November 1, 2010 (Vol. 30, No. 19)
Chang Ahn, Ph.D.
Instead of Fighting Cell-Death Mechanisms, Clavulanic Acid Seeks to Fortify Cell Defenses
High-profile central nervous system (CNS) diseases impose a heavy burden on healthcare systems and pose complex challenges to researchers seeking the causes of these debilitating conditions.
These diseases can be triggered by a range of mechanisms often acting in combination to set off the processes that lead to the disease state. Research programs continue to generate greater appreciations for the complexity of the causes of these CNS diseases, yet to this point have not resulted in the discovery of effective remedies.
Positive results from some preclinical and clinical trials support a novel approach that shifts the focus from a pharmacological intervention that aims to block specific triggers of these diseases to a strategy that seeks to fortify the defenses of the neural cell survival systems that are the target of trigger attacks.
A formulation of clavulanic acid may be able to positively affect neuronal survival, presenting a potential for therapies to slow or halt the progression of both Parkinson and Alzheimer diseases. At the same time, clavulanic acid’s effect of enhancing both serotonergic and dopaminergic systems in the brain can play a central role in the treatment of depression.
As a pharmacologist, I am fascinated by the potential of shielding the cell-survival mechanisms rather than fighting one-by-one the multitude of triggers that can activate the cell-death mechanisms. With at least five major triggers identified for Alzheimer disease (e.g., Aβ plaque, tau tangle, Ca++ overload, cytokines from inflammation, reactive oxygen species) and three major dysfunctioning triggers for Parkinson disease (dysfunction of the lysosomal autophage system, the ubiquitin-proteosomal system, and the mitochondria related to a-synuclein profibrils), neural protection within a solid fortress could present a more elegant, noble defense than attempting to intercept each incoming threat.
The same formulation of clavulanic acid with a variation in the release properties may also have the potential to treat sexual dysfunction. Studies suggest that clavulanic acid may also offer a new approach to erectile dysfunction by asserting that it can be treated as a CNS condition.
Where current therapies for erectile dysfunction center on ameliorating vascular function of the end organ, clavulanic acid works further upstream to directly modulate the brain neurotransmitters that play a key role in male sexual activity. Improving sexual performance through a centrally acting mechanism may also present a potential for treatment of female sexual dysfunction.
The safety profile of clavulanic acid has been consistently demonstrated since its introduction in 1984 as a therapeutic. Additionally, it is possible to achieve the desired efficacy at doses as low as 1/100th of conventional use, presenting a favorable safety profile.
The pharmacological effect of clavulanic acid follows a bell curve such that increasing the dosage after reaching the peak effect diminishes the positive effects without provoking the negative effects for overdosage, as with some CNS medications, that can lead to negative behavioral issues or physiological effects such as impaired motor activity or loss in learning and memory.
Less well understood have been the beneficial effects of clavulanic acid for a range of CNS conditions that recent studies have identified on multiple levels as a beta-lactamase inhibitor for neuronal protection, as well as the dual enhancement of serotonin and dopamine release by neural transmitters.
With anxiolytic-like activity and few side effects, investigations have revealed that clavulanic acid exerts anti-anxiety and antidepression effects at low doses and without unwanted side effects. Clavulanic acid represents a novel approach to anti-depression therapy: it enhances both the serotonin and dopamine activity of neural transmitters, which may be able to help a broader spectrum of patients than the highly targeted inhibitors of previous generations that affect only one type of depression mechanism.
For example, the current antidepression therapy of selective serotonin reuptake inhibitors (SSRIs) reportedly address only the 50% of patients who are responsive to serotonergic therapy. Therefore, given the proportion of the population nonresponsive to serotonin, as well as patients who experience relapse or are noncompliant, the unmet medical need among depressive patients remains significant.
Some patients unresponsive to serotonin treatment have been found to be responsive to a dopamine-based therapy that increases motivation, enhances their receptivity to pleasure, and restores their sense of self-worth. Studies also suggest that patients are not exclusively affected by a single mechanism but require a balance of both serotonin and dopamine to achieve a stable mental state. With such balance, clavulanic acid could be effective in reducing the relapse rate experienced by SSRI patients.
Typically, in a randomized clinical trial, patients receiving the active ingredient being tested report a higher level of side effects than the placebo control group. Yet an unexpectedly positive result from a recent early-stage clinical trial with a formulation of clavulanic acid among depressive patients was that 50% fewer patients reported side effects from the treatment than patients taking the placebos.
We spent a great deal of time analyzing this phenomenon, and our investigation points to the effect of clavulanic acid on dopamine levels. The positive effects of enhanced dopamine levels tend to give patients a greater sense of happiness, higher motivation, and a greater receptiveness to pleasure, which could have led to a tendency not to report complaints. Meanwhile the patients taking placebos, who were also diagnosed as depressive, were experiencing a naturally lowered level of dopamine. The placebos had no effect upon the condition of these patients, so they continued in a depressive state during the trial period.
As a safe dual enhancer of dopamine and seratonin, calvulanic acid is a promising treatment for depression. Its neural-protective properties also make clavulanic acid an intriguing treatment for diseases like Parkinson and Alzheimer diseases.
Chang Ahn, Ph.D. (firstname.lastname@example.org), is CEO of Rexahn Pharmaceuticals.