Effective dose definition

The result of the Phase II trial is information needed to determine the effective dose and the dosing regimen of frequency and duration. Specihc chnical endpoints or markers are used to assess interaction of drug and disease. There are two types of markers definitive and surrogate. For example, in the case of cancer or hypertension, the definitive markers are mortality and stroke, respectively, and the surrogate markers may be tumor size, or cancer-associated proteins p53, TGF-a in the case of cancer, and blood pressure or cholesterol level in hypertension. Statistical analysis is carried out to evaluate the... 

Russia remains secretive about this operation. Reporters learned that they drilled holes in the floor and used vents high on the wall to pump gas into the theater. Regrettably, however, they were unable to learn the precise nature of the gas, beyond the admission by a Russian scientist that it was a derivative of Fentanyl. Several highly potent drugs fit that definition, including carfentanil, sufentanil, alfentanil, remifentanil and etorphine. Any of these can produce anesthesia, lasting from minutes to hours. A Russian medical authority later added that they used 5x the effective dose in order to guarantee a rapid effect on the terrorists. It is not clear exactly what this means. 

Although they are not extensive, the data of Punte et al.l 2 suggest that nonanoyl morpholide Is less toxic than CN or DM. Nonanoyl morpholide appears more irritating than CN or DM, but may have less persistent effects. No definitive Information is available on the possibility of long-term effects of exposure to nonanoyl morpho-llde. However, given the available information on nonanoyl morpholide and the short-term low-dose exposures of Edgewood subjects to It, the Committee believes that long-term health effects on the subjects are unlikely. 

Toxicology studies are conducted to define the safety profile of a candidate and include definition of the no-toxic-effect dose, MTD, potential organs of toxicity, and potential biochemical markers to detect and track toxic events. Most developmental compounds that do not become therapeutic products have unacceptable toxicity in animals or humans. Before the definitive toxicology studies needed to support an IND submission are initiated, a number of animal experiments can be conducted to characterize the potential toxicity of the candidate. These early toxicology evaluations are usually conducted in the same species as used in pharmacology evaluations. As mentioned earlier, the lowest dose that has no toxicity or an acceptable level of toxicity is compared with the dose that gives the desired pharmacologic response in the same animal species to obtain a therapeutic ratio or index for that species. 

The human data, as well as the animal studies indicate that cannabinoids may ameliorate some symptoms of MS. Unfortunately, a definitive large-scale study has yet to be performed. Such a study should take into account that (a) the placebo effect in MS is very high (b) the effective doses recorded are close to, or identical with the doses that cause cannabimimetic effects (c) cannabis (marijuana, hashish) is obviously not identical to zf9-THC, and that other constituents may synergize THC action (d) smoking cannot be compared with oral administration, and (e) the anal route of administration [141] may be a preferred one. 

There is currently no definitive role for adjuvant XRT in colon cancer because most recurrences are extrapelvic and occur in the abdomen. Although local recurrence and debilitating pelvic pain are uncommon, a subset of patients with T3 or T4 tumors located in the cecum, hepatic and splenic flexures, and sigmoid are at increased risk of local recurrence and may benefit from postoperative XRT and chemotherapy. Early trials using effective doses of whole abdominal XRT were limited by considerable toxicity. However, results from studies combining abdominal XRT plus fluorouracil are promising. To date, postoperative local XRT may reduce the risk of local recurrence and improve survival compared to adjuvant chemotherapy alone, but should only be considered for select patients with colon cancer. ... 

After oral ingestion of hexavalent compounds, ascorbic acid has been suggested to assist the conversion of hexavalent to less toxic trivalent compounds. While no definitive studies exist, the treatment is benign and may be helpful. In animal studies the effective dose was 2-4 g of ascorbic acid orally per g of hexavalent chromium compound ingested. 

It is necessary to take into account the different sensitivities of various tissues and organs to the induction of deleterious health effects to the whole organism. The effective dose (E) is defined as a summation of the tissue equivalent doses multiplied by the appropriate tissue weighting factor W[. According to this definition. 

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