Antimalarial Efficacy of a Quantified Extract ofNauclea pobeguiniiStem Bark in Human Adult Volunteers with Diagnosed Uncomplicated Falciparum Malaria. Part 1: A Clinical Phase IIA Trial

Abstract

The aim of this phase IIA clinical trial was to assess the efficacy of an 80 % ethanolic quantified extract (containing 5.6 % strictosamide as the putative active constituent) from Nauclea pobeguinii stem bark denoted as PR 259 CT1 in a small group of adult patients diagnosed with uncomplicated falciparum malaria. Results obtained from a phase I clinical trial on healthy male volunteers indicated that the oral administration during meals of two 500 mg capsules three times daily (each eight hours) during seven days was well tolerated and showed only mild and self-resolving adverse effects. This PR 259 CT1 drug regimen was obtained by mathematical conversion of animal doses obtained in several in vivo studies in mice to human equivalent doses as in falciparum malaria patients. The phase IIA study was an open cohort study in eleven appraisable adult patients suffering from proven Plasmodium falciparum malaria. The study was specifically designed to assess the efficacy of PR 259 CT1 administered with a dose regimen of two 500 mg capsules three times daily for three days, followed by outpatient treatment of one 500 mg capsule three times daily for the next four days, in order to prove that this therapeutic dose, which was calculated from animal doses, was effective to treat adult malaria patients and consequently useful for a future Phase IIB clinical trial. This study would then substitute a dose-escalating trial, which in general is used to find the appropriate dose for clinical studies. The phase IIA clinical trial was carried out according to the WHO 2003 14-day test, and the results revealed that all eleven patients were completely cleared of parasitemia and fever on days 3, 7, and 14 except for one patient, who experienced a recurrence of parasitemia at days 7 until 14. Besides this adequate clinical and parasitological response (ACPR), this trial also demonstrated that PR 259 CT1 was well tolerated with only mild and self-resolving adverse effects including fatigue and headache, which were in accordance with those found in the phase I clinical trial. Moreover, all symptoms progressively disappeared, and no symptoms were observed on day 14. Although the number of patients included in this study was rather limited, the statistical analysis nevertheless suggested the efficacy and tolerability of PR 259 CT1, which indicated that this herbal medicinal product might be considered as a putative candidate for a large scale clinical trial.

Antimalarial Efficacy of a Quantified Extract of Nauclea pobeguinii Stem Bark in Human Adult Volunteers with Diagnosed Uncomplicated falciparum Malaria. Part 2: A Clinical Phase IIB Trial

“…The Phase IIA study was an open cohort study on 11 adult patients suffering from proven Plasmodium falciparum malaria using a therapeutic dose which was calculated from animal doses. This clinical trial was carried out according to the WHO 2003 14-day test, and the results revealed that 10 out of 11 patients were completely cleared of parasitaemia and fever at days 3, 7, and 14, and that the herbal medicinal product was well tolerated with only mild and self-resolving adverse effects including asthenia and headache, confirming the findings of the Phase I clinical trial [9]. Taking into account these promising results, it was decided to assess the putative efficacy and the safety of the oral treatment of PR 259 CT1 on a larger number of patients suffering from uncomplicated Plasmodium falciparum malaria in comparison with an artesunate-amodiaquine (AS-AQ) combination according to the WHO 2003 protocol criteria which could then ultimately lead to a Phase III clinical trial study.…”

“…Follow-up of patients was carried out as reported for the Phase I and IIA studies [8,9] and also included electrocardiogram (ECG) examinations. The 12-derivative standard ECG was recorded using a Cardiofax ECG-6851K electrocardiograph (Nihon Kohden) and analysed manually.…”

“…Quality assurance of data and the ethical conduct of this study were described in detail in the Phase IIA study [9].…”

Ethnobotanical study of plants used against malaria in Sélingué subdistrict, Mali

“…It is also non-toxic: no acute toxicity was observed in mice after a single 2 g/kg oral dose, nor after 4 weekly doses (Mesia et al, 2010). Furthermore it is safe and effective against uncomplicated malaria in humans (Mesia et al, 2011;Mesia et al, 2012a;Mesia et al, 2012b). One of the active compounds is thought to be strictosamide.…”

Antimalarial drug discovery — approaches and progress towards new medicines

“…There are other fever-reducing folk remedies that could yield a next-generation antimalarial. For example, the bark of the plant Nauclea pobeguinii , from the Democratic Republic of Congo, can substantially reduce parasitemia in mice infected with rodent malaria 97 and has shown efficacy in man in phase IIb clinical trials 98 . It is interesting to note that the chemical structure of a possible active ingredient, strictosamide, is similar to that of the spiroindolones 99 .…”