BACKGROUND:

Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers.
METHODS:

Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days.
RESULTS:

The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (C(max)) was 160-200 nM and after 6 hours, the effective concentration (C(eff)) was <150 nM.
CONCLUSION:

Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable C(eff) of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

Phenobarbital is commonly used to treat status epilepticus in resource-poor countries. Although a dose of 20 mg kg(-1) is recommended, this dose, administered intramuscularly (i.m.) for prophylaxis, is associated with an increase in mortality in children with cerebral malaria. We evaluated a 15-mg kg(-1) intravenous (i.v.) dose of phenobarbital to determine its pharmacokinetics and clinical effects in children with severe falciparum malaria and status epilepticus. Methods: Twelve children (M/F: 11/1), aged 7-62 months, received a loading dose of phenobarbital (15 mg kg(-1)) as an i.v. infusion over 20 min and maintenance dose of 5 mg kg(-1) at 24 and 48 h later. The duration of convulsions and their recurrence were recorded. Vital signs were monitored. Plasma and cerebrospinal fluid (CSF) phenobarbital concentrations were measured with an Abbott TDx FLx fluorescence polarisation immunoassay analyser (Abbott Laboratories, Diagnostic Division, Abbott Park, IL, USA). Simulations were performed to predict the optimum dosage regimen that would maintain plasma phenobarbital concentrations between 15 and 20 mg l(-1) for 72 h. Results: All the children achieved plasma concentrations above 15 mg l(-1) by the end of the infusion. Mean (95% confidence interval or median and range for Cmax) pharmacokinetic parameters were: area under curve [AUC (0, infinity)]: 4259 (3169, 5448) mg l(-1).h, t(1/2): 82.9 (62, 103) h, CL: 5.8 (4.4, 7.3) ml kg(-1) h(-1), Vss: 0.8 (0.7, 0.9) l kg (-1), CSF: plasma phenobarbital concentration ratio: 0.7 (0.5, 0.8; n= 6) and Cmax: 19.9 (17.9-27.9) mg l(-1). Eight of the children had their convulsions controlled and none of them had recurrence of convulsions. Simulations suggested that a loading dose of 15 mg kg(-1) followed by two maintenance doses of 2.5 mg kg(-1) at 24 h and 48 h would maintain plasma phenobarbital concentrations between 16.4 and 20 mg l(-1) for 72 h. Conclution:Phenobarbital, given as an i.v. loading dose, 15 mg kg(-1), achieves maximum plasma concentrations of greater than 15 mg l(-1) with good clinical effect and no significant adverse events in children with severe falciparum malaria. A maintenance dose of 2.5 mg kg(-1) at 24 h and 48 h was predicted to be sufficient to maintain concentrations of 15-20 mg l(-1) for 72 h, and may be a suitable regimen for treatment of convulsions in these children

To investigate the pharmacokinetics and clinical efficacy of intravenous (i.v.) and intramuscular (i.m.) lorazepam (LZP) in children with severe malaria and convulsions. METHODS: Twenty-six children with severe malaria and convulsions lasting > or =5 min were studied. Fifteen children were given a single dose (0.1 mg kg(-1)) of i.v. LZP and 11 received a similar i.m. dose. Blood samples were collected over 72 h for determination of plasma LZP concentrations. Plasma LZP concentration-time data were fitted using compartmental models. RESULTS: Median [95% confidence interval (CI)] LZP concentrations of 65.1 ng ml(-1) (50.2, 107.0) and 41.4 ng ml(-1) (22.0, 103.0) were attained within median (95% CI) times of 30 min (10, 40) and 25 min (20, 60) following i.v. and i.m. administration, respectively. Concentrations were maintained above the reported therapeutic concentration (30 ng ml(-1)) for at least 8 h after dosing via either route. The relative bioavailability of i.m. LZP was 89%. A single dose of LZP was effective for rapid termination of convulsions in all children and prevention of seizure recurrence for >72 h in 11 of 15 children (73%, i.v.) and 10 of 11 children (91%, i.m), without any clinically apparent respiratory depression or hypotension. Three children (12%) died. CONCLUSION: Administration of LZP (0.1 mg kg(-1)) resulted in rapid achievement of plasma LZP concentrations within the reported effective therapeutic range without significant cardiorespiratory effects. I.m administration of LZP may be more practical in rural healthcare facilities in Africa, where venous access may not be feasible.

Status epilepticus is common in children with severe falciparum malaria and is associated with poor outcome. Phenytoin is often used to control status epilepticus, but its water-soluble prodrug, fosphenytoin, may be more useful as it is easier to administer. We studied the pharmacokinetics and clinical effects of phenytoin and fosphenytoin sodium in children with severe falciparum malaria and status epilepticus. METHODS: Children received intravenous (i.v.) phenytoin as a 18 mg kg-1 loading dose infused over 20 min followed by a 2.5 mg x kg(-1) 12 hourly maintenance dose infused over 5 min (n = 11), or i.v. fosphenytoin, administered at a rate of 50 mg x min(-1) phenytoin sodium equivalents (PE; n = 16), or intramuscular (i.m.) fosphenytoin as a 18 mg x kg(-1) loading dose followed by 2.5 mg x kg(-1) 12 hourly of PE (n = 11). Concentrations of phenytoin in plasma and cerebrospinal fluid (CSF), frequency of seizures, cardiovascular effects (respiratory rate, blood pressure, trancutaneous oxygen tension and level of consciousness) and middle cerebral artery (MCA) blood flow velocity were monitored. RESULTS: After all routes of administration, a plasma unbound phenytoin concentration of more than 1 microg x ml(-1) was rapidly (within 5-20 min) attained. Mean (95% confidence interval) steady state free phenytoin concentrations were 2.1 (1.7, 2.4; i.v. phenytoin, n = 6), 1.5 (0.96, 2.1; i.v. fosphenytoin, n = 11) and 1.4 (0.5, 2.4; i.m. fosphenytoin, n = 6), and were not statistically different for the three routes of administration. Median times (range) to peak plasma phenytoin concentrations following the loading dose were 0.08 (0.08-0.17), 0.37 (0.33-0.67) and 0.38 (0.17-2.0) h for i.v. fosphenytoin, i.v. phenytoin and i.m. fosphenytoin, respectively. CSF: plasma phenytoin concentration ratio ranged from 0.12 to 0.53 (median = 0.28, n = 16). Status epilepticus was controlled in only 36% (4/11) following i.v. phenytoin, 44% (7/16), following i.v. fosphenytoin and 64% (7/11) following i.m. fosphenytoin administration, respectively. Cardiovascular parameters and MCA blood flow were not affected by phenytoin administration. CONCLUSIONS: Phenytoin and fosphenytoin administration at the currently recommended doses achieve plasma unbound phenytoin concentrations within the therapeutic range with few cardiovascular effects. Administration of fosphenytoin i.v. or i.m. offers a practical and convenient alternative to i.v. phenytoin. However, the inadequate control of status epilepticus despite rapid achievement of therapeutic unbound phenytoin concentrations warrants further investigation

We have investigated the effect of experimental malaria infection on rat cytochrome P450-mediated drug metabolism using ethoxyresorufin and metoprolol as probe compounds. Malaria infection caused a significant reduction in total intrinsic clearance of ethoxyresorufin in both low and high parasitaemia malaria compared with control (control 18.7 +/- 7.2; low parasitaemia 10.5 +/- 4.1; high parasitaemia 4.3 +/- 1.4 mL min-1). However, clearance of metoprolol was unchanged in malaria infection compared with control (control 2.7 +/- 1.2; malaria 4.0 +/- 1.7 mL min-1). The change in clearance of ethoxyresorufin was the result of a decrease in Vmax, with no apparent change in Km. There was no change in either Vmax or Km of metoprolol. These results indicate a possible isozyme-selective effect of experimental malaria.

To determine the population pharmacokinetics of artemether and dihydroartemisinin in African children with severe malaria and acidosis associated with respiratory distress following an intramuscular injection of artemether. METHODS: Following a single intramuscular (i.m.) injection of 3.2 mg kg-1 artemether, blood samples were withdrawn at various times over 24 h after the dose. Plasma was assayed for artemether and dihydroartemisinin by gas chromatography-mass spectrometry. The software program NONMEM was used to fit the concentration-time data and investigate the influence of a range of clinical characteristics (respiratory distress and metabolic acidosis, demographic features and disease) on the pharmacokinetics of artemether and dihydroartemisinin. RESULTS: A total of 100 children with a median age of 36.4 (range 5-108) months were recruited into the study and data from 90 of these children (30 with respiratory distress and 60 with no respiratory distress) were used in the population pharmacokinetic analysis. The best model to describe the disposition of artemether was a one-compartment model with first-order absorption and elimination. The population estimate of clearance (clearance/bioavailability, CL/F) was 14.3 l h-1 with 53% intersubject variability and that of the terminal half-life was 18.5 h. If it was assumed that artemisin displays "flip-flop" kinetics, the elimination half-life was estimated to be 21 min and the corresponding volume of distribution was 8.44 l, with an intersubject variability of 104%. None of the covariates could be identified as having any influence on the disposition of artemether. The disposition of dihydroartemisinin was fitted separately using a one-compartment linear model in which the volume of distribution was fixed to the same value as that of artemether. Assuming that artemether is completely converted to dihydroartemisinin, the estimated value of CL/F for dihydroartemisinin was 93.5 l h-1, with an intersubject variability of 90.2%. The clearance of dihydroartemisinin was formation rate limited. CONCLUSIONS: Administration of a single 3.2 mg kg-1 i.m. dose of artemether to African children with severe malaria and acidosis is characterized by variable absorption kinetics, probably related to drug formulation characteristics rather than to pathophysiological factors. Use of i.m. artemether in such children needs to be reconsidered

Convulsions are a common complication of severe malaria in children and are associated with poor outcome. Diazepam is used to terminate convulsions but its pharmacokinetics and pharmacodynamics have not been studied in this group. Accordingly, we carried out a comparative study of the pharmacokinetics of intravenous (i.v.) and rectal (p.r.) diazepam. Twenty-five children with severe malaria and a convulsion lasting >5 min were studied. Sixteen children received diazepam intravenously (i.v.; 0.3 mg kg−1) and nine rectally (p.r.; 0.5 mg kg−1). Plasma diazepam concentrations were measured by reversed phase high-performance liquid chromatography. The duration of convulsions, depth of coma, respiratory and cardiovascular parameters were monitored.   Median maximum plasma diazepam concentrations of 634 (range 402–1507) ng ml−1 and 423 (range 112–1953) ng ml−1 were achieved at 5 and 25 min following i.v. and p.r. administration, respectively. All patients except three (one i.v. and two p.r.) achieved plasma diazepam concentration >200 ng ml−1 within 5 min. Following p.r. administration, plasma diazepam concentrations were more variable than i.v. administration. A single dose of i.v. diazepam terminated convulsions in all children but in only 6/9 after p.r. administration. However, nine children treated with i.v. and all those treated with p.r. diazepam had a recurrence of convulsions occurring at median plasma diazepam concentrations of 157 (range: 67–169) and 172 (range: 74–393) ng ml−1, respectively. All the children in the i.v. and four in the PR diazepam group who had recurrence of convulsions required treatment. None of the children developed respiratory depression or hypotension.   Administration of diazepam i.v. or p.r. resulted in achievement of therapeutic concentrations of diazepam rapidly, without significant cardio-respiratory adverse effects. However, following p.r. administration, diazepam did not terminate all convulsions and plasma drug concentrations were more variable.

The pharmacokinetics of the schistosomicidal agent oxamniquine (6-hydroxmethyl-2-isopropylaminomethyl-7-nitro-1,2,3,4-tetra hydroquinoline) were studied in 8 (4 male, 4 female) New Zealand White rabbits and 5 female Wistar rats, following intravenous administration (15 mg/kg). The pharmacokinetic parameters (mean +/- SD) in the rabbit and rat, respectively, were as follows: plasma clearance, 65.5 +/- 33 and 17.2 +/- 5.7 ml/min/kg; steady-state volume of distribution, 7.9 +/- 4.5 and 2.1 +/- 0.5 l/kg; terminal elimination half-life, 1.8 +/- 0.3 and 1.8 +/- 0.9 h. Oxamniquine appeared to be widely distributed in both species, although significantly higher in the rabbit. Similarly, plasma clearance was significantly higher in the rabbit. Using reported estimates of liver blood flow and fractions excreted unchanged in urine of the rabbit and rat, calculations based on blood clearances indicated that oxamniquine has a low hepatic extraction ratio (0.2) in the rat and an intermediate hepatic extraction ratio (0.6) in the rabbit. From separate experiments, however, hepatic extraction appeared to be low in the rabbit, suggesting that oxamniquine disposition is probably broadly similar in both rabbit and rat

Elevation of plasma digoxin levels following concurrent administration of nifedipine have previously been reported. The mechanism for this interaction has not been fully explained, but may include a reduction in volume of distribution of digoxin and/or reduction in the renal or non-renal clearance of digoxin by nifedipine. The end result is probably an elevation of plasma concentrations of free (pharmacologically active) digoxin, which may lead to manifestation of side effects of digoxin. This communication highlights the possible pharmacokinetic basis of the reported digoxin-nifedipine interaction.