Aaps J
-
Review
Targeting TRPV1 as an alternative approach to narcotic analgesics to treat chronic pain conditions.
In spite of intense research efforts and after the dedicated Decade of Pain Control and Research, there are not many alternatives to opioid-based narcotic analgesics in the therapeutic armamentarium to treat chronic pain conditions. Chronic opioid treatment is associated with sedation, tolerance, dependence, hyperalgesia, respiratory depression, and constipation. Since the affective component is an integral part of pain perception, perhaps it is inevitable that potent analgesics possess the property of impacting pain pathways in the supraspinal structures. ⋯ In neuropathic pain conditions, the complexity arises because of the notion that neuronal circuitry is altered, as occurs in phantom pain, in that pain is perceived even in the absence of peripheral nociceptive inputs. If the locus of these changes is in the central nervous system, commonly used analgesics may not be very useful. This review focuses on the recent advances in nociceptive transmission and nociceptive transient receptor potential vanilloid 1 channel as a target for treating chronic pain conditions with its agonists/antagonists.
-
Randomized Controlled Trial
Quantitative pharmacology approach in Alzheimer's disease: efficacy modeling of early clinical data to predict clinical outcome of tesofensine.
Effective therapeutic options for Alzheimer's disease (AD) are limited and much research is currently ongoing. The high attrition rate in drug development is a critical issue. Here, the quantitative pharmacology approach (QP-A) and model-based drug development (MBDD) provide a valuable opportunity to support early selection of the most promising compound and facilitate a fast, efficient, and rational drug development process. ⋯ The placebo effect was also implemented in the final PK/PD model based on a published placebo model developed in a large AD cohort. Various internal evaluation techniques confirmed the reliability and predictive performance of the PK/PD model, which also successfully predicted the 14-week PoC data. For tesofensine, the dose concentration-effect relationship has successfully been described in mild AD patients demonstrating the supportive value of PK/PD models in QP-A/MBDD in early phases of clinical development for decision-making.
-
Cannabinoid CB(2) receptors represent a therapeutic target that circumvents unwanted central side effects (e.g., psychoactivity and/or addiction) associated with activation of CB(1) receptors. One of the primary investigative tools used to study functions of the CB(2) receptor is the aminoalkylindole (R,S)-AM1241. However, (R,S)-AM1241 has been described as an atypical CB(2) agonist which produces antinociception mediated indirectly by opioid receptors. (R,S)-AM1241 and its enantiomers, (R)-AM1241 and (S)-AM1241, were evaluated for antinociception in response to thermal (Hargreaves) and mechanical (von Frey) stimulation. ⋯ Similar levels of antinociception were observed at intermediate doses. (R,S)-AM1241, (R)-AM1241, and (S)-AM1241 each produced CB(2)-mediated antinociception that was blocked by SR144528 but not by rimonabant. Local and systemic naloxone blocked morphine-induced antinociception but did not block antinociceptive effects of (R,S)-AM1241, (R)-AM1241, or (S)-AM1241. The antinociceptive effects of the CB(2)-selective cannabinoid (R,S)-AM1241 and its enantiomers, (R)-AM1241 and (S)-AM1241, are not dependent upon opioid receptors.
-
The endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA) produces most of its pharmacological effects by binding and activating CB(1) and CB(2) cannabinoid receptors within the CNS and periphery. However, the actions of AEA are short lived because of its rapid catabolism by fatty acid amide hydrolase (FAAH). Indeed, FAAH knockout mice as well as animals treated with FAAH inhibitors are severely impaired in their ability to hydrolyze AEA as well as a variety of noncannabinoid lipid signaling molecules and consequently possess greatly elevated levels of these endogenous ligands. ⋯ Importantly, FAAH blockade does not elicit any apparent psychomimetic effects associated with THC or produce reinforcing effects that are predictive of human drug abuse. The beneficial effects caused by FAAH blockade in these models are predominantly mediated through the activation of CB(1) and/or CB(2) receptors, though noncannabinoid mechanisms of actions can also play contributory or even primary roles. Collectively, the current body of scientific literature suggests that activating the endogenous cannabinoid system by targeting FAAH is a promising strategy to treat pain and inflammation but lacks untoward side effects typically associated with Cannabis sativa.
-
Comparative Study
Highly variable drugs: observations from bioequivalence data submitted to the FDA for new generic drug applications.
It is widely believed that acceptable bioequivalence studies of drugs with high within-subject pharmacokinetic variability must enroll higher numbers of subjects than studies of drugs with lower variability. We studied the scope of this issue within US generic drug regulatory submissions. ⋯ About 60% of the highly variable drugs we surveyed were highly variable due to drug substance pharmacokinetic characteristics. For about 20% of the highly variable drugs, it appeared that formulation performance contributed to the high variability.