Pharmacokinetics, safety and preliminary pharmacodynamic evaluation of DARE-VVA1: a soft gelatin capsule containing tamoxifen for the treatment of vulvovaginal atrophy.

OBJECTIVE: This study aimed to measure safety, systemic pharmacokinetics and preliminary efficacy of a vaginal tamoxifen capsule (DARE-VVA1) among postmenopausal women with moderate-to-severe vulvovaginal atrophy. METHODS: This was a randomized, placebo-controlled, double-blind, phase 1/2 study of DARE-VVA1, in four doses (1, 5, 10 and 20 mg). RESULTS: Seventeen women were enrolled and 14 completed the 8-week treatment. DARE-VVA1 was safe. All adverse events were of mild or moderate severity and distributed similarly among active and placebo groups. Plasma tamoxifen concentrations were highest among women using DARE-VVA1 20 mg, but the maximum mean (standard deviation) plasma tamoxifen concentrations on day 1 (2.66 ± 0.85 ng/ml) and day 56 (5.69 ± 1.87 ng/ml) were <14% of those measured after one oral tamoxifen dose. Active study product users had significant decreases from pre-treatment baseline in vaginal pH and proportion of vaginal parabasal cells (p = 0.04 for both endpoints), with women randomized to the 10 mg or 20 mg dose experiencing the largest treatment impact. The severity of vaginal dryness and dyspareunia decreased significantly from baseline with active study product use (p = 0.02 for both endpoints). CONCLUSIONS: DARE-VVA1 is safe and results in minimal systemic exposure to tamoxifen. Preliminary efficacy data support further development of this product.

A simple extemporaneous oral suspension of aprepitant yields sufficient pharmacokinetic exposure in children.

INTRODUCTION: Aprepitant is used for the treatment of chemotherapy induced nausea and vomiting. A liquid formulation is needed for treatment of young children. However, the commercial (powder for) suspension was not available worldwide for a prolonged period of time and, therefore, a 10 mg/mL aprepitant oral suspension was extemporarily prepared to prevent suboptimal antiemetic treatment. The current pharmacokinetic study was developed to investigate whether this extemporaneous oral suspension offers an appropriate treatment option. METHODS: From 49 pediatric patients (0.7-17.9 years) 235 plasma concentrations were collected. Patients were either treated with our extemporaneous oral suspension (n = 26; 53%), commercially available capsules (n = 18; 37%), or the intravenous prodrug formulation of aprepitant (fosaprepitant, n = 5; 10%). Pharmacokinetic analyses were performed using nonlinear mixed effects modelling. RESULTS: A one-compartment model adequately described the pharmacokinetics of aprepitant in children. The bioavailability of the extemporaneous oral suspension was not significantly different to that of the capsules (P = 0.26). The observed bioavailability throughout the total population was 83% (95% CI 69%-97%). The absorption of the extemporaneous oral suspension was 39.4% (95%CI 19.5-57.4%) faster than that of capsules (mean absorption time of 1.78 h (95%CI 1.32-2.35), but was comparable to that of the commercial oral suspension. The median area under the curve after (fos)aprepitant was 22.2 mg/L*h (range 8.9-50.3 mg/L*h) on day 1. CONCLUSION: Our extemporaneous oral suspension is an adequate alternative for the commercially (un)available oral suspension in young children. An adequate exposure to aprepitant in children was yielded and the bioavailability of the extemporaneous suspension was comparable to capsules.

Sonosensitive capsules for brain thrombolysis increase ischemic damage in a stroke model.

BACKGROUND: Ischemic stroke is the most common cerebrovascular disease and is caused by interruption of blood supply to the brain. To date, recombinant tissue plasminogen activator (rtPA) has been the main pharmacological treatment in the acute phase. However, this treatment has some drawbacks, such as a short half-life, low reperfusion rate, risk of hemorrhagic transformations, and neurotoxic effects. To overcome the limitations of rtPA and improve its effectiveness, we recently designed sonosensitive sub-micrometric capsules (SCs) loaded with rtPA with a size of approximately 600 nm, synthesized using the layer-by-layer (LbL) technique, and coated with gelatine for clot targeting. In this study, we evaluated the rtPA release of ultrasound (US)-responsive SCs in healthy mice and the therapeutic effect in a thromboembolic stroke model. RESULTS: In healthy mice, SCs loaded with rtPA 1 mg/kg responded properly to external US exposure, extending the half-life of the drug in the blood stream more than the group treated with free rtPA solution. The gelatine coating also contributed to stabilizing the encapsulation and maintaining the response to US. When the same particles were administered in the stroke model, these SCs appeared to aggregate in the ischemic brain region, probably generating secondary embolisms and limiting the thrombolytic effect of rtPA. Despite the promising results of these thrombolytic particles, at least under the dose and size conditions used in this study, the administration of these capsules represents a risk factor for stroke. CONCLUSIONS: This is the first study to report the aggregation risk of a drug carrier in neurological pathologies such as stroke. Biocompatibility analysis related to the use of nano-and microparticles should be deeply studied to anticipate the limitations and orientate the design of new nanoparticles for translation to humans.

Capsule-related dysphagia and the use of netupitant/palonosetron (Akynzeo™) capsules - A report of two cases and a solution.

Netupitant/palonestron (NEPA, Akynzeo™) is a fixed combination of netupitant 300 mg and palonosetron 0.5 mg that is indicated for the prevention of chemotherapy-induced nausea and vomiting (CINV). NEPA is supplied as a hard gelatin capsule and indicated to be administered whole with or without food. The efficacy of NEPA was maintained when administered as an oral dose of netupitant given concomitantly (in separate formulations after removal from the hard gelatin capsule) with a single oral dose of palonosetron. At our institution, two patients experienced difficulty swallowing the capsule leading to opening the capsule and individual administration of the medications. We observed that the efficacy was maintained when the opened NEPA capsule was administered as individual medications. We report the details of these two patient cases.

Antidiarrheal pill in the airway.

Pill aspiration depicts an unusual type of foreign body aspiration necessitating a discrete diagnostic and therapeutic approach.1 Some pills may remain intact in the endobronchial tree for many years without causing much harm, whereas others may dissolve2 The clinical outcomes may also vary, from an asymptomatic granuloma to severe, life-threatening airway complications, depending upon the chemical properties of the pill. We report a compelling case of pill aspiration in a healthy patient.

Real-Time and Wireless Assessment of Adherence to Antiretroviral Therapy With Co-Encapsulated Ingestion Sensor in HIV-Infected Patients: A Pilot Study.

Adherence with antiretroviral therapy is important for preventing disease progression and HIV transmission. The co-encapsulated pill sensor system sends a signal through a cutaneous patch and allows real-time monitoring of pill ingestion. A 16-week pilot study used a sensor system in 15 HIV-infected individuals with real-time monitoring of pill-taking with a personalized short message system text. System acceptability was assessed by survey at weeks 4, 8, 12, and 16. Follow-up occurred in 80% of subjects through 8 weeks. The system effectively collected measures of pill ingestion, which triggered text message reminders. Only 2 of 14 participants stated that co-encapsulated pills were "unable to take" or "poorly tolerated." At least 75% of respondents stated at each visit that the patch was very or somewhat comfortable. With regard to text message reminders, only 10-15% of the participants at any visit did not find the messages to be helpful. Larger studies will define the utility of this system to assess antiretroviral adherence relative to standard measures.

Comparative phase I randomized open-label pilot clinical trial of Gynophilus® (Lcr regenerans®) immediate release capsules versus slow release muco-adhesive tablets.

Gynophilus® (Lcr regenerans®) is a live biotherapeutic product (LBP) that contains the live biotherapeutic microorganism Lactobacillus rhamnosus Lcr35®, which is indicated to restore vaginal health. The aim of the study was to compare the safety, ease of use, and compliance of two formulations (immediate release: IR capsule and slow release: SR muco-adhesive tablets) as well as the colonization of Lcr35® in healthy women. This phase I study (Comprigel) is a parallel, randomized, 4-arm, and open-label clinical trial evaluating an IR daily capsule formulation vs. a SR tablet administered every 3, 4, or 5 days for 21 days. Self-collected vaginal swabs were used to quantify Lcr35® and characterize the composition and structure of the vaginal microbiota. Both LBPs were well-tolerated, and no severe adverse effects were reported. All groups had Lcr35® vaginal concentrations over 107 colony forming unit per milliliter of vaginal secretion on each day in the study. The new Gynophilus® slow release tablets administered either every 3, 4, or 5 days provided vaginal concentrations that were not significantly different from those of classic Gynophilus® (capsule) once-a-day regimen. The LBPs and the different regimens did not adversely influence the abundance of native Lactobacillus spp. and indeed tended to favor their growth and reduce colonization by non-Lactobacillus spp. This study illustrates that the SR muco-adhesive LBP tablet (Gynophilus® SR) administered every 3 or 4 days as a safe, well-tolerated, and efficacious alternative to a more demanding IR daily capsule and could protect women's healthy vaginal microbiome by promoting endogenous Lactobacillus spp.

[Crushing or opening medication: what practices, what risks?] / Écrasement ou ouverture des médicaments : quelles pratiques, quels risques ?

The practice of crushing tablets or opening up capsules to be taken orally, when it is not prescribed, can affect the efficacy of a treatment, or even cause an adverse event. A survey carried out in 2016 revealed that this is a common practice, especially among elderly people. However, alternative forms exist and can be prescribed.

A Phase 1 Study to Assess the Relative Bioavailability of Two Capsule Formulations of Ixazomib, an Oral Proteasome Inhibitor, in Patients With Advanced Solid Tumors or Lymphoma.

The oral proteasome inhibitor ixazomib is approved in multiple countries in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. Two oral capsule formulations of ixazomib have been used during clinical development. This randomized, 2-period, 2-sequence crossover study (Clinicaltrials.gov identifier NCT01454076) assessed the relative bioavailability of capsule B in reference to capsule A in adult patients with advanced solid tumors or lymphoma. The study was conducted in 2 parts. In cycle 1 (pharmacokinetic cycle), patients received a 4-mg dose of ixazomib as capsule A or capsule B on day 1, followed by a 4-mg dose of the alternate capsule formulation on day 15. Pharmacokinetic samples were collected over 216 hours postdose. After the pharmacokinetic cycle, patients could continue in the study and receive ixazomib (capsule B only) on days 1, 8, and 15 of each 28-day cycle. Twenty patients were enrolled; of these, 14 were included in the pharmacokinetic-evaluable population. Systemic exposures of ixazomib were similar after administration of capsule A or capsule B. The geometric least-squares mean ratios (capsule B versus capsule A) were 1.16 for Cmax (90% confidence interval [CI], 0.84-1.61) and 1.04 for AUC0-216 (90%CI, 0.91-1.18). The most frequently reported grade 3 drug-related adverse events were fatigue (15%) and nausea (10%); there were no grade 4 drug-related adverse events. These results support the combined analysis of data from studies that used either formulation of ixazomib during development.

Efficacy of three-in-one capsule bismuth quadruple therapy for Helicobacter pylori eradication in clinical practice in a multinational patient population.

BACKGROUND: Bismuth quadruple therapy (BQT) has been proven superior to standard triple therapy for Helicobacter pylori eradication in randomized clinical trials; however, little is known about the efficacy of BQT in daily routine practice. METHODS: In a single-center cohort study, we analyzed consecutive H. pylori-positive patients in whom three-in-one capsule BQT (Pylera® + omeprazole) has been prescribed. All patients were instructed in a standardized fashion, and a prospective follow-up was planned. PCR on gastric biospies for clarithromycin and levofloxacin resistance was performed before treatment in a subgroup of patients. Treatment outcome was assessed by 13C urea breath test or by histology not earlier than 4 weeks after end of treatment. RESULTS: Three-in-one capsule BQT has been prescribed in 322 patients. Approximately 70.2% of patients had a migrational background. PCR results were available in 163 patients and identified resistance to clarithromycin and levofloxacin in 29 (17.8%) and 20 (12.3%) of cases, respectively. BQT was prescribed as first-line, second-line, and salvage treatments in 74%, 17%, and 9% of cases, respectively. Five patients discontinued treatment due to side effects (1.8%). By modified intention-to-treat and per-protocol analyzes, the overall H. pylori eradication rates were 95.0% (95% CI 94.92%-95.08%) and 96.7% (95% CI 94.6%-98.8%), respectively. The low number of treatment failures (n = 9) did not allow to identify risk factors for failure. CONCLUSION: Three-in-one capsule bismuth quadruple therapy is effective and safe for treatment of H. pylori infection in routine practice, irrespective of the patient's migrational background or the number of previous treatment failures.

Evaluation of polyesteramide (PEA) and polyester (PLGA) microspheres as intravitreal drug delivery systems in albino rats.

PURPOSE: To study the suitability of injectable microspheres based on poly(ester amide) (PEA) or poly lactic-co-glycolic acid (PLGA) as potential vehicles for intravitreal drug delivery in rat eyes. Dexamethasone-loaded PEA microspheres (PEA + DEX) were also evaluated. METHODS: Forty male Sprague Dawley rats were divided into four groups that received different intravitreally injected microspheres: PEA group (n = 12); PLGA group (n = 12); PEA + DEX group (n = 8); and control group (no injection, n = 8). Electroretinography (ERG), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (sdOCT) were performed at baseline, weeks 1 and 2, and months 1, 2, and 3 after intravitreal injection. Eyes were histologically examined using light microscopy and transmission electron microscopy at the end of the in vivo study. RESULTS: There were no statistically significant changes in ERG among the groups. Abnormal FAF pattern and abnormal deposits in OCT were observed after injection but almost completely disappeared between week 2 and month 3 in all injected groups. GFAP staining showed that Müller glia cell activation was most pronounced in PLGA-injected eyes. Increased cell death was not observed by TUNEL staining at month 1. In electron microscopy at month 3, the remnants of microparticles were found in the retinal cells of all injected groups, and loss of plasma membrane was seen in the PLGA group. CONCLUSIONS: Although morphological changes such as mild glial activation and material remnants were observed histologically 1 month and 3 months after injection in all injected groups, minor cell damage was noted only in the PLGA group at 3 months after injection. No evidence of functional abnormality relative to untreated eyes could be detected by ERG 3 months after injection in all groups. Changes observed in in vivo imaging such as OCT and FAF disappeared after 3 months in almost all cases.

[Paediatric pharmacobezoar in vitamin overdose]. / Farmacobezoar pediátrico tras sobreingesta de comprimidos vitamínicos.

BACKGROUND: Pharmacobezoars are aggregates of undigested medications that accumulate in the gastrointestinal tract and can cause obstructive or toxic complications. In this paper, the first case is reported of a paediatric pharmacobezoar formation after a vitamin overdose. The objective of this report is to prevent the occurrence of this complication and the action to be taken. CLINIC CASE: A 6-year-old child, 6h after ingesting 40 chewable tablets of a hydrophobic vitamin E with high capacity to form a pharmacobezoar, underwent urgent oesophagogastroscopy. A viscoelastic mass of 10×4cm was observed stretching from the cardia to the greater curvature. Seventy-five percent of the mass was removed and the remainder was fragmented, hydrated and aspirated. The patient remains asymptomatic to date. CONCLUSIONS: An overdose of hydrophobic drugs can produce a bezoar formation therefore prompt evacuation is recommended with an upper gastrointestinal endoscopy, which is a safe and effective technique in gastric bezoars.

Mesenchymal Stem Cell Magnetization: Magnetic Multilayer Microcapsule Uptake, Toxicity, Impact on Functional Properties, and Perspectives for Magnetic Delivery.

Mesenchymal stem cells (MSCs) are widely used in cell therapy due to their convenience, multiline differentiation potential, reproducible protocols, and biological properties. The potential of MSCs to impregnate magnetic microcapsules and their possible influence on cell function and ability to response to magnetic field have been explored. Interestingly, the cells suspended in media show much higher ability in internalization of microcapsules, then MSCs adhere into the surface. There is no significant effect of microcapsules on cell toxicity compared with other cell line-capsule internalization reported in literature. Due to internalization of magnetic capsules by the cells, such cell engineering platform is responsive to external magnetic field, which allows to manipulate MSC migration. Magnetically sorted MSCs are capable to differentiation as confirmed by their conversion to adipogenic and osteogenic cells using standard protocols. There is a minor effect of capsule internalization on cell adhesion, though MSCs are still able to form spheroid made by dozen of thousand MSCs. This work demonstrates the potential of use of microcapsule impregnated MSCs to carry internalized micron-sized vesicles and being navigated with external magnetic signaling.

Imaging of Drug-induced Complications in the Gastrointestinal System.

Drug-induced injury commonly affects the gastrointestinal and hepatobiliary systems because of the mechanisms of absorption and metabolism. In pill esophagitis, injury is frequently related to direct contact with the esophageal mucosa, resulting in small superficial ulcers in the mid esophagus. Nonsteroidal anti-inflammatory drugs can lead to gastrointestinal tract ulcers and small bowel mucosal diaphragms (thin weblike strictures). Injury to the pancreatic and hepatobiliary systems can manifest as pancreatitis, acute or chronic hepatitis, cholestasis, or steatosis and steatohepatitis (which may progress to cirrhosis). Various drugs may also insult the hepatic vasculature, resulting in Budd-Chiari and sinusoidal obstructive syndromes. Focal lesions such as hepatic adenomas may develop after use of oral contraceptives or anabolic steroids. Ultrasonography, computed tomography, and magnetic resonance imaging can aid in diagnosis of drug-induced injuries and often are necessary to exclude other causes.

Cell encapsulation: technical and clinical advances.

Treating many chronic diseases will require a tight, minute-to-minute regulation of therapeutic molecules that is currently not achievable with most pharmaceutical therapies. For these diseases, implantable living cellular systems may be able to provide unlimited drug delivery, enabling seamless matching of treatment duration with disease longevity. Cell encapsulation is an advanced technology that achieves this goal and represents a viable therapeutic option. The advanced state of the field has allowed researchers to inch forward into therapeutic domains previously untouchable because of the myriad disparate fields that intersect biomaterials and cells. Here, we discuss the next generation of clinical trials and potential approaches, 'smart' and responsive encapsulation systems, sophisticated and multifunctional devices, and novel imaging tools, together with the future challenges in the field.

Incompletely dissolved radioiodine capsule as a likely cause of false-positive whole-body scan in thyroid cancer.

Radioiodine is highly specific for detecting functioning thyroid tissue in the body. However, an unexpected radioiodine uptake can cause various false-positive results in whole-body scanning. We report a case of a 47-year-old woman who showed strong and focal uptake in the right pelvic area suggesting metastasis on the posttreatment whole-body scan. SPECT/CT revealed that the uptake was located in the colon, and the uptake was completely egested after additional bowel preparation.

[Effect of Naoshuantong capsule on change of SSQOL index in patients with ischemic stroke in six mouths follow-up].

To evaluate the effect of Naoshuantong capsule on the life quality of patients with ischemic stroke in six months of follow-up studies, and observe the adverse events. The results would provide reference for the secondary prevention on the recovery stage of ischemic stroke. 696 patients from 12 Class III Grade I hospitals nationwide were divided into 2 groups by central randomization system. The study group, 344 cases, were treated with Naoshuantong capsule plus Aspirin, and the control group, 352 cases, were treated with Aspirin. The patients were treated for 6 months. At the end of treatment, SS-QOL used for evaluating the quality of life was observed. The safety index was defined by adverse observation event. The incidence of adverse events and laboratory tests results were observed before and after treatment at the same time. The results indicated that compared to the control group, the treatment group had significant statistical difference in the impact of effort, self-care ability and the the work or labor ability of patients (P < 0.05). No serious adverse events were observed. Naoshuantong capsule showed some superiority to Asprin on improving the quality of life on patients with ischemic stroke, and it could be used in secondary prevention on the recovery stage of ischemic stroke. Naoshuantong capsule is safe and effective in the treatment of convalescence ischemic stroke.

[Application of in vitro bionic digestion and biomembrane extraction for metal speciation analysis, bioavailability and risk assessment in lianhua qingwen capsule].

One of the causes of the high cost of pharmaceuticals and the major obstacles to rapidly assessing the bioavailability and risk of a chemical is the lack of experimental model systems. A new pre-treatment technology, in vitro bionic digestion was designed for metal analysis in Lianhua Qingwen capsule. The capsule was digested on 37 degrees C under the acidity of the stomach or intestine, and with the inorganic and organic compounds (including digestive enzymes) found in the stomach or intestine, and then the chyme was obtained. Being similar to the biomembrane between the gastrointestinal tract and blood vessels, monolayer liposome was used as biomembrane model Affinity-monolayer liposome metals (AMLMs) and water-soluble metals were used for metal speciation analysis in the capsule. Based on the concentration of AMLMs, the main absorption site of trace metals was proposed. The metal total contents or the concentration of AMLMs in the capsule were compared to the nutritional requirements, daily permissible dose and heavy metal total contents from the "import and export of medicinal plants and preparation of green industry state standards". The metal concentrations in the capsule were within the safety baseline levels for human consumption. After in vitro bionic digestion, most of trace metals were absorbed mainly in intestine. The concentration of As, Cd, Pb was 0.38, 0.07, 1.60 mg x kg(-1), respectively, far less than the permissible dose from the "import and export of medicinal plants and preparation of green industry state standards".