Effect of chronic oral administration of chloroquine on the histology of the liver in wist

British Journal of Pharmacology and Toxicology 2(3): 97-103, 2011ISSN: 2044-2467 Maxwell Scientific Organization, 2011Received: June 27, 2010 Effect of Chronic Oral Administration of Chloroquine on the Histology
of the Liver in Wistar Rats
1A.M. Izunya,1A.O. Nwaopara, 1L.C. Anyanwu, 2M.A.C. Odike, 1G.A. Oaikhena, 3J.K. Bankole and 4O. Okhiai 3Department of Medical Laboratory Sciences, 4Department of Nursing Sciences, College of Medicine, Ambrose Alli University, Ekpoma, Edo State, Nigeria Abstract: The effect of chronic oral administration of chloroquine, an antimalarial and antirheumatic drug on
the histology of the liver in wistar rats was investigated. Ten wistar rats were randomly grouped into two,
control and treated. The treated group rats were administered 20 mg/kg body wt, weekly of chloroquine for
4 weeks while the control group rats were given distilled water for 4 weeks. On day 29th of the experiment,
the rats were weighed and sacrificed by cervical dislocation. The livers were carefully dissected out and quickly
fixed in 10% formal saline for histological studies. The histological findings after H and E methods indicated
that the treated sections of the liver showed cytoplasmic vacuolation; nuclear enlargement and vesiculation of
the hepatocytes when compared with the control. Thus, our result suggests that though chloroquine may be a
widely used antimalarial and antirheumatic drug, its chronic administration may have a deleterious effect on
the liver of wistar rats and by extension may affect its function. It is therefore recommended that the drug be
prescribed with caution in patients with history of liver disease.
Key words: Antimalarial, chloroquine, hepatotoxicity, histology, wistar rats
of Plasmodium falciparium has also been shown to behepatotoxic (Nwanjo et al., 2007; Obi et al., 2004).
A number of research studies have described the Amongst the artemisinims, artesunate used as antimalarial deleterious effect of commonly prescribed anti-malarials against multidrug- resistant strains of plasmodium on the liver. Amodiaquine - formerly widely used as a falciparum (Hien and White, 1993) has also been found to chemoprophylactic against Plasmodium spp. - produces be hepatotoxic (Ngokere et al., 2004; Nwanjo and Oze, significant hepatocellular dysfunction (Larrey et al., 1986; Neftel et al., 1986; WHO, 1990; Pero and Taylor, 2002; Chloroquine is a widely used antimalarial agent Ajani et al., 2008), it is now rarely used due to a causative (Sharma and Mishra, 1999). In most endemic areas, association with bone-marrow depression (Cook, 1994).
chloroquine use to be the main first line therapy for 'Fansidar' (pyrimethamine + sulphadoxine) has been malaria (Olanrewaju and Johnson, 2001) until recently extensively used in chemoprophylaxis, and remains an when WHO succeeded in promoting the combination effective chemotherapeutic agent; it also produces treatment for malaria infection (Nosten and Brasseur, significant hepatocellular dysfunction (Reisinger et al., 2002). It is also used to treat rheumatoid arthritis and 1989). Mefloquine, a compound now widely used both in systemic lupus erytheromatosis (Ducharme and Farinotti, chemoprophylaxis and chemotherapy, can also produce significant changes in liver-function tests (Reisinger et al., Availabe data show that chloroquine is concentrated 1989); it has not, however, been associated with in the liver and many other tissues following its significant histological abnormality (Cook, 1994).
administration (Adelusi and Salako, 1982). In toxic doses, Quinine, again the first-line agent against P.falciparum it is known to cause appreciable cellular damage to liver, infection, is also hepatotoxic (Wernsdorfer and kidney and heart muscle (deGroot et al., 1981; Ngaha, McGregor, 1988; Okonkwo et al., 1997; Debra and Megan, 1999), albeit rarely (Wernsdorfer and McGregor, The liver is the largest solid organ in the body. It is 1988). Halofantrine which is widely prescribed for the the centre of all metabolic activities in the body. Drugs treatment of infections with chloroquine-resistant strains and other foreign substances are metabolized and Corresponding Author: Dr. Al-Hassan M. Izunya, Department of Anatomy, College of Medicine, Ambrose Alli University,
Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011 inactivated in the liver and is therefore susceptible to thetoxicity from these agents. Certain medicinal agents whentaken in overdoses and sometimes even when introducedwithin therapeutic ranges may injure the liver. Reports regarding the effects of chronic oral administration of chloroquine on the histology of the liverare scanty in existing literatures. There is however areport which showed that chloroquine treatment for 12weeks in mice causes cytolysis in hepatocytes (Okonkwoet al., 1997). This study was considered important since rheumatoid arthritis and malaria are common ailments inthe tropics and the need to avoid the risk of hepatitisresulting from prolonged oral administration ofchloroquine. In view of this, the present study wascarried out to investigate the effect of chronic oral Plate 1: (Control Group): Control section of the liver showing administration of chloroquine on the histology of the liver MATERIALS AND METHODS
Location and duration of study: This study was
conducted at the histology laboratory of the College of
Medicine, Ambrose Alli University, Ekpoma, Edo State,
Nigeria. The preliminary studies, animal acclimatization,
drug procurement, actual animal experiment and
evaluation of results, lasted for a period of two months
(February and March, 2010). However, the actual
administration of the drug to the test animals lasted for
one month.
Animals: Experiments were carried out on ten (10)
Wistar rats (150 g) procured and maintained in the
Animal Holdings of the College of Medicine, Ambrose
Plate 2: (Experimental Group): Treatment section of the liver that received 20mg/kg of chloroquine for 28 days, Alli University, Ekpoma, Edo State, Nigeria. The animals showing cytoplasmic vacuolation (CV); nuclear were housed under a controlled room temperature of enlargement and vesiculation (NEV)(Mag. X400) about 25-28ºC, relative humidity of about 60-80% andphoto-periodicity of 12 h day / 12 h night, and fed with Histological Study: For light microscopic examination,
rat pellets (Bendel Feeds and Flour Mills, Ewu, Nigeria) liver tissues from each groups were fixed with 10% and water ad libitum. They were randomly assigned into buffered formalin. The specimens were dehydrated in two groups, the control (n = 5) and treated (n = 5) groups.
ascending grades of ethanol, cleared in xylene andembedded in paraffin wax. Sections of 5 :m in thickness Drug preparation and administration: The chloroquine
were prepared and stained with Haematoxylin and Eosin phosphate tablets used for this experiment were (Drury et al., 1967) and then examined under light manufactured by Emzor Pharmaceutical Industries, microscopy. The photomicrographs of the relevant stained Lagos, Nigeria and certified by National Agency for Food sections were taken with the aid of a light microscope.
Drug Administration and Control (NAFDAC). They werepurchased from Irrua Specialist Teaching Hospital, Irrua,Edo State, Nigeria. Rats in the treatment group received 20 mg/kg body weight of chloroquine phosphatedissolved in distilled water weekly for 4 weeks. Rats in Histological analysis of the livers of rats in control the control group received equal volume of distilled water group showed normal morphological appearance The animals were sacrificed using humane killing Histological analysis of the liver of rats in treated with chloroform 24 h after the last dose on the 29th day group showed cytoplasmic vacuolation; nuclear enlargement and vesiculation (Plate 2).
Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011 DISCUSSION
activities may be diminished or disrupted in sensitivetissues (Oforah et al., 2004). Owing to its weak base Histological results suggested degeneration of the properties, chloroquine also accumulates in lysosomes liver cells of the wistar rats upon chronic oral and may trigger apoptosis via the inhibition of autophagic administration of chloroquine. This was shown by the protein degradation (Amaravadi et al., 2007; Boya et al., cytoplasmic vacuolation, nuclear enlargement and 2005; Fan et al., 2006; Shacka et al., 2006; Maclean vesiculation of the hepatocytes. The findings in this study agree with the work of Okonkwo et al. (1997) in which As an antimalarial, chloroquine acts by inhibiting chloroquine administration for 12 weeks caused cytolysis hemozoin biocrystallization, which gives rise to toxic free heme accumulation that is responsible for the death of the Degenerative changes have been reported to result in parasites (Barennes et al., 2006). Heme (iron cell death, which is of two types, namely apoptotic and protoporphyrin IX) serves as the functional group of necrotic cell death (Cohen, 1993; Vaux et al., 1994).
various proteins, including hemoglobin, myoglobin, nitric These two types differ morphologically and biochemically oxide synthase, and cytochromes (Beri and Chandra, (Bose and Sinha, 1994). Apoptosis or Programmed Cell 1993). Heme is therefore essential for diverse biologic Death (PCD) is a non-inflammatory response to tissue damage characterized by a series of morphological and It has however been shown that heme is a potentially biochemical changes (Sakkas et al., 1999; Sinha and damaging species, which can directly attack and may Swerdloff, 1999; Shen et al., 2002; Grunewald et al., impair intracellular targets including the lipid bilayer, the 2005). Apoptosis can be triggered in two principal ways: cytoskeleton, intermediary metabolic enzymes, and DNA by toxic chemicals or injury leading to damage of DNA or (Wagener et al., 2003). Moreover, excess of free heme of other important cellular targets, and activation or may constitute a major threat because heme catalyzes the inactivation of receptors by growth-regulating signal formation of ROS, resulting in oxidative stress and, factors in the organism (Schulte-Hermann et al., 1999). subsequently, cell injury (Kumar and Bandyopadhyay, Initiation of apoptosis can result from multiple stimuli, including heat, toxins, Reactive Oxygen Species Interestingly, there are reports indicating that high (ROS), growth factor withdrawal, cytokines such as levels of free heme cause severe toxic effects to kidney, transforming growth factor- beta, loss of matrix liver, central nervous system and cardiac tissue (Kumar attachment, glucocorticoid, nitric oxide, and radiation and Bandyopadhyay, 2005; Dhalla et al., 1996).
(Thompson, 1995; Pollman et al., 1996). These stimuli Moreover, free heme is highly lipophilic and will rapidly work in conjunction with other intrinsic factors that intercalate into the lipid membranes of adjacent cells determine the cell's potential to undergo apoptosis (Beri and Chandra, 1993), where it catalyzes the (McConkey and Orrenius, 1991). However, high levels of formation of cytotoxic lipid peroxide via lipid ROS disrupt the inner and outer mitochondrial peroxidation and damages DNA through oxidative stress membranes, inducing the release of the cytochrome-C (Kumar and Bandyopadhyay, 2005). Acworth et al.
protein and activating the caspase cascade which (1997) revealed that increased lipid peroxidation can ultimately results in the fragmentation of a cell's DNA negatively affect the membrane function by decreasing (Wyllie, 1980; Green, 1998; Makker et al., 2009). membrane fluidity and changing the activity of membrane Pathological or accidental cell death is regarded as necrotic and could result from extrinsic insults to the cell ROS generation is a normal component of oxidative such as osmotic, thermal, toxic and traumatic effects phosphorylation and plays a role in normal redox control (Farber et al., 1981). The process of cellular necrosis of physiological signaling pathways (Sawyer et al., 2002; involves disruption of the membranes structural and Giordano, 2005; Murdoch et al., 2006). However, functional integrity. Cellular necrosis is not induced by excessive ROS generation triggers cell dysfunction, lipid stimuli intrinsic to the cells as in apoptosis or peroxidation, and DNA mutagenesis and can lead to Programmed Cell Death (PCD), but by an abrupt irreversible cell damage or death (Sawyer et al., 2002; environmental perturbation and departure from the normal Giordano, 2005; Murdoch et al., 2006), and other physiological conditions (Martins et al., 1978).
ROSmediated alterations in chromatin structure may Chloroquine is an aminoquinolinic membrane- significantly affect gene expression (Konat, 2003; penetratable agent capable of intercalating into double- Rahman, 2003). Modification of proteins by ROS can stranded DNA without causing physical damage to the cause inactivation of critical enzymes and can induce DNA (Mitscher, 2005). The DNA intercalation is non- denaturation that renders proteins nonfunctional selective for malarial parasites as it occurs also with (Lockwood, 2000; Stadtman and Levine, 2003).
mammalian DNA. Thus protein synthesis and enzyme Moreover, there are also reports that cadmium toxicity in Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011 liver may be mediated by the production of reactive ACKNOWLEDGMENT
oxygen species known to induce necrosis in various ratorgans (Hsu et al., 2007; Razinger et al., 2008), lipid The authors thank Mr Charles Idehen of Histology peroxidation (Borges et al., 2008) and a decrease in Laboratory of the College of Medicine Ambrose Alli antioxidant enzymes (El-Sharaky et al., 2007).
University, Ekpoma for his technical assistance.
ROS are small, oxygen-based molecules that are highly reactive because of unpaired electrons (Papa and REFERENCES
Skulachev, 1997). ROS can react with cellularcomponents, especially membrane lipids, and lead to cell Acworth, I.N., D.R. McCabe and T. Maber, 1997. The damage (Rikans and Hornbrook,1997). The most Analysis of Free Radicals, their Reaction Products prominent ROS are the superoxide anion (O •–), hydrogen and Antioxidants. In: Baskin, S.I. and H. Salem peroxide (H O ), and the hydroxyl ion (OH•) (Turner and (Eds.), Oxidants, Antioxidants and Free Radicals.
Lysiak, 2008). Cells also have intrinsic antioxidant Chap. 2, Taylor and Francis, Washington, DC.
systems that counter ROS accumulation. These include Adelusi, S.A. and L.A. Salako, 1982. Tissue and blood enzymes such as catalase, glutathione peroxidases, and concentration of chloroquine following chronic superoxide dismutase, and nonenzymatic antioxidants, administration in the rat. J. Pharm. Pharmacol., 34: such as vitamins E, C, beta carotene, ubiquinone, lipotic acid, and urate (Nordberg and Arner, 2001; Giordano, Ajani, E.O., P.D. Shallie, B.O. Adegbesan, B.A. Salau and M. Adesanya, 2008. Protective effect of garcinia In a normal liver, the level of ROS is low, and kola (kolaviron) extract on predisposition of rats to antioxidant defenses are adequate to protect the liver from cardiovascular diseases following separate oxidative damage (Fernandez et al., 1997). Nevertheless, administration of amodiaquine and artesunate. Afr. J.
under several situations, the rate of generation of ROS exceeds that of their removal and oxidative stress occurs Amaravadi, R.K., D. Yu, J.J. Lum, T. Bui, (Giordano, 2005; Di Giulio et al., 1995; Halliwell and M.A. Christophorou, G.I. Evan, A. Thomas- Gutteridge, 1999; Livingstone, 2001). However, more Tikhonenko and C.B. Thompson, 2007. Autophagy severe oxidative stress can cause cell death and even inhibition enhances therapy-induced apoptosis in a moderate oxidation can trigger apoptosis, while more Myc-induced model of lymphoma. J. Clin. Invest., intense stresses may cause necrosis (Lennon et al., 1991).
However, under the severe levels of oxidative stress that Balla, J., H.S. Jacob, G. Balla, K. Nath, J.W. Eaton and cause necrosis, the damage causes ATP depletion, G.M. Vercellotti, 1993. Enothelial-cell heme uptake preventing controlled apoptotic death and causing the cell from heme proteins: induction of sensitization and to simply fall apart (Lelli et al., 1998; Lee et al., 1999). desensitization to oxidant damage. Proc. Natl. Acad.
In this study, chloroquine may have acted directly through generation of high levels of free heme or ROS on Balla, G., H.S. Jacob, J.W. Eaton, J.D. Belcher and the hepatocytes, affecting their cellular integrity and G.M. Vercellotti, 1991. Hemin: A possible causing defect in membrane permeability and cell volume physiological mediator of low density lipoprotein homeostasis. In cellular necrosis, the rate of progression oxidation and endothelial injury. Arterioscler depends on the severity of the environmental insults. The greater the severity of the insults the more rapid the Barennes, H., T. Balima-Koussoube', N. Nagot, progression of neuronal injury (Ito et al., 2003). The J.C. Charpentier and E. Pussard, 2006. Safety and principle holds true for toxicological insult to the brain efficacy of rectal compared with intramuscular and other organs (Martins et al., 1978). Thus, it may be quinine for the early treatment of moderately severe inferred from this result that chronic oral administration malaria in children: randomised clinical trial. Br.
of chloroquine is toxic to the liver in wistar rats. Beri, R. and R. Chandra, 1993. Chemistry and biology of CONCLUSION
heme: Effect of metal salts, organometals, andmetalloporphyrins on heme synthesis and catabolism, Our study revealed that chronic oral administration of with special reference to clinical implications and chloroquine causes cytoplasmic vacuolation; nuclear interactions with cytochrome P-450. Drug Metab.
enlargement and vesiculation of the hepatocytes. These results have established the hepatotoxic potential of Borges, L.P., R. Brandao, B. Godoi, C.W. Nogueira and chronic oral administration of chloroquine in wistar rats.
G. Zeni, 2008. Oral administration of diphenyl It is therefore recommended that the drug be prescribed diselenide protects against cadmium-induced liver with caution in patients with history of liver disease. damage in rats. Chem. Biol. Interact., 171: 15-25.
Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011 Bose, S. and S.P. Sinha, 1994. Modulation of ochratoxin- Giordano, F.J., 2005. Oxygen, oxidative stress, hypoxia, produced genotoxicity in mice by vitamin C. Food and heart failure. J. Clin. Invest., 115(3): 500-508. Green, D.R., 1998. Apoptotic pathways: The roads to Boya, P., R.A. González-Polo, N. Casares, J.L. Perfettini, P. Dessen, N. Larochette, D. Métivier, D. Meley, S.
Grunewald, S., U. Paasch, T.M. Said, R.K. Sharma, Souquere, T. Yoshimori, G. Pierron, P. Codogno and H.J. Glander and A. Agarwal, 2005. Caspase G. Kroemer, 2005. Inhibition of macroautophagy activation in human spermatozoa in response to triggers apoptosis. Mol. Cell. Biol., 25(3): physiological and pathological stimuli. Fertil Steril, Cohen, J.J., 1993. Apoptosis. Immunol. Today, 14: 126- Halliwell, B. and J.M.C. Gutteridge, 1999. Free Radicals in Biology and Medicine. 3rd Edn., Oxford Cook, G.C., 1994. Malaria in the liver. Postgrad Med. J., Hien, T.T. and N.J. White, 1993. Qinghaosu. Lancet, 341: Debra, K.F. and N.L. Megan, 1999. Quinine-induced hepatotoxicity. Ann. Pharmacother., 33: 32-34. Hsu, C.Y., Y.P. Chan and J. Chang, 2007. Antioxidant deGroot, P.Q., R.Q. Eiferink, M. Hollemans, M. Khand activity of extract from Polygonum cuspidatum. Biol.
and J.M. Tager, 1981. Activation of B galactosidase in cultured human skin fibroblast. Exp. Cell. Res., Ito, U., M. Sparts, J.R. Walker and I. Warzo, 2003.
Experimental Cerebral Ischemia in Magolian Gerbils Dhalla, A.K., M.F. Hill and P.K. Singal, 1996. Role of oxidative stress in transition of hypertrophy to heart failure. J. Am. Coll. Cardiol., 28(2): 506-514.
Izunya, A.M., A.O. Nwaopara, A. Aigbiremolen Di Giulio, R.T., W.H. Benson, B.M. Sanders and M.A.C. Odike, G.A. Oaikhena and J.K. Bankole, P.A. Van Veld, 1995. Biochemical Mechanisms: 2010. Histological effects of oral administration of Metabolism, Adaptation and Toxicity. In: Rand, G.
artesunate on the liver in wistar rat. Res. J. Appl. Sci.
(Ed.), Fundamentals of Aquatic Toxicology. Effects, Environmental Fate and Risk Assessment. Taylor and Konat, G.W., 2003. H O -induced higher order chromatin degradation: a novel mechanism of oxidative Drury, R.A.B., E.A. Wallington and R. Cameron, 1967.
genotoxicity. J. Biosci., 28 :57-60.
Carleton's Histological Techniques. 4th Edn., Oxford Kumar, S. and U. Bandyopadhyay, 2005. Free heme toxicity and its detoxification systems in human.
Ducharme, J. and R. Farinotti, 1996. Clinical pharmacokinetics and metabolism of chloroquine.
Larrey, D., A. Castot, D. Pessayre, P. Merigot, Focus on recent advancements. Clin. Pharm., 31: J.P. Machaye khy, G. Feldmann, A. Lenoir, B. Rueff and J.P. Benha mou, 1986. Amodiaquine Dubois, E. L., 1978. Antimalarials in the management of induced hepatitis: A report of seven cases. Ann. Int.
discoid and systemic lupus erythematorus. Semin Lee, Y.J. and E. Shacter, 1999. Oxidative stress inhibits El-Sharaky, A.S., A.A. Newairy, M.M. Badreldeen, apoptosis in human lymphoma cells. J. Biol. Chem., S.M. Eweda and S.A. Sheweita, 2007. Protective 274(28): 19792-19798, doi: 10.1074/jbc.274.28.
role of selenium against renal toxicity induced by cadmium in rats. Toxicology, 235(3): 185-193 Lelli, J.L., L.L. Becks, M.I. Dabrowska and Fan, C., W. Wang, B. Zhao, S. Zhang and J. Miao, 2006.
D.B. Hinshaw, 1998. ATP converts necrosis to Chloroquine inhibits cell growth and induces cell apoptosis in oxidant-injured endothelial cells. Free death in A549 lung cancer cells. Bioorg. Med.
10.1016/S0891-5849(98)00107-5. PMID: 9801070.
Farber, J.L., K.R. Chein and S. Mittnacht, 1981. The Lennon, S.V., S.J. Martin and T.G. Cotter, 1991. Dose- pathogenesis of Irreversible cell injury in ischemia.
dependent induction of apoptosis in human tumour cell lines by widely diverging stimuli. Cell Prolif., Fernandez-Checa, J.C., N. Kaplowitz, C. Garcia-Ruiz, 24(2): 203-214. doi: 10.1111/j.1365-2184.tb01150.x.
A. Colell, M. Miranda, M. Mari, E. Ardite and A. Morales, 1997. GSH transport in mitochondria: Livingstone, D.R., 2001. Contaminated-stimulated Defense against TNFinduced oxidative stress and reactive oxygen species production and oxidative alcohol-induced defect. Am. J. Physiol. Gastrointest damage in aquatic organisms. Mar. Poll. Bull., 42: Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011 Lockwood, T.D., 2000. Redox control of protein Oforah, E., B.J. Idang and N. Kalu, 2004. Chronic degradation. Antioxid. Redox Signal., 2: 851-878.
chloroquine administration causes low circulating Maclean, K.H., F.C. Dorsey, J.L. Cleveland and plasma testosterone and low luteinizing hormone M.B. Kastan, 2008 Targeting lysosomal degradation associated with testicular lesion in rat. Acta Pharm.
induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis. J. Clin.
S.K. Akindele, 1997. A study of the hepatotoxicity of Makker, K., A. Agarwal and R. Sharma, 2009. Oxidative chloroquine (SN-7618) in mice. Nig. Qt. J. Hosp.
stress and male infertility. Indian J. Med. Res., 129: Olanrewaju, W.I. and A.W.B.R. Johnson, 2001.
Martins, L.J., N.A. Al-Abdulla, J.R. Kirsh, F.E. Sieber Chloroquine-resistance Plasmodium falciparummalaria in Ilorin, Nigeria: Prevalence and risk factors and C. Portera-Cailliau, 1978. Neurodegeneration in for treatment failure. Afr. J. Med. Sci., 30: 165-169.
excitotoxicity, global cerebral ischaemia and target Papa, S. and V.P. Skulachev, 1997. Reactive oxygen Deprivation: A perspective on the contributions of species, mitochondria, apoptosis and aging. Mol.
apoptosis and necrosis. Brain Res. Bull., 46(4): Pero, O. and W.R.J. Taylor, 2002. Amodiaquine for the McConkey, D.J. and S. Orrenius, 1991. In: Tomei, L.D.
treatment of uncomplicated Falciparum malaria.
and F.O. Cope (Eds.), Apoptosis: The Molecular Basis of Cell Death. Cold Spring Harbor Laboratory Pollman, M.J., T. Yamada, M. Horiuchi and G.H. Gibbons, 1996. Vasoactive substances regulate Mitscher, L.A., 2005. Bacterial topoisomerase inhibitors: vascular smooth muscle cell apoptosis. Circ. Res., Quinolone and pyridone antibacterial agents. Chem.
Rahman, I., 2003. Oxidative stress, chromatin remodeling Murdoch, C.E., M. Zhang, A.C. Cave and A.M. Shah, and gene transcription in inflammation and chronic 2006. NADPH oxidase-dependent redox signalling in lung diseases. J. Biochem. Mol. Biol., 36: 95-109.
cardiac hypertrophy, remodelling and failure.
Razinger, J., M. Dermastia, J.D. Koce and A. Zrimec, 2008. Oxidative stress in duckweed (Lemna minor Neftel, K.A., W. Woodtly, M. Schmid, P.G. Frick and L.) caused by short-term cadmium exposure.
J. Fehr, 1986. Amodiaquine induced agranulocytosis and liver damage. Br. Med. J., 292: 721-723. Reisinger, E.C., R.D. Horstmann and M. Dietrich, 1989.
Ngaha, E.O., 1982. Some biochemical changes in the rat Tolerance of mefloquine alone and in combination during repeated chloroquine administration. Toxicol.
with sulfadoxine-pyrimethamine in the prophylaxis of malaria. Trans. R. Soc. Trop. Med. Hyg., 83: Ngokere, A.A., T.C. Ngokere and A.P. Ikwudinma, 2004.
Acute study of histomorphological and biochemical Rikans, L.E. and K.R. Hornbrook, 1997. Lipid changes caused by artesunate in visceral organs of peroxidation, antioxidant protection and aging.
the Rabbit. J. Exp. Clin. Anat., 3(2): 11-16(s).
Biochem. Biophys. Acta, 1362: 116-127.
Nordberg, J. and E.S. Arner, 2001. Reactive oxygen Sakkas, D., E. Mariethoz, G. Manicardi, D. Bizzaro, P.G. Bianchi and U. Bianchi, 1999. Origin of DNA species, antioxidants, and the mammalian thioredoxin damage in ejaculated human spermatozoa. Rev.
system. Free Radic. Biol. Med., 31: 1287-1312. Nosten, F. and P. Brasseur, 2002. Combination therapy Sawyer, D.B., D.A. Siwik, L. Xiao, D.R. Pimentel, for malaria: The way forward? Drug, 62(9): K. Singh and W.S. Colucci, 2002. Role of oxidative stress in myocardial hypertrophy and failure. J. Mol.
Nwanjo, H., I. Iroagba, I. Nnatuanya and N. Eze, 2007.
Antifertility activity of dihydroartemisinin in male Schulte-Hermann, R., W. Bursch, B. Marian and Albino rats. Internet J. Endocrinol., 4(1), ISSN: B. Grasl-Kraupp, 1999. Active cell death (apoptosis) and cellular proliferation as indicators of exposure to Nwanjo, H. and G. Oze, 2007. Acute hepatotocixity carcinogens. IARC Scientific Publications (Lyon), following administration of artesunate in guinea pigs.
Internet J. Toxicol., 4(1), ISSN: 1559-3916 Shacka, J.J., B.J. Klocke, M. Shibata, Y. Uchiyama, Obi, E., O.E. Orisakwe, L.A. Asomugha and G. Datta, R.E. Schmidt and K. A. Roth, 2006.
O.O. Udemezue, 2004. The hepatotoxic effect of Bafilomycin A1 inhibits chloroquine-induced death halofantrine in guinea pigs. Indian J. Pharm., 36(5): of cerebellar granule neurons. Mol. Pharmacol., 69: Br. J. Pharmacol. Toxicol., 2(3): 97-103, 2011 Sharma, A. and M.C. Mishra, 1999. Inhibition of a Vaux, D.L., G. Haecker and A. Strasser, 1994. An protein tyrosine kinase activity in Plasmodium evolutionary perspective on apoptosis. Cell, 76: falciparum by chloroquine. Indian J. Biochem.
Wagener, F.A., H.D. Volk, D. Willis, N.G. Abraham, Shen, H.M., J. Dai, S.E. Chia, A. Lim and C.N. Ong, M.P. Soares, G.J. Adema and C.G. Figdor, 2003.
2002. Detection of apoptotic alterations in sperm in Different faces of hemeoxygenase system in subfertile patients and their correlations with spermquality. Hum. Reprod., 17: 1266-1273.
inflammation. Pharmacol. Rev., 55: 551-571.
Sinha, H.A.P. and R.S. Swerdloff, 1999. Hormonal and Wernsdorfer, W.H. and I. McGregor, 1988. Malaria: genetic control of germ cell apoptosis in the testis.
Principles and Practice of Malariology. Churchill Stadtman, E.R., and R.L. Levine, 2003. Free World Health Organization, 1990. Practical chemotherapy radicalmediated oxidation of free amino acids and of malaria. Report of a WHO scientific group, amino acid residues in proteins. Amino Acids, 25: Geneva. World Health Organization Technical Thompson, C.B., 1995. Apoptosis in the pathogenesis and Wyllie, A.H., 1980. Glucocorticoid-induced thymocyte treatment of disease. Science, 267: 1456-1462.
Turner, T. and J.J. Lysiak, 2008. Oxidative stress: A common factor in testicular dysfunction. J. Androl., endonuclease activation. Nature, 284: 555-556.
29(5): 488-498. doi: 10.2164/jandrol.108.005132.

Source: http://maxwellsci.com/print/bjpt/v2-97-103.pdf

Microsoft word - hydroxycut review

Hydroxycut Review   By Elizabeth Myers, RD Hydroxycut is currently of the most familiar weight-loss supplements on the market. It is heavily advertised on television and sold in 70 countries worldwide. Hydroxycut claims to cause fast weight loss, increased energy, and a controlled appetite. The supplement costs $44.99/bottle for 150 capsules, which is quite expensive for a weight loss sup


Chapter 2. Empiric Therapy: CNS Infections Encephalitis Usual Pathogens IV-to-PO Switch Acyclovir 10 mg/kg (IV) q8h x 7 days, then if able to take oralmedications, complete 14-21 days of total therapy withacyclovir 400 mg (PO) 5x/day or valacyclovir 1 gm (PO) q8h or famciclovir 500 mg (PO) q8hUsual PathogensCalifornia encephalitis (CE), Western equine encephalitis (WEE), Venezuelan e

Copyright © 2014 Articles Finder