Short-Term Studies

Some of the most difficult problems in defining expressions used in the GLP Principles can be seen as originating from the wide diversity of study types that are to be covered by these Principles. One of the most hotly debated issues has been, and still is, the problem of short-term studies . 

The expression Short-Term Studies encompasses in itself such a wide variety of study types that it is indeed very difficult, if not impossible, to arrive at a comprehensive list of short-term studies, let alone a meaningful, all-embracing and clear-cut, but nevertheless concise definition. The revised OECD Principles could thus do no better than to define Short-Term Studies as studies of short duration with widely used, routine methods , a definition which still leaves the expression short duration open to interpretation. 

As an aside This latter point even should make it advisable to treat biological studies differently from physical-chemical ones with regard to the application of the provisions for short-term studies. Indeed the Consensus Document on short-term studies (OECD No. 7, 1999) started to differentiate these two types without, however, carrying this principle fully through. 

One may consider, for instance, the determination of a melting point as a truly short-term study, because the whole experimental activity is terminated within a few minutes, and nobody would object to calling such a study short-term . But what about an environmental fate study in a lysimeter There the test item is applied to the test system (an activity taking a few minutes), then the whole system is left undisturbed for two years, after which the distribution of the test item in the column of soil is determined, again an activity of a few days at most. Is this a two year, long-term study, or has it to be labelled short-term , because for 99.9 % of the time the test system is just left alone with no experimental activity whatsoever occurring  

For this reason it is certainly more useful not to become fixed exclusively on the issue of defining short in precise time of duration terms, or on editing a comprehensive listing of Short-Term Studies , but rather to concentrate on two pertinent questions  

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Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

Ibid, Toxicity ofEPIKOTE 828 Results ofPreliminaj Short-Term Studies, SheU Report TLGR.0009.77. SheU Chemical Corp., Houston, Tex., 1977. 

Danner SA, Carr A, Leonard JM, Lehman LM, Gudiol F, Gonzales J, Raventos A, Rubio R, Bouza E, Pintado V et al (1995) A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease, European-Australian Collaborative Ritonavir Study Group, N Engl J Med 333 1528-1533... 

Pure paper-based data collection systems are most suitable for small and short-term studies. Their advantages are that no computer hardware or software is needed at the participating sites because data are recorded manually on paper forms that are transferred to the centralized location in batches. A major drawback is that participating sites do not have real-time access to their data because no database is created locally. However, both hardware and software are needed at the centralized location for the data management system. The type of hardware and software used is determined by the configuration of the centralized computer. The most commonly used platforms include Open VMS, Unix, or PC, and one of the most widely used software packages is SAS [16]. 

A final report should be prepared for each regulatory study. In the case of short-term studies, a standardized final reporf accompanied by a sfudy-specific extension may be prepared. Reports of Principal Investigators or scientists involved in the regulatory study should be signed and dated by them. They should contain a Principal Investigator statement and QA statement if the Principal Investigator is not linked to the Study Director organization. 

Leukotriene modifiers (e.g., zafirlukast and montelukast) have not been adequately evaluated in COPD patients and are not recommended for routine use. Small, short-term studies showed improvement in pulmonary function, dyspnea, and quality of life when leukotriene modifiers were added on to inhaled bronchodilator therapy.27,28 Additional long-term studies are needed to clarify their role. 

It is very easy to understand that attempting to design and conduct research trials to ascertain the effect of one or multiple changes on production, economics, and GHG emissions from a dairy production system would be expensive and time consuming. Therefore, the use of whole farm models, with short-term studies for validation, is an attractive alternative. The integrated... 

Neurotoxicity. Clinical signs indicative of disturbances of the nervous system in exposed humans have been well documented in short-term studies at high doses and appear to be reversible. These effects are characteristic of cyanide toxicity. Animal studies confirm findings in humans. In longer-term studies, effects on the nervous system have also been reported, but it is not certain if these effects are permanent or reversible following termination of acrylonitrile exposure. 

Kwabiah AB, Stoskopf NC, Palm CA, Voroney RP, Rao MR, Gacheru E (2003) Phosphorus availability and maize response to organic and inorganic fertilizer inputs in a short term study in western Kenya. Agric Ecosyst Environ 95 49-59... 

Chu I, Villeneuve DC, Becking GC, et al. 1980a. Short-term study of the combined effects of mirex, photomirex, and Kepone with halogenated biphenyls in rats. J Toxicol Environ Health 6 421-432. 

Hickey AJ, Carcia-Contrenas L (2001) Immunological and toxicological implications of short-term studies in animals of pharmaceutical aerosol delivery to the lungs relevance to humans. Crit Rev Ther Drug Carrier Syst 18 387-431. 

When developing a method, it is very important to have the intended use of the method clear in mind. Is the method to be transferred to a QC lab for use year after year, or is it only intended for a short-term study by experienced CE specialists If a QC method is intended, often the more simple the BGE composition, the more robust the method. This means that a balance has to be found between a simple and robust BGE and sufficient separation, which can be quite difficult at times. But often it proves that the time spent on this process is worth it in the end. 

Antidepressants. Short-term studies of desipramine and fluoxetine indicate that both medications reduce binging in patients with BED. In addition, fluoxetine-treated patients may also experience a modest reduction in weight during short-term treatment. However, this early weight loss with fluoxetine may not be sustained despite continued treatment. 

Non-clinical health and environmental safety study Short term study Study plan... 

A short-term study of guinea pigs exposed to zinc oxide fume 3 hours/day for 6 days at the threshold limit value (TLV) of 5mg/m revealed pulmonary function changes and morphologic evidence of small airway inflammation and edema. Pulmonary flow resistance increased, compliance decreased, and lung volumes and carbon monoxide diffusing capacity decreased. Some of these changes persisted for the 72-hour duration of postexposure follow-up. 

Suicidaiity in chiidren and adoiescents Antidepressants increased the risk of suicidal thinking and behavior (suicidaiity) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone... 

Suicidality in children and adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of trazodone or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Trazodone not approved for use in pediatric patients (see Clinical worsening and suicide risk and Children sections in Warnings). 

Similarity to TCAs Cyclobenzaprine is closely related to the TCAs. In short-term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses greater than those recommended, some of the more serious CNS reactions noted with the TCAs have occurred. Pregnancy Category B. 

Absorption, Distribution, Metaboiism, and Excretion. There is relatively little quantitative information on the systemic absorption of inhaled carbon tetrachloride in animals and humans, with estimates ranging from 30% to 60% (Lehmann and Schmidt-Kehl 1936 McCollister et al. 1951). In order to confirm the dose absorbed during inhalation exposures to carbon tetrachloride, it would be useful to determine the systemic uptake of carbon tetrachloride in additional animal experiments, with special attention to concentration- and time-dependency of absorption. It may be useful to conduct short-term studies of the relative absorption, disposition, and toxicity of inhaled versus ingested carbon tetrachloride. Such studies can yield information pertinent to route-to-route extrapolation and may be more economical than conducting a 2-year inhalation cancer bioassay of carbon tetrachloride. 

The FDA has made it clear that the duration of the study and the place where the study is conducted do not determine whether or not the study is GLP-regulated. Thus, the GLPs apply to short-term studies (e.g., median lethal dose studies and irritation studies) as well as long-term studies that meet all of the above criteria, and the GLPs apply to such studies whether conducted in a manufacturer s lahora-tories, in a university laboratory, or at a contract or subcontract facUity. The FDA expects GLP compliance for studies conducted in foreign countries as well as for those conducted within the United States. 

Identification other than a cage card is not required for short-term studies in which an animal is never taken from and returned to its cage during the course of a study. The preamble ( I 35) to the GLP revisions of 1987 [4] also indicates that when animals are housed individually in cages. 

The use of certified feeds for short-term studies is probably not justified unless a laboratory maintains only stocks of certified feeds to ensure that such feeds are used in longer-term studies. Such a policy also eliminates the need to maintain inventories of two t5T>es of feed for each species of animal. 

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