Agile Therapeutics (United States)

Enterally-administered nimodipine is the only approved drug formulation available in the United States for treatment of patients with aneurysmal subarachnoid hemorrhage. Intravenous nimodipine is available in other countries but it contains a high concentration of ethanol that is irritating to the vasculature, can alter the effects of other medications, impair neurological assessments and is potentially harmful to the liver. We developed a sterile aqueous solution of nimodipine solubilized in polysorbate 80 micelles (GTX-104) that circumvents these problems. GTX-104 has been administered to 168 healthy human volunteers in 2 studies. We report the second study here, a phase 1, single center, randomized, 2-period cross over study that assessed the pharmacokinetics of GTX-104 and oral nimodipine capsules, which is the reference standard, in 58 healthy human volunteers. GTX-104 was administered for 72 hours as a continuous infusion of 0.15 mg/hour with a 30 minute bolus infusion of 4 mg every 4 hours. Nimodipine capsules were administered orally at a dose of 60 mg every 4 hours for 72 hours. The maximum plasma concentrations (geometric least square means) after the first dose of each formulation were similar (GTX-104: 63 ng/mL, n = 57 versus nimodipine capsules: 69 ng/mL, n = 56, ratio and 90% confidence interval [CI] of geometric LSmeans: 92% [90% CI: 82–104%]). The areas under the concentration-time curves on the 3rd day at steady state also were the same (GTX-104: 492 ng*h/mL, n = 56 versus nimodipine capsules: 462 ng*h/mL, n = 55, ratio and 90% CI of geometric LSmeans: 106% [90% CI: 99–114%]). The secondary pharmacokinetic parameters (daily maximum concentration at steady-state and time to maximum concentration) were also similar for the 2 formulations. The variability in PK parameters was less for GTX-104 compared to nimodipine capsules. The average oral bioavailability for nimodipine capsules was 7%. These results enabled a Phase 3 safety study of GTX-104 in humans with aneurysmal subarachnoid hemorrhage.

PurposeThere is a growing interest in nutraceutical supplements for ameliorating skin disorders owing to their multifaceted role and tolerability. In this study, we investigated the safety and efficacy of a unique herbal formulation (KūlarisTM) containing Commiphora wightii (guggul) and Amorphophallus konjac tuber extracts for the treatment of mild-to-severe acne.Patients and MethodsIn a randomized, placebo-controlled, parallel-group study design, 100 male and female subjects (18–40 years) with mild to severe acne were allocated (1:1 ratio) to receive 450 mg capsules of either Kūlaris or placebo once daily for 12 weeks.ResultsKūlaris treatment markedly reduced acne severity, with the majority of subjects achieving success in the Investigator Global Assessment (IGA) score (odds ratio = 7.88, p<0.0001) compared with placebo. Kūlaris administration significantly reduced the inflammatory and non-inflammatory acne lesion counts (p<0.0001 vs placebo). The Cardiff Acne Disability Index (CADI) score was reduced significantly in the Kūlaris group after 6 (p<0.0001) and 12 weeks (p<0.001) from baseline, indicating an improvement in quality of life. However, the subjective assessment showed no significant changes in general skin health measures, such as skin quality, color, wrinkle reduction, and skin hydration, in either group. Kūlaris was well tolerated among study participants, with no reported adverse effects or observable clinical signs throughout the intervention period.ConclusionThis study provides compelling evidence to support the potential use of Kūlaris as a therapeutic supplement or an adjunctive therapy to treatment of acne vulgaris.

Upon the induction of general anesthesia, a predictable sequence of physiological changes occurs within the respiratory and neuromuscular systems. The sequelae of these changes include an assortment of postoperative pulmonary complications (PPCs), including postoperative respiratory depression (PORD), that are observed during the immediate postoperative period and in the post-anesthesia care unit (PACU). These adverse events are anticipated, because several of the drugs that are used during surgery (e.g., opioids, which are traditionally used to manage pain during and after surgery), albeit therapeutically beneficial, have these adverse effects as part of their pharmacology. Nevertheless, the effects are traditionally considered transitory. However, several studies provide evidence suggesting that PPC-related morbidity and mortality extend 30, 60, and even 90 days after discharge from the hospital. These studies are summarized and assessed in this narrative review. Although exact estimates vary depending on the definitions used, the type of surgery, patient population, and risk factors (such as age), it is clear that PORD and other PPCs can be severe postoperative complications with significant associated mortality risks that extend weeks to months after discharge from the hospital.

Many premature infants less than 37weeks gestational age (GA), and almost all infants less than 28weeks GA, will experience apnoea of prematurity (AOP)-a cessation of respiration for 20 or more seconds (or less than 20s if accompanied by other signs). Because the treatment options for AOP are so limited, we explore its epidemiology, with the ultimate hope of learning how to decrease its incidence. Although AOP usually resolves with maturation of the respiratory system, many short- and long-term negative effects are correlated statistically with AOP (although direct causality has not been established). The primary risk factor for AOP is preterm birth, but delivery technique, genetics, socioeconomic status, racial disparities and other influences are suspected to be involved. Anaemia, asthma and gastric reflux have also been associated with preterm birth, but the relationship with AOP is unclear. The postulated associations and the strength of the evidence are briefly reviewed and discussed. Attempts to elucidate the epidemiology of apnoea of prematurity have been challenging. Studies of AOP are hampered in part by challenges in monitoring the condition, the interplay of multiple comorbidities in preterm neonates and lack of expert consensus definitions. However, since the primary risk factor is preterm birth, efforts to decrease the prevalence of preterm birth would have a positive secondary effect on the prevalence of AOP. Until then, better pharmacotherapeutic options are needed.

About 10% of all infants are born prematurely. Almost all of those of gestational age less than about 30weeks, and about half of those of gestational age up to about 35weeks, are subject to unpredictable interruptions of breathing-known as "apnoea of prematurity" (AOP). We present a synopsis of the problem and point out the limited management options. A basal rate for spontaneous breathing is normally maintained by integrated action of generator cells in the brainstem and feedback from central and peripheral chemosensors. In AOP, there are intermittent periods (seconds) lacking spontaneous firing, which results in hypoxia and hypercapnia. The long-term consequences of these interruptions in oxygen supply to tissues are not known. Although many treatment modalities are used, including drug therapy, nonpharmacologic care and mechanical intervention, there is no universally effective first-line management for AOP. Caffeine citrate is generally the most frequently used pharmacotherapeutic agent, but its side effect profile narrows with higher doses and the upper limit is still being investigated to discern the greatest benefit-to-risk ratio; thus, most infants do not achieve complete resolution of apnoeas. Given the widespread and serious nature of the problem of AOP, there is a surprising lack of treatment options. A more consistent and effective treatment, alone or as adjunct, would be welcome.