Experimental drugs

The term analeptics refers to convulsants and respiratory stimulants (i.e. central nervous system stimulants). They comprise a reverse group of agents (for example amphifrnazole and doxapram (respiratory stimulants) and strychnine, biculline and picrotoxin). Analeptics are mainly experimental drugs. Only amphifrnazole and doxapram are occasionally used for the treatment of acute ventilatory failure. 

This experimental drug is a derivative of myriocin. After phosphorylation FTY720 modulates chemotactic responses and lymphocyte trafficking, leading to reversible lymphocyte sequestration in secondary lymphoid tissues. It is in clinical trials for the treatment of multiple sclerosis. 

This is generally accepted as the term to describe the absorption distribution and metabolism of a drug in vivo and it is these factors which determine how quickly and how much of the administered drug can actually reach its site of action (in the CNS) and be maintained there for the required time (see Fig. 5.4). Experimentally drugs are... 

Khazan, N. The implication and significance of EEG and sleep-awake activity in the study of experimental drug dependence on morphine. In Ehrenpreis, S., and Neidle, A., eds. Methods in Narcot.i cs Research. New York Marcel Dekker, Inc., 1975. pp. 521-531. 

The effects of placebo treatment were even more dramatic than those obtained with the experimental drug. Once again the tumour masses melted away and Mr Wright remained symptom-free for two more months. Then he read an announcement by the American Medical Association concluding that the drug he thought he was getting was worthless . He died a few days later. 

Treatment — No specific antiviral therapy exists to treat Venezuelan equine encephalitis. Treatment is geared toward relieving headache or myalgia, controlling convulsions, and aiding breathing difficulties. Several experimental drugs (e.g., vaccines TC-83 and TC-84) have shown some promise in the treatment of this virus, but current data on their effectiveness in humans is insufficient.3... 

This protection-freedom dynamic is even more intensive when it comes to drugs that are being tested for use in pahents with terminal illnesses that have no other viable treatment options. In these situations, the FDA receives tremendous pressure to approve these drugs rapidly. The rationale is that the most serious risk of death from an experimental drug is no risk at all compared with the certainty of death in patients with a lethal disease. 

Regulations on experimental drugs for patients with serious diseases and no alternative therapies. 

These criteria set out the conditions under which a person may or may not be included in the trial. The criteria may include the disease type, medical history, age group, gender, and so on. It is necessary to set out the parameters for the criteria to enable meaningful analysis to be made for assessment of the safety and effectiveness of the experimental drug. Subjects are screened before commencement to ensure that they meet the recruitment criteria before being admitted to the trial. 

SCH 28191 (experimental drug) Probe 6. beta-carotene Probe 7. LDH isoenzymes Probe 8. HGH tryptic digest Probe 9. urea, thiourea Probe 10. tricyclic antidepressants Probe 11. avermectins... 

As a typical example, the separation of the enantiomeric separation for an experimental drug R209130 (Figure 7), a compound with three chiral centers, resulting in eight... 

FIGURE 16 Determination of the enantiomeric impurity (migration time = 6.102 min) of an experimental drug. At optimal conditions the detectability can be very good, even with the typical shortcomings of an UV detector in CE. 

VolSurf was also successfully applied in the literature to predict absorption properties [156] from experimental drug permeability data of 55 compounds [165] in Caco-2 cells (human intestinal epithelial cell line derived from a colorectal carcinoma) and MDCK cell monolayers (Madin-Darby canine kidney). In this interesting case, it was shown that models including counterions for charged molecules clearly show significantly better quality and overall performance. The final model was also able to correctly predict, to a great extent, the relative ranking of molecules from another Caco-2 permeability study by Yazdanian et al. ]166]. 

The rate-limiting step in the synthesis of the catecholamines from tyrosine is tyrosine hydroxylase, so that any drug or substance which can reduce the activity of this enzyme, for example by reducing the concentration of the tetrahydropteridine cofactor, will reduce the rate of synthesis of the catecholamines. Under normal conditions tyrosine hydroxylase is maximally active, which implies that the rate of synthesis of the catecholamines is not in any way dependent on the dietary precursor tyrosine. Catecholamine synthesis may be reduced by end product inhibition. This is a process whereby catecholamine present in the synaptic cleft, for example as a result of excessive nerve stimulation, will reduce the affinity of the pteridine cofactor for tyrosine hydroxylase and thereby reduce synthesis of the transmitter. The experimental drug alpha-methyl-para-tyrosine inhibits the rate-limiting step by acting as a false substrate for the enzyme, the net result being a reduction in the catecholamine concentrations in both the central and peripheral nervous systems. 

Free tryptophan is transported into the brain and nerve terminal by an active transport system which it shares with tyrosine and a number of other essential amino acids. On entering the nerve terminal, tryptophan is hydroxylated by tryptophan hydroxylase, which is the rate-limiting step in the synthesis of 5-HT. Tryptophan hydroxylase is not bound in the nerve terminal and optimal activity of the enzyme is only achieved in the presence of molecular oxygen and a pteridine cofactor. Unlike tyrosine hydroxylase, tryptophan hydroxylase is not usually saturated by its substrate. This implies that if the brain concentration rises then the rate of 5-HT synthesis will also increase. Conversely, the rate of 5-HT synthesis will decrease following the administration of experimental drugs such as para-chlorophenylalanine, a synthetic amino acid which irreversibly inhibits the enzyme. Para-chloramphetamine also inhibits the activity of this enzyme, but this experimental drug also increases 5-HT release and delays its reuptake thereby leading to the appearance of the so-called "serotonin syndrome", which in animals is associated with abnormal movements, body posture and temperature. 

Approximately 30 years ago, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression. Evidence in favour of this hypothesis was provided by the observation that the antihypertensive drug reserpine, which depletes both the central and peripheral vesicular stores of catecholamines such as noradrenaline, is likely to precipitate depression in patients in remission. The experimental drug alpha-methyl-paratyrosine that blocks the synthesis of noradrenaline by inhibiting the rate-limiting enzyme tyrosine hydroxylase was also shown to precipitate depression in patients during remission. While such findings are only indirect indicators that noradrenaline plays an important role in human behaviour, and may be defective in depression, more direct evidence is needed to substantiate the hypothesis. The most obvious approach would be to determine the concentration of noradrenaline and/or its major central... 

Most UK ethics committees will look for confirmation of the intention to apply the ABPl guidelines in the case of company-sponsored studies, even from non-member companies. Where the research is non-therapeutic, ABPl guidance provides for a contractual promise to be made to the volunteer to pay for injury sustained by reason of participation in the study (whether due to the experimental drugs used or to procedures required by the study protocol), irrespective of whether anyone conducting or responsible for the project was at fault. In therapeutic research, no such contractual relationship or obligation is required, and there are some limitations to the circumstances in which voluntary payment will be made. 

Sponsors are not required, as a matter of routine, to submit individual patient reports to the TGA of suspected adverse drug reactions occurring with use of the same product in another country, even if a trial is ongoing at Australian sites. However, the TGA requires that sponsors advise the Experimental Drugs Section of DSEB within 72 h of any significant safety issue which has arisen from an analysis of overseas reports or action with respect to safety taken by another country s regulatory agency. This advice must include the basis for such action. 

Ifosfamide is an experimental drug that is analogous to cyclophosphamide. Synonyms of this drug are goloxan and mitoxan. 

Novel and experimental drug treatments. A variety of alternative drug treatments have been used in OCD. Of those considered here, intravenous clomipramine is the only treatment supported by a reasonable degree of empirical evidence. Several open-label trials suggest that intravenous administration of clomipramine may be helpful in patients with OCD that is refractory to oral clomipramine (Fallon et al. 1992 Thakur et al. 1991 Warneke 1989]. 

We statistically summarize drug outcome studies, producing a bottom-line quantitative assessment of the difference between an experimental drug and placebo or other standard agent (see Drug Management later in this chapter). 

Equally critical to a properly designed study is sample adequacy (i.e., size and appropriateness). It is hard to make definitive conclusions with very small sample sizes (e.g., five per group) because variation is too great. The minimal sample size needed to make inferences also depends on how large the experimental drug-placebo effect size is (i.e., the larger the effect size, the smaller the sample needed). 

The effect size of a continuous variable is frequently expressed as the difference between the mean of the experimental minus the mean of the control group divided by the pooled standard deviation. For example, in Chapter 5, data from the National Institute of Mental Health collaborative study demonstrated that antipsychotic-treated patients averaged a 4.2-point increase on a 6-point improvement scale, whereas the placebo patients averaged only a 2.2-point increase (i.e., an average difference of 2 points). The standard deviation of these data was approximately 1.7, so in effect size units, the improvement was approximately 1.2 (i.e., 2.0 1.7) SD units. For discontinuous data, the effect size for a drug-placebo comparison is usually expressed as the difference between the percent improvement with the experimental drug and the percent improvement with placebo. 

From the perspective of clinical trial methodology, concurrent medications can create a dilemma for the investigator by complicating the interpretation of results. Intermediate rescue medications are often required, however, because mood stabilizers are relatively slow in their onset of action. Further, if rescue medications are avoided, this usually introduces the confound of dropouts before the experimental drug can be fully effective. When feasible, a reasonable compromise is the use of modest amounts of a benzodiazepine (BZD), such as lorazepam, only when necessary for a limited time (e.g., 7 to 10 days) into the active phase of treatment. This can reduce the number of nonresponding, highly agitated patients who may otherwise drop out of treatment and in a trial of several weeks, the initial lorazepam effect should have dissipated by the final assessments. 

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