Wash-out periods

Two studies have been performed so far on women with breast cancer complaining of hot flushes - neither showed an improvement (Table 4.4). Quella et al. (2000) did not show any reduction in hot flushes in breast cancer survivors using 150 mg of phytoestrogen in tablets. The study was a cross-over design and had two phases lasting only four weeks, which were not separated by a wash-out period thus a carry-over effect cannot be excluded. 

Besides the poor specificity of many of the assays used to determine plasma drug concentrations, another problem which has arisen from these studies has been the length of the "wash-out" period necessary before the patient is given the neuroleptic under investigation. As a result of the prolonged duration of blockade of dopamine receptors in the brain by conventional neuroleptics and their metabolites, it is necessary to allow a wash-out period of several weeks before the patients are subject to a pharmacokinetic study. This raises serious ethical questions. Perhaps with the advent of new imaging techniques it may be possible in the near future actually to determine the rate of disappearance of neuroleptics from the brain of the patient. This may enable the relationship between plasma concentration and clinical response to be accurately determined. 

Changing a patient from one MAOI to another, or to a TCA, requires a "wash-out" period of at least 2 weeks to avoid the possibility of a drug interaction. There is evidence to suggest that a combination of an MAOI with clomipramine is more likely to produce serious adverse effects than occurs with other TCAs. Regarding the newer non-tricyclic antidepressants, it is recommended that a "wash-out" period of at least 5 weeks be given before a patient on fluoxetine is given an MAOI this is due to the very long half-life of the main fluoxetine metabolite norfluoxetine. 

The FIA valve is connected after the pump, approximately 25 cm from the nebulizer to minimize dispersion (this is the shortest distance attainable between the valve and the DCP jet). When attempting a new procedure, a IS s wash-out period should be allowed between injections this was found to be adequate to minimize any memory effects . However, the time can be shortened to 1—2 s for most applications, once the optimal experimental conditions have been established. 

Serotonin syndrome is best prevented by not using serotonergic drugs in combination. Special care is needed when changing from an SSRI to an MAOI and vice versa. The SSRIs, particularly fluoxetine, have long half-lives and serotonin syndrome may occur if a sufficient wash-out period is not allowed before switching from one to the other. When changing... 

Typical patches of estradiol contain 50 micrograms, but there are important differences between the wanted and unwanted effects of the available products, because of the ways in which they are formulated. The wash-out period of estradiol after transdermal administration is about 6 weeks. Transdermal estrogens can also be supplemented periodically by an oral progestogen (222). New topical formulations of estrogens continue to be studied and... 

There was a significant rise in baseline serum prolactin concentration in 10 patients after they had taken risperidone for a mean of 12 weeks compared with 10 patients who were tested after a neuroleptic drug-free wash-out period of at least 2 weeks (1014). A non-significant increase in serum prolactin has also been observed in an open comparison of risperidone with other neuroleptic drugs in 28 patients (1015). However, in a meta-analysis of two independent studies (n = 404), prolactin was greatly increased by risperidone (mean change 45-80 ng/ml), a larger effect than with olanzapine and haloperidol (1016). 

We recently investigated whether the administration of a selective serotonin reuptake inhibitor, fluvoxamine, could interfere with the sleep patterns induced after TED. In this double-blind placebo-controlled cross-over study, 12 healthy male volunteers aged 18-40 years were assigned to two treatment conditions tryptophan or sham depletion and fluvoxamine or placebo. During each session, separated by a 2-day wash-out period, subjects took either fluvoxamine or placebo and either tryptophan... 

Three healthy male beagles receive an intravenous dose into a jugular vein or into the vena cephalica antebrachii (typically 1-5 mg/kg b.w.). After a wash out period dependent on the duration of excretion of the drug/metabolites (typically 4 weeks at minimum), the same animals are dosed orally by using a stomach tube (typical dose 10 mg/kg b.w.). Normally, 5-10 MBq/animal is a sufficient radioactive dose for a 14C-label, in case of 3H about 50 MBq/animal could be used. Up to 168 h after administration, blood, urine and feces are collected. At each collection time about 3.5 mL of blood are taken for radioanalysis (2-3 aliquots) and for processing plasma for subsequent radio- and bioanalysis in plasma (also 2-3 aliquots each). The plasma is aliquoted immediately after centrifugation without warm-up. At a few preselected time points additional blood is collected for metabolite investigations (about 5 mL). 

Rather, the persons should be randomised to two different treatments, placebo and active treatment one after the other, with a wash-out period between, the randomisation gives the random order of the treatments. By such a design effects e.g. due to season is randomly allocated to the groups. The advantage of the paired design is that each person serves as his own control, and the number of subjects in the trial is reduced compared with the un-paired trial. Among the disadvantages are that every time a person drops out the first measurement he/she cannot be included in the analysis. Furthermore, if the variation within individuals is comparable with that between individuals, extra power is not obtained. 

All SSRIs have common 5-HT agonistic effects and because of this, SSRIs have common interactions and side effects. SSRIs are potent inhibitors of serotonin reuptake by CNS neurons and may interact with other drugs such as monoamine oxidase inhibitors (MAOIs) or circumstances which cause serotonin release. A minimum 2 weeks wash-out period should be observed between stopping a MAOI and starting an SSRI. Conversely, a MAOI should not be started for at least 1 week after an SSRI has been stopped, 5 weeks after fluoxetine, and 2 weeks for paroxetine and sertraline. Escitalopram and citalopram are hypersensitive to each other. 

Kava is currently promoted for relief of anxiety, stress, and insomnia. Stress may be prolonged and difficult to cope with and affected individuals may suffer from insomnia. Kava has been promoted as an axiolytic agent with little risk for dependence or adverse reactions. An unblinded, comparative, crossover trial of kava (120 mg) and valerian (600 mg) was conducted, each agent administered for 6 weeks with a 2-week wash-out period between. This was followed with administration of a combination of the two compounds. Both stress and insomnia were measured regarding social, personal, and life... 

A single-dose cross-over pharmacokinetic bioequivalence study of an orally administered product with a long elimination half-life can be conducted provided an adequate wash-out period is used between admnistrations of the treatments. The interval between study days should be long enough to permit elimination of essentially all of the previous dose from the body. Ideally, the interval should not be less than five terminal elimination half-lives of the active compound or metabolite, if the latter is measured. Normally the interval between study days should not exceed 3-4 weeks. If the crossover study is problematic, a pharmacokinetic bioequivalence study with a parallel design may be more appropriate. 

Phenotyping could also be important for safety reasons, determination of sampling times and wash-out periods in cross-over design studies. 

When measuring the active metabolites wash-out period and sampling times may need to be adjusted to enable adequate characterization of the pharmacokinetic profile of the metabolite. 

Wash-out periods of no treatment introduce new difficulties with sudden cessation... 

A wash-out period, i.e., a minimum number of days between administration of each formulation, is needed in order to avoid influence of the previous administration on the plasma concentration profile of the following formulation. As a rule of thumb, the wash-out period should be at least five times the elimination half-life of the drug under investigation. 

Johnson [226] included 12 healthy volunteers in a double-blind cross-over EEG trial. In a randomized sequence, each subject took 2 x 300 mg per day of the Hypericum extract LI 160 for six weeks and placebo for the same period of time, with a two-week wash-out period in between. The resting EEG and evoked potentials were registered 2.5 hours after drug intake. 

Most commonly, a single dose of each of test and reference is given on particular days well separated by a wash-out period of at least five half-lives of the drug and a number of blood (or possibly urine) samples are taken until at least three half-lives of the drug have been passed or sometimes until the concentration has passed the limits of detection. These samples are analysed before breaking the blind and the concentration for a given time point is obtained for each individual. Summary statistics such as the area under... 

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