Jane Achan; Ambrose O Talisuna; Annette Erhart; Adoke Yeka; James K Tibenderana; Frederick N Baliraine; Philip J Rosenthal; Umberto D'Alessandro

“ However, it is unclear whether supplies will be sufficient for the thousands of patients in need. Until these procurement and supplies issues are resolved, intravenous quinine may remain the only readily available drug for treating severe malaria in sub-Saharan Africa and other resource-limited settings. Furthermore, there are several health systems challenges related to the management of severe malaria in resource limited settings that impact on treatment outcomes, independent of the parenteral anti-malarial drugs used. ”

“ Several pharmacokinetic characteristics of quinine differ according to the age of the subject and are also affected by malaria. The volume of distribution is less in young children than in adults, and the rate of elimination is slower in the elderly than in young adults. In patients with acute malaria the volume of distribution is reduced and systemic clearance is slower than in healthy subjects; these changes are proportional to the severity of the disease. As a result, plasma quinine levels are higher in patients with malaria. ”

“ Additional evidence for the impact of unusual quinine pharmacokinetics on treatment outcomes was provided by a more recent study describing early treatment failure in a patient with severe malaria with an abnormally high volume of distribution and increased quinine clearance, resulting in abnormally low quinine concentrations [ [96] . A few studies have proposed that an increase in the quinine dosage after the third day could compensate for declines in plasma drug levels during recovery, especially in areas with resistant P. falciparum [93] . ”

“ Potential explanations for quinine treatment failure Quinine resistance
Parasite drug resistance is probably the greatest problem faced by malaria control programs worldwide and is an important public health concern. Over the years, malaria parasites have developed resistance to a number of commonly used anti-malarial drugs. ”

“ Interesting observations of the effect of combined quinine and rifampicin therapy were additionally reported in Thai patients with uncomplicated malaria [ [66] . In this study, parasite clearance times were shorter in the quinine-rifampicin group than in the group given quinine monotherapy, suggesting that the anti-malarial activity of rifampicin augmented that of quinine initially. However, recrudescence rates were five times higher in the quinine-rifampicin group than in the quinine-alone group [ [66] . ”

“ Purified quinine then replaced the bark as the standard treatment for malaria [5] . Quinine and other cinchona alkaloids including quinidine, cinchonine and cinchonidine are all effective against malaria. The efficacies of these four alkaloids were evaluated in one of the earliest clinical trials, conducted from 1866 to 1868 in 3600 patients using prepared sulfates of the alkaloids. With the main outcome measure of "cessation of febrile paroxysms", all four alkaloids were found to be comparable, with cure rates of >98% [ [6] . ”

“ Interactions between HIV and malaria remain a major public health concern in areas affected by both diseases. Very few studies have evaluated the role of quinine in the management of malaria in HIV infected populations. ”

“ Ideally, branded anti-malarial drugs should be used, but unfortunately, branded quinine products are not universally available in Africa and other malaria endemic settings. In addition, national drug regulators need to strengthen their roles in the monitoring of anti-malarial drug quality. ”

“ Nevertheless, despite their scale up in Africa, the cost and availability of ACT in the public sector remains a major challenge. In 2008, ACT coverage in the public sector in high-burden African countries was only 42% [46] . Similarly, a survey carried out during the same year in seven African countries showed that the percentage of fever cases in children < 5 years treated with ACT was only 16% [ [46] . The sustainability of ACT supplies in resource limited settings therefore presents a huge problem, with stock-outs consistently occurring in health facilities [ [47] . ”

“ This study also reported that treatment failure rates with quinine remained stable over the five-year period of surveillance.
Even with seven-day treatment durations, evaluations of different quinine dosage regimens have revealed interesting trends. Doses of 10 mg/kg/day given twice daily for 7 days were associated with day 28 treatment failure rates as high as 30% [38] . Increasing the quinine dosage to 15 mg/kg/day or 20 mg/kg/day improved treatment outcomes, with failure rates ranging from 8% to 14% [ [38] , although potential increases in toxicity with higher dosages are a concern. ”

“ Despite these anecdotal observations, there is little evidence for large variations in quinine pharmacokinetics [ [97] and the exact role that variations in drug levels play in quinine treatment responses is unclear.
Quinine drug quality and treatment compliance
The quality of quinine used in routine care could play a key role in clinical outcomes. Poor quality drugs remain a problem worldwide and are a serious public health threat. ”

“ Cardoso, BS & Boulos, M (2006) , Successful treatment of Plasmodium falciparum malaria with a six-dose regimen of artemether-lumefantrine versus quinine-doxycycline in the Western Amazon region of Brazil, vol. 74, pp. 20–25, 16407341, pmid:16407341 1 2 World Malaria Report 2009, 2009 ↑ Kangwana, BB; Njogu, J; Wasunna, B; Kedenge, SV; Memusi, DN; Goodman, CA; Zurovac, D & Snow, RW (2009) , Malaria drug shortages in Kenya: a major failure to provide access to effective treatment, vol. ”