Up-and-down procedure

Up-and-down procedure (UDP), also known as the Dixon's up-and-down method, is a sequential analysis technique used primarily in pharmacology and toxicology for estimating the median lethal dose (LD50) or the median effective dose (ED50) of a substance. This method involves administrating a series of doses to groups of subjects, where the dose for the next group is determined by the response of the previous group. The procedure continues until a predetermined number of "reversals" (a change from a non-lethal to lethal outcome or vice versa) is observed. The UDP is a refinement of the traditional dose-response studies, aiming to reduce the number of animals required for testing while still providing accurate estimations of a substance's toxicity or efficacy.

Procedure

The up-and-down procedure starts with the administration of a dose to a single subject or a small group of subjects. If the outcome is negative (e.g., the subject survives in a toxicity study or does not show the desired effect in an efficacy study), the dose is increased for the next subject or group. Conversely, if the outcome is positive (e.g., the subject dies in a toxicity study or shows the desired effect in an efficacy study), the dose is decreased. This process continues, alternating up and down in response to the outcomes observed, until a specific number of reversals is achieved. The final estimate of the LD50 or ED50 is calculated based on the doses that resulted in reversals, using statistical methods designed for sequential analysis.

Applications

The up-and-down procedure is widely used in various fields, including:

• Pharmacology: For determining the therapeutic index of new drugs.
• Toxicology: For assessing the safety of chemicals, including pharmaceuticals, environmental toxins, and consumer products.
• Material science: In evaluating the biocompatibility and toxicity of new materials intended for medical use.

Advantages

• Reduction in animal use: By focusing on the doses around the LD50 or ED50, the UDP significantly reduces the number of animals required for testing compared to traditional methods.
• Efficiency: The method is more efficient in terms of time and resources, as fewer subjects are needed to reach a conclusion.
• Adaptability: The procedure can be adapted for various endpoints, such as efficacy, toxicity, or side effects.

Limitations

• Statistical complexity: The analysis of data from UDP requires specialized statistical methods, which may be a barrier for some researchers.
• Assumption of monotonicity: The method assumes that the dose-response relationship is monotonic, which may not hold true for all substances.
• Sensitivity to initial dose selection: The accuracy of the final estimate is influenced by the choice of the initial dose, which can be challenging to determine for new substances.

See also

• Dose-response relationship
• Median lethal dose
• Sequential analysis