Pharmacological agents used for treatment and prevention in noise-induced hearing loss

In a review by Sakat and colleagues, pharmacological treatment options of noise-induced hearing loss (NIHL) were investigated. Both genetic and environmental factors are involved in NIHL, which is a preventable health problem. Prophylactic prevention of NIHL is primarily protective by nature, though there exist pharmaceutical interventions.

NIHL begins as high-frequency hearing loss, moving to loss of frequencies around 4000-6000 Hz, which proceeds to spread to both lower and higher frequencies, ending with loss at approximately 4000 Hz in the worst cases. NIHL is physiologically characterized by degeneration of hair cells, supporting cells, and eventually afferent nerve fibers. This thorough review of the literature reveals that the most commonly used agents for NIHL treatment are steroids, though antioxidants show promise as well, especially N-acetyl cysteine (NAC). The studies reviewed in this article indicare that NAC has been proven effective in both the protection against and treatment of NIHL.

Other promising pharmacological agents have been reported in animal studies, though further clinical studies are needed to determine their practical use. I think the findings of this review show potential for blossoming interprofessional collaboration between the worlds of pharmacy and audiology. Hopefully innovative pharmacological treatment will relieve many people of the burden of hearing devices and restore or, at the very least, prevent the loss of such a vital sense.

Sakat MS, Kilic K, Bercin S. Pharmacological agents used for treatment and prevention in noise-induced hearing loss. Eur Arch Otorhinolaryngol. doi:10.1007 (published 16 February 2016)

Medication Nonadherence and Effectiveness of Preventive Pharmacological Therapy for Kidney Stones

In a recent study conducted by Dauw and colleagues, the effects of nonadherence were observed among patients with kidney stone disease. Adherence to primary treatment with thiazide diuretics, alkali citrate, and allopurinol among 8,890 patients was studied over a period of two years.

Adherence to kidney stone therapy within the first six months of initiating treatment was studied, with adherence defined as a proportion of days covered (PDC) at or above 80%. PDC is calculated as the number of days available or “covered” by a certain medication divided by the total number of days in the followup period, multiplied by 100. In addition, they assessed whther each patient had an emergency room visit, hospitalization, and/or surgery for kidney stone disease within two years of his/her initial prescription fill.

Of the patients in the study, 51.1% were adherent to their pharmacological kidney stone therapy. Adherence to therapy showed 27% lower odds of an emergency department visit, 41% lower odds of hospitalization, and 23% lower odds of a surgical procedure for kidney stones compared to nonadherent patients. This evidence clearly outlines the consequences of nonadherence to reventative treatment of kidney stone disease. In general, adherence rates among this patient population are very low. Realizing that improved medication adherence is associated with tangible benefits for patients with kidney stones, healthcare providers should be vigilant in their counseling of patients with kidney stone disease on the use of preventative pharmacological therapy.

Dauw CA, Yi Y, Bierlein MJ, et al. Medication Nonadherence and Effectiveness of Preventive Pharmacological Therapy for Kidney Stones. J Urol. 2016;195(3):648-652

Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical serotonin/glutamate neurotransmission

In a novel study by Linge and colleagues, cannabidiol (CBD) was shown to exhibit strong anxiolytic and antidepressant effects in mice. The study also elucidated CBD’s mechanism of action on serotonin receptors in the brain. Their findings indicate that CBD could represent a novel fast-acting antidepressant drug.

CBD is the main non-psychotomimetic component of marijuana. This means that behind THC, the compound responsible for many of the mind-altering affects we collectively refer to as a “high,” CBD produces the majority of it’s therapeutic benefit without inducing highness. Utilizing the olfactory bulbectomy (OBX) mouse model of depression, researchers studied the behavioral efficacy of CBD via the enhancement of serotonergic and glutamatergic transmission through the modulation of 5-HT 1A receptors. Classical antidepressants act through similar serotonergic attenuation whereas the effects of fast-acting antidepressants seem to be mediated mainly by glutamatergic signalling.

The results of this study shows that CBD exerts rapid antidepressant-like effects as evidenced by the reversal of OBX-induced hyperactivity immediately after the first injection. Additionally, its efficacy is maintained and improved with the repeated administration, as anhedonia (inability to feel pleasure) was completely relieved after one week of treatment with a dose of 50 mg/kg. The findings also revealed a crucial role of 5-HT 1A and CB1 receptors in the behavioral and anxiolytic effects of CBD. As anxiety is a complex syndrome affected by different brain processes, the two receptors could be implicated in the anxiety outcome at different levels.

In summary, the fast onset of antidepressant action of CBD and the simultaneous anxiolytic effects, combined with the broad range for therapeutic dosage and the lack of psychotomimetic effects shows a strong therapeutic advantage for its use in clinical practice compared to other antidepressant alternatives.

Linge R, Jiménez-Sánchez L, Campa L, et al. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuopharmacology 2016;103:16-26

From non-pharmacological treatments for post-traumatic stress disorder to novel therapeutic targets

This paper touches on the complexity of post-traumatic stress disorder and the challenges associated with finding new treatment for patients with the condition. Like other anxiety disorder, PTSD is often treated with selective serotonin reuptake-inhibiting medications, and has been for decades. Psychological therapies are time-consuming and laborious, while pharmacological treatment with SSRIs suffers from lack of effect, relapse, and side effects. On top of that, both type of treatments seem to work only in a subset of patients. More effective treatment with fewer side effects is needed.

One large obstacle to pharmacological and non-pharmacological treatment of this disease is the establishment of an animal model. The large number of PTSD symptoms and the strong cognitive component in this anxiety disorder make it difficult to find a valid animal model for PTSD that meets all the criteria. There exists three animal models for PTSD currently: early life stress, inescapable foot shock (IFS), and social defeat. No model is perfect though the IFS model does provide a reproducible traumatic event, allowing researchers to manipulate the severity of the trauma for experimental reasons. While the early life stress and social defeat models may provide a benefit for the research on sensitivity to trauma, the IFS model is generally regarded as the best. However, symptoms that are not likely to be modeled in animals, such as flashbacks, intrusive memories, and nightmares, will still remain.

In an effort to reduce anxiety from PTSD via non-pharmacological means, two therapies have been identified: environmental enrichment combined with voluntary exercise and methods for re-exposure to the fear-eliciting stimulus in order to initiate extinction. Environmental enrichment enhances neurogenesis in the dentate gyrus and stimulates dendritic branching and spine forming in the hippocampus, effects also often seen after treatment with anti-depressants. By understanding the mechanisms underlying the beneficial behavioral changes of environmental enrichment, we may be able to elucidate future pharmacological treatment possibilities.

Re-exposure treatment is also an effective non-pharmacological psychological therapy option because exposure to a fearful stimulus in a safe environment can decrease the emotional reaction that this stimulus elicits in future exposures. This treatment involves an associative learning process known as ‘extinction’. MRI scans have shown that the areas involved in extinction, amygdala, hippocampus, and prefrontal cortex, are affected in PTSD patients. It is likely that re-exposure induces many other changes in gene expression. The challenge is how to identify those molecular changes that are causally related to the beneficial effects of this non-pharmacological treatment.

From the animal models discussed in the paper, the IFS model shows the most potential for patients with PTSD though it still is not perfect. Animal models help to acquire knowledge of the mechanisms underlying non-pharmacological interventions that can point out neurobiologically relevant processes leading to behavioral recovery. If we understand why the behavioral therapies are good for the brain, we may be able to identify new therapeutic targets.

Hendrikus Hendriksen, Berend Olivier, Ronald S. Oosting, From non-pharmacological treatments for post-traumatic stress disorder to novel therapeutic targets, Eur J Pharmacol. 2014;732:139-158

Safety Concerns Surrounding Quinolone Use in Children.

In a study published in The Journal of Clinical Pharmacology, the clinical use of fluoroquinolones to treat infections in children beyond a few select and extreme indications, most notably anthrax inhalation, is examined. The paper attempts to elucidate the existing challenges for clinicians in assessing both the risks and benefits when prescribing fluoroquinolones to children based on the currently available safety data and drug label restrictions.

Fluoroquinolones are extremely common in adult treatment because they have proven to be highly effective in the treatment of infections due to their broad spectrum of activity, excellent tissue and intracellular penetration, high oral bioavailability, and overall good tolerability profile. However, studies from the beginnings of fluoroquinolone development show that juvenile animal subjects showed the development of damage to immature cartilage of weight-bearing joints. Because of concerns raised about similar effects in infants, pediatric fluoroquinolone studies were halted.

The study found that the only frequent musculoskeletal adverse events observed in neonates, infants, and children are transient arthralgias that resolve themselves soon after discontinuation of fluoroquinolone therapy. Of course, risk of emerging bacterial resistance is also a concern with administration of fluoroquinolones in the pediatric population, though it presents no more threat than the same risk in adult populations due to over use of the drugs. Optimization of fluoroquinolone use should always be considered when implementing antimicrobial therapy as to limit unnecessary administration.

Citation:

Patel K, Goldman JL. Safety Concerns Surrounding Quinolone Use in Children. Journal of Clinical Pharmacology. 2016 Feb 10. doi: 10.1002/jcph.715. [Epub ahead of print]

Recent advances in management of the HIV/HCV coinfected patient

This paper discusses recent advances in the therapeutic treatment of patients infected with both the human immunosuppressant virus (HIV) and the hepatitis C virus (HCV). Approximately 150 million people across the globe have chronic HCV, which causes inflammation of the liver. The yearly global death toll from diseases related to HCV is at least 350,000. The most common route of HIV/HCV coinfection arises from HIV acquisition via injection drug use. Coinfection of these viruses causes increased risk of fibroses and increased rate of cirrhosis and end-stage liver disease development.

Direct-acting antivirals (DAAs) offer increased efficacy against these viral infections as well as shorter duration of treatment and diminished adverse events. In October and December of 2014, the fixed-dose combination DAA regimens of ledipsavir/sofosbuvir, and ombitasvir/paritaprevir/ritonavir plus dasabuvir were approved, respectively. These new agents have varying mechanisms of action, including NS3/4A protease inhibitors, nucleos(t)ide and non-nucleoside polymerase inhibitors and NS5A replication complex inhibitors. The new HCV treatment regimens have equivalent sustained virologic response rates for HIV/HCV coinfected individuals as they do for HCV monoinfected individuals.

However, complex drug-drug interactions can arise from DAA treatment regimens when used in HIV/HCV coinfection. Many new DAA agents affect or are affected by metabolizing enzymes and membrane transporters because many antiretrovirals are substrates, inhibitors and inducers of metabolizing enzymes, and inhibitors of membrane transporters.

The review also briefly touches on pharmacogenomic testing for HIV/HCV coinfected patients since DAAs are substrates of drug transporters and CYP450 enzymes. Because of this, pharmacokinetics and treatment outcomes could be influenced by genetic variability.

Future Virology Aug. 2015: 981+