Expert evidence: do you have all the facts?

As a practising expert witness, or an accident and emergency nurse considering the move into the challenging world of litigation, do you have all the facts about expert evidence to hand? What is your role in the proceedings? When could you be sued for the advice you give? Should you ever accept a case on a no-win, no-fee basis?

Pharmacokinetics and metabolism of allopurinol riboside.

There are no safe and effective oral drugs to treat leishmaniasis and Chagas' disease. The safety, pharmacokinetics, and metabolism of single and multiple oral doses of allopurinol riboside, an investigational antiparasitic agent, were evaluated in a randomized, double-blinded, placebo-controlled study in 32 healthy male volunteers, at levels up to 25 mg/kg q.i.d. for 13 doses. No significant toxicity was detected. Allopurinol riboside peaks in plasma 1.6 hours after administration, has an elimination half-life of 3 hours, and steady-state concentrations in the therapeutic range. However, in contrast to preclinical studies in dogs (plasma levels proportional to oral doses up to 200 mg/kg), we found that plasma levels were unexpectedly low and did not rise with increasing dose. Furthermore, allopurinol and oxypurinol (unanticipated metabolites) were detected at levels proportional to the dose of allopurinol riboside. We present a model that includes incomplete absorption, metabolism of residual drug by enteric flora, and absorption of bacterial metabolites to explain these findings in humans.

Atropine pharmacokinetics are affected by moderate hemorrhage and hypothyroidism.

Atropine is used both to treat a variety of clinical disorders and as an antidote to cholinesterase poisoning. While various conditions affect the physiologic responses to atropine, little is known of the pharmacokinetics of this drug except under resting conditions. Pharmacokinetic studies were performed in mongrel dogs under two experimental conditions, moderate hemorrhage and hypothyroidism, to determine whether im absorption and elimination of atropine (0.05 mg/kg body weight) were affected by changes in hemodynamic or metabolic status. Using a randomized, crossover experimental design, it was found that during hypovolemia the mean volume of distribution was reduced by 22% (2.50 +/- 0.62 vs. 3.21 +/- 0.63 L/kg), with no changes in peak serum level, total atropine availability, elimination half-life, or whole-body clearance. Hypothyroidism was associated with a significant increase in peak serum atropine concentration (26.4 +/- 3.9 vs. 20.6 +/- 4.9 ng/ml) and drug bioavailability (48.5 +/- 8.8 vs. 30.0 +/- 10.7 ng/ml.h), while the clearance was reduced by 39% (426 +/- 34 vs. 696 +/- 187 ng/ml.min). These results suggest that atropine kinetics are not altered appreciably during moderate hemorrhage. In hypothyroidism, alterations in atropine pharmacokinetics may warrant modification of drug dose and frequency of administration.

Effect of exercise in sheep on the absorption of intramuscular atropine sulfate.

In normal female sheep, we investigated effects of exercise on the absorption of atropine sulfate (0.02 mg/kg) given intramuscularly. The exercise regime consisted of treadmill running (20 min at 3-4 mph at 0 degrees grade) starting immediately after intramuscular atropine injection into the biceps femoris. Six normal female sheep received intramuscular atropine and 7-14 days later an identical intramuscular dose of atropine with exercise. Serum levels of atropine measured by radioimmunoassay were monitored over a 6-hour period. The time to peak concentration was significantly less with exercise than without, 2.9 +/- 2.1 and 13.7 +/- 5.4 min, respectively (p less than 0.005). In addition, peak serum atropine concentrations tended to be higher, 9.7 +/- 1.3 ng/ml with exercise versus 7.1 +/- 2.9 ng/ml without exercise; however, the difference did not attain statistical significance (p less than 0.08). This study demonstrates that exercise increases the early absorption of intramuscularly administered atropine sulfate.

American cutaneous leishmaniasis: a comparison of three sodium stibogluconate treatment schedules.

Thirty-six patients with American cutaneous leishmaniasis were randomized to receive intravenous sodium stibogluconate for 10 days at a dose of 600 mg antimony (Sb) per day by one of three schedules: once daily by rapid infusion (A), by continuous 24 hr infusion (B), or in divided doses every eight hours by rapid infusion (C). Patients not cured after initial treatment were rerandomized to one of the other treatment schedules. An additional 19 patients who were not part of the randomized study received standard (STD) sodium stibogluconate treatment (600 mg Sb once daily by rapid infusion for 10 days, identical with schedule A). In the randomized study, the overall cure rate after the first course of treatment was 64%, but was higher for schedule A (100%) than for B (50%) or C (42%) (P less than 0.01). Considering all courses of treatment, schedule A was more effective (94%) than B (53%) or C (43%) (P less than 0.01). Paradoxically, patients in group A had a higher cure rate than patients in group STD (42% after the first course of treatment and 51% when all courses of treatment were considered). Side effects were mild and well tolerated. Total side effects were more frequent in groups B + C (52%) than A + STD (23%) due to an increased incidence of subjective complaints (26% vs. 10%, P less than 0.05) in patients receiving other than once daily rapid infusion. We conclude that giving the same total amount of sodium stibogluconate in three divided doses or by continuous infusion offers no advantage over standard, once daily treatment of American cutaneous leishmaniasis.

Mefloquine failure in a case of falciparum malaria induced with a multidrug-resistant isolate in a non-immune subject.

In a volunteer with infection induced by injection of the mefloquine-sensitive, multidrug-resistant Vietnam Smith isolate of P. falciparum, parasitemia recurred following treatment with the candidate antimalarial drug enpiroline. Parasitemia also recurred after subsequent treatment with mefloquine and again after retreatment with the same drug. All recurrences were at the RI level. Parasite drug sensitivities determined by a semi-automated isotope microdilution method after the second and third recurrences revealed a progressive decrease in sensitivity to all arylaminoalcohols tested (halofantrine, enpiroline, and mefloquine). Decreased sensitivity persisted after 30 days of isolate culture. The parallel changes in parasite sensitivity to the synthetic arylaminoalcohols argue for development of drugs which are chemically dissimilar.

Evaluation of the 4-pyridinemethanol WR 180,409 (enpiroline) in the treatment of induced Plasmodium falciparum infections in healthy, non-immune subjects.

WR 180,409 (enpiroline) was administered to 22 non-immune subjects infected with the multi-drug resistant Vietnam Smith isolate of Plasmodium falciparum. It was curative in single day treatment regimens with a minimum curative dose of approximately 10 mg/kg body weight. At this dose level it was well tolerated and produced rapid clearance of parasitemia in every case.

Comparison of in vitro and in vivo antimalarial activities of 9-phenanthrenecarbinols.

Analysis of the antimalarial activity of a selected series of 17 9-phenanthrenecarbinols against cultured strains of Plasmodium falciparum and against P. berghei in mice following oral administration indicated that the rankings of activities within the series were influenced by substituents on the 9-carbinol and the route of administration. Compounds with alkylamino-alkyl groups were ranked as most active by an in vitro screening system which assayed activity against chloroquine-sensitive and chloroquine-resistant strains of cultured P. falciparum by the inhibition of uptake of radiolabelled hypoxanthine. There were few differences in ranking of activities between the two strains. Although there was a significant difference between activities of an erythro- and a threo-racemate, activities of the four optical isomers of this compound were comparable. Among the series, compounds with a 2-piperidyl substituent on the 9-carbinol were ranked most active by the oral route of administration as assayed by the cure rates of mice infected with P. berghei. Correlation of these observations with previously published data on the activity of these compounds against P. falciparum in Owl monkeys and P. berghei in mice following subcutaneous administration suggested that neither species of host nor strains of parasite significantly influenced the ranking of activities of this class of compound.

Evaluation of the antimalarial activity of the phenanthrenemethanol halofantrine (WR 171,669).

Halofantrine (WR 171,669) was administered to 27 nonimmune subjects infected with the multi-drug resistant Vietnam Smith strain of Plasmodium falciparum. It was also administered to three other subjects, one infected with the Cambodian Buchanan strain of P. falciparum, and two with blood-induced infection with the Chesson strain of P. vivax. It cured infections with all three parasites. Against the highly chloroquine-resistant Smith strain, it was curative in single day treatment regimens. The drug was well tolerated and produced rapid clearance of parasitemia in every case.

Pituitary and thyroid function in male cynomolgus monkeys.

In four male cynomolgus monkeys, serum thyroxine was 6.2 +/- 0.9 micrograms/dl, and triiodothyronine was 207 +/- 12 ng/dl (mean +/- SE). Kinetic studies using 131I-thyroxine and 125I-triiodothyronine showed that the disappearance of both hormones was non-linear and best fit a biexponential equation. The metabolic clearance rates and production rates for thyroxine were 21.5 +/- 0.6 ml/kg/day and 1.34 +/- 0.23 micrograms/kg/day, respectively, and T1/2(beta) = 29.6 +/- 2.0 hours. For triiodothyronine, the metabolic clearance rate was 156.6 +/- 12.0 ml/kg/day, the production rate was 0.33 +/- 0.04 micrograms/kg/day, and T1/2 (beta) was 13.3 +/- 1.3 hours. Basel serum thyrotropin levels in five euthyroid animals were 1.4 +/- 0.6 microU/ml and increased after thyrotropin-releasing hormone to 6.7 +/- 2.2 microU/ml. Serum prolactin was 5.8 +/- 0.7 ng/ml, and it increased to 26.6 +/- 4.5 ng/ml after thyrotropin-releasing hormone. Four animals received chronic dexamethasone therapy (1 mg twice daily for 5.5 months). While baseline and thyrotropin-releasing hormone stimulated thyrotropin values were lower (0.8 +/- 0.2 microU/ml and 3.2 +/- 0.5 microU/ml, respectively), these reductions were not significant.