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Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis
Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
Microbiology and Tumour Biology Centre, Karolinska Institute, Stockholm, Sweden and Armauer Hansen Research Institute (AHRI), Addis Ababa.
Gondar College of Medical Sciences (GCMS), Gondar, Ethiopia .
Gondar College of Medical Sciences (GCMS), Gondar, Ethiopia .
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2003 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 21, no 3, 483-488 p.Article in journal (Refereed) Published
Abstract [en]

Nitric oxide (NO) is involved in the host defence against tuberculosis (TB). Patients with TB exhibit increased catabolism and reduced energy intake. Thus the hypothesis for this study was that restoring a relative deficiency in the amino acid arginine, the substrate for mycobactericidal NO production, would improve the clinical outcome of TB by increasing NO production.

In a randomised double-blind study, patients with smear-positive TB (n=120) were given arginine or placebo for 4 weeks in addition to conventional chemotherapy. Primary outcomes were sputum conversion, weight gain, and clinical symptoms after week 8. Secondary outcomes were sedimentation rate and levels of NO metabolites, arginine, citrulline, and tumour necrosis factor‐α.

Compared with the human immunodeficiency virus (HIV)−/TB+ placebo group, the HIV−/TB+ patients in the arginine group showed significant improvement, defined as increased weight gain, higher sputum conversion rate and faster reduction of symptoms, such as cough. The arginine level increased after week 2 in the HIV−/TB+ arginine group (100.2 µM (range 90.5–109.9) versus 142.1 µM (range 114.1–170.1)) compared with the HIV−/TB+ placebo group (105.5 µM (range 93.7–117.3) versus 95.7 µM (range 82.4–108.9)). HIV seroprevalence was 52.5%. No clinical improvement or increase in serum arginine was detected in arginine supplemented HIV+/TB+ patients compared with placebo.

Arginine is beneficial as an adjuvant treatment in human immunodeficiency virus-negative patients with active tuberculosis, most likely mediated by increased production of nitric oxide.

Place, publisher, year, edition, pages
2003. Vol. 21, no 3, 483-488 p.
Keyword [en]
arginine, human immunodeficiency virus, Mycobacterium tuberculosis, nitric oxide, tuberculosis, tumour necrosis factor-alpha
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-47812DOI: 10.1183/09031936.03.00090702OAI: diva2:268708
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2012-09-21Bibliographically approved
In thesis
1. Nitric oxide in tuberculosis and leprosy
Open this publication in new window or tab >>Nitric oxide in tuberculosis and leprosy
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global disease that kills about two million people each year. Leprosy is caused by Mycobacterium leprae, and primarily affects the skin and peripheral nervous system. About 10-20% of leprosy patients suffer from reactions associated with acute inflammation that can lead to rapid and severe nerve damage. Most individuals infected with Mtb or M leprae do not develop clinical disease, which indicates that human hosts have effective defence mechanisms. In macrophages activated by cytokines such as IFN-γ, inducible nitric oxide synthase (iNOS) catalyses the production of nitric oxide (NO) from L-arginine. In an inflammatory environment, NO reacts with the superoxide radical (O2-) to yield peroxynitrite, an unstable metabolite that can rapidly nitrosylate tyrosine residues on proteins to form the stabile end product nitrotyrosine (NT). Many studies using experimental models have indicated that NO is important in host response to M leprae and Mtb, but this is controversial in human disease. Thus, our aim was to investigate the presence and the role of NO in the human mycobacterial infectious diseases TB and leprosy.

Levels of the NO metabolites nitrite and nitrate were initially increased in urine from patients with reactional leprosy but were normalised by treatment with prednisolone, and this was associated with clinical improvement. Immunohistochemistry revealed local production of NO in skin biopsies from patients with borderline leprosy and reversal reactions, which was detected as reactivity to iNOS and NT in macrophage-rich granulomas. Ultrastructural studies showed NT-positive aggregations of neurofilaments in dermal nerves from leprosy patients. Patients with active tuberculosis had increased urinary levels of NO metabolites, which were normalised after anti-TB treatment. Household contacts of patients with tuberculosis had increased levels of NO metabolites in plasma and serum. Immunohistochemical examination of biopsies from patients with TB indicated local, iN OS-mediated generation ofNO in macrophage-rich granulomas. In an experimental model of TB, local production of NO in the lungs was substantial in the acute phase of infection, and immunoelectron microscopy detected NT in phagosomes containing Mtb and on the surface of the bacteria. In an in vitro model, NO and peroxynitrite killed Mtb H37Ra and induced upregulation of several bacterial proteins. Peroxynitrite also mediated tyrosine nitration of albumin associated with the surface of Mtb. In a randomised, double-blind trial in Ethiopia, arginine supplementation in patients receiving conventional chemotherapy increased sputum conversion and reduced the prevalence of cough in HIV -negative, smear-positive patients with active TB.

In conclusion, these results demonstrate that iNOS-mediated production of NO occurs in human tuberculosis and leprosy; NO and peroxynitrite can kill Mtb and modify protein expression in the bacteria; and arginine leads to clinical improvement in TB patients.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2002. 106 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 749
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-26667 (URN)11233 (Local ID)91-7373-193-5 (ISBN)11233 (Archive number)11233 (OAI)
Public defence
2002-11-01, Berzeliussalen, Hälsouniversitetet, Linköping, 13:00 (Swedish)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-21Bibliographically approved

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