Trial clinical

Four clinical phase 1 studies involving 72 healthy elderly subjects have been performed and have showed that administration of ZT-1 in humans seems to be safe and well tolerated. The incidence of possibly drug-related adverse events, in particular nervous system and gastrointestinal symptoms, was similar to placebo for doses up to 1.5 mg. An international multicenter phase II trial for dose finding and efficacy assessment, in mild-to-moderate AD patients, is underway in 28 hospitals in Europe. 

The initial assessment of the potential of ZT-1 to improve cognition showed that it could antagonize the cognitive impairment induced by scopolamine in healthy elderly volunteers. The study was conducted according to a randomized, placebo and positive-controlled, double-blind and crossover design. Donepezil was a positive internal control. 

Overall, ZT-1 reduced the cognitive impairments produced by scopolamine on tasks measuring attention, working memory, episodic secondary memory, and eye-hand coordination. These findings suggest that ZT-1 may be an effective symptomatic treatment for the cognitive deficits associated with AD. 

50% inhibitory concentration long-term retrievel Mini-Mental State Examination A-methyl-D-aspartate 

Pharmacological profile of huperzine A, a novel acetylcholinesterase inhibitor from Chinese herb. CNS Drug Rev., 1999, 5(3) 281-300. 

Clinical trials serve to assess the safety and efficacy of any potential new therapeutic intervention in its intended target species. In our context, an intervention represents the use of a new biopharmaceutical. Examples of other interventions could be, for example, a new surgical procedure or a novel medical device. Veterinary clinical trials are based upon the same principles, but this discussion is restricted to investigations in humans. Clinical trials are also prospective rather than retrospective in nature, i.e. participants receiving the intervention are followed forward with time. 

Clinical trials may be divided into three consecutive phases (Table 4.4). During phase I trials, the drug is normally administered to a small group of healthy volunteers. The aims of these studies are largely to establish  

During product development, many of the initial non-clinical studies were undertaken in GAA knockout mice (i.e. mice devoid of a functional GAA gene), which serves as an animal model for Pompe s disease. The mice proved useful in assessing the pharmacodynamic effect of Myozyme on glycogen depletion and helped establish appropriate dosage regimens. The mice were also used to evaluate pharmacokinetics and biodistribution of GAA following its administration at clinically relevant doses. 

Initial safety tests were carried out in beagle dogs and subsequently in cynomolgus monkeys. Single bolus i.v. doses of up to 100 mg kg-1 were used and were found to exert no negative effect upon general condition, blood pressure, heart or cardiovascular parameters, respiration rate or body temperature. No safety tests evaluating potential product effects upon the central nervous system were undertaken, as the protein is considered unlikely to cross the blood-brain barrier. 

Repeat dose pharmacokinetic studies were undertaken in Sprague-Dawley rats and in monkeys. Biodistribution studies were carried out in both normal and knockout mice, with the majority of product distributed to the liver. No specific studies on product metabolism or excretion were undertaken, as the protein is almost certainly degraded via normal protein degradation mechanisms. 

Clinical trials are studies to evaluate the effectiveness, pharmacokinetics, and safety of medications or medical devices by monitoring their effects on large groups of people. Clinical research trials may be conducted by government health agencies, researchers affiliated with a hospital or university, independent researchers, or private industry. The use of an approved medicinal product in nonapproved conditions (different administration route, dose, clinical indications, etc.) requires also a new clinical trial. 

All clinical trials must be carried out according to a protocol approved by an ethical committee and according to the GCP rules. Participants must be volunteers. Clinical trials with radiopharmaceuticals must be performed in suitable patients rather than in healthy people in order to avoid any unnecessary exposure to radiation. In addition, administrative authorization is needed in some countries, as well as other specific requirements. Only results obtained by authorized clinical trials may be used in support of a clinical indication for an application for marketing authorization. 

The conduct of clinical trials is regulated in all the countries, except Cypms. In Cypms, the policy of the Ministry of Health is not to permit clinical trials for experimental medical products. Multicountry clinical trials for products licensed in developed countries are undertaken in some institutions and regulated by ethics committees (Table 8.5). In these countries, approval of clinical trials is carried out either by the DRA, as in Estonia, Malaysia, Tunisia, Venezuela and Zimbabwe, or by ethics committees. When the DRA itself is responsible for control, information about the trials is processed centrally. In Tunisia, clinical trials form part of the registration process. Trials are requested, when deemed necessary, by the specialized committee charged with reviewing the new dmg. The trial proposal is then evaluated by the technical committee, and forwarded to the Health Minister for final approval. Cuba has a National Centre for the Coordination of 

Regulation of clinical trials through use of a specialized ethics committee at the trial site constitutes a decentralized approach. This approach is used in the Netherlands, where a local medical ethics committee at the site of the trial is responsible for the evaluation. 

In Australia, approval of clinical trials involves both the regulatory authority and an ethics committee. Under the Clinical Trial Exemption (CTX) scheme, a clinical trial proposal must first be evaluated by the TGA, and then approved by an ethics committee on-site. Under the Clinical Trial Notification (CTN) scheme, a trial is evaluated and approved by the local ethics committee, and then notified to the TGA. 

Differences in the systems used to regulate clinical trials in Australia and the Netherlands illustrate how the delegation of authority affects the ability of the central agency to monitor the working of the entire system. In Australia, all approved clinical trials must be notified to the TGA. There is no such reporting requirement for the MEB in the Netherlands. Information about the number and details of clinical trials conducted in the Netherlands is therefore not readily available to the MEB. 

Approving body Local ethics committees DRA N/A DRA regional ethics committees DRA Local medical ethics committees Specialized commission but approved by Min of Health NDA INH As part of MCAZ 

The overall objective of clinical trials is to establish a drug therapy that is safe and effective in humans, to the extent that the risk-benefit relationship is acceptable. The ICH process has developed an internationally accepted definition of a clinical trial as Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy.  

The process of conducting dinical trials for drug approval may be broken down into three consecutive phases of  

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The preclinical trials are performed in in vitro and animal studies to assess the biological activity of the new compound. In phase 1 of the clinical trials the safety of a new drug is examined and the dosage is determined by administering the compound to about 20 to 100 healthy volunteers. The focus in phase II is directed onto the issues of safety, evaluation of efficacy, and investigation of side effects in 100 to 300 patient volimteers. More than 1000 patient volunteers are treated with the new drug in phase 111 to prove its efficacy and safety over long-term use. 

Cling control agents Cbnical analyses Clinical chemistry Clinical performance Clinical trials Clinique aromatics Clinker... 

Human growth hormone, used as a human pharmaceutical, is approved for only one indication in the United States, treatment of growth failure owing to hGH deficiency, a condition known as pituitary dwarfism. However, clinical trials are under way to test its efficacy in Turner s syndrome, bums, wound healing, cachexia, osteoporosis, constitutional growth delay, aging, malnutrition, and obesity. 

Turner s Syndrome. Turner s syndrome is a genetic disorder of females characterized by short stature, nonfunctioning ovaries, and failure to develop secondary sexual characteristics. Several clinical trials in the United States, Europe, and Japan have demonstrated that hGH can accelerate... 

Clinical trials for r-IEN-y in RA indicated that the dmg is well tolerated (52). Consistent improvement in tender and swollen joint scores was observed, but a large number of patients were needed in the trial to show statistical significance for r-IEN-y treatment. In certain individuals, responses were remarkable. An additive effect between r-IEN-y and penicillamine was detected. Efficacy was lower when r-IEN-y was combined with gold therapy. Research is continuing. 

Acetyl-i-carnitine (4) is marketed in Italy for dementia as of this writing it is also in Phase III clinical trials in the United States and Europe. In a double-blind, placebo-controUed clinical trial over a one-year period involving 130 patients with clinically diagnosed AD, a slower rate of deterioration in 13 of the 14 outcome measures was observed in the dmg-treated group (28). Earfler smaller scale pilot studies in demented patients had also shown some improvement of various behavioral and cognitive functions (29). 

DuP 753 is an orally active AT receptor antagonist and as of this writing is in clinical trials as an antihypertensive (see Cardiovascularagents). AT-11 antagonists affect the brain RAS system to enhance ACh release offering the possibiUty that these agents may function as cognition enhancers. 

The first SRS-A antagonist, FPL-55712 (26) (149), was discovered before the stmctures of the leukotrienes were detemiined. Although this compound is relatively weak as an antagonist and suffers from a very short half-life in vivo, it played an important role both in leukotriene stmcture elucidation and as a model for later antagonists. In work stmcturaHy related to FPL-55712, LY-171883 was developed (27) (150). LY-171883 was evaluated in several clinical trials before development was stopped. Orally adrninistered, LY-171883 blocked slightly the response to aerosol LTD improved pulmonary function (FEV ) in mild asthmatics (151), decreased the sensitivity of asthmatics to cold air-induced bronchoconstriction (152), and significantly reduced the bronchoconstrictor response to inhaled antigen (153). However, in all these studies the beneficial effects were minimal. 

Certain neutral technetium complexes can be used to image cerebral perfusion (Fig. 4). Those in Figure 4a and 4b have been approved for clinical use. Two other complexes (Fig. 4c and 4d) were tested in early clinical trials, but were not developed further. An effective cerebral perfusion agent must first cross the blood brain barrier and then be retained for the period necessary for image acquisition. Tc-bicisate is retained owing to a stereospecific hydrolysis in brain tissue of one of the ester groups to form the anionic complex TcO(ECD) , which does not cross the barrier. This mechanism of retention is termed metaboHc trapping. 

A clinical trial to evaluate misoprostol as a protector of normal tissue during a course of XRT in cancer patients suggests a reduction in acute normal tissue injury (215). A randomized, prospective, double-blind study indicates that topical misoprostol, administered as an oral rinse 15-20 min before irradiation using conventional 2-Gy (200 rad) fractions, five days a week over 6—7 weeks, significantly protects the oral mucosa from radiomucositis, a frequently observed normal tissue complication during XRT for head and neck cancer (215). 

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