Single-day Treatment Research Articles

Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058.

Serotonin type-3 receptor (5-HT3R) antagonists show potential as a treatment for cognitive deficits in schizophrenia. CVN058, a brain-penetrant, potent and selective 5-HT3R antagonist, shows efficacy in rodent models of cognition and was well-tolerated in Phase-1 studies. We evaluated the target engagement of CVN058 using mismatch negativity (MMN) in a randomized, double-blind, placebo-controlled, cross-over study. Subjects were stable outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics. Subjects were not permitted to use other 5-HT3R modulators or serotonin reuptake inhibitors. Each subject received a high (150 mg) and low (15 mg or 75 mg) oral dose of CVN058 and placebo in a randomized order across 3 single-day treatment visits separated by at least 1 week. The primary pre-registered outcome was amplitude of duration MMN. Amplitude of other MMN deviants (frequency, intensity, frequency modulation, and location), P50, P300 and auditory steady-state response (ASSR) were exploratory endpoints. 19 of 22 randomized subjects (86.4%) completed the study. Baseline PANSS scores indicated moderate impairment. CVN058 150 mg led to significant improvement vs. placebo on the primary outcome of duration MMN (p = 0.02, Cohen's d = 0.48). A significant treatment effect was also seen in a combined analysis across all MMN deviants (p < 0.001, d = 0.57). Effects on location MMN were independently significant (p < 0.007, d = 0.46). No other significant effects were seen for other deviants, doses or EEG measures. There were no clinically significant treatment related adverse effects. These results show MMN to be a sensitive target engagement biomarker for 5-HT3R, and support the potential utility of CVN058 in correcting the excitatory/inhibitory imbalance in schizophrenia.

Rituximab Plus Bortezomib Still Represents an Effective Treatment Option for Patients with Relapsed or Refractory Mantle Cell Lymphoma

Introduction.Mantle Cell Lymphoma (MCL) represents 5-7% of all non-Hodgkin Lymphomas (NHL) and is still an incurable disease. In recent years first line treatment approaches were strongly improved both for younger (i.e. high-dose cytarabine regimens) and for elderly patients (pts) (i.e. bendamustine-including regimens or Rituximab maintenance after RCHOP therapy). However, MCL retains a strong tendency to recurrence with shorter Duration of Response (DOR) after any further line of therapy. Furthermore, in recent years many drugs were developed, that have demonstrated strong efficacy in the treatment of relapsed/refractory (R/R) MCL. In particular, the BTK inhibitor Ibrutinib is currently used in the treatment of R/R MCL worldwide with the highest single-agent efficacy in terms of Overall Response (ORR) and Complete Response Rate (CRR) and DOR. With the wide use of Ibrutinib new problems are emerging, for example a certain aggressiveness of MCL relapsing after or resistant to this drug. Furthermore, some patients present one or more co-morbidities that preclude or at least contraindicate Ibrutinib treatment, especially atrial fibrillation or the needing for anti-coagulation. Finally, many treatments of R/R MCL are currently available (Bendamustine, Bortezomib, Lenalidomide, etc…) and there are no data suggesting which could be the more effective “treatment-sequence” for MCL pts. The proteasome inhibitor Bortezomib demonstrated its efficacy in the treatment of R/R MCL with good ORR and DOR, both as single drug and in association with Rituximab. However, due to rapid availability of new drugs, its role as a potential treatment of R/R MCL is under-explored, even if a good toxicity profile was also observed. Here we report our experience of Rituximab plus Bortezomib (R+B) as salvage therapy for pts with R/R MCL.Materials and Methods.We retrospectively analyzed a cohort of R/R MCL pts treated from January 2008 to December 2013 with the following regimen: i.v. Bortezomib 1.6 mg/m2 on days 1, 8, 15 and 22 of a 35-days cycle for 6 cycles; i.v. Rituximab 375 mg/m2 administered on the same treatment days for 2 cycles. The aims of this study are an analysis of efficacy (in terms of ORR, CRR, PFS, DOR, OS) and of (hematological and non hematological) toxicity. Response to treatment was evaluated by chest-abdomen and pelvis CT scan; for the evaluation of response Cheson 2007 criteria were applied. Patients also underwent bone marrow evaluation and endoscopy, if positive at baseline.Results.Nineteen pts were treated according to the R+B regimen. Pts' characteristics are summarized in table 1. A median of 4.5 cycles were administered (range 1-6).Efficacy analysis . The ORR was 63% (12 pts) and the CRR was 53% (10 pts), while one pt experienced a stable disease and in the remaining 6 cases a progression of disease was observed. The median PFS and OS (Figure 1) were 32,6 and 45,7 months respectively, while median DOR was 28,6 months (with no significant differences between pts reaching CR or PR after treatment).Toxicity analysis . Grade (g) 3-4 neutropenia was observed in 6/19 pts but no cases of FN were observed, even if 14/19 pts received some G-CSF prophylaxis. One pt with g3 anemia at the start of R+B treatment experienced g4 anemia and received multiple RBC support, while g3 and 4 thrombocytopenia were experienced by 3 pts and 1 pt respectively with no major bleeding events and no need for transfusions. The most frequent extra hematological toxicities were gastrointestinal (6 pts; all g1), neurological (5 pts; 3 g2 and 2 g1), asthenia (4 pts; 2 g2 and 2 g1), while 4 pts experienced infections (1 g1, 2 g2, 1 g3). Because of toxicity, 7 pts had a dose reduction (mainly related to neurological symptoms) and 9 pts experienced some delay in treatment administration or single-day treatment interruption. There were no deaths related to hematological or non-hematological toxicity.Conclusion.Even in the era of the new drugs for the treatment of R/R MCL, R+B still represents an attractive treatment option due to its high efficacy and its low toxicity profile and should be strongly considered in the armamentarium of MCL therapies that should be offered to our pts [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets.

Schistosomes are responsible for the parasitic disease schistosomiasis, an acute and chronic parasitic ailment that affects >240 million people in 70 countries worldwide. It is the second most devastating parasitic disease after malaria. At least 200,000 deaths per year are associated with the disease. In the absence of the availability of vaccines, chemotherapy is the main stay for combating schistosomiasis. The antischistosomal arsenal is currently limited to a single drug, Praziquantel, which is quite effective with a single-day treatment and virtually no host-toxicity. Recently, however, the question of reduced activity of Praziquantel has been raised. Therefore, the search for alternative antischistosomal drugs merits the study of new approaches of chemotherapy. The rational design of a drug is usually based on biochemical and physiological differences between pathogens and host. Pyrimidine metabolism is an excellent target for such studies. Schistosomes, unlike most of the host tissues, require a very active pyrimidine metabolism for the synthesis of DNA and RNA. This is essential for the production of the enormous numbers of eggs deposited daily by the parasite to which the granulomas response precipitates the pathogenesis of schistosomiasis. Furthermore, there are sufficient differences between corresponding enzymes of pyrimidine metabolism from the host and the parasite that can be exploited to design specific inhibitors or "subversive substrates" for the parasitic enzymes. Specificities of pyrimidine transport also diverge significantly between parasites and their mammalian host. This review deals with studies on pyrimidine metabolism in schistosomes and highlights the unique characteristic of this metabolism that could constitute excellent potential targets for the design of safe and effective antischistosomal drugs. In addition, pyrimidine metabolism in schistosomes is compared with that in other parasites where studies on pyrimidine metabolism have been more elaborate, in the hope of providing leads on how to identify likely chemotherapeutic targets which have not been looked at in schistosomes.

Retinal Neuroprotective Effects of Flibanserin, an FDA-Approved Dual Serotonin Receptor Agonist-Antagonist.

PurposeTo assess the neuroprotective effects of flibanserin (formerly BIMT-17), a dual 5-HT1A agonist and 5-HT2A antagonist, in a light-induced retinopathy model.MethodsAlbino BALB/c mice were injected intraperitoneally with either vehicle or increasing doses of flibanserin ranging from 0.75 to 15 mg/kg flibanserin. To assess 5-HT1A-mediated effects, BALB/c mice were injected with 10 mg/kg WAY 100635, a 5-HT1A antagonist, prior to 6 mg/kg flibanserin and 5-HT1A knockout mice were injected with 6 mg/kg flibanserin. Injections were administered once immediately prior to light exposure or over the course of five days. Light exposure lasted for one hour at an intensity of 10,000 lux. Retinal structure was assessed using spectral domain optical coherence tomography and retinal function was assessed using electroretinography. To investigate the mechanisms of flibanserin-mediated neuroprotection, gene expression, measured by RT-qPCR, was assessed following five days of daily 15 mg/kg flibanserin injections.ResultsA five-day treatment regimen of 3 to 15 mg/kg of flibanserin significantly preserved outer retinal structure and function in a dose-dependent manner. Additionally, a single-day treatment regimen of 6 to 15 mg/kg of flibanserin still provided significant protection. The action of flibanserin was hindered by the 5-HT1A antagonist, WAY 100635, and was not effective in 5-HT1A knockout mice. Creb, c-Jun, c-Fos, Bcl-2, Cast1, Nqo1, Sod1, and Cat were significantly increased in flibanserin-injected mice versus vehicle-injected mice.ConclusionsIntraperitoneal delivery of flibanserin in a light-induced retinopathy mouse model provides retinal neuroprotection. Mechanistic data suggests that this effect is mediated through 5-HT1A receptors and that flibanserin augments the expression of genes capable of reducing mitochondrial dysfunction and oxidative stress. Since flibanserin is already FDA-approved for other indications, the potential to repurpose this drug for treating retinal degenerations merits further investigation.

Efficacy of mitiglinide and sitagliptin, alone or in combination, on postprandial excursion and glycemic variability assessed by continuous glucose monitoring: a post hoc analysis with single-day treatment

Objective: To compare the efficacy of mitiglinide and sitagliptin, alone or in combination, on postprandial excursion and glycemic variability assessed by continuous glucose monitoring (CGM) in a single-day treatment setting.Methods: This was a post hoc analysis of a randomized crossover study comparing the efficacy of sitagliptin, mitiglinide and the combination of these two drugs. Twenty-four hour CGM was performed before and after a single-day treatment with each drug alone or in combination.Results: Mean glucose levels were decreased in all groups. The average of three postprandial glucose excursions AUC (average of all three 4-h postprandial periods throughout the day) (AUCpp-average) decreased in the mitiglinide and combination treatment groups, but not in the sitagliptin group. The lowering effect on AUCpp-average was greater in patients given mitiglinide (–47 mg/dl, p < 0.001) or combination treatment (–66 mg/dl, p < 0.001) compared with sitagliptin alone (–18 mg/dl). The reduction in mean amplitude of glycemic excursion was greater with mitiglinide (–29.3 mg/dl, p < 0.001) and combination treatment (–28.3 mg/dl, p < 0.01) than with sitagliptin alone (–8.9 mg/dl).Conclusions: Mitiglinide or combination treatment resulted in lower glycemic variability and postprandial glucose excursion than sitagliptin alone; however, the results of this single-day pharmacodynamics study cannot be generalized to a clinical setting.

A Single-Day Treatment with Mifepristone Is Sufficient to Normalize Chronic Glucocorticoid Induced Suppression of Hippocampal Cell Proliferation

BackgroundChronic stress or prolonged administration of glucocorticoids suppresses proliferation and/or survival of newborn cells in adult rat dentate gyrus. Earlier we showed that administration of the glucocorticoid receptor antagonist mifepristone during the final 4 days of a 21 days period of corticosterone treatment fully normalized the number of newborn cells. Here we aimed to better understand how mifepristone achieves this effect and questioned whether an even shorter (single day) mifepristone treatment (instead of 4 days) also suffices to normalize neurogenesis.MethodsWe investigated various steps of the neurogenic process, using the immunohistochemical markers BrdU, doublecortin, proliferating cell nuclear antigen as well as glial fibrillary acidic protein, after 17 or 21 days of corticosterone (versus vehicle) treatment.ResultsCorticosterone primarily attenuates the proliferation of cells which subsequently develop into neurons; this is fully reversed by mifepristone. Surprisingly, the corticosteroid effects on neurogenesis can even be fully re-set by a single-day treatment with mifepristone (on day 18), despite the continued corticosterone exposure on subsequent days.ConclusionsOur results emphasize that studies into the therapeutical efficacy of new antidepressants, especially those targeting HPA-activity or the glucocorticoid receptor, should explore the possibility to reduce treatment duration.

Abstract 1276: A novel targeted oral insulin-like growth factor 1 (IGF-1) receptor inhibitor and its implications for patients with squamous cell lung carcinoma

Abstract Background The incidence of lung cancer has increased throughout the twentieth century and is today the most common cancer in the Western World. Lung cancer is divided into two major histological subtypes, non-small cell lung cancer (NSCLC) accounting for approximately 80% of all lung cancer cases and small cell lung cancer (SCLC) accounting for approximately 20 % of all lung cancer cases. The median age at diagnosis is 68 years for patients with non-small cell lung cancer (NSCLC) and 20% of lung cancer deaths occur in patients aged 80 or more. The overall objective of the present abstract is to identify a novel compound targeting the Insulin-Like Growth Factor 1 receptor (IGF-1R) without influencing the closely related Insulin receptor and its impact in patients with especially NSCLC. Methods AXL1717 is a compound that has been optimized to inhibit the IGF-1R without inhibiting closely related receptors including IR. AXL1717 is presently studied in a Phase I/II clinical trial on advanced-stage cancer patients with progressive solid tumors and no remaining treatment options. The primary objective of the study is to identify and confirm a recommended Phase II dose. AXL1717 has been administered every third week as a single-day BID oral treatment in consecutively increasing doses as the only treatment with anti-tumor efficacy. Doses have been increased both within and between patients. The single-day oral dosing part of the ongoing Phase I/II clinical trial on cancer patients with AXL1717 has successfully been concluded. The results show that AXL1717 can be administered as a single-day BID treatment in very high doses with excellent tolerability. Dose-limiting toxicity has not been reported. The second part of the study is ongoing where consecutive cohorts of advanced-stage cancer patients are given 7-28 days of increasing BID doses of AXL1717. Results In the present abstract we describe our experience with the four patients with progressive squamous non-small cell lung cancer (NSCLC) that have received treatment with AXL 1717. Despite the fact that at inclusion these patients had already received third or fourth line treatment, treatment with AXL1717 resulted in more than seven months of treatment response within the study protocol and the reported patients did not develop any additional metastases. Furthermore, these patients demonstrated large central necrotic areas, which may suggest tumor response. Conclusion This first clinical study of AXL1717 has shown that the agent can be administrated safely orally to advanced stage cancer patients resulting in good bioavailability and tolerability. Encouraging signs of tumor response were seen in patients with NSCLC. Further update of these patients as well as a compilation of all included patients with NSCLC, as well as their toxicity, will be reported at the meeting Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1276. doi:10.1158/1538-7445.AM2011-1276

Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: An assessment of clinical potential

The purpose of this analysis was to assess the potential of BNCT, with L-boronophenylalanine (L-BPA), as first line radiotherapy for glioblastoma multiforme (GBM). The survival of patients with newly diagnosed GBM from a phase II BNCT study was compared with those from the two arms of a phase III study with conventional radiotherapy (RT) vs. RT plus concomitant and adjuvant medication with temozolomide (TMZ). A small subgroup, for which the methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) DNA-repair gene was known, was also considered. The results indicated that the use of BNCT with BPA should be explored in a stratified randomized phase II trial in which patients with the unmethylated MGMT DNA-repair gene are offered BNCT vs. RT plus TMZ.

Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: an assessment of clinical potential

The purpose of this study was to assess the potential of boron neutron capture therapy (BNCT), with a 6-h infusion of the boron carrier l-boronophenylalanine as a fructose preparation (BPA-f), as first-line radiotherapy for newly diagnosed glioblastoma multiforme (GBM). Patient survival data from a Phase II study using BNCT were compared with retrospective data from the two arms of a Phase III study using conventional radiotherapy (RT) in the reference arm and using RT plus concomitant and adjuvant medication with temozolomide (TMZ) in the experimental arm, and were also compared with small subgroups of these patients for whom the methylation status of the MGMT (O(6)-methylguanine-DNA methyltransferase) DNA repair gene was known. Differences in the baseline characteristics, salvage therapy after recurrence and levels of severe adverse events were also considered. The results indicate that BNCT offers a treatment that is at least as effective as conventional RT alone. For patients with an unmethylated MGMT DNA repair gene, a possible clinical advantage of BNCT over RT/TMZ was suggested. BNCT is a single-day treatment, which is of convenience to patients, with mild side effects, which would offer an initial 6 weeks of good-quality life during the time when patients would otherwise be undergoing daily treatments with RT and TMZ. It is suggested that the use of BNCT with a 6-h infusion of BPA-f should be explored in a stratified randomised Phase II trial in which patients with the unmethylated MGMT DNA repair gene are offered BNCT in the experimental arm and RT plus TMZ in the reference arm.

Boron Neutron Capture Therapy for glioblastoma multiforme: advantage of prolonged infusion of BPA-f

To assess possible improved efficacy of Boron Neutron Capture Therapy (BNCT) for glioblastoma multiforme (GBM) using prolonged infusion and a correspondingly higher dose of l-boronophenylalanine, as the fructose complex (BPA-f). The benefit of prolonged infusion was analyzed by comparing the results from a Phase II study using 6 h infusion of BPA-f with those obtained from a Phase I/II study using 2 h of infusion. Median survival time (MST) from diagnosis, patient baseline characteristics, salvage treatment and severe adverse events were considered in the comparison. MST increased significantly, from 12.8 (95% confidence interval or CI: 10.3-14.0) months with 2 h infusion to 17.7 (95% CI: 13.6-19.9) months with 6 h of infusion. The fraction of patients with WHO grade 3-4 adverse events was similar in the two studies at 13% and 14%, respectively. Prolonged infusion was found to be beneficial for the efficacy of BNCT and it is suggested that 6 h infusion of BPA-f should be used in future trials of BNCT for GBM. BNCT, which is a single-day treatment with mild side effects, should be assessed in a controlled trial, as an alternative to 30 daily fractions of conventional fractionated photon therapy over a period of 6 weeks.

Effect of multiple- and single-day enrofloxacin medications against dual experimental infection with avian pneumovirus and Escherichia coli in turkeys

Escherichia coli infections are a common cause of respiratory disease in turkeys. To control these respiratory infections in turkeys, drinking water treatment with enrofloxacin is widely used. The current treatment schedule advises a 5-d treatment at 10 mg/kg of BW. Because enrofloxacin exerts a concentration-dependent activity, it might be useful to provide this 50 mg/kg total dose in a single-day treatment regimen. Therefore, we assessed whether a single-day treatment schedule with 50 mg/kg of BW was clinically equivalent to the advised multiple-day treatment schedule with 10 mg/kg of BW for 5 d. For this purpose, 3 groups of seventeen 22-d-old turkeys were experimentally inoculated with avian metapneumovirus and 3 d later with E. coli. One group received 10 mg of enrofloxacin/kg of BW in the drinking water for 5 successive days. The second group received 50 mg of enrofloxacin/kg of BW for 20 h in the drinking water. The third group was enclosed as an untreated positive control group. Both the multiple- and the single-day enrofloxacin treatment regimens reduced E. coli multiplication in the respiratory tract tissues (turbinates, trachea and lung), but the 5-d treatment with 10 mg of enrofloxacin/kg in turkeys provided the best results by shortening the course of clinical disease, by eliminating E. coli from the respiratory tract without remultiplication, and by reducing macroscopic lesions. The efficacy of the single-day treatment did not equal that of the 5-d treatment, possibly by not eliminating E. coli from the respiratory organs, which made it possible for the remaining bacteria to reemerge in those organs. None of the used treatment regimens promoted the selection of bacterial clones with reduced susceptibility or resistance.

Efficacy of four enrofloxacin treatment regimens against experimental infection in turkey poults with avian pneumovirus and Ornithobacterium rhinotracheale

Drinking-water treatment with enrofloxacin is widely used to cure respiratory infections in turkeys. The current treatment regimen advises a 5-day treatment at 10 mg/kg body weight. Since enrofloxacin exerts a concentration-dependent activity it might be useful to provide the total treatment dose of 50 mg/kg total dose in a single-day treatment regimen. We therefore assessed whether single-day treatment regimens with 50 mg/kg body weight were clinically equivalent to the advised multiple-day treatment regimen with 10 mg/kg body weight for 5 days. For this purpose, five groups of 16 turkeys, 22 days old, were experimentally inoculated with avian metapneumovirus (APV) and Ornithobacterium rhinotracheale and subsequently treated in the drinking water with enrofloxacin, using either a single-day treatment regimen at 50 mg/kg body weight during a 5-h, 10-h or 20-h period or a standard 5-day treatment regimen at 10 mg/kg body weight/ day for 20 h. Although initially all dosage regimens cleared O. rhinotracheale from the trachea, 4 days after onset of treatment O. rhinotracheale bacteria were re-excreted in the single-day regimens but without worsening of the clinical symptoms. The 5-day treatment with 10 mg enrofloxacin/kg in turkeys provided the best results for the treatment of an O. rhinotracheale infection in turkeys by shortening the course and reducing the severity of clinical disease and by eliminating O. rhinotracheale from the respiratory tract without re-emergence. None of the used treatment regimens promoted the selection of bacterial clones with reduced susceptibility or resistance.

Comparison of the efficacy and safety of arformoterol 15 μg twice daily and arformoterol 30 μg once daily in COPD: A single-dose, multicenter, randomized, modified-blind, two-way crossover study

Objective: The aim of this study was to compare the efficacy and safety of nebulized arformoterol 15 μg/2 mL twice daily (ARF15 BID) and 30 μg/4 mL once daily (ARF30 QD) in subjects with moderate to severe chronic obstructive pulmonary disease (COPD). Methods: In this single-dose, multicenter, randomized, modified-blind, 2-way crossover study, subjects aged ≥45 years with moderate to severe COPD, a forced expiratory volume in 1 second (FEV 1) ≥0.7 L, and ≤65% predicted FEV1, and a FEV 1:forced vital capacity ratio ≤70% were randomly assigned to receive single-day treatment with ARF15 BID or ARF30 QD in random order, separated by a 5 ± 2-day washout period. The primary efficacy end point was time-normalized AUC of FEV 1 from baseline (hour 0) to 24 hours (FEV 1AUC 0–24). Secondary efficacy end points were time-normalized AUC of FEV 1 from baseline to 12 hours (FEV 1AUC 0–12) and from 12 to 24 hours (FEV 1AUC 12–24), and FEV 1 at 24 hours after administration of the morning dose (trough FEV 1). Equivalence of the 2 therapies was assessed by comparing the 90% CI value for the difference of the least squares mean (LSM) to a study-specific predefined equivalence range for change in FEV 1AUC 0–24 of −0.07 to 0.07 L. Results: A total of 33 subjects were enrolled (20 men, 13 women; mean [SD] age, 64.5 [8.8] years; 15 subjects received ARF15 BID first; 18 received ARF30 QD first). ARF15 BID and ARF30 QD were associated with similar improvements from baseline in (FEV 1AUC 0–24, LSM 0.15 and 0.16 L, respectively; Δ, 0.01 L; 90% CI, −0.02 to 0.04) and trough FEV 1 (LSM, 0.15 and 0.12 L, respectively; Δ, −0.03 L; 90% CI, −0.09 to 0.03). FEV 1AUC 0–12 was improved more with ARF30 QD than ARF15 BID (Δ, 0.06 L; 90% CI, 0.04 to 0.09), and FEV 1AUC 12–24 was improved more with ARF15 BID than ARF30 Qd (Δ, −0.04 L; 90% CI, −0.08 to 0.01). The 90% CI for FEV 1AUC 0–24 for the treatment difference between ARF15 BID and ARF30 QD was within the prespecified range of −0.07 to 0.07 L, indicating that both treatments resulted in equivalent FEV 1AUC 0–24 values. Conclusions: In these subjects with moderate to severe COPD, single-day administrations of ARF15 BID or ARF30 QD were associated with FEV 1 responses over a period of 24 hours that were considered equivalent per the protocol definition employed in the present study. FEV1 improvement over 12 hours was greater for ARF30 QD after the morning dose and for ARF15 BID after the evening dose. ClinicalTrials.gov Identifier: NCT00571428

Single-day treatment for orolabial and genital herpes: a brief review of pathogenesis and pharmacology

Herpes simplex virus (HSV) infection is a highly prevalent condition responsible for significant morbidity and occasional mortality each year. Approximately half of all patients infected by HSV will experience at least one recurrence in their lifetime. For these recurrences, traditional therapy has included both suppressive and episodic treatment with nucleoside analogs. In regards to episodic treatment, 2- to 5-day oral regimens are best studied and most commonly reported. As with any medical condition having a well-understood mechanism of action and targeted treatment, therapeutic intervention is only as effective as allowed by patient compliance. Based on these concerns, recent studies have focused on shorter, less complicated, and more affordable options. This review delineates the evidence for single-day treatments of orolabial and genital herpes. Randomized, double-blind studies of both valacyclovir and famciclovir as single-day episodic therapy for HSV have been reported in the literature. Although no head-to-head studies between the drugs have been performed, both regimens produced significant improvement in healing time and symptom resolution over placebo. Single-day therapy for HSV infection is appealing for multiple reasons. First, it simplifies the regimen, increasing likelihood of patient compliance. Additionally, it allows complete delivery of the medication at the onset of symptoms, when viral replication is highest and intervention has greatest effect. Lastly, the reduced number of pills necessary for single versus multiple day therapy decreases the overall cost of treatment per episode, an important factor in modern-day healthcare.

Famciclovir for recurrent genital herpes

Recurrent genital herpes is a significant problem for patients worldwide. Not only is the infection painful, but patients are affected by its emotional and psychological burden. Famciclovir, an orally administered prodrug of the antiviral agent penciclovir, is an excellent option for patients with recurrent genital herpes. While genital herpes has no cure, infected patients can treat their outbreaks episodically or they can choose suppressive therapy. Famciclovir can be used in both cases. Famciclovir has a safety profile that is comparable to placebo, acyclovir and valacyclovir, and is the only oral antiviral that has been proven effective to date in preventing a full herpes outbreak using a single-day treatment.

Bronchodilation of formoterol administered with budesonide: Device and formulation effects

Background Previous single-dose crossover studies have established therapeutic equivalence of formoterol when administered at the same nominal dose via a dry powder inhaler (DPI) or pressurized hydrofluoroalkane (HFA) metered-dose inhaler (pMDI). Demonstration of equivalent bronchodilation for formoterol administered as formoterol DPI or combined with budesonide in one pMDI (budesonide/formoterol pMDI) would indicate that the greater clinical efficacy of the budesonide/formoterol pMDI combination is due to the budesonide contribution and not to differences in formoterol formulation or delivery device. Objective To determine whether the formoterol-related bronchodilatory effects of formoterol DPI and budesonide/formoterol pMDI are similar, despite formoterol formulation and delivery device differences. Methods This was a multicenter, open-label, five-period crossover study conducted in 201 adult patients with stable asthma. The study included a screening visit, a 7- to 14-day run-in period, during which patients were treated with budesonide pMDI (80 μg per inhalation, two inhalations twice daily), and a randomized treatment period that included five single-day treatment periods, during which patients received single-dose crossover treatments, each of which was separated by a 3- to 14-day washout period. Patients were randomized to five of seven single-dose treatments (one, two, or four inhalations of budesonide/formoterol pMDI 80/4.5 μg; four inhalations of budesonide pMDI 80 μg plus one, two, or four inhalations of formoterol DPI 4.5 μg; or four inhalations of budesonide pMDI 80 μg alone). At clinic visits, the budesonide pMDI dose was coordinated with the budesonide dose delivered via the budesonide/formoterol pMDI such that all patients received a 320-μg dose of budesonide. The primary variable was average forced expiratory volume in 1 s (FEV 1) from the area under the curve divided by time from 12-h serial spirometry. Results Average 12-h FEV 1 values were similar, regardless of delivery device, among treatments with the same nominal formoterol doses and dose-ordered within each device; mean FEV 1 values were significantly higher for treatments containing formoterol versus budesonide alone. The formoterol dose potency ratio for budesonide/formoterol pMDI:formoterol DPI (0.97; 95% confidence interval, 0.73–1.27) demonstrated clinical equivalence in bronchodilation at the same formoterol dose. Conclusion Budesonide/formoterol pMDI affords equivalent formoterol-related bronchodilatory effects versus formoterol DPI at formoterol doses of 4.5, 9, and 18 μg, indicating that practitioners can expect and patients will experience similar bronchodilation from the same dose of formoterol whether it is delivered as monotherapy via a DPI or as combination therapy with budesonide via one pMDI.

Famciclovir for the treatment of recurrent genital herpes: a clinical and pharmacological perspective

Herpes simplex virus is one of the most common causes of genital ulcer disease worldwide. Herpes simplex virus-2 is the more common cause of genital herpes, a chronic infection that is characterised by periodic reactivation, with the capacity to produce recurrent symptomatic disease in the host (e.g., vesicular eruption), as well as intermittent asymptomatic shedding. Relapsing episodes may be physically and psychologically distressing. Shedding accounts for the majority of cases of transmission of genital herpes to sexual partners. Pregnant women who are shedding may transmit the virus at the time of delivery, with severe and potentially fatal consequences to the baby. Famciclovir, a synthetic acyclic guanine derivative, is the prodrug of penciclovir, which demonstrates in vitro antiviral activity against various types of herpes virus, including herpes simplex virus-2. Its pharmacokinetics allow for administration in a convenient dosing regimen compared with acyclovir, which may improve compliance. Clinical studies have demonstrated its efficacy in the episodic treatment of relapses, with the most recent report demonstrating its efficacy and tolerance as a single-day treatment. It is also efficacious and well tolerated for the suppression of frequently recurring episodes. These results have been demonstrated in various patient populations, including immunocompetent patients and those infected with HIV. Famciclovir is well tolerated, with an adverse events profile similar to placebo.

Single-day therapy: an expert opinion on a recent development for the episodic treatment of recurrent genital herpes.

One common method for treating recurrent genital herpes outbreaks is 3–5 day episodic therapy with nucleoside analogues. However, since maximum viral replication occurs within 24 h after the onset of symptoms, short-term patient-initiated episodic therapy started at prodromal onset or at the first appearance of lesions in patients without a prodrome may represent an important option. In a recent randomized trial, single-day famciclovir treatment decreased lesion healing time and the duration of pain and other symptoms by approximately 2 days compared to placebo, and prevented progression to a full outbreak in almost one in four patients. Because single-day treatment is more convenient than traditional therapies, it may lead to improved patient compliance and better overall management of recurrent genital herpes outbreaks.

Single-Day Therapy for Recurrent Genital Herpes

Genital herpes, an incurable viral disease that can have a devastating impact on affected patients, is a serious public health concern affecting one in four Americans. Episodic treatment with nucleoside analogs for 3-5 days is the most common method of treatment; however, since maximum viral replication occurs within 24 hours after the onset of symptoms, single-day patient-initiated episodic treatment may be a better option. A recent study evaluated the effectiveness of patient-initiated single-day famciclovir versus placebo in the treatment of genital herpes and found that single-day famciclovir decreased healing time and the duration of pain and other symptoms, and increased the proportion of patients who did not progress to a full outbreak. Compared with previous studies, the results of single-day therapy are similar to or better than the results of conventional therapies of 2-5 days' duration. In addition, the convenience of single-day treatment may lead to greater patient adherence and improved overall management of recurrent herpes outbreaks.

Pimecrolimus does not affect Langerhans cells in murine epidermis.

Langerhans cells (LCs) function as specialized antigen-presenting cells in the epidermis, and therefore play a critical role in cutaneous immunological reactions. Topical treatment with corticosteroids is associated with a decrease in epidermal LC number and antigen-presenting capacity in laboratory animals and humans. To examine whether pimecrolimus, a nonsteroidal inflammatory cytokine inhibitor recently introduced for the topical treatment of atopic dermatitis, differs from corticosteroids in effects on LCs. Groups of BALB/c mice were treated twice daily on one to five consecutive days on the inner surface of the right ear with 10 micro L of ethanolic solutions of the test compounds at their clinically used concentrations (1% pimecrolimus, 0.1% betamethasone-17-valerate, 1% hydrocortisone and 0.05% clobetasol propionate) or with the vehicle (controls) alone. At selected time points after the treatment epidermal sheets were prepared and examined histomorphometrically for LCs immunolabelled with antibodies to major histocompatibility complex (MHC) class II and DEC 205, and adenosine diphosphatase staining. No changes in number or morphology of LCs were observed in epidermal sheets of mice treated for 5 days with pimecrolimus. In contrast, an almost complete depletion of LCs was observed in skin samples treated with hydrocortisone, betamethasone or clobetasol. Even a single-day treatment schedule with hydrocortisone, betamethasone or clobetasol caused a significant reduction in MHC class II+ LCs, by 31%, 62% and 87%, respectively. It is therefore unlikely that topically applied pimecrolimus affects epidermal LCs, in contrast to corticosteroids.