Lack of fluconazole effects on human chemosensation.

OBJECTIVE: Drug effects on the function of smell and taste are occasionally mentioned in prescription information however, most originate from anecdotal reports without even distinguishing between gustatory or olfactory deteriorations. This includes the antifungal fluconazole. MATERIAL AND METHODS: In a randomized, placebo-controlled, double-blind, two-way crossover study, 12 healthy men and 9 healthy women (age 26.8 ± 3.7 years) took oral doses of 400 mg fluconazole or placebo once daily for 8 days. Gustatory and olfactory functions were tested before and after the treatment using clinically validated tests ("Taste Strips" and "Sniffin' Sticks", respectively). RESULTS: Baseline taste scores of 12.3 ± 2.2 and 12.5 ± 1.7 for the fluconazole and placebo conditions, respectively, corresponded to normative values. Similarly, baseline (pretreatment) composite olfactory TDI scores (odor "€œthreshold discrimination identification"€) of 35.0 ± 3.2 and 35.7 ± 4.3 for men and 34.8 ± 4.2 and 35.5 ± 2.8 for women during the fluconazole or placebo conditions, respectively, corresponded to normative values. Neither gustation nor olfaction was significantly affected by the fluconazole treatment. CONCLUSIONS: The present study provided a negative result regarding fluconazole effects contrasting, for example, with those of sildenafil in a comparatively powered study [1]. Up to the tested dose of 400 mg/d, fluconazole does not have general and reproducible effects on taste and smell in healthy humans. However, it was unlikely to detect rare disturbances with the present study cohort size, and, therefore, rare fluconazole side effects on human chemosensation, as occasionally reported, remain a possibility.

Necessity and risks of arterial blood sampling in healthy volunteer studies.

Arterial blood sampling is necessary when drugs such as the fast-acting opioid analgesic remifentanil exhibit relevant differences between arterial and venous blood concentrations. Arterial cannulation is generally considered to be clinically safe and has thus become a standard procedure in pharmacokinetic-pharmacodynamic assessments. However, rare cases of arterial occlusions have to be considered in risk-benefit assessments of arterial sampling in pharmacokinetic studies, especially when including healthy volunteers. In an actual case, arterial occlusion requiring surgical repair was caused by a factor V Leiden thrombophilia associated genetic variant F5 1691G>A (rs6025) and aggravated by a hypoplastic radial artery. Neither risk factor had been identified prior to enrolment by routine laboratory tests such as the prothrombin time (international normalized ratio), partial thromboplastin time and the clinical Allen's test of arterial function. Re-assessment of the necessity of arterial sampling showed that none of the potential alternatives, target concentrations of computerized infusions or venous concentrations during non-steady-state and steady-state conditions could provide the arterial concentrations. Relying on venous concentrations may result in erroneous pharmacodynamic parameters. Accurate pharmacokinetic-pharmacodynamic studies relying on precisely measured blood concentrations require serial sampling techniques during both steady-state and non-steady-state conditions. However, as illustrated by the presented case, incidents involving the generally safe procedure of arterial sampling are possible, although rare. To further minimize the risks, screening of subjects for prothrombotic risks and careful assessment of the suitability of the artery should be considered in pharmacokinetic studies requiring arterial cannulation.