary infection, but nevertheless in it is only the second one of these phases that primarily reaches the hands of the physician. Primary tuberculosis The primary infection with the bacilli is the one occurring in a previously non-sensitised person or rarely in an elderly or immunocompromised person, who has lost immunity to the bacillus. The bacilli implant in the lower part of the upper lobe or the upper part of the lower lobe and usually close to the pleura, causing inflammatory consolidation.and caesation, not only in the parechymal tissue but also in the lymph nodes. This pattern of disease is the Ghon complex. If the host has effective immunity the Ghon complex will undergo fibrosis and calcification (the Ranke complex). In some cases the lesions are latent where and the organism remains dormant, with potential reactivation if the host immunity decreases. During the first few weeks of infection there may be lymphatic and haematogenous dissemination to other parts of the body. In about 5% of the cases, in immunocompromised patients, the reaction may not be controlled and the bacterium continues to induce increasing tissue destruction within the lung tissue causing progressive primary TB. This presents like acute pneumonia with lower and middle lobe consolidation, hilar lyphadenopathy and pleural effusion1. Secondary tuberculosis Secondary TB is the disease that arises in a previously sensitised host usually from reactivation of the dormant lesions many decades after the initial infection, or reinfection from an exogenous source. Less commonly, secondary TB may shortly follow the primary infection. The infection is primarily made visible at the apex of the upper lobes of one or both lungs possible because the high O2 tension at this site encourages the growth of the organism1. Due to the presensitisation, the hypersensitivity reaction is more localised causing circumscribed foci with central caesation and peripheral fibrosis, and the lymph nodes are less commonly involved than in the primary infection. However this secondary pattern may cause cavitation in the airways with consequent production of infective sputum and dissemination of the organisms through the lymphatics. In an immunocompromised patient the apical lesion may expand causing progressive pulmonary TB. Erosion of the bronchi and even blood vessels causes haemoptysis, bronchiectasis and even lobar collapse. Miliary tuberculosis in the spleen Miliary TB occurs most commonly with secondary TB when the organisms disseminate into the lymphatics, then into the right side of the heart and the pulmonary arteries. The organism therefore spreads in the lung causing foci of con-

13 EΠIΣTHMONIKH EΠIΣKOΠHΣH solidation which may coalesce, affecting not only the parechymal tissue but also the pleural cavity, causing effusions, empyema or fibrous pleuritis. In the systemic form of this pattern, the systemic arterial supply may cause the miliary pattern to be seen in organs like the liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes and epididymis. Isolated-organ tuberculosis This pattern of disease occurs as a consequence of the haematogenous spread of the organism during the primary or secondary TB infection and, as seen in this report, it can be the presenting complaint for the disease. Several organs of the body can be affected: the meninges (presenting as tuberculous meningitis), the kidneys, the adrenals (causing Addison s disease), the bones and especially the vertebrae (Pott s disease), the fallopian tubes, the skin (lupus vulgaris), the eyes (choroiditis) and the heart (pericarditis). The most frequent presentation of extrapulmonary disease in TB is the lymphadenitis caused in the cervical neck chain. This presents as a fluctuant mass in the anterior or supraclavicular region, the scrofula. This may have discharging sinuses of foul smelling turbid liquid. Intestinal tuberculosis also used to be quite common even as the initial infection by TB, since is was caused by drinking contaminated milk6. Nowadays, most commonly it occurs as the consequence of swallowing infective sputum causing inflammation of the lymphoid aggregations within the bowel and ulceration of the mucosa The clinical features of the disease Primary TB usually passes unnoticed by the patient although sometimes there maybe some cough and wheezing or even erythema nodosum2. In secondary TB the patient typically presents with tiredness, anorexia, weight loss, fever, night sweats, wheezing and coughing which may be productive or non-productive. Recurrent chest infections, or chest pain may also be the presenting complaint and some may present with pleural effusions or even pneumonia. On examination, little can be revealed apart from possibly crackles and the physical signs of effusion and consolidation, if a pleural effusion or pneumonia has occurred. Finger clubbing is very uncommon and presents in very advanced disease. As discussed already, TB can be isolated as extrapulmonary disease in various parts of the body, presenting with organ-specific symptoms. In HIV patients the disease may present with the pattern of primary progressive pulmonary TB with acute pneumonia, hilar lymphadenopathy and extrapulmonary involvement affecting primarily lymph nodes, liver and bone marrow The Diagnosis Apical and hilar reticulonodular shadows in tuberculosis The chest X-ray is a useful tool of diagnosing TB since, radiologic abnormalities are seen even in the absence of profound symptoms and, in the presence of symptoms, the X-ray is almost always abnormal. Patchy shadows are seen in the apical zones of the lungs with evidence of fibrosis and maybe cavitation. Sometimes calcification is present. This radiologic evidence is supplemented with microbiological evidence to confirm diagnosis and exclude other causes of similar X-ray appearance, which would include fungal infections such as aspergillosis and cryptococcosis and even bronchial carcinoma. If sputum is available, this is stained with Ziehl-Nielsen stain for the acid and alcohol-fast bacilli and it is cultured, a process which takes around 6 weeks. A quicker method, but not as reliable, is the use of 13

14 EΠIΣTHMONIKH EΠIΣKOΠHΣH Moreover, patients should be warned about the orange coloration of body fluids (tears, sweat and urine) that it causes7. 14 Cavitation caused by tuberculosis in the right upper lobe PCR to identify the bacterial DNA. Sensitivity of the bacillus to antibiotics can also be obtained. If sputum is not available, gastric washings or more commonly nowadays, washings from fibreoptic bronchoscopy can be used. Biopsies from the infected tissue in extrapulmonary disease and from the pleura and lymph nodes in pulmonary TB may also be the way to the diagnosis, as in the case in this report The treatment The treatment of TB comprises commonly of a regimen of four drugs: rifampicin and isoniazid, which are taken for six months, and pyrazinamide and ethambutol, which are taken for the first two months of treatment. The choice of these drugs is based on the fact that different drugs are directed against different populations of the organism and that the possibility of resistance of the Mycobacterium to treatment must be as small as possible. Rifampicin inhibits the DNA-dependent RNA polymerase and has bactericidal action. It is the essential drug for the treatment of TB but resistance develops rapidly. It induces liver enzymes and therefore it reduces the effectiveness of other drugs such as warfarin, steroids and oestrogen in oral contraceptives. It can cause gastrointestinal disturbance and transient increase in plasma transaminases. Hepatotoxicity and thrombocytopenia have also been reported. Isoniazid inhibits the production of long-chain mycolic acids which are only found in the cell wall of mycobacteria7. It is bactericidal for the dividing population of the organism and bacteriostatic for the non-dividing population. Resistance is not as common as rifambicin. Isoniazid is known to cause peripheral neuropathy and can be therefore co-prescribed with oral pyridoxine, especially in high-risk patients such as diabetics and alcoholics. It can also cause hepatotoxicity as was the case in this report, which can sometimes be fatal. It may also cause a systemic lupus erythrematosus-like syndrome8. Pyrazinamide is metabolised by the bacterial enzyme pyrazinamidase into its metabolite, pyrazinoic acid, which in turn decreases the intracellular ph and destroys the bacterium. It is bactericidal to the semi-dormant population of cells. Resistance develops rapidly if it is used alone. It may cause hepatotoxicity with a rise in plasma bilirubin and since it reduces renal excretion of uric acid in may precipitate gout7. Ethambutol is mainly bacteriostatic and it acts by impairing the synthesis of the cell wall of mycobacteria 7. Resistance develops slowly. Its main side effects are headaches and dizziness but it can also cause optic neuritis with initial red/green colour blindness and then reduced visual acuity. Other drugs Other drugs used in the treatment of TB mostly as second-line treatment in multidrug resistance TB, include streptomycin, ciprofloxacin, levofloxacin and cycloserine. Multi-drug resistance is a major problem in TB and is found primarily in HIV patients. Multi-drug resistance is one of the main factors that make TB such a big public health hazard. In this case streptomycin and levofloxacin were chosen to replace isoniazid and pyrazinamide and these are discussed in more detail here.

15 EΠIΣTHMONIKH EΠIΣKOΠHΣH Streptomycin is an aminoglycoside inhibiting protein synthesis in bacteria by binding irreversibly to the 30S ribosomal subunit and stopping translation if the mrna7. As all aminoglycosides, side effects include ototoxicity and nephrotoxicity and therefore care must be taken in treating patients with renal impairment. Levofloxacin as all quinolones inhibits replication of the bacterial DNA by blocking the activity of DNA gyrase, the enzyme that forms DNA supercoils and is essential for DNA replication7. Levofloxacin has a post-antibiotic effect as it continues to inhibit growth even if concentrations of the drug have fallen to undetectable levels. The incidence of unwanted effects is low, these including gastrointestinal disturbance and photosensitive skin rashes. The use of levofloxacin in TB is discussed in more detail later Follow up and prevention Patients are followed regularly for the duration of their treatment and once more after 3 months in case of relapse. Patients with multi-drug resistance should be followed for at least 1 year after treatment is completed. Prevention of TB is by the BCG (Bacille Calmette-Guerin) vaccine and was given in schoolchildren in the UK since It is a live vaccine from Mycobacterium bovis and it has been shown to decrease the risk of developing TB by about 70%2. The immunisation procedure has been stopped in many parts of the UK due to the decrease of TB but among immigrant populations and neonates in high risk areas the vaccine is still given. Screening procedures and contact tracing involve screening all close family members or close contacts at work or school. Those close contacts with symptoms should be thoroughly investigated for TB. Screening is carried out by the tuberculin test where the patient is tested with Purified Protein Derivative (PPD) of Mycobacterium bovis. The protein induces cell-mediated immunity causing T-lymphocyte infiltration and inflammation at the site of the infection. The test may be in the form of the Mantoux test which is PPD injected intradermally. The induration is measured after 72 hours, giving a positive result if it is 10mm or more in diameter. The Heaf test is simpler, with a small amount of PPD placed on the forearm though a 6-point apparatus. The reaction is graded 0-4 depending on the induration. If after a maximum of 10 days the grade is 0 or 1, the test is considered negative. These tests cannot distinguish between immunity and active disease and in patients with AIDS they may give a false positive result owing to the impairment of delayed hypersensitivity 2,8. If the screening of contacts is negative in children and young adults it is repeated at 6 weeks and if still negative the BCG is administered. If it is positive in children, infection is assumed and treatment is started. If it is positive in adults, a chest-x ray is carried out to exclude active disease. In children under the age of 1 year with an infected family member a daily dose of isoniazid is given additional to the BCG vaccine Discussion Peritoneal TB The first case of peritoneal TB was described in humans in It occurs in about 3.5 % of cases of pulmonary TB and it is found in 31-58% of cases of abdominal TB10. Populations of increased risk for peritoneal TB seem to be patients with chronic renal failure undergoing continuous ambulatory peritoneal dialysis (CAPD) especially within the first 12 months of treatment11 and also HIV patients. The diagnosis of peritoneal TB poses a challenge for the physician due to the variability of clinical presentation. The delay in clinical diagnosis and investigations can be hazardous for the patient. In fact studies have shown that about 80% of the patients with peritoneal TB show marked clinical deterioration during the diagnosis procedure with a mortality of 35%12. Abdominal pain seems to be a common symptom, followed by abdominal distension. Fever, night 15

16 EΠIΣTHMONIKH EΠIΣKOΠHΣH 16 sweats and weight loss are reported in about half of the cases. On the other hand, diarrhoea (like the patient in this report) or constipation seem to be relatively uncommon presenting symptoms (about 20%). On examination, ascites is found in about 70% of the cases whilst splenomegaly or hepatomegaly are relatively uncommon11. Investigations for making the diagnosis of peritoneal TB are based on ascitic fluid analysis and laparoscopy. The ascitic fluid investigations may include lymphocyte count, levels of lactate dehydrogenase (LDH) and adenosine deaminase (ADA),and smear testing with culture. Of these, the ADA and LDH levels seem to confer the highest sensitivity ADA has a sensitivity of %13 when values are greater than 30 U/l whilst LDH seems to have a sensitivity of 77%. The high sensitivity of these tests is important since they may serve as a way of avoiding invasive procedures like laparoscopy in the diagnosis of peritoneal TB Ziehl-Neelsen's staining, PCR, and ascitic fluid cultures seem to have a low sensitivity for the isolation of the bacterium with smear testing having sensitivities of only around 3%11, 16. Although CT imaging can be useful as a preliminary investigation for peritoneal TB laparoscopy seems to be the investigation of choice. Several patterns of macroscopic appearances of the peritoneum have been described. A thickened, oedematous peritoneum associated with the military nodules, as was the case in this report, is the most common pattern17. The sensitivity of laparoscopy when combined with histologic analysis is about 98% for the diagnosis of peritoneal TB Hepatotoxicity and antituberculous therapy Three out of the four drugs comprising the treatment of tuberculosis have been shown to have CT of the abdomen showing ascites and a thicknened peritoneum in peritoneal TB an increased risk of hepatotoxicity, these being rifambicin, pyrazinamide and isoniazid. Hepatotoxicity is most common in the first 2 months of treatment 18,19.Of the three drugs rifambicin seems to be associated with the lowest incidence of hepatotoxicity (around 1.1%)20and it is recommended that after a drug-induced hepatitis, rifampicin is the first drug that is restarted 21.On the other hand, pyrazinamide is associated with the highest incidence of hepatotoxicity and this seems to be dose related 22.Studies have shown that isoniazid, which seems to be the drug that induced the hepatitis in the patient discussed, has an incidence of hepatotoxicity just above that of rifampicin with an incidence of 1.6%. However when the two drugs are combined the incidence rises to around 2.6%20. The mechanism by which hepatotoxicity is induced by antituberculous drugs is still unclear. The effect seems to be dose-related and this may have implications on whether monitoring of drug levels may prove useful in its prevention, although this is still controversial23.hypersensitivity to antituberculous drugs has been suggested to be one mode of induction of hepatotoxicity, since some patients present simultaneously with rash, fever, eosinophilia and arthralgia24.other studies suggest that hepatotoxicity is induced through oxidative stress since an alteration in the lipid peroxidation is seen with isoniazid and rifambicin25.of particular interest, is the synergistic effect of the two latter drugs by the production of monoacetyl hydralazine, hydralazine and other compounds, through the induction of liver enzymes that occurs with rifampicin and alcohol26.the figure below shows the possible mechanism by which isoniazid may produce its hepatotoxic action if used in combination with alcohol or rifambicin. Several factors seem to increase the risk of druginduced hepatotoxicity including old age, female gender, alcoholism, malnutrition and extensive tuberculosis infection27. Moreover, the risk of hepatotixicity is 3-5 times higher in patients with chronic viral hepatitis or HIV infection28. Polymorphisms associated with the HLA-DQ alleles and the cytochrome

17 EΠIΣTHMONIKH EΠIΣKOΠHΣH p450 2EI have also been shown to produce an increased risk for drug-induced hepatotoxicity29, 30. Diagnosis of the drug-induced hepatitis is especially important as it implies the cessation of all antituberculous medication. The diagnosis can be somewhat tricky as antituberculous drugs (particularly rifambicin) may increase the liver transaminases without necessarily signifying toxicity, and, on the contrary, in cases where liver biochemistry is indeed greatly abnormal, viral and not drug-induced hepatitis might be the real cause31.the British Thoracic Society recommends that patients should have their liver biochemistry tested before the start of antituberculous medication and if this is abnormal or the patient is alcohol dependent he must be closely monitored, especially in the first 2 months. An increase of five times the normal transaminase levels or symptom presentation by the patient indicates stopping the antituberculous medication. Patients should be advised to look out for anorexia, vomiting, nausea and abdominal distension that may suggest hepatitis. In the case described in this report, all these symptoms were presented by the patient but they could easily be misinterpreted as the symptoms of his peritoneal TB The use of levofloxacin in antituberculous therapy The use of fluoroquinolones for the treatment of tuberculosis has been studied since the 1980 s with both in vitro and in vivo studies. These drugs are now included in the management of multidrug resistance of tuberculosis 33,34. Several factors make fluoroquinolones good candidates for this purpose including their good oral bioavailability and the fact that they are generally well tolerated in a long duration of treatment35. Levofloxacin in particular has been studied for its effects in multidrug resistant-tb with success rates of around 80% in a 14 month treatment. When studied in vitro, levofloxacin has been shown to have a greater activity against the bacterium compared to other fluoroquinolones36. Moreover, when tested clinically it was shown to be well tolerated and safe for up to 24 months of treatment37. A case-control analysis has shown that the use of levofloxacin in patients with a history of adverse effects when the first-line antituberculous medication, showed a lower rate of these effects. This was reversed when controlling for the concomitant use of isoniazid, rifambicin and pyrazinamide, implying that levofloxacin had no significant additional toxicity in longterm use38. Another factor that makes fluoroquinolones favourable candidates as alternatives, which also arises from this case report, is that they have a low incidence of hepatotoxicity in a majority of patients with drug-induced hepatitis due to first line antituberculous drugs39. In a study with liver transplant patients who developed hepatitis after the conventional treatment for tuberculosis, most patients were cured after a change of their regime to ethambutol with fluoroquinolone, without any further adverse effects Conclusion Tuberculosis is a major health hazard worldwide due to the development of treatment resistance, its increased frequency in immunocompromised individuals and the easy dissemination of the disease not only within the host but also within the population. The pathology of tuberculosis helps to explain the dissemination of the disease in various parts of the body and the variability in its clinical presentations due to this extrapulmonary nature. An example of such a presentation is peritoneal tuberculosis which may present with a wide range of symptoms and requires a high level of suspicion to diagnose it clinically. 17

18 EΠIΣTHMONIKH EΠIΣKOΠHΣH Investigations for its diagnosis tend to be rather specific in nature since the conventional smear of ascitic fluid carries very low sensitivity. Ultimately, it is invasive procedures like laparoscopy with tissue biopsy that are needed to make the diagnosis. Due to the above reasons, the delay in the diagnosis may cause serious deterioration in the patient s health. Another major issue around the tuberculosis infection is the multi-drug regime that is used. Apart from problems in Mycobacterium resistance to this treatment, three out of the four drugs conventionally used, carry a risk for hepatotoxicity which can be potentially fatal. Although the mechanisms of this are yet unclear, rifampicin seems to be the least hepatotoxic and pyrazinamide the most, with isoniazid having an intermediate risk but a synergistic effect with rifambicin. Symptoms like nausea vomiting and abdominal pain should always raise the suspicion for hepatitis and patients must be educated to recognise these. In the case of hepatotoxicity, alternatives in antituberculous medication must be searched and fluoroquinolones seem to be good candidates. They have a low risk of adverse effects in a long duration treatment for tuberculosis. In particular, this class of drugs seem to cause relatively low hepatotoxicity and are therefore potential alternatives for treatment after druginduced hepatitis. Out of this class, levofloxacin has been shown to be the most active against the bacterium and is simultaneously safe for long term treatment. References: 1. Kumar V, Abbas AK, Fausto N: Robbins and Cotran Pathologic Basis of Disease. Philadelphia. Elsevier Saunders, Kumar P, Clark M: Clinical Medicine. Edinburgh.WB Saunders, Glickman MS, Jacobs WR Microbial pathogenesis of Mycobacterium tuberculosis: dawn of a discipline.cell ; 104(4): Flynn JL, Chan J. Immunology of tuberculosis. Annu. Rev. Immunol. 2001; 19: Bellamy R, Ruwende C, Corrah T, Mc Adam KP.Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med ; 338(10): Al Quorain AA, Satti MB, Alfreihi Hm. Abdominal tuberculosis in Saudi Arabia : a clinico-apthological study of 65 cases. Am J Gastroenetrol 1993:88: Waller DG, Renwick AG, Hillier K. Medical Pharmacology and Therapeutics.London. W. N Saunders Pgs British National Formulary pg Dinnen P, Homan WP, Grafe WR, Tuberculous peritonitis:43 years experience in diagnosis and treatement. Ann Surg 1976:184: Sanai FM, Bzeizi KI.Systematic review: tuberculous peritonitis--presenting features, diagnostic strategies and treatment.aliment Pharmacol Ther ; 22(8): Quantrill SJ, Woodhead MA, Bell CE, Hutchison AJ, Gokal R. Peritoneal tuberculosis in patients receiving continuous ambulatory peritoneal dialysis. Nephrol. Dial Transplant (5):1204-7) 12. Chow KM, Chow VCY, Hung LCT. Tuberculous peritonitis-associated mortality is high among patients waiting for the results of Mycobacterial culture of ascitic fluid samples. Clin. Infec. Dix. 2002:35: Fernandez, E., García, S.,Gutiérrez, F., Ocio, G., Rodrigo, L. and Riestra, S. Diagnostic value of adenosine deaminase isoenzymes in ascitic fluid. AJG ; Marshall, JB.Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol ; Burgess, LJ, Swanepoel, CG and Taljaard, JJ. (2001) The use of adenosine deaminase as a diagnostic tool for 18

19 EΠIΣTHMONIKH EΠIΣKOΠHΣH peritoneal tuberculosis. Tuberculosis (Edinb) Schwake, L., Von Herbay, A., Junghanss, T., Stremmel, W. and Mueller, M Peritoneal tuberculosis with negative polymerase chain reactions results: report of 2 cases. Scand J Gastroenterol , Bhargava DK. Shriniwas, Chopra P. Peritoneal tuberculosis laparoscopic patterns and its diagnostic accuracy. Am J Gastroenerol 1992:87: Worlds Health Organization. Treatment of Tuberculosis: Guidelines for National Programmes. 3rd Edition. World Health Organization. Geneva Girling DI. Adverse effects of anti-tuberculosis drugs. Drugs. 1982: 23: Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifambicin. A meta-analysis. Chest 1991:99: American Thoracic Society/ Centres for disease Control and prevention/ infectious diseases society of America. Treatment of tuberculosis. Am J Respir. Crit. Car. Med 2003: 167: Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first line anti-tuberculosis drugs among patients treated for active tuberculosis. Am. J. Respit. Crit. Care Med :197: Yew WW. Therapeutic drug monitoring in anti-tuberculosis chemotherapy. Ther. Drug. Monit. 1998:20: Schreiber J, Zissel G, Greinert U, Schlaak M, Muller- Quernheim J. Lymphocyte transformation test for the evaluation of adverse effects of the antituberculous drugs. Eur. J Med. Res. 1999; 4: Sodhi CP, Rana SV, Mehta SK, Vaphei K, Attari S, Mehta S. Study of oxidative stress in isoniazidrifampbicin induced hepatic injury in young rats. Drug Chem. Toxicl. 1997:20: Askgaard DS, Wilcke T, Dossing M. Hepatotoxcity caused by the combined action of isoniazid and rifampicin. Thorax 1995:50: Fernandesz- Villat A, Sopena B, Fernandez-Villar J. The influence of risk factors on the severity of anti tuberculosis drug-induced hepatotoxicity. Int. J. Tuberc. Lung Dis 2004:8: Ungo IR, Jones D, Askin D. Anti-tuberculosis druginduced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency vitus. Am. J. Respir. Crit. Care Med. 1998:158: Sharma SK, Balamurugan A, Saha PK, Pandey RM, Mehra NK. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during anti-tuberculosis treatment. Am. J. Respr. Crit. Care Med 2002:166: Huang YS, Chern HD, Su WI. Cytochrome P450 2E1 genotype and the susceptibility to anti-tuberculosis drug-induced hepatitis. Hepatology. 2003:37: Turktas H, Unsal M, Tulek N, Oruc O. Hepatotoxicity of anti-tuberculosis therapy( rifampicin, isoniazid and Pyrazinamide) or viral hepatitis. Tuber. Lung. Dis. 1994:75: Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United kingdom recommendations Thorax 1998; 53: Young, LS, Berlin, OGW, Inderlied, CB. Activity of ciprofloxacin and other fluorinated quinolones against mycobacteria. Am J Med (suppl 4A), Kennedy, N, Berger, L, Curram, J.Randomized controlled trial of a drug regimen which includes ciprofloxacin in the treatment of pulmonary tuberculosis. Clin Infect Dis , Berning, SE, Madsen, L, Iseman, MD. Long-term safety of ofloxacin and ciprofloxacin in the treatment of mycobacterial infections. Am J Respir Crit Care Med , Yew WW, Chan CK, Chau CH, Tam CM, Leung CC, Wong PC, Lee J. Outcomes of patients with multidrugresistant pulmonary tuberculosis treated with oflaxacin/ levofloxacin-containing regimens.chest Mar:117 (3): Richeldi L, Covi M, Ferrata G, Franco F, Vailati P, Meschiari E, Fabbri LM, Velluti G. Clinical use of levofloxacin in the long-term treatment of drug resistant tuberculosis.monaldi. arch Chest Dis Feb:57(1): Marra F, Marra CA, Moadebi S. Levofloxacin treatment of active tuberculosis and the risk of adverse events. Chest. 1005:128: Yew WW, Lee J, Wong PC, Kwan SY. Tolerance of ofloxacin in the treatment of pulmonary tuberculosis in the presence of hepatic dysfunction. Int. J Clin. Pharmacol. Res. 1992:12(4): Meyers BR,Papanicolaou GA, Sheiner P. Emre S. Miller C. Tuberculosis in the orthotopic liver transplant patients: increased toxicity of recommented agents; cure of disseminated infection with the nonconventional regimens.transplation ; 69(1):

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