Effectiveness of 8- or 12-weeks of ledipasvir and sofosbuvir in real-world treatment-naïve, genotype 1 hepatitis C infected patients

Summary

Background

Treatment of genotype 1 hepatitis C virus (HCV) infection with combination direct acting anti-virals is associated with very high rates of sustained virological response (SVR). Daily combination of ledipasvir and sofosbuvir for 12 weeks is approved for the treatment of genotype 1 HCV patients, though noncirrhotic patients who are naïve to treatment with a baseline HCV RNA <6 million IU/mL can be treated for 8 weeks. This guidance stemmed from a post hoc analysis of the ION 3 clinical trial, which demonstrated similar SVR for patients treated with ledipasvir and sofosbuvir with or without ribavirin for 8 or 12 weeks.

Aim

To compare the SVR for 8 weeks vs 12 weeks of ledipasvir and sofosbuvir in HCV infected patients in a real-world setting.

Methods

We performed an observational real-world cohort study of treatment success following 8 or 12 weeks of ledipasvir and sofosbuvir for treatment-naïve genotype 1 HCV patients.

Results

A total of 826 patients were treated for either 8 (n=252) or 12 weeks (n=574) with ledipasvir and sofosbuvir and achieved SVR rate of 95.3% and there was no statistical difference in SVR rates in the two groups irrespective of any clinical or virological variables.

Conclusions

In treatment-naïve HCV genotype 1 patients, SVR was 95% in those treated for either 8 weeks or 12 weeks with ledipasvir and sofosbuvir. 8 week ledipasvir and sofosbuvir can reduce costs without compromising outcomes for those patients who qualify for such regimen.

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Anticonvulsant effect of cannabinoid receptor agonists in models of seizures in developing rats

Summary

Objective

Although drugs targeting the cannabinoid system (e.g., CB1 receptor agonists) display anticonvulsant efficacy in adult animal models of seizures/epilepsy, they remain unexplored in developing animal models. However, cannabinoid system functions emerge early in development, providing a rationale for targeting this system in neonates. We examined the therapeutic potential of drugs targeting the cannabinoid system in three seizure models in developing rats.

Methods

Postnatal day (P) 10, Sprague–Dawley rat pups were challenged with the chemoconvulsant methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) or pentylenetetrazole (PTZ), after treatment with either CB1/2 mixed agonist (WIN 55,212-2), CB1 agonist (arachidonyl-2′-chloroethylamide [ACEA]), CB2 agonist (HU-308), CB1 antagonist (AM-251), CB2 antagonist (AM-630), fatty acid amide hydrolase inhibitor (URB-597), or G protein–coupled receptor 55 agonist (O-1602). P20 Sprague–Dawley pups were challenged with DMCM after treatment with WIN, ACEA, or URB. Finally, after pretreatment with WIN, P10 Sprague–Dawley rats were challenged against acute hypoxia-induced seizures.

Results

The mixed CB1/2 agonist and the CB1-specific agonist, but no other drugs, displayed anticonvulsant effects against clonic seizures in the DMCM model. By contrast, both CB1 and CB2 antagonism increased seizure severity. Similarly, we found that the CB1/2 agonist displayed antiseizure efficacy against acute hypoxia-induced seizures (automatisms, clonic and tonic–clonic seizures) and tonic–clonic seizures evoked by PTZ. Anticonvulsant effects were seen in P10 animals but not P20 animals.

Significance

Early life seizures represent a significant cause of morbidity, with 30–40% of infants and children with epilepsy failing to achieve seizure remission with current pharmacotherapy. Identification of new therapies for neonatal/infantile epilepsy syndromes is thus of high priority. These data indicate that the anticonvulsant action of the CB system is specific to CB1 receptor activation during early development and provide justification for further examination of CB1 receptor agonists as novel antiepileptic drugs targeting epilepsy in infants and children.

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Mortality with brainstem seizures from focal 4-aminopyridine–induced recurrent hippocampal seizures

Summary

Objective

Sudden unexplained death in epilepsy is the leading cause of death in young adult epilepsy patients, typically occurring during the early postictal period, presumably resulting from brainstem and cardiorespiratory dysfunction. We hypothesized that ictal discharges in the brainstem disrupt the cardiorespiratory network, causing mortality. To study this hypothesis, we chose an animal model comprising focal unilateral hippocampal injection of 4-aminopyridine (4-AP), which produced focal recurrent hippocampal seizures with secondary generalization in awake, behaving rats.

Methods

We studied ictal and interictal intracranial electrographic activity (iEEG) in 23 rats implanted with a custom electrode array into the hippocampus, the contralateral cortex, and brainstem. The hippocampal electrodes contained a cannula to administer the potassium channel blocker and convulsant (4-AP). iEEG was recorded continuously before, during, and after seizures induced by 4-AP infusion into the hippocampus.

Results

The control group (n = 5) was monitored for 2–3 months, and the weekly baseline iEEG recordings showed long-term stability. The low-dose group (1 μL 4-AP, 40 mm, n = 5) exhibited local electrographic seizures without spread to the contralateral cerebral cortex or brainstem. The high-dose group (5 μL 4-AP, 40 mm, n = 3) had several hippocampal electrographic seizures, which spread contralaterally and triggered brainstem discharges within 40 min, and were associated with violent motor seizures followed by dyspnea and respiratory arrest, with cortical and hippocampal iEEG flattening. The group that received high-dose 4-AP without brainstem implantation (n = 5) had similar seizure-related respiratory difficulties. Finally, five rats that received high-dose 4-AP without EEG recording also developed violent motor seizures with postictal respiratory arrest. Following visualized respiratory arrest in groups III, IV, and V, manual respiratory resuscitation was successful in five of 13 animals.

Significance

These studies show that hippocampal seizure activity can spread or trigger brainstem epileptiform discharges that may cause mortality, possibly mediated by respiratory network dysfunction.

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Effect of vigabatrin on seizure control and safety profile in different subgroups of children with epilepsy

Summary

Objective

To evaluate the efficacy and safety of vigabatrin in pediatric epilepsy.

Methods

We retrospectively reviewed patients with epilepsy treated with vigabatrin over a 2-year period at a pediatric tertiary center. We assessed the relationship between seizure frequency, etiology, vigabatrin dose, adverse events, medication discontinuation reasons, and electroencephalography (EEG) characteristics.

Results

One hundred three patients followed at Boston Children's Hospital were treated with vigabatrin and had complete medical records. Within the follow-up interval, 69 (67%) of 103 patients had discontinued vigabatrin therapy. Two patients (1.9%) died during therapy for unknown reasons. Median age at vigabatrin initiation was 8 months (interquartile range [IQR] 5–15). Median starting dose was 48.1 mg/kg per day (IQR 29.8–52.3) with a median target of 100 mg/kg (IQR 81.9–107.9). Median treatment duration was 12.1 months (n = 89, IQR 5.0–22.9) overall, and 13.3 months (IQR 5.2–23.2) for patients who discontinued vigabatrin. The most common reasons for discontinuation were controlled seizures in 31 (43.7%) of 71 and unsatisfactory therapeutic effect in 23 (32.4%) of 71. Median percent seizure reduction from baseline to first follow-up was 83.3% (IQR 27.4–99.8) and 96.7% (IQR 43.3–100) to last follow-up. Twenty-four (38.7%) of 62 patients with a follow-up posttreatment remained seizure-free. Four patients who had initially achieved seizure freedom relapsed. Patients with structural/metabolic etiology had greater median percent seizure reduction at first follow-up than patients with genetic etiology (98.7% vs. 61.4%, respectively, p = 0.001). Hypsarrhythmia resolved after therapy in 18 of 20 (90%, 95% confidence interval [CI] 70–97) patients with pretreatment hypsarrhythmia, and 2 patients presented with hypsarrhythmia posttreatment. Risk of having hypsarrhythmia was reduced by 32% (95% CI 14.9–49.1) posttreatment.

Significance

Vigabatrin is efficacious in all seizure types and resolved hypsarrhythmia in most patients. In this series with a median treatment duration of 12.1 months, vigabatrin had a good safety profile with a low rate of discontinuation due to nonophthalmologic and ophthalmologic adverse effects.

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Dexpanthenol: An Overview of its Contribution to Symptom Relief in Acute Rhinitis Treated with Decongestant Nasal Sprays

Abstract

Nasal blockage is the most bothersome symptom of acute rhinitis. Nasal decongestant sprays containing alpha-sympathomimetics, such as oxymetazoline and xylometazoline, have a rapid onset of action. However, this effect decreases with repeated application and, furthermore, the ciliary function of the nasal mucosa is practically paralyzed. Dexpanthenol promotes cell proliferation and protects the epithelium. Combining these two agents has demonstrated beneficial synergetic effects on the symptoms of acute rhinitis. In a post hoc analysis of a large-scale double-blind, active-controlled study including 152 patients, we could demonstrate that the benefit of added dexpanthenol appears as early as on the third day of the combined application of xylometazoline and dexpanthenol in terms of complete or near-to-complete freedom from symptoms. After 5 days, 47% of the patients were cured under the combined treatment compared with only 1% under xylometazoline monotherapy. These data show that the addition of dexpanthenol to an alpha-sympathomimetic nasal spray not only improves its tolerability but also further increases its effectiveness and leads to expedited cure.

Funding: Klosterfrau Healthcare Group.

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Resource Utilization Among Glaucoma Patients in the UK Treated with Beta-Blocker and Non-Beta-Blocker Adjunctive Therapy: A Retrospective Cohort Analysis

Abstract

Introduction

Few studies have examined outcomes and potential complications among glaucoma patients who are prescribed topical beta-blockers. This study examined resource usage (number of GP visits and hospitalizations) and diagnoses of respiratory or cardiovascular conditions among glaucoma patients prescribed beta-blockers compared to patients not prescribed beta-blockers.

Methods

A retrospective cohort analysis was conducted using data from the UK Clinical Practice Research Datalink (CPRD) database over the period January 1, 2006 to March 31, 2014. Adult patients with at least one diagnosis of glaucoma were categorized into beta-blocker users and non-beta-blocker users. Beta-blocker users were further separated into patients that maintained beta-blocker therapy and patients that discontinued beta-blocker treatment in year 2 of the post-index period. The CPRD data was queried directly to obtain the number of GP visits, and hospitalizations were extracted by linking the CPRD and Hospital Episode Statistics (HES) patient-level data.

Results

In the 12 months after being prescribed beta-blockers, patients that later discontinued beta-blocker treatment had a significantly higher average number of hospitalizations than patients that maintained beta-blocker therapy and the non-beta-blocker users (p < 0.05). In the year after beta-blocker initiation, there was a statistically significant within-group difference pre- and post-beta-blocker initiation for all groups, but the greatest number of GP visits occurred in the patients that subsequently discontinued beta-blocker treatment (mean 19.27). Patients that discontinued beta-blocker treatment were significantly more likely to have cardiovascular events than non-beta-blocker users in the post-index period (p < 0.05).

Conclusion

This study suggests that the introduction of beta-blockers in a certain group of patients who later discontinue their use is associated with increased use of medical resources (higher number of GP visits and hospitalizations) in glaucoma patients in the UK, which may be indicative of a potential relationship between use of topical beta-blockers in glaucoma therapy and adverse outcomes.

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Cancer adaptations: Atavism, de novo selection, or something in between?

From an evolutionary perspective, both atavism and somatic evolution/convergent evolution theories can account for the consistent occurrence, and astounding attributes of cancers: being able to evolve from a single cell to a complex organized system, and malignant transformations showing significant similarities across organs, individuals, and species. Here, we first provide an overview of these two hypotheses, including the possibility of them not being mutually exclusive, but rather potentially representing the two extremes of a continuum in which the diversity of cancers can emerge. In reviewing the current literature, we also discuss the criteria that should be applied to discriminate between the two competing theories and to determine their relevant contributions to oncogenesis and cancer progression. Finally, we deliberate on the potential applications of this conceptual framework in developing novel treatment strategies.

Evolution theories, atavism initiating from the Precambrian and somatic/convergent evolution can both account for cancer adaptations. While they have distinct implications for therapies, the extent to which both contribute to tumorigenesis remains to be explored. Here we discuss this issue and suggest directions to discriminate between the two competing theories.

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