Drugs early studies

Half-life can be readily determined from a plot of log plasma concentration versus time and was for many years considered to be the most important characteristic of a drug. Early studies examining drug disposition in disease states were compromised, by a reliance on half-life as a sole measure of disposition changes. It is now appreciated that half-life is a secondary, derived parameter that relates to and depends on the primary parameters of clearance (CL) and volume of distribution (E) according to the following relationship in Eq. (25) ... 

The earliest reports of controlled release steroids were those of Jackanicz (63), Yolles (64), Anderson (65), and Wise (66). Most of those early studies were based on poly[ (L+)-lactic acid). Implants and granular particles were fabricated with progesterone, norgestrel, and norethisterone. In vivo urinary excretion studies were conducted on [I Cjprogesterone beads (64). The reported results were somewhat questionable as only 20% of the original implanted drug could be accounted for. 

Many early studies of transmitter release depended on measuring its concentration in the effluent of a stimulated, perfused nerve/end-organ preparation. This technique is still widely used to study drug-induced changes in noradrenaline release from sympathetic neurons and the adrenal medulla. However, it is important to realise that the concentration of transmitter will represent only that proportion of transmitter which escapes into the perfusate ( overflow ) (Fig. 4.2). Monoamines, for instance, are rapidly sequestered by uptake into neuronal and non-neuronal tissue whereas other transmitters, such as acetylcholine, are metabolised extensively within the synapse. Because of these local clearance mechanisms, the amount of transmitter which overflows into the perfusate will depend not only on the frequency of nerve stimulation (i.e. release rate) but also on the dimensions of the synaptic cleft and the density of innervation. 

O DONAHUE has isolated a naturally occurring peptide from brain that can produce responses similar to PCP when administered to animals. The results are reminiscent of the early studies of the opiopeptides that interact with opiate receptors and produce effects like narcotic drugs when administered to animals. 

Methyldopa Preferred first-line therapy on the basis of long-term follow-up studies supporting safety after exposure in utero. Surveillance data do not support an association between drug and congenital defects when the mother took the drug early in the first trimester. 

Some patients, in particular those with genetic forms of hypercholesterolemia (Table 9-2), will require three or more drugs to manage their disorder. Regimens using a statin, resin, and niacin were found to reduce LDL cholesterol up to 75%.42 These early studies were conducted with lovastatin, so larger reductions would be expected with the more potent statins available today. 

All antidepressant drugs have some effects on sleep architecture. Suppression of REM sleep associated with the treatment of depression was such a consistent finding in early studies that it was seen as essential for the antidepressant action. 

Phenylropanolamine was initially believed to have a very low risk of side effects, and the FDA allowed it to be available over the counter, without a prescription. After some time, phenylpropanolamine became the active ingredient in many nonprescription diet pills, such as Acutrim , Dexatrim , and Protrim. Early studies demonstrated that the drug s main side effect was an increase in energy that sometimes led to insomnia or agitation. 

Powder flow is most frequently thought of as relevant to formulation development, and there are numerous references attempting to correlate any one of a number of measures of powder flow to the manufacturing properties of a formulation [34—40]. In particular, the importance of physical properties in affecting powder flow has been well documented. Research into the effect of the mechanical properties on powder flow has, however, been very limited. It is, of course, important to be able to determine and quantitate the powder flow properties of formulations. It is of equal importance, however, to determine the powder flow characteristics of bulk drug early in the development process (preformulation phase). Often, the preformulation or formulation scientist is constrained by time, materials, and manpower. Yet certainly the preformulation studies carried out should be meaningful. Well-defined experimental methods and procedures should be used the information generated should be reproducible and permit useful predictions to be made. 

The use of BRMs to treat human disease has its origins in the use of bacterial toxins to treat cancer by William B. Coley.73 These early studies resulted in the use of microbi-ally-derived substances such as BCG, Picibanil, carbohydrates from plants or fungi such as Krestin and Lentinan, other products such as Biostim and Broncho-Vaxom, as well as thymic extracts (Table 9.4). However, the lot-to-lot variation in the manufacture of these drugs has dampened enthusiasm. Equally, the focus on MOAs in drug development strategies has also dampened developmental efforts. The particulate nature of some BRMs can also result in pulmonary thrombosis and respiratory distress following i.v. injection. However, BRMs are commonly used to treat bladder cancer and derivatives of natural products are routinely used clinically. 

A landmark study reported that 40% of failures in clinical studies were due to PK problems.1-3 This led to the need to develop drug metabolism studies that could be performed on a compound before it was recommended for development. The early drug metabolism and pharmacokinetic (DMPK) studies were used to assess the ADME/PK properties of NCEs. The major pharmaceutical companies were very successful at setting up exploratory drug metabolism departments using various models. This led to an explosion of new higher throughput ADME/PK assays that provided medicinal chemists with the necessary tools to improve the ADME/PK properties of NCEs. 

Lin, J.H. and Rodrigues, A.D. 2001. In vitro models for early studies of drug metabolism. In Pharmacokinetic Optimization in Drug Research Biological, Physicochemical and Computational Strategies. Testa, B. et al., Eds., Wiley, New York, p. 217. 

Drug development is ideally a logical, step-wise procedure in which information from small early studies is used to support and plan later larger, more definitive studies. To develop new drugs efficiently, it is essential to identify characteristics of the investigational drugs in the early stages of development and to plan an appropriate development based on this profile. 

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