Unexpected outcome ( positive or negative) including adverse drug reactions
CASE REPORT
Haemolytic anaemia after ingestion of Neem (Azadirachta indica) tea Cristy Page, Emily M Hawes Department of Family Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA Correspondence to Dr Emily Morris Hawes, [email protected]
SUMMARY The authors report a clinically relevant and possible cause of haemolytic anaemia from ingestion of a Mexican tea from the Neem tree, also known as Azadirachta indica, in a 35-year-old Hispanic man who was found to have glucose-6-phosphate dehydrogenase deficiency.
BACKGROUND This case highlights a possible adverse reaction of drinking Neem (Azadirachta indica) tea, which is a plant marketed worldwide due to its versatile medicinal properties. In this case of haemolytic anaemia with no known cause, the authors emphasise the value of readdressing a history with collateral sources and asking specifically about herbal medicines and other alternative modalities.
CASE PRESENTATION A 35-year-old Hispanic male with type 2 diabetes presented to a community health center with profound jaundice, dizziness and weakness and was subsequently admitted to the hospital. He denied symptoms of fever, cough, bleeding, changes in bowel movements or other signs of illness. He denied taking oral medications other than metformin. Positive alcohol screen for up to 20 beers on the weekend. The patient worked as a painter, originally from Guerrero, Mexico and no recent travel with no history of liver disease, blood disease, including anaemia or haemolysis, or jaundice, and also no known family history of blood disorders or liver problems. On physical examination, he appeared jaundiced with scleral icterus. He was afebrile and vitals were stable. His heart, lung and abdominal examination were normal. His initial blood work revealed a haemoglobin 8.5 g/dL, haematocrit 25%, total bilirubin 5.2 mg/ dL (unconjugated 4.9 mg/dL), normal transaminases, lactate dehydrogenase (LDH) 983 U/L and normal chemistries except for glucose 266–475 mg/ dL. He had a normal blood gas with no ketoacidosis and a glycosylated haemoglobin of 7.6. Haptoglobin less than 20 mg/dL, direct Coombs negative and reticulocyte count 6.5%. A 35-year-old hispanic male who presented with hyperglycaemia and jaundice and was found to have significant anaemia. To cite: Page C, Hawes EM. BMJ Case Rep Published online: [ please include Day Month Year] doi:10.1136/ bcr-2013-200890
cause remained unclear. Collateral history from his family revealed that his wife first noticed his yellow skin about 2–3 weeks ago, 1 week before he became lightheaded. She stated that he stopped taking his metformin 4 months prior to this, and instead, as stated by his daughter, 3 weeks ago he started drinking large quantities of a Mexican tea that was supposed to help his diabetes. Further investigation identified Neem (A indica) tea. Despite package labelling recommending ingestion of only one cup daily, he reported drinking several litres of the tea daily over the past 3 weeks, which coincided with the timing of his wife noticing his yellow skin. The patient denied taking any other over the counter medications or supplements. Initial laboratory findings were consistent with a Coombs negative haemolytic anaemia (unconjugated hyperbilirubinaemia, elevated LDH and decreased haptoglobin). Given his elevated reticulocyte count, his bone marrow response seemed appropriate, which suggests against anaemia from ineffective erythropoiesis. The differential for non-antibody-mediated haemolytic process includes red blood cell membrane protein dysfunction disorders (including hereditary spherocytosis, paroxysmal nocturnal haemoglobinuria and elliptocytosis), enzyme disorders, (glucose6-phosphate dehydrogenase deficiency (G6PD), pyruvate kinase deficiency), haemoglobinopathies (thalassmias, sickle cell), trauma, toxic exposure and lysis from hypotonic fluids. Given that he has not had prior episodes, many of these hereditary disorders were much less likely. However, some disorders, like G6PD are episodic and usually require an inciting event (such as infection, systemic inflammation, diabetic ketoacidosis (DKA), medications and foods). He presented with hyperglycaemia but had no ketoacidosis. Additional studies including G6PD assay and Heinz bodies were ordered.
TREATMENT After discontinuing the tea, his blood parameters began to improve with discharge haemoglobin 7.9 g/dL and haematocrit 25.4%. G6PD assay confirmed a new diagnosis of G6PD deficiency, which was likely triggered by the consumption of large quantities of Neem tea. At discharge, his blood sugar was 74 mg/dL and he was instructed to resume taking metformin.
INVESTIGATIONS AND DIFFERENTIAL DIAGNOSIS
OUTCOME AND FOLLOW-UP
The day following admission, with a haemoglobin/ haematocrit of 7.4 g/dL/21.7%, the underlying
During the following 3 months, the patient did not ingest Neem tea and his haemoglobin/haematocrit
Page C, et al. BMJ Case Rep 2013. doi:10.1136/bcr-2013-200890
1
Unexpected outcome ( positive or negative) including adverse drug reactions
Figure 1 Photograph of Neem tree.5
normalised to 15.9 g/dL/46.7%. In addition, the G6PD test at 3 months confirmed that the patient does have underlying G6PD deficiency (0.3 U/GM/DL HGB).
DISCUSSION G6PD deficiency, an inherited condition typically found in patients of Mediterranean, African and Asian descent, was first described in the 1950s after the occurrence of haemolysis in a patient taking primaquine.1–3 G6PD is the most common human enzyme defect impacting more than 400 million people worldwide. This genetic X linked disorder causes red cell destruction in the presence of certain infections or medications, such as dapsone, methylthioninium chloride (methylene blue), nitrofurantoin, phenazopyridine, primaquine and rasburicase.1 2 Since several medications can precipitate haemolysis in people with G6PD, it is important to query about medications and herbal products for any patient with unexplained haemolysis. Neem (A indica) tea, derived from the Neem tree (see figure 1), is thought to have originated in northeast India.4 5 It is marketed worldwide, including Mexico, India and the USA, as an oral and topical formulation for many different medicinal purposes based on its antiviral, antimicrobial, anti-inflammatory, antiulcer, anticancer, antipyretic, antifungal and antihyperglycaemic properties. Some of the documented adverse reactions to Neem ingestion at various doses, include vomiting, hypoglycaemia, mild transient eosinophilia, encephalopathy, ventricular fibrillation and cardiac arrest.4 6–8
Table 1
There are currently no available case reports documenting the development of haemolytic anaemia after consumption of Neem (A indica) tea and the pathogenesis of Neem-induced haemolysis is unknown. Given that Neem appears to have antioxidant properties, it would be suspected that Neem could substitute for G6PD and prevent haemolysis.9 However, some reports demonstrate that this plant extract is able to generate reactive oxide species and a superoxide that could be a potential mechanism for G6PD-deficient erythrocytes haemolysing in the presence of this agent.10 11 Furthermore, other compounds with cytotoxic effects have been isolated from Neem, including nimbolide and quercetin.12 These cytotoxic compounds could be the cause of haemolysis. This case report highlights the need for further research regarding the above proposed mechanisms, especially because there is interest in further developing the cytotoxic components of Neem as an anticancer agent, which has already demonstrated proapoptotic effects of neoplastic cells in human and murine origins.12–14 This case illustrates a possible and clinically relevant interaction between Neem (A indica) tea, a main ingredient of an herbal tea marketed for diabetes, and blood haemolysis in the setting of G6PD deficiency. Using the Naranjo scoring system, a method to determine the relative probability of an adverse event associated with drug administration, the interaction was classified as ‘possible’ based on a total score of 3 (see table 1). The Naranjo scoring system categorises adverse reactions as follows: 9 is definite, 5–8 is probable, 1–4 is possible and 0 is doubtful.15 The appearance of the patient’s jaundice coincides with the timing of tea consumption, which was ingested at a larger quantity than recommended by manufacturer labelling. When Neem tea intake was discontinued, the patient’s haematocrit increased and haemolysis stopped even though his blood sugars remained high during admission. However, hyperglycaemia can be associated with G6PD-deficient haemolysis and it would have been ideal to rechallenge him after discharge when he had normal blood sugars.16 17 This interaction has the potential to have implications for clinicians who are often asked by patients about unconventional remedies for conditions such as cancer and on the management of G6PD deficiency in patients consuming herbal medications, such as Neem (A indica) tea and other similar products, across the globe. This plant extract should be used with caution in patients with G6PD deficiency. Owing to the widespread availability and marketing of A indica products worldwide, there is a considerable need for caution and monitoring as more literature becomes available regarding the possible induction of haemolysis in patients with G6PD deficiency.
Naranjo scoring for the probability of Neem (Azadirachta indica) tea ingestion leading to haemolytic anaemia.15
Naranjo Questionnaire9
Yes
No
Do not know
Case score
1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reaction reappear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? 6. Did the reaction reappear when a placebo was given? 7. Was the drug detected in blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drug in any previous exposure? 10. Was the adverse event confirmed by any objective evidence? Total score
1 2 1 2 −1 −1 1 1 1 1
0 −1 0 −1 2 1 0 0 0 0
N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
N/A 2 1 N/A −1 N/A N/A N/A N/A 1 3
N/A, not applicable.
2
Page C, et al. BMJ Case Rep 2013. doi:10.1136/bcr-2013-200890
Unexpected outcome ( positive or negative) including adverse drug reactions 4
Learning points 5
▸ Taking a thorough history, including specific questions about herbal and complementary medicines, is critical. ▸ Patients who consume herbal supplements or teas, specifically Neem (Azadirachta indica) tea, should be made aware of the potential for an adverse reaction, particularly in the setting of glucose-6-phosphate dehydrogenase (G6PD) deficiency. ▸ Patients should be encouraged to speak with healthcare providers before starting any herbal or dietary supplement. ▸ More research is needed to determine the clinical relevance of A indica ingestion in the setting of G6PD deficiency. This plant extract should be used with caution in G6PD deficient individuals.
6
7
8 9
10
11
Contributors CP and EMH were involved in the conception and design, acquisition of data or analysis and interpretation of data, drafting the article, revising the manuscript critically for important intellectual content, and final approval of the version published. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.
12 13
14 15
REFERENCES 1 2 3
Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008;371:64–74. Beutler E. G6PD deficiency. Blood 1994;84:3613–36. Beutler E. The hemolytic effect of primaquine and related compounds: a review. Blood 1959;14:103–39.
16
17
Neem (Azadirachta indica). In: Natural Standard: the authority on integrative medicine [database on the Internet]. Cambridge, MA: Natural Standard, 2008 [cited 12 May 2013]. http://www.naturalstandard.com. Subscription required to view. Neem (Azadirachta indica) in Hyderabad [image on the Internet]. 2009 March 21 [cited 2013 July 18]. http://en.wikipedia.org/wiki/File:Neem_(Azadirachta_indica) _in_Hyderabad_W_IMG_6976.jpg Bandyopadhyay U, Biswas K, Sengupta A, et al. Clinical studies on the effect of Neem (Azadirachta indica) bark extract on gastric secretion and gastroduodenal ulcer. Life Sci 2004;75:2867–78. Dutta A, Kundabala M. Antimicrobial efficacy of endodontic irrigants from Azadirachta indica: an in vitro study. Acta Odontol Scand. Published Online First: 3 May 2013. doi:10.3109/00016357.2013.780290 Biswas K, Chattopadhyay I, Banerjee RK, et al. Biological activities and medicinal properties of neem (Azadirachta indica). Curr Sci 2002;82:1336–45. Manikandan P, Anandan R, Nagini S. Evaluation of Azadirachta indica leaf fractions for in vitro antioxidant potential and protective effects against H2O2-induced oxidative damage to pBR322 DNA and red blood cells. J Agric Food Chem 2009;57:6990–6. Dallaqua B, Saito FH, Rodrigues T, et al. Treatment with Azadirachta indica in diabetic pregnant rats: negative effects on maternal outcome. J Ethnopharmacol 2012;143:805–11. Tripathi A, Shrivastav TG, Chaube SK. Aqueous extract of Azadirachta indica (neem) leaf induces generation of reactive oxygen species and mitochondria-mediated apoptosis in rat oocytes. J Assist Reprod Genet 2012;29:15–23. Chen J, Chen J, Sun Y, et al. Cytotoxic triterpenoids from Azadirachta indica. Planta Med 2011;77:1844–7. Bharati S, Rishi P, Koul A. Azadirachta indica exhibits chemopreventive action against hepatic cancer: studies on associated histopathological and ultrastructural changes. Microsc Res Tech 2012;75:586–95. Paul R, Prasad M, Sah NK. Anticancer biology of Azadirachta indica L (neem): a mini review. Cancer Biol Ther 2011;12:467–76. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45. Carette C, Dubois-Laforgue D, Gautier JF, et al. Diabetes mellitus and glucose-6-phosphate dehydrogenase deficiency: from one crisis to another. Diabetes Metab 2011;37:79–82. Zhang Z, Yang Z, Zhu B, et al. Increasing glucose 6-phosphate dehydrogenase activity restores redox balance in vascular endothelial cells exposed to high glucose. PLoS ONE 2012;7:e49128.
Copyright 2013 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit http://group.bmj.com/group/rights-licensing/permissions. BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission. Become a Fellow of BMJ Case Reports today and you can: ▸ Submit as many cases as you like ▸ Enjoy fast sympathetic peer review and rapid publication of accepted articles ▸ Access all the published articles ▸ Re-use any of the published material for personal use and teaching without further permission For information on Institutional Fellowships contact [email protected] Visit casereports.bmj.com for more articles like this and to become a Fellow
Page C, et al. BMJ Case Rep 2013. doi:10.1136/bcr-2013-200890
3
CASE REPORT
Haemolytic anaemia after ingestion of Neem (Azadirachta indica) tea Cristy Page, Emily M Hawes Department of Family Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA Correspondence to Dr Emily Morris Hawes, [email protected]
SUMMARY The authors report a clinically relevant and possible cause of haemolytic anaemia from ingestion of a Mexican tea from the Neem tree, also known as Azadirachta indica, in a 35-year-old Hispanic man who was found to have glucose-6-phosphate dehydrogenase deficiency.
BACKGROUND This case highlights a possible adverse reaction of drinking Neem (Azadirachta indica) tea, which is a plant marketed worldwide due to its versatile medicinal properties. In this case of haemolytic anaemia with no known cause, the authors emphasise the value of readdressing a history with collateral sources and asking specifically about herbal medicines and other alternative modalities.
CASE PRESENTATION A 35-year-old Hispanic male with type 2 diabetes presented to a community health center with profound jaundice, dizziness and weakness and was subsequently admitted to the hospital. He denied symptoms of fever, cough, bleeding, changes in bowel movements or other signs of illness. He denied taking oral medications other than metformin. Positive alcohol screen for up to 20 beers on the weekend. The patient worked as a painter, originally from Guerrero, Mexico and no recent travel with no history of liver disease, blood disease, including anaemia or haemolysis, or jaundice, and also no known family history of blood disorders or liver problems. On physical examination, he appeared jaundiced with scleral icterus. He was afebrile and vitals were stable. His heart, lung and abdominal examination were normal. His initial blood work revealed a haemoglobin 8.5 g/dL, haematocrit 25%, total bilirubin 5.2 mg/ dL (unconjugated 4.9 mg/dL), normal transaminases, lactate dehydrogenase (LDH) 983 U/L and normal chemistries except for glucose 266–475 mg/ dL. He had a normal blood gas with no ketoacidosis and a glycosylated haemoglobin of 7.6. Haptoglobin less than 20 mg/dL, direct Coombs negative and reticulocyte count 6.5%. A 35-year-old hispanic male who presented with hyperglycaemia and jaundice and was found to have significant anaemia. To cite: Page C, Hawes EM. BMJ Case Rep Published online: [ please include Day Month Year] doi:10.1136/ bcr-2013-200890
cause remained unclear. Collateral history from his family revealed that his wife first noticed his yellow skin about 2–3 weeks ago, 1 week before he became lightheaded. She stated that he stopped taking his metformin 4 months prior to this, and instead, as stated by his daughter, 3 weeks ago he started drinking large quantities of a Mexican tea that was supposed to help his diabetes. Further investigation identified Neem (A indica) tea. Despite package labelling recommending ingestion of only one cup daily, he reported drinking several litres of the tea daily over the past 3 weeks, which coincided with the timing of his wife noticing his yellow skin. The patient denied taking any other over the counter medications or supplements. Initial laboratory findings were consistent with a Coombs negative haemolytic anaemia (unconjugated hyperbilirubinaemia, elevated LDH and decreased haptoglobin). Given his elevated reticulocyte count, his bone marrow response seemed appropriate, which suggests against anaemia from ineffective erythropoiesis. The differential for non-antibody-mediated haemolytic process includes red blood cell membrane protein dysfunction disorders (including hereditary spherocytosis, paroxysmal nocturnal haemoglobinuria and elliptocytosis), enzyme disorders, (glucose6-phosphate dehydrogenase deficiency (G6PD), pyruvate kinase deficiency), haemoglobinopathies (thalassmias, sickle cell), trauma, toxic exposure and lysis from hypotonic fluids. Given that he has not had prior episodes, many of these hereditary disorders were much less likely. However, some disorders, like G6PD are episodic and usually require an inciting event (such as infection, systemic inflammation, diabetic ketoacidosis (DKA), medications and foods). He presented with hyperglycaemia but had no ketoacidosis. Additional studies including G6PD assay and Heinz bodies were ordered.
TREATMENT After discontinuing the tea, his blood parameters began to improve with discharge haemoglobin 7.9 g/dL and haematocrit 25.4%. G6PD assay confirmed a new diagnosis of G6PD deficiency, which was likely triggered by the consumption of large quantities of Neem tea. At discharge, his blood sugar was 74 mg/dL and he was instructed to resume taking metformin.
INVESTIGATIONS AND DIFFERENTIAL DIAGNOSIS
OUTCOME AND FOLLOW-UP
The day following admission, with a haemoglobin/ haematocrit of 7.4 g/dL/21.7%, the underlying
During the following 3 months, the patient did not ingest Neem tea and his haemoglobin/haematocrit
Page C, et al. BMJ Case Rep 2013. doi:10.1136/bcr-2013-200890
1
Unexpected outcome ( positive or negative) including adverse drug reactions
Figure 1 Photograph of Neem tree.5
normalised to 15.9 g/dL/46.7%. In addition, the G6PD test at 3 months confirmed that the patient does have underlying G6PD deficiency (0.3 U/GM/DL HGB).
DISCUSSION G6PD deficiency, an inherited condition typically found in patients of Mediterranean, African and Asian descent, was first described in the 1950s after the occurrence of haemolysis in a patient taking primaquine.1–3 G6PD is the most common human enzyme defect impacting more than 400 million people worldwide. This genetic X linked disorder causes red cell destruction in the presence of certain infections or medications, such as dapsone, methylthioninium chloride (methylene blue), nitrofurantoin, phenazopyridine, primaquine and rasburicase.1 2 Since several medications can precipitate haemolysis in people with G6PD, it is important to query about medications and herbal products for any patient with unexplained haemolysis. Neem (A indica) tea, derived from the Neem tree (see figure 1), is thought to have originated in northeast India.4 5 It is marketed worldwide, including Mexico, India and the USA, as an oral and topical formulation for many different medicinal purposes based on its antiviral, antimicrobial, anti-inflammatory, antiulcer, anticancer, antipyretic, antifungal and antihyperglycaemic properties. Some of the documented adverse reactions to Neem ingestion at various doses, include vomiting, hypoglycaemia, mild transient eosinophilia, encephalopathy, ventricular fibrillation and cardiac arrest.4 6–8
Table 1
There are currently no available case reports documenting the development of haemolytic anaemia after consumption of Neem (A indica) tea and the pathogenesis of Neem-induced haemolysis is unknown. Given that Neem appears to have antioxidant properties, it would be suspected that Neem could substitute for G6PD and prevent haemolysis.9 However, some reports demonstrate that this plant extract is able to generate reactive oxide species and a superoxide that could be a potential mechanism for G6PD-deficient erythrocytes haemolysing in the presence of this agent.10 11 Furthermore, other compounds with cytotoxic effects have been isolated from Neem, including nimbolide and quercetin.12 These cytotoxic compounds could be the cause of haemolysis. This case report highlights the need for further research regarding the above proposed mechanisms, especially because there is interest in further developing the cytotoxic components of Neem as an anticancer agent, which has already demonstrated proapoptotic effects of neoplastic cells in human and murine origins.12–14 This case illustrates a possible and clinically relevant interaction between Neem (A indica) tea, a main ingredient of an herbal tea marketed for diabetes, and blood haemolysis in the setting of G6PD deficiency. Using the Naranjo scoring system, a method to determine the relative probability of an adverse event associated with drug administration, the interaction was classified as ‘possible’ based on a total score of 3 (see table 1). The Naranjo scoring system categorises adverse reactions as follows: 9 is definite, 5–8 is probable, 1–4 is possible and 0 is doubtful.15 The appearance of the patient’s jaundice coincides with the timing of tea consumption, which was ingested at a larger quantity than recommended by manufacturer labelling. When Neem tea intake was discontinued, the patient’s haematocrit increased and haemolysis stopped even though his blood sugars remained high during admission. However, hyperglycaemia can be associated with G6PD-deficient haemolysis and it would have been ideal to rechallenge him after discharge when he had normal blood sugars.16 17 This interaction has the potential to have implications for clinicians who are often asked by patients about unconventional remedies for conditions such as cancer and on the management of G6PD deficiency in patients consuming herbal medications, such as Neem (A indica) tea and other similar products, across the globe. This plant extract should be used with caution in patients with G6PD deficiency. Owing to the widespread availability and marketing of A indica products worldwide, there is a considerable need for caution and monitoring as more literature becomes available regarding the possible induction of haemolysis in patients with G6PD deficiency.
Naranjo scoring for the probability of Neem (Azadirachta indica) tea ingestion leading to haemolytic anaemia.15
Naranjo Questionnaire9
Yes
No
Do not know
Case score
1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reaction reappear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? 6. Did the reaction reappear when a placebo was given? 7. Was the drug detected in blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drug in any previous exposure? 10. Was the adverse event confirmed by any objective evidence? Total score
1 2 1 2 −1 −1 1 1 1 1
0 −1 0 −1 2 1 0 0 0 0
N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
N/A 2 1 N/A −1 N/A N/A N/A N/A 1 3
N/A, not applicable.
2
Page C, et al. BMJ Case Rep 2013. doi:10.1136/bcr-2013-200890
Unexpected outcome ( positive or negative) including adverse drug reactions 4
Learning points 5
▸ Taking a thorough history, including specific questions about herbal and complementary medicines, is critical. ▸ Patients who consume herbal supplements or teas, specifically Neem (Azadirachta indica) tea, should be made aware of the potential for an adverse reaction, particularly in the setting of glucose-6-phosphate dehydrogenase (G6PD) deficiency. ▸ Patients should be encouraged to speak with healthcare providers before starting any herbal or dietary supplement. ▸ More research is needed to determine the clinical relevance of A indica ingestion in the setting of G6PD deficiency. This plant extract should be used with caution in G6PD deficient individuals.
6
7
8 9
10
11
Contributors CP and EMH were involved in the conception and design, acquisition of data or analysis and interpretation of data, drafting the article, revising the manuscript critically for important intellectual content, and final approval of the version published. Competing interests None. Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed.
12 13
14 15
REFERENCES 1 2 3
Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008;371:64–74. Beutler E. G6PD deficiency. Blood 1994;84:3613–36. Beutler E. The hemolytic effect of primaquine and related compounds: a review. Blood 1959;14:103–39.
16
17
Neem (Azadirachta indica). In: Natural Standard: the authority on integrative medicine [database on the Internet]. Cambridge, MA: Natural Standard, 2008 [cited 12 May 2013]. http://www.naturalstandard.com. Subscription required to view. Neem (Azadirachta indica) in Hyderabad [image on the Internet]. 2009 March 21 [cited 2013 July 18]. http://en.wikipedia.org/wiki/File:Neem_(Azadirachta_indica) _in_Hyderabad_W_IMG_6976.jpg Bandyopadhyay U, Biswas K, Sengupta A, et al. Clinical studies on the effect of Neem (Azadirachta indica) bark extract on gastric secretion and gastroduodenal ulcer. Life Sci 2004;75:2867–78. Dutta A, Kundabala M. Antimicrobial efficacy of endodontic irrigants from Azadirachta indica: an in vitro study. Acta Odontol Scand. Published Online First: 3 May 2013. doi:10.3109/00016357.2013.780290 Biswas K, Chattopadhyay I, Banerjee RK, et al. Biological activities and medicinal properties of neem (Azadirachta indica). Curr Sci 2002;82:1336–45. Manikandan P, Anandan R, Nagini S. Evaluation of Azadirachta indica leaf fractions for in vitro antioxidant potential and protective effects against H2O2-induced oxidative damage to pBR322 DNA and red blood cells. J Agric Food Chem 2009;57:6990–6. Dallaqua B, Saito FH, Rodrigues T, et al. Treatment with Azadirachta indica in diabetic pregnant rats: negative effects on maternal outcome. J Ethnopharmacol 2012;143:805–11. Tripathi A, Shrivastav TG, Chaube SK. Aqueous extract of Azadirachta indica (neem) leaf induces generation of reactive oxygen species and mitochondria-mediated apoptosis in rat oocytes. J Assist Reprod Genet 2012;29:15–23. Chen J, Chen J, Sun Y, et al. Cytotoxic triterpenoids from Azadirachta indica. Planta Med 2011;77:1844–7. Bharati S, Rishi P, Koul A. Azadirachta indica exhibits chemopreventive action against hepatic cancer: studies on associated histopathological and ultrastructural changes. Microsc Res Tech 2012;75:586–95. Paul R, Prasad M, Sah NK. Anticancer biology of Azadirachta indica L (neem): a mini review. Cancer Biol Ther 2011;12:467–76. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45. Carette C, Dubois-Laforgue D, Gautier JF, et al. Diabetes mellitus and glucose-6-phosphate dehydrogenase deficiency: from one crisis to another. Diabetes Metab 2011;37:79–82. Zhang Z, Yang Z, Zhu B, et al. Increasing glucose 6-phosphate dehydrogenase activity restores redox balance in vascular endothelial cells exposed to high glucose. PLoS ONE 2012;7:e49128.
Copyright 2013 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit http://group.bmj.com/group/rights-licensing/permissions. BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission. Become a Fellow of BMJ Case Reports today and you can: ▸ Submit as many cases as you like ▸ Enjoy fast sympathetic peer review and rapid publication of accepted articles ▸ Access all the published articles ▸ Re-use any of the published material for personal use and teaching without further permission For information on Institutional Fellowships contact [email protected] Visit casereports.bmj.com for more articles like this and to become a Fellow
Page C, et al. BMJ Case Rep 2013. doi:10.1136/bcr-2013-200890
3
