Skip to main page content

• HOME
• Current Issue
• Archive
• Alerts
• About ASM
• Contact us
• Tech Support
• Journals.ASM.org

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pussard, E. Articles by Barennes, H. Search for Related Content PubMed PubMed Citation Articles by Pussard, E. Articles by Barennes, H.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, November 2004, p. 4422-4426, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4422-4426.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Dose-Dependent Resorption of Quinine after Intrarectal Administration to Children with Moderate Plasmodium falciparum Malaria

Eric Pussard,^1* Celine Straczek,¹ Idrissa Kaboré,² Auguste Bicaba,² Tatiana Balima-Koussoube,² Patrice Bouree,¹ and Hubert Barennes²

Services de Pharmacologie et de Parasitologie, CHU du Kremlin-Bicêtre, Le Kremlin-Bicêtre, France,¹ Unité d'Épidémiologie, Centre Muraz, Bobo Dioulasso, Burkina Faso²

Received 18 February 2004/ Returned for modification 24 May 2004/ Accepted 26 July 2004

Top Abstract Text References

 
The pharmacokinetics of increasing doses of an intrarectal Cinchona alkaloid combination containing 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine (Quinimax) was compared to that of parenteral regimens in 60 children with moderate malaria. Quinine exhibited a nonlinear pharmacokinetics, suggesting a saturation of rectal resorption. When early rejections appeared, blood quinine concentrations decreased by 30 to 50% and were restored by an immediate half-dose administration of the drug. Rectal administration of doses of 16 or 20 mg/kg of body weight led to concentration-time profiles in blood similar to those of parenteral regimens and could be an early treatment of childhood malaria.

Top Abstract Text References

 
Intrarectal administration represents a promising administration route of antimalarial drugs in the field, especially convenient for patients unable to swallow and when parenteral formulations are unavailable. Its efficacy has been demonstrated with artemisinin derivatives for the treatment of moderate to severe Plasmodium falciparum malaria, especially in Southeast Asia (7, 9). In Africa, artemisinin derivatives are not readily available, and quinine remains one of the most widely used antimalarial drugs at the primary health center level. We previously showed that intrarectal administration of various formulations of quinine was as effective as the currently used intramuscular treatment of childhood malaria (2, 3). Nevertheless, a large interindividual variability was observed in quinine bioavailability and concentrations in blood according to the galenic formulation and the administered dose (2, 4, 6). Whatever rectal formulation is used, the drug may be extruded spontaneously without being noticed, leading to a decrease of clinical efficacy. Then, we compared the absorption characteristics of increasing doses of a rectally administered Cinchona alkaloid combination (containing 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine [Quinimax]; Sanofi, Chantilly, France) with those of the currently used parenteral regimens.

This open and randomized study took place in the children's ward of the Sanou Sourou Hospital, Bobo Dioulasso, Burkina Faso, and was approved by the Ethical Committee of the Burkina Faso Health Ministry. Children with moderate malaria (having more than 1,000 asexual P. falciparum parasites per microliter of blood and requiring a parenteral treatment) were eligible after full informed consent was given by a parent or guardian. Exclusion criteria included severe malaria (cerebral malaria, severe hypoglycemia, or anemia) (19), diarrhea, anatomical abnormalities of the rectum, and antimalarial treatment within the preceding week.

Quinine was administered as a gluconate salt of the Cinchona alkaloid formulation. Sixty children were randomly administered one of the following treatments, repeated for 48 h. Quinine was given either intramuscularly at a dose of 12 mg per kg of body weight every 12 h (IM12), intravenously as a slow infusion of 8 mg per kg over 4 h every 8 h (IV8), or rectally at doses of 8 mg/kg (IR8) or 16 mg/kg (IR16) every 8 h and at 12 mg/kg (IR12) or 20 mg/kg (IR20) every 12 h.

The solution was administered via a plastic syringe after one-third dilution in water. Children were placed in a decubitus position for 5 min and watched closely for the first hour. If rectal solution was expelled, the child was excluded from the kinetic study and received a parenteral treatment. The effect of early rejections was evaluated for some children excluded from groups IR12 (n = 6) and IR20 (n = 6). Four children with early rejection after a 20-mg/kg dose received a further half-dose. At 48 h, all the children were able to tolerate oral medication and quinine was given per os to complete a 5-day treatment.

Physical signs, rectal temperature, and parasitemia were recorded at inclusion and once daily until day 7. Two hundred microliters of blood was collected in EDTA tubes before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, and 24 h after the start of therapy. In the groups receiving quinine twice daily, additional samples were collected at 10 and 12 h. Whole-blood quinine concentrations were determined by high-performance liquid chromatography with fluorometric detection (16).

Concentrations of quinine in whole blood were fitted by using an iterative least-squares curve-fitting program (APIS) (10). Peak concentrations (C_max) and the times to C_max were observed values. The area under the concentration-time curve (AUC) was calculated according the trapezoidal rule. The bioavailability of the rectal quinine was calculated as the ratio of the rectal AUC from 0 to 8 h (AUC_{0-8 h}) to the parenteral AUC_{0-8 h}. Normally distributed data were compared by parametric tests, and abnormally distributed data were compared by the Kruskal-Wallis test. A P value of 0.05 was considered to be statistically significant.

Baseline clinical and biological parameters were comparable among all the groups (Table 1). All the children had recent vomiting, and nine (15.0%) were prostrate. The main clinical symptoms reported were headache (58.3%), abdominal pain (33.3%), and coughing (35.0%).

View this table: [in this window] [in a new window]

TABLE 1. Parasitological and clinical data at admission and after administration of the Cinchona alkaloid combinationa

The concentration-time profiles in whole blood and the pharmacokinetic parameters of quinine are displayed in Fig. 1 and Table 2. Blood quinine C_maxs were similar for the IM12 and IV8 groups but occurred more quickly after intramuscular administration. The AUC_{0-8 h} of quinine in blood was higher after intramuscular injection than after intravenous infusion, but trough concentrations were similar after the first drug administration and at 24 h.

View larger version (20K): [in this window] [in a new window]

FIG. 1. Profiles for children with P. falciparum malaria of concentrations of quinine in blood versus time after the following treatments: IV8 (•), IM12 (), IR8 (), IR12 (), IR16 (), and IR20 () (data are median values).

View this table: [in this window] [in a new window]

TABLE 2. Pharmacokinetic parameters of quinine in the blood of children with P. falciparum malaria after administration of the Cinchona alkaloid combinationa

Peak and trough concentrations and AUC_{0-8 h}s of quinine in blood were lower in the IR8, IR12, and IR16 groups than in the IM12 group but similar for the IR20 and parenteral groups. In the IM12 group, the resorption rate of quinine was higher than in the IV8 and IR8 groups and similar to that of the IR12, IR16, and IR20 groups. The rectal bioavailability of quinine markedly decreased from 96 to 54% when the rectal dose was increased. When early rejection of liquid stools occurred in the first hour of rectal treatment, both the C_maxs and AUC_{0-8 h}s of quinine in blood decreased by 30 to 50%. The administration of a further half-dose restored values to levels similar to those observed in patients in the IR20 group who did not reject the treatment (Table 2 and Fig. 2).

View larger version (15K): [in this window] [in a new window]

FIG. 2. Profiles for children with P. falciparum malaria of concentrations of quinine in blood versus time after IR20 treatment without () and with (•) early rejections. Early rejections were immediately followed by the administration of a half-dose () of 10 mg/kg (data are median values).

The change in pharmacodynamic parameters at 24 h reflects the effect of the two or three first administrations of the Cinchona alkaloid combination (Table 1). Parasitemia and body temperature clearance times were similar in all groups. All children were apyretic at 72 h, had cleared their parasites at 96 h, and remained so until day 7. There were no major adverse events attributable to the administration route or the drugs. After intramuscular administration, all children complained of pain at the injection point. Intrarectal administration was associated with an increasing frequency of mucoid stools.

Most of the parenteral formulations of quinine were acidic (pH, 2.0), leading to local discomfort and a low rate of observance of intramuscular treatment (1). The substitution of the hydrochloride for a gluconate salt and an increase in the pH value to 4.5 improve the local tolerance but may affect the extent of drug distribution (18). The kinetics profiles obtained after intravenous and intramuscular administrations are similar to those previously reported for hydrochloride salt (4, 5). In contrast, after rectal administration of 8 mg/kg, the bioavailability of the gluconate form is higher than that previously observed with the more acidic formulations (3, 5, 6). The main mechanism of rectal absorption is a passive transport that depends mainly on the molecular weight, the lipophilicity, and the degree of ionization of molecules (19). Basic drugs like quinine may be absorbed faster at this higher pH value.

After rectal administration, blood quinine concentrations did not rise proportionally in response to the rectal dose, suggesting a saturability of drug absorption by the human rectal mucosa. This dose-dependent absorption seems to be characteristic of the rectal route because a linear relationship between the dose (4 to 16 mg/kg) and the AUC of quinine was previously observed after oral administration (17). A negative relationship between the dose and the bioavailability was also reported for suppositories of artesunate in Ghanaian children (12) and of chloroquine in healthy subjects (14). Because no argument exists in favor of a saturable transporter in the rectal mucosa, many other biological factors influence the bioavailability. The spread of a large volume of enemas or multiple suppositories appears not to be limited to the rectal area, and its migration into the ascending colon with more-limited resorption capacity may result in a lower bioavailability (18). The decrease in bioavailability may also be ascribed to the adherence of drug to the stools or its degradation by microorganisms and to the variability in the rectal mucosa blood flow (8, 18). According to the level of the spread in the rectum, the drug partly avoids first-pass clearance by the liver, but similar concentrations of the 3-hydroxyquinine in blood were previously observed after both parenteral and rectal administrations, suggesting more a loss of aqueous formulation itself than a hepatic first-pass transformation (5). Nevertheless, this saturability of rectal absorption may limit the rise in blood quinine concentrations often required in areas where strains became resistant, like in Southeast Asia.

The main disadvantage of a rectal route is that the drug may be extruded spontaneously and require careful monitoring (8). The frequency of early rejections of quinine enemas was estimated to be about 20% of children in Togo (1). Rejections decrease the bioavailabilities of the 12- and 20-mg/kg doses by 30 and 50%, respectively, but do not significantly affect the parasitological and clinical efficacy. Nevertheless, in order to avoid subtherapeutic concentrations in blood during the critical initial 24 h, the immediate administration of a half-dose restores effective concentrations in blood especially in the treatment of potentially evolving cases of P. falciparum malaria.

Similar concentration-time profiles in blood and pharmacodynamic efficacy were obtained with the recommended intravenous regimen at 8-h intervals and the intramuscular schedule at 12-h intervals widely used in peripheral health centers of West Africa (13, 15). The rate and the extent of quinine absorption with the 16- and 20-mg/kg rectal doses are comparable to those obtained with the 12-mg/kg intramuscular treatment. Such fast drug delivery may be of clinical relevance, especially at the onset of treatment of severe malaria, when effective drug concentrations must be rapidly achieved.

Despite a large difference in blood quinine concentrations, no regimens revealed any pharmacodynamic difference. Although it has low bioavailability, the 8-mg/kg rectal regimen ensured a clearance of parasitemia that was as effective as parenteral treatments. Similarly, in Guinea-Bissau, complete therapeutic efficacy was reported for a single daily 12-mg/kg oral dose (11). Together, these results confirm that in West Africa, all these regimens ensured blood quinine concentrations far above the minimum effective concentration.

Such tolerance and pharmacodynamic outcomes require investigation in larger studies. To provide this information, a phase III study has recently been completed in Burkina Faso (H. Barennes, T. Balima-Koussoube, E. Kambole, A. Hema, A. Ouedraogo, T. R. Guiguemde, T. R. Sawadogo, and N. Nagot, abstract from the Third European Congress on Tropical Medicine and International Health, Acta Trop. 2002:S176). Nevertheless, rectal administration of 20 mg of quinine base per kg twice a day or 16 mg/kg three times a day is an alternative to parenteral administration when safe injections are not possible, especially for the treatment of potentially evolving forms of malaria in children.

 
We are grateful to the staffs of the Epidemiological Unit of the Centre Muraz (N. Diallo, I. Valea, N. Nagot, and P. Vandeperre) and the Malaria Unit (R. T. Guiguemde and F. Barennes-Rasoanandrasana) for their technical assistance. We deeply thank the medical, nursing, and laboratory staffs (B. Nacro) of the hospital Souro Sanou.

We also thank the Sanofi Company and the French Ministry of Foreign Affairs for their kind help and financial support of the study.

 
* Corresponding author. Mailing address: Service de Pharmacologie, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France. Phone: 33-1-45-21-35-92. Fax: 33-1-45-21-35-91. E-mail: eric.pussard{at}bct.ap-hop-paris.fr.

Top Abstract Text References

 

1
1. Assimadi, J. K., A. D. Gbadoe, O. Agbodjan-Djossou, S. E. Larsen, K. Kusiaku, K. Lawson-Evi, D. Redah, A. Adjogble, and A. Gayibor. 2002. Diluted injectable quinine in the intramuscular and intrarectal route: comparative efficacy and tolerance in malaria treatment for children. Med. Trop. 62:158-162. (In French.)
2
2. Barennes, H., F. Kahitani, E. Pussard, F. Clavier, D. Meynard, S. Njifountawouo, and F. Verdier. 1995. Intrarectal Quinimax (an association of Cinchona alkaloids) for the treatment of Plasmodium falciparum malaria in children in Niger: efficacy and pharmacokinetics. Trans. R. Soc. Trop. Med. Hyg. 89:418-421.[CrossRef][Medline]
3
3. Barennes, H., J. Munjakazi, F. Verdier, F. Clavier, and E. Pussard. 1998. An open randomized clinical study of intrarectal versus infused Quinimax for the treatment of childhood cerebral malaria in Niger. Trans. R. Soc. Trop. Med. Hyg. 92:437-440.[CrossRef][Medline]
4
4. Barennes, H., E. Pussard, A. Mahaman Sani, F. Clavier, F. Kahiatani, G. Granic, D. Henzel, L. Ravinet, and F. Verdier. 1996. Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria. Br. J. Clin. Pharmacol. 41:389-395.[CrossRef][Medline]
5
5. Barennes, H., H. Sterlingot, N. Nagot, H. Meda, M. Kaboré, M. Sanou, B. Nacro, P. Bourée, and E. Pussard. 2003. Intrarectal pharmacokinetics of two formulations of quinine in children with falciparum malaria. Eur. J. Clin. Pharmacol. 58:649-652.[Medline]
6
6. Barennes, H., F. Verdier, F. Clavier, and E. Pussard. 1999. Pharmacokinetics of Quinimax suppositories in children with malaria. Clin. Drug Investig. 17:287-291.
7
7. Barradell, L. B., and A. Fitton. 1995. Artesunate. A review of its pharmacology and therapeutic efficacy in the treatment of malaria. Drugs 50:714-741.[Medline]
8
8. De Boer, A. G., L. G. J. De Leede, and D. D. Breimer. 1984. Drug absorption by sublingual and rectal routes. Br. J. Anaesth. 56:69-79.[Free Full Text]
9
9. Hien, T. T., and N. J. White. 1993. Qinghaosu. Lancet 341:603-608.[CrossRef][Medline]
10
10. Iliadis, A., C. Brown, and M. L. Huggins. 1992. APIS: a software for model identification, simulation and dosage regimen calculations in clinical and experimental pharmacokinetics. Comput. Methods Programs Biomed. 38:227-239.[CrossRef][Medline]
11
11. Kofoed, P. E., F. Co, A. Poulsen, C. Cabral, K. Hedegaard, P. Aaby, and L. Rombo. 2002. Treatment of Plasmodium falciparum malaria with quinine in children in Guinea-Bissau: one daily dose is sufficient. Trans. R. Soc. Trop. Med. Hyg. 96:185-188.[CrossRef][Medline]
12
12. Krishna, S., T. Planche, T. Agbenyega, C. Woodrow, D. Agranoff, G. Bedu-Addo, A. K. Owusu-Ofori, J. Adabie Appiah, S. Ramanathan, S. M. Mansor, and V. Navaratnam. 2001. Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria. Antimicrob. Agents Chemother. 45:509-516.[Abstract/Free Full Text]
13
13. Krishna, S., and N. J. White. 1996. Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications. Clin. Pharmacokinet. 30:263-299.
14
14. Minker, E., and J. Ivan. 1991. Experimental and clinicopharmacological study of rectal absorption of chloroquine. Acta Physiol. Hung. 77:237-248.[Medline]
15
15. Pasvol, G., C. R. Newton, P. A. Winstanley, W. M. Watkins, N. M. Peshu, J. B. Were, K. Marsh, and D. A. Warrell. 1991. Quinine treatment of severe falciparum malaria in African children: a randomized comparison of three regimens. Am. J. Trop. Med. Hyg. 45:702-713.
16
16. Pussard, E., A. Bernier, E. Fouquet, and P. Bourée. 2003. Quinine distribution in mice with Plasmodium berghei malaria. Eur. J. Drug Metab. Pharmacokinet. 28:11-20.[Medline]
17
17. Sowunmi, A., and Salako, L. A. 1996. Effect of dose size on the pharmacokinetics of orally administered quinine. Eur. J. Clin. Pharmacol. 49:383-386.[CrossRef][Medline]
18
18. Van Hoogdalem, E. J., A. G. de Boer, and D. D. Breimer. 1991. Pharmacokinetics of rectal drug administration, part I. General considerations and clinical applications of centrally acting drugs. Clin. Pharmacokinet. 21:11-26.[Medline]
19
19. Warrell, D. A., M. E. Molyneux, and P. F. Beales. 1990. Severe and complicated malaria. Trans. R. Soc. Trop. Med. Hyg. 84:1-65.

---

Antimicrobial Agents and Chemotherapy, November 2004, p. 4422-4426, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4422-4426.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Barennes, H, Pussard, E (2006). Rectal quinine for malaria: Authors' reply. BMJ 332: 1216-1216 [Full Text]  
• Barennes, H., Balima-Koussoube, T., Nagot, N., Charpentier, J.-C., Pussard, E. (2006). Safety and efficacy of rectal compared with intramuscular quinine for the early treatment of moderately severe malaria in children: randomised clinical trial.. BMJ 332: 1055-1059 [Abstract] [Full Text]  

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pussard, E. Articles by Barennes, H. Search for Related Content PubMed PubMed Citation Articles by Pussard, E. Articles by Barennes, H.