A tale of two parasites: the comparative epidemiology of cryptosporidiosis and giardiasis.

New Zealand has a higher reported incidence of cryptosporidiosis and giardiasis than most other developed countries. This study aimed to describe and compare the epidemiology of these infections in New Zealand, to better understand their impact on public health and to gain insight into their probable modes of transmission. We analysed cryptosporidiosis and giardiasis notification data for a 10-year period (1997-2006). Highest rates for both diseases were in Europeans, children aged 0-5 years, and those living in low-deprivation areas. Cryptosporidiosis distribution was consistent with mainly farm animal (zoonotic) reservoirs. There was a dose-response relationship with increasing grades of rurality, marked spring seasonality, and positive correlation with farm animal density. Giardiasis distribution was consistent with predominantly human (anthroponotic) reservoirs, with an important contribution from overseas travel. Further research should focus on methods to reduce transmission of Cryptosporidium in rural areas and on reducing anthroponotic transmission of Giardia.

Tiagabine, a novel antiepileptic agent: lack of pharmacokinetic interaction with digoxin.

OBJECTIVE: To assess the possibility of any clinically relevant pharmacokinetic interactions between tiagabine, a novel antiepileptic drug, and digoxin. METHODS: Potential pharmacokinetic interactions between tiagabine and digoxin were investigated in an open-label, two-period cross-over study in healthy male volunteers. Thirteen volunteers, aged between 18 and 43 years, were randomised to receive digoxin (0.5 mg twice a day for 1 day, then 0.25 mg once a day for 8 days) either alone or co-administered with tiagabine (4 mg three times daily for 9 days). Following a 7-day washout period, volunteers crossed over to the other dosing regimen. Peak serum concentration, time to maximum serum, concentration, area under the serum concentration-time curve from zero to 24 h and steady state serum concentration were calculated for digoxin and compared between treatment groups. RESULTS: No statistically significant differences between treatment groups were observed for any of the derived digoxin pharmacokinetic parameters. The most common adverse events reported during digoxin alone and in combination with tiagabine were somnolence and headache; an overall greater frequency of adverse events was reported during combined treatment. Adverse events were generally mild in nature; no serious adverse events were reported. CONCLUSIONS: At the doses administered, there is no evidence of a pharmacokinetic interaction between digoxin and tiagabine in healthy male volunteers.

Absence of interaction between tiagabine, a new antiepileptic drug, and the benzodiazepine triazolam.

In a randomised, double blind, placebo-controlled, four-period cross-over study in 12 healthy volunteers, the potential pharmacodynamic and pharmacokinetic interactions between the new antiepileptic drug, tiagabine, and the benzodiazepine, triazolam, were investigated. A single dose of tiagabine HCl 10 mg did not enhance the sedative or cognitive effects of a single dose of the benzodiazepine triazolam 0.125 mg, although the time-course of the effects was prolonged. Furthermore, tiagabine did not produce any statistically significant effects on the pharmacokinetics of triazolam. Similarly, the pharmacokinetics of tiagabine were not modified by triazolam. Tiagabine was well tolerated when administered alone or with triazolam.

The pharmacokinetics of tiagabine in healthy elderly volunteers and elderly patients with epilepsy.

The pharmacokinetics of tiagabine after single-dose (8 mg) and multiple-dose (3 mg, three-times daily for four days) administration of tiagabine HCl were investigated in healthy elderly volunteers (n = 8; Group 1), elderly patients with epilepsy receiving at least one hepatic enzyme-inducing antiepileptic drug (AED) (n = 8; Group 2), and healthy young volunteers (n = 8; Group 3). Participants were matched by gender, age (Groups 1 and 2), alcohol intake, body weight, and whether they smoked tobacco. The pharmacokinetic parameters of tiagabine following single- and multiple-dose administration were similar in both healthy elderly and young volunteers except for a small but significant difference in the area under the concentration-time curve after multiple-doses (103 +/- 29 ng.hr/mL/mg in the elderly versus 72 +/- 20 ng.hr/mL/mg in younger participants). This is not expected to have any clinical relevance because of the large intersubject variability in this parameter. In contrast, and as expected, the pharmacokinetics of tiagabine were altered in the presence of enzyme-inducing antiepileptic drugs: Time to reach maximum plasma concentration, area under the concentration-time curve, and elimination half-lives were significantly lower (e.g. 39 +/- 13 ng.hr/mL/mg for AUC after multiple-dose) compared with corresponding values in the healthy volunteers. These findings suggest that adjusting the dose of tiagabine on the basis of the age of the patient is not necessary, although, irrespective of age, higher doses and/or more frequent administrations will be required in patients taking concomitant enzyme-inducing antiepileptic drugs.

Tolerability, safety and pharmacokinetics of single dose and multiple dosing of the selective D1 antagonist NNC 01-0687 in healthy subjects.

Selective dopamine D1-receptor antagonists have been shown to exhibit similar effects in animal models for antipsychotic action as the selective D2 antagonists. NNC 01-0687, a benzazepine with selective and high affinity to the D1-receptor, was well tolerated by healthy subjects allocated to double blind, placebo controlled studies. Complaints of moderate restlessness and drowsiness were reported after administration of 25 mg NNC 01-0687, indicating the dose to be the maximum tolerated single dose. The highest multiple dose level of a daily dose of 45 mg NNC 01-0687 administered t.i.d. for 14 days was assessed as safe and well-tolerated with few reports of adverse events. Some alanine aminotransferase (ALT) elevations appeared in both treatment groups (active and placebo) and no evident influence of NNC 01-0687 on the liver function could be derived. No statistically significant or clinically relevant effects were observed in haematological parameters, urinalyses, blood pressure, heart rate, ECG or plasma levels of prolactin, cortisol or growth hormone. The plasma drug concentration curves indicated a fast absorption with tmax at 0.5-1 h and an apparent elimination half-life of 3-4 h. Both AUC and Cmax appeared to be linearly correlated to the dose, indicating linear pharmacokinetics. With similar Cmax and AUC on day 1 and day 10 no accumulation was observed. When administered just after lunch, the Cmax was reduced by 50-60% and the tmax increased to 3 h, but without change of AUC.

Nonlinear multiple-dose pharmacokinetics of the dopamine reuptake inhibitor vanoxerine.

The human pharmacokinetics of vanoxerine (GBR 12909) were studied in 14 normal subjects with a multiple-dose regimen. In a crossover design, each subject received daily oral doses of 25, 75, and 125 mg for 14 days at each dose level with washout periods of 7 days duration. Drug concentrations in serum during and after dosing were estimated by an HPLC method sensitive to 2 nmol/L (corresponding to 1.04 ng/mL). Drug accumulation was observed during dosing at the two highest dose levels, but near steady-state conditions were attained within 9-11 days of dosing. Estimates of steady-state concentrations all showed statistically significant deviations from dose linearity in the form of disproportionately higher concentrations at higher dose levels than expected from drug concentrations in serum at lower doses. The nonlinear pharmacokinetics was most likely due to increasing bioavailability with dose. The mean elimination half-lives were 53.5 and 66.0 h at 75 and 125 mg/day, respectively, in accordance with the observed time to reach near steady-state conditions. These estimates were higher than previous estimates in less extensive studies.

CCNU, melphalan, methotrexate, and prednisone (CAMP) versus cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in the treatment of advanced breast cancer in postmenopausal women.

Sixty-nine postmenopausal patients with advanced breast cancer were randomized to receive treatment with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or CCNU, melphalan, methotrexate, and prednisone (CAMP). Response rate (partial and complete remission) was significantly higher with CMF (50%) than with CAMP (20%). Hematologic toxic effects were equally pronounced with the two combinations as were the other side effects with the exception of alopecia, which occurred most frequently with CMF.