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Ophthalmic timolol solution is increasingly being repurposed as a topical therapeutic for a variety of dermatologic diseases, including pyogenic granulomas, infantile hemangiomas, and chronic wounds. There are no published guidelines or protocols for use in these indications in adults, and the dermatologic community may not be familiar with adverse events that have been extensively documented relating to its ophthalmic use. We review the evidence available relating to adverse events to topical timolol use to evaluate its safety in dermatologic applications and to alert clinicians to screening and monitoring that is needed when repurposing this drug for dermatologic use. The majority of serious adverse events associated with ophthalmic timolol were reported in the first 7 years of use, between 1978 and 1985, of which most common were cardiovascular and respiratory events, but also included 32 deaths. The available evidence suggests that ophthalmic timolol safety profiling may have been incomplete prior to widespread use. Recent clinical trials for dermatologic indications have focused on documenting efficacy and have not had rigorous monitoring for potential adverse events. Topical timolol may be safe and effective for the treatment of various dermatologic conditions in patients whose medical histories have been carefully reviewed for evidence of pre-existing cardiac or pulmonary disease and are monitored for potential adverse events. Despite the wide use of timolol in ophthalmologic practice, safe dermatologic repurposing requires recognition of the potential for facilitated systemic absorption though the skin and appreciation of its history of adverse events. [ABSTRACT FROM AUTHOR]

The prevalence of infection in chronic wounds is well documented in the literature but not optimally studied due to the drawbacks of current methodologies. Here, we describe a tractable and simplified ex vivo human skin model of infection that addresses the critical drawbacks of high costs and limited translatability. Wounds were generated from excised abdominal skin from cosmetic procedures and cultured, inoculated with Staphylococcus aureus strain UAMS‐1, or under aseptic conditions. After three days, the infected wounds exhibited biofilm formation and significantly impaired reepithelialization compared to the control. Additionally, promigratory and proreparative genes were significantly downregulated, while proinflammatory genes were significantly upregulated, demonstrating molecular characterizations of impaired healing as in chronic wounds. This model allows for a simplified and versatile tool for the study of wound infection and subsequent development of novel therapies. [ABSTRACT FROM AUTHOR]

Context: Drug-induced pancreatitis (DIP) is rare, but as there are no systematic data on it, the true incidence is not known. Although numerous and varied drugs have been associated with DIP, the clinical evidence on doxycycline-induced pancreatitis is sparse. Case Report: We present the case of a 58-year-old female who presented with complaints of nausea and severe epigastric pain. Her medications included doxycycline which she had been on for only 2 days. Computed tomography of her abdomen showed mild enlargement of body of the pancreas with peripancreatic fatty infiltration, along with lipase level suggestive of acute pancreatitis. In the absence of classical risk factors for acute pancreatitis, a diagnosis of DIP secondary to doxycycline therapy was made. Immediate withdrawal of the drug was accompanied by relief of symptoms and resolution of pancreatitis. Conclusion: This report implicates doxycycline as an etiological factor for acute pancreatitis. Knowledge regarding doxycycline related pancreatitis is of paramount importance in order to diagnose cases early and institute effective treatment in patients who are undergoing therapy with this drug. [ABSTRACT FROM AUTHOR]

Non‐healing wounds are a major medical challenge, affecting over 6.5 million people in the US alone, with associated healthcare costs of about $16 billion annually. They can result in prolonged hospitalizations, work loss, disability, poor quality of life, and in diabetic patients with foot ulcers, amputation of the affected limb in 25% of patients. Though chronic ulcers may arise from different underlying diseases, the unifying feature is chronic infection, driving persistent inflammation that prolongs the healing process. One of the most frequently cultured or genetically identified pathogens in skin wounds is Pseudomonas aeruginosa. This species avidly forms biofilms in the wound that impede bacterial eradication by the host's immune mechanisms and limit efficacy of systemic antibiotics. Thus, non‐antibiotic approaches to limit the growth and biofilm formation of this wound pathogen would be an advance in the treatment of chronic wounds. Prior work has demonstrated that the growth of other microbial species can be modulated by catecholamine agonists and antagonists of the adrenergic receptors (ARs). Here, we demonstrate that not only can the growth of this common wound pathogen be modulated by catecholamines, but also that the beta‐AR antagonists can significantly decrease their growth, and importantly, limit their ability to form biofilms. These findings suggest that beta adrenergic antagonists may have a therapeutic role in the treatment of chronic skin wounds. [ABSTRACT FROM AUTHOR]

Background: Diabetic foot ulcers (DFUs) are the most common cause of leg amputations and their management is extremely challenging. Despite many advances and expensive therapies, there has been little success in improving outcomes of DFUs. In prior work our laboratory has examined the effects of beta-adrenergic antagonists (βAAs) on skin and skin-derived cells. We have shown that βAAs enhance the rate of keratinocyte migration, promote angiogenesis, and hasten wound healing in scratch wounds in vitro, in animal wound models, and in anecdotally reported cases of chronic wounds that healed successfully after topical application of the βAA timolol. Thus, we propose to test timolol directly on DFUs to determine if it improves healing above the current standard of care (SOC). This study will examine the efficacy and safety of topically applied beta-antagonist Timoptic-XE® (timolol maleate ophthalmic gel forming solution) in subjects with DFUs.Methods/design: This is a phase two, randomized, double-blinded, controlled, and parallel-group clinical trial with two treatment arms, SOC plus topical Timoptic-XE® and SOC plus a non-biologically active gel (hydrogel, as placebo drug). Study subjects with a DFU will be selected from the Veterans Affairs Northern California Health Care System (VANCHCS). Study duration is up to 31 weeks, with three phases (screening phase for two weeks, active phase for up to 12 weeks, with an additional second consecutive confirmatory visit after 2 weeks, and follow-up phase comprising monthly visits for 4 months). Subjects will apply daily either the topical study drug or the placebo on the foot ulcer for 12 weeks or until healed, whichever comes first. Measurements of wound size and other data will be collected at baseline, followed by weekly visits for 12 weeks, and then a monthly follow-up period.Discussion: This is a clinical translation study, moving the investigators' pre-clinical laboratory research into a translational study in which we will analyze clinical outcomes to assess for safety and estimate the efficacy of a topical beta-antagonist in healing of DFUs. The results from this trial may establish new treatment paradigms and safety profile for DFU treatment.Trial Registration: ClinicalTrials.gov, NCT03282981. Registered on June 14th, 2018. [ABSTRACT FROM AUTHOR]

Context. Polyacrylamide hydrogel (PAAG) has gained importance as a synthetic soft tissue filling agent. It has been commonly employed by physicians in Europe for facial contouring and soft tissue augmentation. Previously, PAAG is considered nontoxic and well tolerated with a few mild procedural complications. Case Presentation. A 26-year-old female was hospitalized for dry cough, worsening dyspnea, and chest discomfort after 3 hours of multiple PAAG injections in buttocks. The patient’s condition deteriorated and rapidly advanced to acute respiratory failure. Therein, the diagnosis of nonthrombotic pulmonary embolism (NTPE) was established on standard set of investigations. She was intubated; corticosteroid and empiric antibiotic therapy was initiated resulting in improvement of her condition. Subsequently, extubation was done, and she was discharged from the hospital after an uneventful recovery. On 1-month follow-up, the patient had no previous symptoms. Conclusion. This report implicates clinicians to maintain a high index of suspicion for NTPE in patients presenting with respiratory symptoms following PAAG usage. [ABSTRACT FROM AUTHOR]

Repeated exposure to cocaine produces changes in the nervous system that facilitate drug-seeking behaviors. These drug-seeking behaviors have been studied with animal models, such as cocaine-induced locomotor sensitization. Cocaine is hypothesized to induce locomotor sensitization by neural changes, including an increase in the density of spines on the dendrites of neurons in the nucleus accumbens (NAC). However, how cocaine increases dendritic spine density in the NAC has been difficult to discern because cocaine inhibits the function of multiple targets, including the transporters for dopamine, serotonin, and norepinephrine. Previously, our lab created a tool that is useful for determining how inhibiting the dopamine transporter (DAT) contributes to the effects of cocaine by generating mice that express a cocaine-insensitive DAT (DAT-CI mice). In this study, we used DAT-CI mice to determine the contribution of DAT inhibition in cocaine-induced increases in dendritic spine density in the NAC.We repeatedly injected DAT-CI mice with either cocaine or saline, and measured both dendritic spine density in the NAC and locomotor activity. Unlike wild-type mice, DAT-CI mice did not show an increase in dendritic spine density in the NAC or in locomotor activity inresponse to repeated injections of cocaine. These data show that cocaine-induced increases in dendritic spine density in the NAC require DAT inhibition. Thus, DAT-inhibition may play a role in mediating the long-lasting neural changes associated with drug addiction. [ABSTRACT FROM AUTHOR]