Therapeutic trials

Chemokines/Chemokine Receptor Based Therapeutics Trials and Tribulations... 

Beletsky V, Nadareishvili Z, Lynch J, Shuaib A, Woolfenden A, Norris JW, for the Canadian Stroke Consortium. Cervical arterial dissection time for a therapeutic trial Stroke 2003 34 2856-2860. 

The empiric use of a standard-dose (or double-dose) PPI as a therapeutic trial may be used in diagnosing GERD. This approach is less expensive, more convenient, and more readily available than ambulatory pH monitoring. Problems with this diagnostic approach include lack of a standardized dosing regimen and duration of the diagnostic trial. 

Patients presenting with normal esophageal mucosa on endoscopy may undergo 24-hour ambulatory pH testing or a therapeutic trial with a PPI to further confirm the diagnosis of GERD. 

Foster Development of Prophylactic and Antidotal Measures. The stimulation of laboratory and clinical research on prophylactic and treatment measures for many of the newer economic poisons is much needed at the present time. Considerable laboratory and animal work remains to be done before investigations can be undertaken. The therapeutic trials committee of the Council on Pharmacy and Chemistry of the AMA has had considerable experience in the organization of impartial clinical trials on remedial agents, and its knowledge and facilities would be offered freely in such matters. However, at the present time, the field of study is so broad that these investigations must be restricted to individual agents which show promise of wide acceptance and use. 

A variety of experimental therapeutic strategies have been tested in mutant SOD1 mice. Lines of mutant SOD1 mice have been used for pharmacological and genetic therapeutic trials [10,21,22,25,137-139]. Selected examples of these approaches are briefly described below. 

Age, calcium intake, hormonal status, exercise and vitamin status have all been implicated in the development of osteoporosis. Estrogen levels represent an important factor in skeletal calcium retention and homeostasis. In therapeutic trials in which post-menopausal women were given daily doses of estrogens, such therapy has been demonstrated to be partially effective in reducing the rate of bone resorption. However, this therapy has the concomitant hazard of endometrial cancer (10). Vitamin D and its hormones have been given considerable attention in the more recent studies. Without adequate dietary and tissue levels of such vitamins, calcium absorption and bone status will be impaired. 

Total Blood That May Be Taken from Patients. The total amount of blood that may be taken from a subject in most therapeutic trials should be limited to one unit (about 460 ml) per 8-week period. 

Surrogate endpoints, a subset of biomarkers, are laboratory measurements or physical signs used in therapeutic trials as a substitute for clinical endpoints expected to predict the effect of the therapy. A fully validated, surrogate endpoint predicts the clinically meaningful endpoint of a therapy consistently. ... 

At-MNDP 31-33, 36, 108), whose mechanism of intracellular localization is related to the presence of oncogenically expressed tumor-membrane alkaline phosphatase isoenzymes 42, 108), has been demonstrated strikingly effective in an animal tumor model 33, 34, 38, 39). It has also served as a concomitant analytical probe for identifying the intracellular locus of radiotherapeutic action of this class of drug by a-particle track autoradiography 33,106-109). Phase I and II human therapeutic trials are shortly envisaged 33, 34). 

Phase III. Formal therapeutic trials (randomised, controlled, in hundreds or thousands of patients) to determine efficacy and safety on a substantial scale comparison with existing drugs usually include two or more doses of test drugs usually an international programme. 

The statistical significance relates strictly to the conditions under which the trial was conducted and will tell how often a difference of the observed size could occur by chance alone if there is, in reality, no difference between the treatments. The most widely accepted level of probability in therapeutic trials is set at 5%,... 

The advent of a more active monitoring role by the sponsor and audits with the global framework of ICH GCP and other guidelines has significantly increased the quality of therapeutic trials sponsored by pharmaceutical companies. The new standards now also apply to trials conducted independently by individual clinicians. 

The ICF should be written in a language that can be understood by the average study subject.Simple words should be used wherever possible for example, stop instead of discontinue, avoid instead of abstain and cause instead of induce. Many study subjects will not understand technical words such as placebo and erythema. Measurements of volumes should be described in domestic measurement such as teaspoonfuT rather than in millilitres. For therapeutic trials ICFs should include a description or mention of alternative procedures or courses of treatment. 

The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorder. The treatment-related adverse events that most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances. 

Skeletal myoblasts are viewed as an attractive alternative by some [76]. The first therapeutic trials used skeletal myoblasts obtained under sterile conditions and local anesthesia from 0.5- to 5.0-g muscle biopsy specimens. Individual cells were isolated by digestion with trypsin and collagenase, washed to remove red blood cells and debris, plated, and cultured to obtain the numbers necessary for therapeutic use. 

To understand the context of these other techniques, one should put them in perspective. One can rank methods for obtaining information in order of increasing confidence that the conclusions are valid. The order would be a single memorable case, a series of memorable cases, and a series of consecutive cases. The control observations for these would be historical controls, either articulated by the observer or merely understood. The assumption with the use of historical controls is that the controls are comparable to the patients and that the outcome of the treated patients if not given the new treatment would be identical to the historical controls. Often initial therapeutic trials of new cancer drugs are done in a consecutive series of treated patients and compared to historical controls. In these studies, the controls are usually not articulated. The authors assume that the natural course of the disease is so predictable in these patients that change from the predicted course is due to the drug. The validity of this assumption must be carefully examined when one interprets any study that is a case series. 

Pathophysiologically, there is a macrocytic anaemia with megaloblastic haematopoiesis that occurs in the face of normal folate and vitamin B12 and is refractory to therapeutic trials of these two nutrients. Patients are characterized as having a preleukaemic syndrome, which is currently regarded by many as a neoplastic process arising in the haematopoietic stem cells that is analogous to early acute myeloblas-tic leukaemia. 

The MAOIs are as effective as the heterocyclic antidepressants and the newer agents, such as the SSRIs. However, at least two forms of life-threatening toxicity (hepatotoxicity and dietary tyramine-induced hypertensive crisis ) have been associated with their chronic use. For this reason, the MAOIs are not considered first-line agents in the treatment of depression. They are generally reserved for treatment of depressions that resist therapeutic trials of the newer, safer antidepressants. However, a new transdermal formulation of selegiline undergoing clinical trials demonstrates antidepressant efficacy without concerns of liver toxicity or dietary tyramine-induced hypertension. 

Hunt, R.D., Minderaa, R.B., and Cohen, D.J. (1985) Clonidine benefits children with attention deficit disorder and hyperactivity re-port of a double-blind placebo-crossover therapeutic trial. / Am Acad Child Adolesc Psychiatry 24 617-629. 

Berney, T, Kolvin, L, Bhate, S.R., Garside R.F., Jeans, J., Kay, B., and Scarth, L. (1981) School phobia a therapeutic trial with clomipramine and short-term outcome. Br J Psychiatry 138 110-118. 

Berney, T, Kolvin, I., Bhate, R.F., Carsioe, R.F, Jeans, J. Kay, B. and Scarth, L. (1981) School phobia a therapeutic trial with clomipramine and short—term outcome. Br J Psychiatry 138 110—118. Bernstein, C.A., Borchardt, C.M., Perwein, A.R., et al. (2000) Imip-ramine plus cognitive-behavioral therapy in in the treatment of school refusal./ Am Acad Child Adolesc Psychiatry 39 276—283. Bernstein, C.A., Crosby, R.D. Perwein, A.R., and Borchardt, C.M. 

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