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ORIGINAL ARTICLE
Year : 2017  |  Volume : 5  |  Issue : 1  |  Page : 1-4

Sulfadoxine-pyrimethamine toxicity among malaria patients in a developing tertiary institution: A 10 year assessment


Department of Pharmacy, Accident and Emergency Centre, University of Benin Teaching Hospital, P.M.B 1111, Benin City, Nigeria

Date of Web Publication28-Sep-2018

Correspondence Address:
Mr. S E Aghahowa
Department of Pharmacy, Accident and Emergency Centre, University of Benin Teaching Hospital, P.M.B 1111, Ugbowo, Benin City
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2348-053X.242446

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  Abstract 


Background: Adverse effects such as Stevens Johnson syndrome and Toxic Epidermal Necrolysis following the use of sulfonamide containing antimalarials seems to be on the increase despite the adoption of the new policy for malaria treatment in Nigeria. Aim: To assess the pattern and prevalence of Stevens Johnson syndrome and Toxic Epidermal Necrolysis in the use of sulfadoxine-pyrimethamine as reported in the Accident and Emergency Centre of the University of Benin Teaching Hospital, Benin City, Nigeria between the year 2001 and 2010. Materials and Methods: Reported cases of Stevens Johnson syndrome and Toxic Epidermal Necrolysis were assessed retrospectively by using patient records. Results: Twenty-one patients reported with Stevens Johnson syndrome and Toxic Epidermal Necrolysis. The male to-female? of 2.8:1, 26 ± 1.6 years (mean ± standard deviation). Three of the victims had their drugs after obtaining standard prescription and 18 self-administered their drugs. Eighteen of them claimed to have been treating malaria while three had theirs for prophylaxis. The highest incidence was in the year 2008 and 2010. Sixteen (76.19 %) of the cases or patients procured their drugs from unregistered shops. Nine (42.58 %) cases or patients repeated their drugs during therapy when they felt that the dosage at initiation of therapy did not work for them. Two of the patients were known HIV/AIDS patients. Zinc-oxide powder was the most common topical drug applied during hospitalization. Severity was paramount in all at the time of report. Skin eruption was very common. Only two of them did not survive after management. Conclusions: The study showed that fatalities associated with the use of sulfadoxine-pyrimethamine were severe. Therefore, adequate measures are recommended through public enlightenment in ensuring adherence to regulatory policies.

Keywords: Malaria, Stevens-Johnson syndrome, sulfadoxine-pyrimethamine, Toxic epidermal necrolysis


How to cite this article:
Aghahowa S E, Eze C I. Sulfadoxine-pyrimethamine toxicity among malaria patients in a developing tertiary institution: A 10 year assessment. Niger J Exp Clin Biosci 2017;5:1-4

How to cite this URL:
Aghahowa S E, Eze C I. Sulfadoxine-pyrimethamine toxicity among malaria patients in a developing tertiary institution: A 10 year assessment. Niger J Exp Clin Biosci [serial online] 2017 [cited 2018 Dec 16];5:1-4. Available from: http://www.njecbonline.org/text.asp?2017/5/1/1/242446




  Introduction Top


Malaria infection still remains one of the most common tropical diseases that afflict humans. It accounts for 300 million acute illnesses and kills at least one million people every year.[1] Ninety percent of deaths due to malaria occur in Africa, South of the Sahara, and most deaths occur in children under the age of 5.[2],[3],[4] The use of combination drugs has been identified as a strategic and viable option in improving efficacy, delaying development and selection of resistance parasites.[1],[5],[6],[7]. Resistance has been reported in virtually all these diverse drugs.[8] In endemic areas, challenges may not be resistance to conventional drugs but toxicities due to irrational use. Toxicities of antimalarials vary because of their different chemical structures irrespective of the type of malaria. The primary concern is the possibilities of interactions between the additive or synergistic components in the combination with particular reference to sulfadoxine-pyrimethamine as a nonartemisinin combination. Meanwhile, published data on sulfadoxine-pyrimethamine toxicities has been observed to be rare.[9],[10] Toxicities can be frequent when recommended doses are exceeded.[11] These could be reversible to irreversible and may be influenced by age, sex, race, disease, and pharmacokinetic disposition of the drug.[12],[13] Many residents of Benin City and environs often complain of malaria thereby they are subjected to frequent and irregular of doses antimalarials through self-medication. This study assessed reported cases sulfadoxine-pyrimethamine toxicities reported in 10 years.


  Materials and Methods Top


Due to the rare cases published data on sulphadoxine-pyrimethamine toxicities, it became necessary to assess the pattern retrospectively in the Accident and Emergency Centre of the University of Benin Teaching Hospital, Benin City, Nigeria. Data were collected from reported cases of severe adverse effects of sulphadoxine-pyrimethamine using individual records between April 2009 and March 2010. Data were categorized as year, age, sex, identification of drug, number of repeated doses, previous illness, other drugs co-administered with sulfadoxine-pyrimethamine, severity, duration of hospitalization, complication and outcome of therapy. Three records of incomplete data were excluded.

Statistical analysis

Data collected were entered into Microsoft Excel, SPSS version 11.0 (SPSS, Inc., Chicago, IL) Microsoft coorporation (Redmond, Washington). Where necessary, data were computed as percentage. Continuous data were expressed as mean ± standard deviation (SD), whereas categorical data were subjected to Chi-square test. P< 0.05 was regarded as significant.


  Results Top


Twenty-one patients reported with Stevens Johnson syndrome and Toxic Epidermal Necrolysis. [Figure 1] shows a patient with  Stevens-Johnson syndrome More Details. The male to-female ratio was 2.8:1. The age range was 19-43 years with a mean age of 26 ± 1.6 years (mean ± SD). Three of the victims had their drugs after obtaining standard prescription and 18 self-administered their drugs. Eighteen of them claimed to have been treating malaria while three had theirs for prophylaxis. The highest incidence was in the year 2008 and 2010. Sixteen percentage of the patients procured their drugs from unregistered shops. Nine patients or cases repeated their drugs during therapy when they felt that the dosage at initiation of therapy did not work for them. Two of the patients were known HIV/AIDS patients. Zinc-oxide powder was the most common topical drug applied during hospitalization. Severity was paramount in all at the time of report. Skin eruption was very common. Only two of them did not survive after management.
Figure 1: Reporte case of sulfadoxine-pyrimethamine toxicity after self-medicating

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Acetaminophen and ferrous sulfate were the commonest co-administered drugs. Other major antibiotics were intravenous ciprofloxacin and metronidazole. Frequent morbidities were conjunctivitis, mouth ulcers, itching, jaundice, hematuria, and oral thrush.


  Discussion Top


The use of antimalarials irrespective of the type of malaria can be fatal if adequate doses are not utilized conventionally. Victims may have been exposed to harmful doses due to self-medication and repeated doses of the prescribed drug as observed in [Table 1]. There have been frequent reports of drug failures in the country due to substandard preparations or inherent ineffectiveness of the drugs (personal communication). The effort of the regulatory agency; the National Agency for Food, Drug Administration and Control has helped in ameliorating these hazards to a great extent.
Table 1: Variation among males and females in the report of sulphadoxine-pyrimethamine toxicities

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Seeking alternatives to antimalarials is a predisposing factor to toxicities. Many casualties may have switched from one brand to another without knowing the actual composition of the drug. Packaging of drugs in different sachets can lead to difficulty in distinguishing. This is more obvious among illiterates or patients that do not have access to pharmacist for adequate counseling.

Most cases seen in this report were skin eruptions penetrating into the dermal layers as seen in [Figure 1] represents a typical Toxic Epidermal Necrolysis. These eruptions seem more pronounced in cases of repeated administration. The bio-fluid emanating from necrolyzed skin can serve as a diagnostic tool in assessing the causative agent. The syndrome manifested as dark patches or an entire change in skin color. Even when the therapeutic-index seems to be wide, the pharmacologic fate of the drug can be altered due to irrational use, thus this can lead to possible toxicities. The common impression of ineffectiveness associated with the antimalarial therapy may have led to irrational use. Potentiating effect from the use of plant concoctions/decoctions of Azadirachta indica, Carica papaya, Momordica charantia, Parguetina nigrescence as alternatives in therapy cannot be ignored.[14] It is a common practice among residents of Benin City to use herbal preparations, which can influence outcome of therapy. Another predisposing factor is the consequence of irregular purchase of drugs from patent medicine shops not registered with the Federal Ministry of Health as seen in some cases in [Table 1]. These shops are frequently manned by unskilled personnel who may not have good knowledge of drugs and therapeutics. Patients may not know that he or she has taken such drug previously, which may alter toxico-kinetic fate. Other influential factors such as race could not be ascertained; but all of them were blacks and residents of the area. However, Stevens-Johnson syndrome has been reported to occur in any race.[14]

It was observed that two of the patients did not survive after the hours of hospitalization. This may not be due to irreversible damage to various organs most especially kidney or liver skin. Some persons in Benin City and environs still adopt the practices of self-medication being that rules regulating such practices are not fully enforced. Toxicities reported in this center cannot be associated with sulfadoxine alone, it has been reported that pyrimethamine alone can also cause toxicity.[14] The overall phenomenon may be additive or synergistic. The use of other sulfonamide containing drugs such as sulfamethoxazole-trimethoprim could have worsened the toxic effect due to the cumulative sulfamide components synergistically.

Co-morbidities may have predisposed individuals to these fatalities. Patient that had primary infection such as HIV/AIDS may have been predisposed to harmful conditions because there might be necessity of using other drugs.

Generally, the mechanism of toxicity can be complex, sulfonamide metabolites can act as haptens that interact with host tissues rendering them antigenic.[15],[16] This phenomenon is not clear but could be aggravated due to chemical, biological and pharmaceutical interactions thus leading to fatal cutaneous reactions after series of cascade events as identified.[14],[17],[18],[19] The influence of excipients cannot be overlooked, many manufacturers tend to be silent on the type of excipients used in order to have improved the pharmacokinetic profile without considering the health hazard they may pose to patients during therapy.

Other complications as observed may be attributed to severity. Some authors have previously reported fatal hepatic necrosis due to sulfadoxine-pyrimethamine.[20] Considering these fatalities as reported in this study, it is necessary to be very careful in the use of drugs that have sulfonamide components because the effect can be deleterious during therapy or prophylaxis. Therapeutic failures as a contributory factor in using repeated doses of the same drug within the same period should be discouraged. Where necessary, a particular brand should be allowed in circulation to avoid the consequence of repeated doses of the same drug in different brands that can be confused as alternative regimen most especially in rural communities. Finally, excipients used in improving pharmacokinetic profile should be stated in the label of drugs by manufacturers.


  Conclusions Top


The consequence of self-medication through the procurement of over-the-counter drugs can be fatal. Policies regulating the use of drugs should be adequately enforced by regulatory agencies to prevent hazards associated with drugs most especially in a malaria endemic areas like ours. When sulfonamide containing drugs are prescribed, close monitoring should be ensured to avoid possible predisposing factors to toxicities. Health education on the harmful effects of drugs is strongly recommended for all categories of persons to reduce this burden appreciably.

Acknowledgments

We wish to appreciate the staff of Pharmacy and record. Department of the Accident and Emergency Centre, University of Benin Teaching Hospital, Benin City Nigeria, for their various contributions in the collection of data.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
World Health Organisation. Expert Committee on Malaria, (WHO) Technical Report Series No. 899; 1998. p. 1-64.  Back to cited text no. 1
    
2.
World Health Organisation. Assessment and Monitoring of Antimalarial Drug Efficacy for the Treatment of Uncomplicated Falciparum Malaria. Vol. 50. Geneva: WHO/HTM/RBM; 2003. p. 1-66.  Back to cited text no. 2
    
3.
Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 2005;434:214-7.  Back to cited text no. 3
    
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Greenwood BM, Bojang K, Whitty CJ, Targett GA. Malaria. Lancet 2005;365:1487-98.  Back to cited text no. 4
    
5.
White N. Antimalarial drug resistance and combination chemotherapy. Philos Trans R Soc Lond B Biol Sci 1999;354: 739-49.  Back to cited text no. 5
    
6.
White NJ, Nosten F, Looareesuwan S, Watkins WM, Marsh K, Snow RW, et al. Averting a malaria disaster. Lancet 1999;353:1965-7.  Back to cited text no. 6
    
7.
Price RN, Nosten F, Luxemburger C, ter Kuile FO, Paiphun L, Chongsuphajaisiddhi T, et al. Effects of artemisinin derivatives on malaria transmissibility. Lancet 1996;347:1654-8.  Back to cited text no. 7
    
8.
World Health Organization. Antimalarial Drug Combination Therapy, (WHO) Technical Report Series No. 875.1.30; 2001.  Back to cited text no. 8
    
9.
Lindberg A, Bergqvist Y, Rombo L. Accidental overdose of pyrimethamine and sulphadoxine for malaria prophylaxis without adverse effects. Eur J Clin Pharmacol 1986;31:253-4.  Back to cited text no. 9
    
10.
Burgmann H, Winkler S, Uhl F, Feucht M, Hellgren U, Bergqvist Y, et al. Mefloquine and sulfadoxine/pyrimethamine overdose in malaria tropica. Wien Klin Wochenschr 1993;105:61-3.  Back to cited text no. 10
    
11.
Luzzi GA, Peto TE. Adverse effects of antimalarials. An update. Drug Saf 1993;8:295-311.  Back to cited text no. 11
    
12.
AlKadi HO. Antimalarial drug toxicity: A review. Chemotherapy 2007;53:385-91.  Back to cited text no. 12
    
13.
Winstanley P, Ward S, Snow R, Breckenridge A. Therapy of falciparum malaria in Sub-Saharan Africa: From molecule to policy. Clin Microbiol Rev 2004;17:612-37.  Back to cited text no. 13
    
14.
De Rojas MV, Dart JK, Saw VP. The natural history of Stevens Johnson syndrome: Patterns of chronic ocular disease and the role of systemic immunosuppressive therapy. Br J Ophthalmol 2007;91:1048-53.  Back to cited text no. 14
    
15.
Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol 2003;139:1051-9.  Back to cited text no. 15
    
16.
Assier-Bonnet H, Aractingi S, Cadranel J, Wechsler J, Mayaud C, Saiag P. Stevens-Johnson syndrome induced by cyclophosphamide: Report of two cases. Br J Dermatol 1996;135:864-6.  Back to cited text no. 16
    
17.
Foster CS, Fong LP, Azar D, Kenyon KR. Episodic conjunctival inflammation after Stevens-Johnson syndrome. Ophthalmology 1988;95:453-62.  Back to cited text no. 17
    
18.
French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: Our current understanding. Allergol Int 2006;55:9-16.  Back to cited text no. 18
    
19.
French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: Our current understanding. Int Immunopharmacol 2006;6:543-9.  Back to cited text no. 19
    
20.
Zitelli BJ, Alexander J, Taylor S, Miller KD, Howrie DL, Kuritsky JN, et al. Fatal hepatic necrosis due to pyrimethamine-sulfadoxine (Fansidar). Ann Intern Med 1987;106:393-5.  Back to cited text no. 20
    


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