Correlation between electrocardiographic changes, serum digoxin, and total body digoxin content.

Serial electrocardiograms and serum digoxin levels were obtained in four healthy volunteers receiving daily doses of digoxin, 0.25 mg for the first two weeks and 0.5 mg for two more weeks. We found a linear relationship between serum digoxin levels and the "PTQ index" (a function of the PR-interval, corrected QT-time, and T-wave depression). In 3 of the 4 subjects the correlation was statistically significant. The degree of linear correlation was improved when PTQ was correlated with the computer-calculated total body burden of digoxin.

Sodium salicylamide: relative bioavailability and subjective effects.

The bioavailability of sodium salicylamide (NaSAM) in solution of salicylamide (SAM) tablets was compared in 6 healthy human volunteers. Bioavailability was assessed by plasma level determinations of nonmetabolized salicylamide (free SAM) and salicylamide plus conjugated metabolites (total SAM) for 3 hr following oral doses of 0.65, 1.30, 1.95, and 2.60 gm of salicylamide. The availability of NaSAM was found to be superior to SAM and dose-dependent. Mean peak levels of free SAM and total SAM were higher and were reached earlier after NaSAM liquid than after SAM tablets. Significantly higher mean levels of free SAM were found at the 1.95 and 2.60 gm dose levels after NaSAM administration than after SAM. Mean total SAM concentration was significantly higher after NaSAM at all dosage levels. The sedative effects of salicylamide were assessed with a self-scoring questionnaire. Sedation seemed to increase with increasing dose of both NaSAM and SAM. The sedative response occurred earlier after NaSAM than after SAM. Side effects were minor and transient in nature, occurred at the higher dosage levels, and were predominantly lightheadedness and dizziness. Because NaSAM produces higher drug levels and has a more rapid onset of subjective effects, we conclude that it represents a potentially superior dosage form.

Mefloquine kinetics in cured and recrudescent patients with acute falciparum malaria and in healthy volunteers.

Mefloquine pharmacokinetics were compared in a randomized clinical trial in Thailand among patients with malaria and healthy volunteers. A single oral dose of 1500 mg mefloquine hydrochloride was administered to 11 patients and 5 volunteers and 750 mg was given to 16 patients and 5 volunteers. Efficacy was 82% for 1500 mg and 63% for 750 mg. In cured patients taking 750 mg mefloquine, peak plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) were significantly greater than in the patients for whom treatment failed (p less than 0.0005 and p less than 0.01, respectively), and plasma mefloquine levels were significantly higher from 8 hours to 18 days after treatment. Mefloquine AUC was reduced and variable in the presence of diarrhea. Compared with noninfected volunteers, clinically ill patients displayed a delayed time to reach peak concentration (p less than 0.01) and significantly higher mefloquine plasma levels in the first 2 days after administration of either the 750 mg or the 1500 mg dose. Mefloquine AUC was similar in patients with malaria and healthy volunteers. Because plasma levels increased in temporal relationship with clinical illness, mefloquine volume of distribution or clearance (or both) was reduced during the acute phase of illness.

Pharmacokinetics of an extended-dose halofantrine regimen in patients with malaria and in healthy volunteers.

The pharmacokinetics and tolerance of a 4.5 gm 7-day halofantrine loading dose regimen were evaluated in 10 Thai patients with malaria and in 10 noninfected volunteers. Halofantrine peak plasma concentrations and bioavailability on the first day of treatment were significantly lower in patients with malaria than in healthy volunteers. Halofantrine elimination half-life was significantly shorter in patients with malaria than healthy control subjects (9.5 versus 15.8 days). These data show a distinct effect of acute malaria on the absorption and elimination of the drug. In addition, marked intersubject and intrasubject variability in peak and trough halofantrine levels was observed, indicating variable drug absorption. This dosing regimen was effective and well tolerated, with mild transient diarrhea during the first few days of treatment in both groups. To produce consistently effective drug levels, the currently recommended dosing regimens may be suboptimal. Slow halofantrine elimination raises concern for induction of parasite resistance when the drug is used in endemic areas of the world.

Pharmacokinetic justification of antiprotozoal therapy. A US perspective.

Infections with parasitic protozoa have always been problems for the developing world and are becoming of greater importance to the developed world in this age of easy international travel. The major human protozoal diseases are summarised with an emphasis on their presentation in normal hosts and in immunocompromised individuals and current US drug treatment recommendations are discussed. Present antiprotozoal regimens are based either on a pharmacokinetic rationale or on clinical trial and error. Regimens based on trial and error include amphotericin B against leishmaniasis and arsenic against African trypanosomiasis. Regimens which are to some extent driven by pharmacokinetic or biochemical considerations include paromomycin and metronidazole against amoebiasis, sodium stibogluconate against leishmaniasis, halofantrine and mefloquine against malaria, dihydrofolate reductase (DHFR) inhibitors against Pneumocystis carinii and toxoplasmosis and aerosolised pentamidine against P. carinii pneumonia. The majority of pharmacokinetic studies have been performed only on agents which have some therapeutic activity against other diseases of the developed world. Despite the trend toward rational treatment regimens, no studies have been performed that permit optimisation of antiprotozoal treatment regimens on the basis of clinical conditions such as renal failure.

Disposition of the antimalarial, mefloquine, in the isolated perfused rat liver.

The disposition of mefloquine has been investigated in the isolated perfused rat liver (IPRL) preparation after the administration of [14C]mefloquine HCl (3.8 mg, 4 microCi, quinoline ring labeled). Mefloquine underwent avid hepatic uptake within 10 min of dosing. Also at this point, hepatic oxygen consumption was reduced markedly in four of the six IPRL preparations, but was restored completely by approximately 30 min post-dose. The drug concentration profile underwent a biexponential decline over the 4-hr study period, with a terminal T1/2 of 1.0 +/- 0.3 hr. The area under the perfusate plasma concentration/time curve (AUC0-infinity) was 4.0 +/- 1.8 micrograms.hr.ml-1. Mefloquine was a high clearance compound (956.0 +/- 390 ml/hr) with a large apparent volume of distribution (1416 +/- 819 ml) in the IPRL. Biliary excretion accounted for 7.5 +/- 6.5% of the dose. Mefloquine was quantitated by HPLC analysis as approximately half (3.3 +/- 1.8%) of biliary label, the remainder consisting of highly polar metabolites of mefloquine. By 4 hr, a total of 64.8 +/- 4.4% of the [14C] dose was recovered from the livers. Subsequent HPLC analysis revealed this to be mostly unchanged mefloquine. Subcellular fractionation of the homogenized livers revealed that 50.6 +/- 6.8% of the dose of mefloquine was located in the 10,000 g pellet. In summary, mefloquine was cleared rapidly from the IPRL and underwent avid hepatic uptake into the lipid-rich fractions of rat liver.

The disposition of ethiofos (WR-2721) in the isolated perfused rat liver.

We have investigated the disposition of ethiofos (20 mg, 4 microCi [14C]ethiofos) in the isolated perfused rat liver preparation to determine the hepatic contribution to the poor oral bioavailability of the drug. Ethiofos clearance (10.6 +/- 3.3 ml h-1) was only a small fraction (1.2 +/- 0.03%) of the perfusate flow rate. The elimination half-life was calculated at 7.1 +/- 1.9 h. The area under curve, AUC0-4 h, for ethiofos (2858 +/- 314 nM h ml-1) was not significantly different from that of 14C (3038 +/- 692 nM h ml-1) or total material convertible to WR-1065 (total WR-1065, 3324 +/- 612 nM h ml-1), indicating a low level of metabolism. The AUC0-4 h for free WR-1065 (37.5 +/- 23.3 nM h ml-1) was less than 2% of ethiofos. Biliary elimination of ethiofos, WR-1065, and 14C was below 1%. At 4 h postdose, 7.9 +/- 1.9% of the dose of radioactivity remained in the liver. Less than 1.5% could be identified as ethiofos (0.12 +/- 0.09%) or total WR-1065 (1.09 +/- 0.05%). Ethiofos, 14C, and total WR-1065 were approximately evenly distributed between the 10,000-g pellet and supernatant. However, significantly more ethiofos, WR-1065, and 14C were recovered from the 105,000-g supernatant compared with the pellet. In summary, both the metabolism and biliary elimination of ethiofos and its derivatives were sparing. Hence it is likely that in the rat, the contribution of the liver to the presystemic biotransformation and poor bioavailability of ethiofos is relatively minor.

Transdermal artelinic acid: an effective treatment for Plasmodium berghei-infected mice.

Artelinic acid, a derivative of the naturally occurring antimalarial artemisinin, has been incorporated into a gel suitable for transdermal administration. The formulation was tested for efficacy in Plasmodium berghei-infected mice for both curative and prophylactic properties by application to their partially denuded backs, beginning on days 3 and 0, respectively, after injection of parasitized erythrocytes. In the curative experiments, rapid elimination of the parasitemia and 60-day survival of five of five mice was achieved by dermal application of gel containing 0.9 mg of artelinic acid that was administered twice a day, beginning on day 3 after infection, for three days (total dosage of 270 mg/kg). In the prophylactic trials, the establishment of parasitemia was prevented and 60-day survival was achieved in five of five mice at a dose of 0.9 mg of artelinic acid administered twice a day, beginning on the day of inoculation, for two days (total dosage of 180 mg/kg). The transdermal medium, with or without drug, caused no topical or systemic toxicity.

Pharmacokinetics of UMF-078, a candidate antifilarial drug, in infected dogs.

The pharmacokinetics of the filaricidal benzimidazole compounds UMF-078 and UMF-289 were evaluated in beagle dogs experimentally infected with Brugia pahangi. Twenty-four infected microfilaremic beagles were selected and randomly allocated into 4 treatment groups of 6 dogs each: oral (PO) UMF-078, PO UMF-289 (the HCl salt form of UMF-078), intramuscular (IM) UMF-078, and untreated controls. Equivalent doses of 50 mg/kg of the free base were given twice a day for 3 days to the 3 groups of treated dogs. Oral absorption is rapid compared with IM dosing; the absorption half-life (K01-HL) for the IM treatment is approximately 14 hr compared with 1 and 2 hr for the PO regimen of salt and free base forms, respectively. The elimination half-lives (K10-HL) for the PO regimens are 13 and 15 hr for the salt and free base forms, respectively. Because of sustained absorption following IM dosing, the K10-HL is prolonged. In contrast to oral administration, IM dosing of UMF-078 provides sustained, relatively low plasma drug levels, with good tolerance and efficacy.

Efficacy and tolerance of extended-dose halofantrine for drug-resistant falciparum malaria in Thailand.

New treatments for malaria are urgently needed in areas such as Thailand where highly drug-resistant strains of Plasmodium falciparum are prevalent. Mefloquine is rapidly losing efficacy and conventional doses of halofantrine are infective. We therefore used pharmacokinetic stimulation to design an extended-dose halofantrine regimen and tested it in 26 soldiers stationed along the Thai-Cambodian border. Halofantrine was given after meals as three doses of 500 mg each at 4-hr intervals on the first day, followed by 500 mg a day for six days (total dose 4.5 g). Twenty-six soldiers treated with quinine-tetracycline for seven days (Q7T7) served as controls. There were no significant differences in efficacy between halofantrine and Q7T7 (P > 0.1) as assessed by cure rate (92% versus 85%), mean parasite clearance time (82 hr versus 81 hr), or mean fever clearance time (93 hr versus 99 hr). Halofantrine was better tolerated than Q7T7. The side effects score was lower (2 versus 11; P < 0.001), there were less days on which side effects occurred (2.0 days versus 5.5 days; P < 0.001), and fewer patients had adverse effects on every treatment day (4% versus 42%; P < 0.01). High-dose halofantrine is as effective and better tolerated than quinine-tetracycline for multidrug-resistant falciparum malaria.

Pharmacokinetics of antimony during treatment of visceral leishmaniasis with sodium stibogluconate or meglumine antimoniate.

5 patients with visceral leishmaniasis were treated with sodium stibogluconate (2 patients) or meglumine antimoniate (3 patients) given intramuscularly at a dose of 10 mg antimony (Sb) per kg body weight daily for 30 d. Blood samples were obtained at intervals during treatment and blood Sb concentrations measured by anodic stripping voltametry. The pharmacokinetics of both drugs were remarkably similar, with peak concentrations of approximately 10 mg/litre occurring 2 h after the initial dose. Most of the Sb was eliminated rapidly, but nadir Sb concentrations increased gradually during treatment from 0.04-0.08 mg/litre 24 h after the first dose to 0.19-0.33 mg/litre 24 h after the 30th dose. For both drugs, the data were best described by a two compartment, three term pharmacokinetic model representing an initial absorption phase with a mean half-life of 0.85 h, a rapid elimination phase with a mean half-life of 2.02 h, and a slow elimination phase with a mean half-life of 76 h. The slow terminal elimination phase may be related to in vivo conversion of pentavalent Sb to trivalent Sb, which could contribute to the toxicity associated with long-term high dose therapy.

Safety, tolerability, efficacy and plasma concentrations of diethylcarbamazine and albendazole co-administration in a field study in an area endemic for lymphatic filariasis in India.

Filariasis control programmes are moving towards a strategy of repeated single-dose mass treatment of endemic populations. Using a combination, such as albendazole (ALB) to diethylcarbamazine (DEC) gives both macrofilaricidal and anti-helmintic activity. However, the safety of the combination versus DEC alone should be established in field studies in large populations prior to incorporation into national programmes. The present study compared the safety, tolerability, and efficacy of single doses of DEC 6 mg/kg + ALB placebo with DEC 6 mg/kg + ALB 400 mg in populations living in two filariasis endemic villages in the district of Wardha in western India. The study was double blind, parallel group, and randomized. Safety and tolerability study were studied in males and females older than 5 years. Safety was assessed by monitoring if adverse events (AEs) over 5 days affected daily acivities. Subjects in the 2 treatment groups experienced insignificantly different effects on daily activities and the combination was shown to be safe. Efficacy was evaluated by microfilaraemia (Mf), immunochromatographic test (ICT) and ultrasonography (USG) at 0, 3, 6, and 12 months of follow up. The efficacy study enrolled 103 male patients (aged 18-50 years) in microfilariae positive, clinical disease and asymptomatic, amicrofilaremic groups. There was no significant difference in efficacy between groups at 12 months. Within the Mf positive group, significant differences were seen in microfilaraemia (P < 0.001) with both treatments, and in USG (P < 0.001 and P < 0.004 respectively), at 12 months. The present field study has shown the combination of DEC + ALB to be as safe as the single drug DEC and thus the combination can be put in use in the national filariasis control programmes. Both drugs were adequately absorbed. The study at present does not provide evidence for the greater efficacy of the combination at 12 months follow up. While the safety of the combination has been ascertained, the incorporation or otherwise of ALB into national programmes for greater efficacy must await results of studies with longer follow up.

A urine metabolic ratio of dextromethorphan and 3-methoxymorphinan as a probe for CYP3A activity and prediction of cyclosporine clearance in healthy volunteers.

Dextromethorphan (DM) is metabolized in the body to dextrophan (DT) and 3-methoxymorphinan (3-MM) by cytochrome P450 (CYP) 2D6 and 3A4, respectively, and cyclosporine (CsA) is a known substrate of CYP3A4. We attempted to determine if the urine metabolic ratio of DM:3-MM at various time intervals during 24 hours is predictive of CsA clearance in 11 healthy volunteers. Each subject took DM 30 mg orally, and serial urine samples were collected at 0-4, 4, and 4-24, and 0-24 hours. Subjects then were randomly assigned to receive either oral microemulsion CsA 5 mg/kg or intravenous CsA 1.5 mg/kg in a crossover fashion in a two-sequence pharmacokinetic study with a wash-out period of at least 7 days. A total of 17 blood samples were collected from each subject in the CsA pharmacokinetic study over 24 hours. Urinary DM, DT, and 3-MM were quantified by high-performance liquid chromatography (HPLC) with a fluorescence detector, and blood CsA concentrations were analyzed by HPLC with ultraviolet detection. All subjects were extensive metabolizers of CYP2D6 as determined by metabolic ratios of DM:DT (mean+/-SD 0.0255+/-0.048). There was no correlation between CYP2D6 and CYP3A4 (p=0.38). The metabolic ratios of DM:3-MM in any urine samples during the 24-hour collection period did not predict CsA pharmacokinetics, although the 0-24 hour sample had an unexpected positive correlation with CsA clearance (r2 = 0.38, p<0.0001). The correlation was similar for metabolic ratios of DM:3-MM with intravenous CsA clearance (r2 = 0.5, p<0.0001). Metabolic ratios of DM:3-MM based on 24-hour cumulative urine collection did not appear to have clinical utility in predicting CYP3A activity measured by CsA clearance.

Gas chromatographic assay of diethylcarbamazine in human plasma for application to clinical pharmacokinetic studies.

A sensitive and selective gas chromatography method using flame ionization detection was developed for the determination of diethylcarbamazine (DEC) in human plasma. DEC and the internal standard, 1-diethylcarbamyl-4-ethyl piperazine HCl (E-DEC), were extracted from human plasma after loading onto a conditioned C(18) solid phase extraction cartridge, rinsed with water and eluted with methanol. After evaporation under a stream of nitrogen and reconstitution in methanol, 3 microl were injected onto the GC system. Separation was achieved on a A Heliflex(R) AT-35 capillary column (length 30 m, internal diameter 0.32 mm). Gas flow rates were: hydrogen, 35 ml/min; carrier gas (helium), 1.5 ml/min, make-up gas (helium), 25 ml/min; and air 420 ml/min. The retention times of DEC and internal standard were approximately 5.5 and 7.28 min, respectively. The GC run time was 22 min. The assay was linear in concentration range 100-2000 ng/ml for DEC in human plasma. The analysis of quality control samples for DEC (120, 1000, 2000 ng/ml) demonstrated excellent precision with coefficients of variation of 4.5,1.3, and 1.6%, respectively (n=6). The method was accurate with all intra-day (n=6) and inter-day (n=12) mean concentrations within 4.3% from nominal at all quality control sample concentrations. DEC was found to be stable after 3 freeze-thaw cycles, and with storage at -20 degrees C for 12 weeks. The method is currently being used for pharmacokinetic studies of DEC in healthy volunteers.

The disposition of quinine in the rat isolated perfused liver: effect of dose size.

We have investigated the pharmacokinetics of both free and total quinine in the rat isolated perfused liver at three doses, 6.25, 12.5 and 25 mg. The plasma concentrations of free and total quinine decayed biexponentially over 4 h. However, on increasing dose, the terminal half-life of free and total quinine showed marked increases ranging from 12.4 +/- 3.7 min at 6.25 mg to 176.0 +/- 153 min at 25 mg (total quinine). Quinine clearance was reduced approximately by half as the dose was doubled. At 10 min post dosage, quinine extraction at the 6.25 mg dose (56 +/- 16.3%) was more than twice that of the highest dose (25 mg, 25.0 +/- 6.5%). Free quinine at the 6.25 mg dose was cleared at approximately 100% of perfusate flow, whereas at 25 mg, clearance was less than one fifth of that value. Unchanged quinine elimination in bile was low, with less than 1% of the parent drug being detected at the 12.5 and 25 mg doses. Relatively little parent drug was recovered from the liver at 4 h. At the 25 mg dose, less than or equal to 6% was recovered as parent drug. HPLC analysis revealed some polar metabolites of quinine in the bile and in the liver homogenates. Dose dependent kinetics of quinine were demonstrated in this study, as hepatic extraction of quinine decreased with increasing dose and input concentration.

The pharmacokinetics and bioavailability of dihydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats.

The pharmacokinetics and bioavailability of dihydroartemisinin (DQHS), artemether (AM), arteether (AE), artesunic acid (AS) and artelinic acid (AL) have been investigated in rats after single intravenous, intramuscular and intragastric doses of 10 mg kg(-1). Plasma was separated from blood samples collected at different times after dosing and analysed for parent drug. Plasma samples from rats dosed with AM, AE, AS and AL were also analysed for DQHS which is known to be an active metabolite of these compounds. Plasma levels of all parent compounds decreased biexponentially and were a reasonable fit to a two-compartment open model. The resulting pharmacokinetic parameter estimates were substantially different not only between drugs but also between routes of administration for the same drug. After intravenous injection the highest plasma level was obtained with AL, followed by DQHS, AM, AE and AS. This resulted in the lowest steady-state volume of distribution (0.39 L) for AL, increasing thereafter for DQHS (0.50 L), AM (0.67 L), AE (0.72 L) and AS (0.87 L). Clearance of AL (21-41 mL min(-1) kg(-1)) was slower than that of the other drugs for all three routes of administration (DQHS, 55-64 mL min(-1) kg(-1); AM, 91-92 mL min(-1) kg(-1); AS, 191-240 mL min(-1) kg(-1); AE, 200-323 mL min(-1) kg(-1)). In addition the terminal half-life after intravenous dosing was longest for AL (1.35 h), followed by DQHS (0.95 h), AM (0.53 h), AE (0.45 h) and AS (0.35 h). Bioavailability after intramuscular injection was highest for AS (105%), followed by AL (95%) and DQHS (85%). The low bioavailability of AM (54%) and AE (34%) is probably the result of slow, prolonged absorption of the sesame-oil formulation from the injection site. After oral administration, low bioavailability (19-35%) was observed for all five drugs. In-vivo AM, AE, AS and AL were converted to DQHS to different extents; the ranking order of percentage of total dose converted to DQHS was AS (25.3-72.7), then AE (3.4-15.9), AM (3.7-12.4) and AL (1.0-4.3). The same ranking order was obtained for all formulations and routes of administration. The drug with the highest percentage conversion to DQHS was artesunic acid. Because DQHS has significant antimalarial activity, relatively low DQHS production could still contribute significantly to the antimalarial efficacy of these drugs. This is the first time the pharmacokinetics, bioavailability and conversion to DQHS of these drugs have been directly compared after different routes of administration. The results show that of all the artemisinin drugs studied the plasma level was highest for artelinic acid; this reflects its lowest extent of conversion to DQHS and its slowest rate of elimination.

Comparative bio-availability characteristics of different brands of chloroquine available in Nigeria.

The disintegration, dissolution and bio-availability characteristics of six of the most popular brands of chloroquine used in Nigeria were determined in order to test the hypothesis that there are no significant differences among the different brands. The disintegration times of all the six brands ranged from 8.9 to 40.4 min while the dissolution times ranged from 17.5 to 60 min. All passed the U.S. Pharmacopoiea (USP) XX disintegration test. Bio-availability studies done on two brands, Avloclor (ICI) with the fastest dissolution rate and Pfizerquine (Pfizer) with the slowest dissolution rate, showed similar areas under the curve (AUC). Furthermore, their peak height concentration (Cmax) and time of peak height concentration (Tmax) did not show any significant differences. Consequently, statements about any of these six brands of cloroquine having a greater efficacy than the other may be pure conjecture.