Population pharmacokinetic and pharmacodynamic properties of intramuscular quinine in Tanzanian children with severe Falciparum malaria.

Although artesunate is clearly superior, parenteral quinine is still used widely for the treatment of severe malaria. A loading-dose regimen has been recommended for 30 years but is still often not used. A population pharmacokinetic study was conducted with 75 Tanzanian children aged 4 months to 8 years with severe malaria who received quinine intramuscularly; 69 patients received a loading dose of 20 mg quinine dihydrochloride (salt)/kg of body weight. Twenty-one patients had plasma quinine concentrations detectable at baseline. A zero-order absorption model with one-compartment disposition pharmacokinetics described the data adequately. Body weight was the only significant covariate and was implemented as an allometric function on clearance and volume parameters. Population pharmacokinetic parameter estimates (and percent relative standard errors [%RSE]) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 liters/h (6.50%), 16.7 liters (6.39%), and 1.42 h (21.5%), respectively, for a typical patient weighing 11 kg. Quinine exposure was reduced at lower body weights after standard weight-based dosing; there was 18% less exposure over 24 h in patients weighing 5 kg than in those weighing 25 kg. Maximum plasma concentrations after the loading dose were unaffected by body weight. There was no evidence of dose-related drug toxicity with the loading dosing regimen. Intramuscular quinine is rapidly and reliably absorbed in children with severe falciparum malaria. Based on these pharmacokinetic data, a loading dose of 20 mg salt/kg is recommended, provided that no loading dose was administered within 24 h and no routine dose was administered within 12 h of admission. (This study has been registered with Current Controlled Trials under registration number ISRCTN 50258054.)

Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies

<p>Abstract</p> <p>Background</p> <p>Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria.</p> <p>Methods</p> <p>Individual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of <it>Plasmodium falciparum </it>parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success.</p> <p>Results</p> <p>Artemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether.</p> <p>Conclusion</p> <p>Artemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy.</p

Characterization of a monoclonal antibody that neutralizes the hyaluronidase activity of Russell's viper venom.

Three monoclonal antibodies (WPN1, WPN2 and WPN3) raised against a partially purified fraction of Russell's viper venom (RVV) were characterized. All three monoclonal antibodies reacted with crude RVV when tested by ELISA, but only two (WPN1, WPN2) neutralized its hyaluronidase activity. WPN1 was the more potent and was effective at an antigen: antibody ratio of 1:3. Furthermore, WPN1 was shown to recognize only the 14,000 MW component of crude RVV. This has been identified in a previous study to be hyaluronidase. This antibody was also found to recognize some components of Calloselasma rhodostoma venom which also possesses potent hyaluronidase activity. The potential therapeutic role of antibodies that neutralize the hyaluronidase component of snake venoms should be investigated further

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether &gt; 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P = 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity was further increased; ED50 = 150 mg/kg/day (P = 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, presumably because the central nervous system is exposed transiently, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential

Antimalarial activity and interactions between quinine, dihydroquinine and 3-hydroxyquinine against Plasmodium falciparum in vitro.

The antimalarial activities of quinine, dihydroquinine (a natural impurity found in commercial pharmaceutical formulations of quinine) and 3-hydroxyquinine (the principal metabolite of quinine in humans) were tested both individually and in pairs against 5 strains of Plasmodium falciparum isolated from patients in Thailand. The median inhibitory concentrations (IC50) were similar for quinine (168 nmol/L, range 68-366), and dihydroquinine (129 nmol/L, range 54-324), and both were significantly lower than that of 3-hydroxyquinine (1160 nmol/L, range 378-3154) (P = 0.027). When these drugs were tested in combination, there was no evidence of synergy or antagonism, as determined by fractionary inhibitory indices and isobolograms. Quinine and its impurity, dihydroquinine, have equivalent antimalarial activities which are approximately 10 times greater than that of the metabolite 3-hydroxyquinine. These 2 compounds, which are not usually measured in specific drug assays, contribute to antimalarial activity after quinine administration

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether > 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P = 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity was further increased; ED50 = 150 mg/kg/day (P = 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, presumably because the central nervous system is exposed transiently, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential

Neuropathologic toxicity of artemisinin derivatives in a mouse model.

Intramuscular administration of high doses of artemether and arteether to experimental mammals produces selective damage to brain stem centers involved predominantly in auditory processing and vestibular reflexes. The relationship between clinical signs of neurotoxicity and neuropathologic toxicity was studied in the mouse. Intramuscular artemether (50-100 mg/kg/day for 28 days) caused dose-dependent neuropathologic damage to the brain stem. There was no pathologic evidence of neuronal death in mice receiving either oral artemether, or oral or intramuscular artesunate, in doses up to 300 mg/kg/day. The neurons in the lower brain stem trapezoid nucleus, the gigantocellular reticular nucleus, and the inferior cerebellar peduncle were the most sensitive to the toxic effects of artemether. All mice with neuropathologic changes also showed behavioral changes, whereas in some mice with gait disturbance, no corresponding histopathologic damage could be detected. Thus clinical assessment was a sensitive measure of neurotoxicity. There may be a reversible component to artemether neurotoxicity

Assessment of the neurotoxicity of oral dihydroartemisinin in mice.

High doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether, given by intramuscular injection to experimental mammals, produce an unusual pattern of selective damage to brainstem centres predominantly involved in auditory processing and vestibular reflexes. We have shown recently, in adult Swiss albino mice, that constant exposure either from depot intramuscular injection of oil-based artemisinin derivatives, or constant oral intake carries relatively greater neurotoxic potential than other methods of drug administration. Using the same model, oral dihydroartemisinin suspended in water was administered once or twice daily at different doses ranging from 50 to 300 mg/kg/day for 28 days. The neurotoxic potential of the oral dihydroartemisinin was assessed and compared to that of oral artemether and artesunate. Oral artemether, artesunate, and dihydroartemisinin had similar neurotoxic effects with no significant clinical or neuropathological evidence of toxicity at doses below 200 mg/kg/day. These data indicate that once and twice daily oral administration of artemether, artesunate and dihydroartemisinin is relatively safe when compared to intramuscular administration of the oil-based compounds

Therapeutic responses to antibacterial drugs in vivax malaria.

Some antibacterial drugs have antimalarial activity that can be exploited for the prevention or treatment of malaria. Monotherapy with tetracycline, doxycycline, clindamycin or azithromycin was assessed in 1995-98 in 92 adult patients in Thailand with Plasmodium vivax malaria. All patients recovered following treatment and the early therapeutic responses were similar among the 4 groups. The overall median fever clearance time was 57 h and the mean (SD) overall time to parasite clearance was 134 (48) h. Of 66 patients who completed a 28-day follow-up, reappearances of vivax infection occurred in 27 patients (41%) from all groups; delayed appearances of falciparum malaria occurred in 6 patients (9%), only from the azithromycin group. The overall mean (SD) time to reappearance of P. vivax was 23 (5) days and time taken for detection of falciparum malaria was 13 (4) days after starting treatment for vivax malaria. The 28-day cumulative cure rates of clindamycin (n = 12), tetracycline (n = 18) and doxycycline (n = 18) groups were similar (P > or = 0.14) and all were significantly higher compared to the azithromycin group (n = 18; P < or = 0.04). The intervals until vivax reappearance were also significantly shorter in the azithromycin group [mean (SD) = 21 (6) vs 25 (3) days, P < 0.05] suggesting that some of these were recrudescences. The apparent success rate (no subsequent appearances of either vivax or falciparum infection) was significantly lower for the azithromycin group (11%) compared to the other groups (34-78%; P < 0.01). In current antibacterial treatment regimens, short-course azithromycin has inferior antimalarial activity compared to clindamycin or the tetracyclines

Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether > 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P = 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity was further increased; ED50 = 150 mg/kg/day (P = 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, presumably because the central nervous system is exposed transiently, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential