Population Pharmacokinetics and Exposure-Response Analysis of a Fixed-Dose Combination of Ivermectin and Albendazole in Children, Adolescents, and Adults.

Trichuris trichiura is a soil-transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co-administered with ivermectin. A fixed-dose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure-response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T. trichiura. Nonlinear mixed-effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure-response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two-compartmental model with first-order absorption and the pharmacokinetics of ivermectin was described using a two-compartmental model with zero-order followed by first-order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure-response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T. trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.

An adaptive phase II/III safety and efficacy randomized controlled trial of single day or three-day fixed-dose albendazole-ivermectin co-formulation versus albendazole for the treatment of Trichuris trichiura and other STH infections. ALIVE trial protocol.

Background: Soil-transmitted helminths (STH) are targeted for control through mass drug-administration campaigns to prevent morbidity affecting at-risk groups in endemic regions. Although broadly successful, the use of albendazole and mebendazole achieved variable progress, with deficiencies against Trichuris trichiura and a predictable low efficacy against Strongyloides stercoralis. Novel drug combinations offer a potential solution, providing they can be delivered safely and maintain efficacy against all STH species. Here we present the protocol of a clinical trial to evaluate a fixed-dose combination (FDC) tablet containing albendazole and ivermectin that will be compared against albendazole against STH . Methods: An adaptive phase II/III randomized controlled trial will be undertaken in STH endemic sites in Ethiopia, Kenya and Mozambique to evaluate an oral FDC of 400 mg albendazole and either 9- or 18 mg ivermectin. FDC will be administered as a single dose or single doses over three-consecutive days and assessed against a single dose of 400 mg albendazole. In the phase II trial, 126 T. trichiura-infected children weighting 15 to 45 kg will be treated in a dose-escalation manner to determine safety objectives. In the phase III trial, 1097 participants aged 5 to 18 years old infected with T. trichiura, hookworm and S. stercoralis will be recruited to determine safety and efficacy. The trial will be open-label with blinded outcome assessors. Cure rate measured 21-days after-treatment in duplicate Kato-Katz is the primary efficacy outcome. Secondary objectives include efficacy evaluation by quantitative polymerase chain reaction (PCR) as an outcome measurement, description of pharmacokinetic parameters, palatability and acceptability evaluations, and monitoring of anthelmintic resistance. Conclusions: This trial with registrational goals seeks to evaluate an innovative fixed-dose combination of albendazole and ivermectin co-formulated tablets, with the goal of providing an anthelmintic regimen with improved efficacy and spectrum of coverage against STH. ClinicalTrials.gov registration: NCT05124691 (18/11/2021).

Pharmacokinetic Characterization and Comparative Bioavailability of an Innovative Orodispersible Fixed-Dose Combination of Ivermectin and Albendazole: A Single Dose, Open Label, Sequence Randomized, Crossover Clinical Trial in Healthy Volunteers.

Soil-transmitted helminths are intestinal worm diseases transmitted through the soil. Available treatments are albendazole and/or ivermectin. The co-administration of existing drugs is an appropriate strategy. A fixed-dose combination adds practical advantages mainly considering mass drug administration. The aim is to characterize pharmacokinetics and to evaluate the comparative bioavailability of an innovative fixed-dose combination of ivermectin/albendazole 18/400 mg compared with the marketed references. Seventy-eight healthy volunteers were included in this laboratory-blinded, randomized, three-treatment, three-period crossover study. Each subject received a single dose of ivermectin/albendazole 18/400 mg (1 tablet); ivermectin 3 mg (6 tablets); and albendazole 400 mg (1 tablet). Serial blood samples for the pharmacokinetic analysis were obtained pre-dose and up to 72 h post-dose. Plasma concentrations of ivermectin H2B1a, ivermectin H2B1b, albendazole, and albendazole sulfoxide were analyzed by LC-MS/MS. Pharmacokinetic parameters were estimated by a non-compartmental analysis and bioavailability compared through a bioequivalence analysis. Safety and tolerability were assessed throughout the study. Main pharmacokinetic parameters of the fixed combination were estimated for both, ivermectin [Cmax (mean, confidence interval): 86.40 (30.42-39.23) ng/ml; AUC0-72 (mean, CI): 1,040 (530-1,678) ng·h/mL; tmax (median, min., and max.); 4.50 (2.50-5.50)] and albendazole [Cmax (mean, CI): 22.27 (1.89-111.78) ng/ml; AUC0-72 (mean, CI): 94.65 (11.65-507.78) ng·h/mL; tmax (median, min., and max.): 2.50 (1.00-12.00) h]. The 90% confidence interval of the geometric mean ratios demonstrated the bioequivalence in the case of ivermectin (Cmax: 110.68%-120.49%; AUC0-72: 110.46%-119.60%) but not in the case of albendazole (Cmax: 53.10%-70.34%; AUC0-72: 61.13%-76.54%). The pharmacokinetic profile of a new fixed-dose combination of ivermectin and albendazole was characterized. The bioequivalence versus the reference ivermectin was demonstrated, though bioequivalence versus albendazole was not shown. The three medications analyzed were well tolerated. The results allow the advancement to the next phase of the clinical program to demonstrate efficacy and safety in patients affected by soil-transmitted helminths. Clinical Trial Registration: https://www.clinicaltrialsregister.eu/ctr-search/search/, identifier Nr. 2020-003438-19.

Efectividad de tianeptina en pacientescon depresión mayor y trastorno poruso de sustancias / Effectiveness of tianeptine in patients with major depressive disorder and substance use disorder

Introducción: La depresión coexiste frecuentemente conlos trastornos por uso de sustancias (TUS), lo que conllevaun peor pronóstico. Existe una importante falta de evidenciasobre las intervenciones terapéuticas más efectivas para estacomorbilidad. Los estudios existentes sugieren que los antidepresivos disponibles actualmente son poco eficaces paraestos pacientes. La disponibilidad terapéutica de antidepresivos con mecanismos neurobiológicos diferentes podría seruna alternativa. El objetivo es describir la evolución de ungrupo de pacientes con esta comorbilidad que han realizadotratamiento con tianeptina en condiciones de práctica clínica habitual en consultas de deshabituación.Metodología. Se diseñó un estudio postautorización,multicéntrico, retrospectivo y observacional de práctica clínica habitual. Se revisaron las historias clínicas de los 100últimos pacientes diagnosticados de depresión mayor y TUS,tratados con tianeptina durante al menos 3 meses. Se evaluaron en tres ocasiones (inicial, intermedia y final a los 3meses) las siguientes escalas: Escala de Evaluación para laDepresión de Hamilton (HDRS), Escala de Impresión ClínicaGlobal (ICG) y Escala de Gravedad de la Adicción (SDS).Resultados. La mayoría de los pacientes fueron tratadoscon una combinación de psicofármacos y psicoterapia. Alfinal del seguimiento 70 pacientes (70 %) obtuvieron unaremisión clínica según la escala HDRS y 76 pacientes (76 %)se clasificaron con mucha o moderada mejoría según ICG.Respecto al consumo, los descensos más destacados se produjeron en los trastornos por uso de alcohol y cocaína.Conclusión. Tianeptina, en monoterapia o en combinación, puede ser un tratamiento de utilidad para pacientescon depresión dual de forma conjunta con otras medidasterapéuticas que traten de forma integrada estos pacientescomplejos. (AU)

Introduction: The depressive disorder coexists in a highprevalence with a substance-related disorder, which is associated with a worst prognosis. The therapeutic interventions for this co-morbidity lack of the appropriate scientificsupport. The existing evidence suggest that the currentlyavailable anti-depressive drugs are of minor efficacy in thisgroup of patients. An alternative would be the use of different drugs with distinctive neurobiological mechanismof action. The aim of this study was to describe the clinicaldevelopment of a series of patients affected by this comorbidity under treatment with tianeptine under usual clinicalpractices.Methods. Study design corresponds to a post-authorization, observational, retrospective, multicentric, study underusual clinical practice study. The clinical history of the lastconsecutive 100 patients diagnosed of major depressive andsubstance-related disorders under treatment with tianeptinefor at least 3 months was reviewed. The following scales wereevaluated in 3 times (basal, intermediate, final): HDRS, ICGand SDS. Results. Most patients were treated by a combinationof anti-depressive drugs together with psychotherapy. Atthe end of follow-up, 70 % patients had a clinical remissionin accordance with HDRS and 76 % of them had a mild orsignificant improvement in ICG. Regarding the use of substances, the most remarkable decreases were obtained in theconsumption of alcohol, and cocaine.Conclusion. Tianeptine could be a useful drug for thetreatment of patients with dual diagnosis of depression andsubstance-related disorder, together with other therapeuticinterventions. (AU)

Effectiveness of tianeptine in patients with major depressive disorder and substance use disorder.

The depressive disorder coexists in a high prevalence with a substance-related disorder, which is asso- ciated with a worst prognosis. The therapeutic interventions for this co-morbidity lack of the appropriate scientific sup- port. The existing evidence suggest that the currently avail- able anti-depressive drugs are of minor efficacy in this group of patients. An alternative would be the use of different drugs with distinctive neurobiological mechanism of action. The aim of this study was to describe the clinical develop- ment of a series of patients affected by this comorbidity un- der treatment with tianeptine under usual clinical practices.

Omalizumab efficacy in cases of chronic spontaneous urticaria is not explained by the inhibition of sera activity in effector cells.

Omalizumab (OmAb) is a humanized anti-IgE antibody approved for the treatment of chronic spontaneous urticaria (CSU). OmAb's mechanism of action is known to include actions on free IgE and on pre-bound IgE. However, OmAb is equally and rapidly effective against autoimmune and non-autoimmune urticaria where IgE involvement is not clear, suggesting the involvement of additional mechanisms of action. In this study, we sought to investigate the ability of OmAb to inhibit mast cell and basophil degranulation induced by sera from CSU patients. For this purpose, we performed a comparison between the in vitro incubation of sera from CSU patients treated with OmAb and the in vivo administration of OmAb in a clinical trial. We found that OmAb added in vitro to sera from CSU patients did not modify the ability of the sera to induce cell degranulation. Similarly, the sera from patients treated with OmAb in the context of the clinical trial who had a good clinical outcome maintained the capacity to activate mast cells and basophils. Thus, we conclude that the beneficial activity of OmAb does not correlate with the ability of patient sera to induce cell degranulation.

Pharmacokinetic bioequivalence, safety and acceptability of Ornibel®, a new polymer composition contraceptive vaginal ring (etonogestrel/ethinylestradiol 11.00/3.474 mg) compared with Nuvaring® (etonogestrel/ethinylestradiol 11.7/2.7 mg).

OBJECTIVE: To show the clinical development of Ornibel® (ExeltisHealthcare, Spain) a contraceptive vaginal ring manufactured with a new polymer composition and containing etonogestrel/ethinylestradiol, compared to Nuvaring® (MSD, Spain). SUBJECTS AND METHODS: Randomised, single dose, 2-period, 2-sequence, 2-stage crossover, comparative bioavailability study conducted in 40 healthy female subjects. All subjects received both treatments for 28 days in each of two periods, separated by a 28 days washout. Ornibel® contains etonogestrel/ethinylestradiol 11.00/3.47 mg and Nuvaring® contains etonogestrel/ethinylestradiol 11.7/2.7 mg, both rings delivering 120/15 µg/day. For the calculation of pharmacokinetic parameters, 37 blood samples were collected up to 840 h after each ring insertion to quantify plasma concentrations of etonogestrel and ethinylestradiol using a validated MS/MS-HPLC. Safety was assessed by adverse events recording, clinical laboratory and vital signs and tolerability by vaginal examination. Acceptability was investigated by a 5-point scale questionnaire. RESULTS: Bioequivalence was demonstrated in the first stage as the 94.12% Confidence Intervals of the primary parameters laid within the 80-125% acceptance range for both etonogestrel (Cmax: 96.81-112.20%; AUC0-504h: 98.71-108.61%; AUC0-t: 100.14-109.10%) and ethinylestradiol. (Cmax: 105.91-120.62%; AUC0-504h: 105.47-114.59%; AUC0-t: 108.31-117.61%). During the first day of use a burst effect was observed with Nuvaring®, with significantly higher level of ethinylestradiol (Cmax0-24h ratio: 78.34%, 94.12CI: 73.55-83.45%). Both products were well tolerated and accepted, without significant differences between them. CONCLUSION: Ornibel® is bioequivalent to Nuvaring® in terms of efficacy, safety, tolerability and acceptability. The new polymer composition provides Ornibel® with more stability and gradual hormonal release during the first day of use, particularly for ethinylestradiol.

Pharmacokinetic Bioequivalence of Two Inhaled Tiotropium Bromide Formulations in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: A novel tiotropium bromide monodose capsule dry powder inhaler (DPI) formulation and device have been developed. The formulation was based on a spray-dried matrix that enhances the aerosolizaton properties, allowing a less active tiotropium metered dose (13 µg/capsule) while maintaining the same delivered dose (10 µg/actuation). This study describes the pharmacokinetic bioequivalence to the reference product. METHODS: This randomized, two-stage, crossover, semi-replicate (three-way) study was performed in healthy volunteers. In each study period, subjects received a single dose of two capsules (20 µg delivered dose) of the study medication, separated by a 14-day washout period: tiotropium 10 µg delivered dose (Laboratorios Liconsa, Spain) and Spiriva HandiHaler(®) (Boehringer Ingelheim Pharma GmbH & Co KG, Germany). Blood samples were obtained up to 48 h post-dose to evaluate the comparative bioavailability. Tiotropium was measured in plasma by means of dual stage liquid-liquid extraction followed by the two-dimensional ultra-high performance liquid chromatography sensitive sub-pg/mL bioanalytical method. The main pharmacokinetic parameters were maximum plasma concentration (C max), area under the concentration-time curve (AUC) from time zero hours to the last observed concentration at time t (AUC t ), and AUC from time zero hours to 30 min (AUC0.5). Bioequivalence was accepted if the 90.20 % confidence interval (CI) for the ratio test/reference of the primary pharmacokinetic parameters lay within the acceptance range of 80-125 %. Safety assessment was a secondary endpoint. RESULTS: A total of 30 subjects were randomized and bioequivalence was demonstrated for all primary pharmacokinetic parameters: C max (CI 87.26-106.60 %), AUC t (CI 101.33-111.64 %), and AUC0.5 (CI 97.95-113.49 %). Both study treatments were well tolerated (four non-serious adverse events [AEs] were reported in four subjects: one AE before any product administration, two AEs after test product administration; and one AE after reference product administration). CONCLUSIONS: Both products containing tiotropium 10 µg delivered-dose DPI were bioequivalent and showed good tolerability and a similar safety profile.

New clues to the evolutionary history of the main European paternal lineage M269: dissection of the Y-SNP S116 in Atlantic Europe and Iberia.

The dissection of S116 in more than 1500 individuals from Atlantic Europe and the Iberian Peninsula has provided important clues about the controversial evolutionary history of M269. First, the results do not point to an origin of M269 in the Franco-Cantabrian refuge, owing to the lack of sublineage diversity within M269, which supports the new theories proposing its origin in Eastern Europe. Second, S116 shows frequency peaks and spatial distribution that differ from those previously proposed, indicating an origin farther west, and it also shows a high frequency in the Atlantic coastline. Third, an outstanding frequency of the DF27 sublineage has been found in Iberia, with a restricted distribution pattern inside this peninsula and a frequency maximum in the area of the Franco-Cantabrian refuge. This entire panorama indicates an old arrival of M269 into Western Europe, because it has generated at least two episodes of expansion in the Franco-Cantabrian area. This study demonstrates the importance of continuing the dissection of the M269 lineage in different European populations because the discovery and study of new sublineages can adjust or even completely revise the theories about European peopling, as has been the case for the place of origin of M269.

The expanded mtDNA phylogeny of the Franco-Cantabrian region upholds the pre-neolithic genetic substrate of Basques.

The European genetic landscape has been shaped by several human migrations occurred since Paleolithic times. The accumulation of archaeological records and the concordance of different lines of genetic evidence during the last two decades have triggered an interesting debate concerning the role of ancient settlers from the Franco-Cantabrian region in the postglacial resettlement of Europe. Among the Franco-Cantabrian populations, Basques are regarded as one of the oldest and more intriguing human groups of Europe. Recent data on complete mitochondrial DNA genomes focused on macrohaplogroup R0 revealed that Basques harbor some autochthonous lineages, suggesting a genetic continuity since pre-Neolithic times. However, excluding haplogroup H, the most representative lineage of macrohaplogroup R0, the majority of maternal lineages of this area remains virtually unexplored, so that further refinement of the mtDNA phylogeny based on analyses at the highest level of resolution is crucial for a better understanding of the European prehistory. We thus explored the maternal ancestry of 548 autochthonous individuals from various Franco-Cantabrian populations and sequenced 76 mitogenomes of the most representative lineages. Interestingly, we identified three mtDNA haplogroups, U5b1f, J1c5c1 and V22, that proved to be representative of Franco-Cantabria, notably of the Basque population. The seclusion and diversity of these female genetic lineages support a local origin in the Franco-Cantabrian area during the Mesolithic of southwestern Europe, ~10,000 years before present (YBP), with signals of expansions at ~3,500 YBP. These findings provide robust evidence of a partial genetic continuity between contemporary autochthonous populations from the Franco-Cantabrian region, specifically the Basques, and Paleolithic/Mesolithic hunter-gatherer groups. Furthermore, our results raise the current proportion (≈ 15%) of the Franco-Cantabrian maternal gene pool with a putative pre-Neolithic origin to ≈ 35%, further supporting the notion of a predominant Paleolithic genetic substrate in extant European populations.

Plasma rich in growth factors in arthroscopic rotator cuff repair: a randomized, double-blind, controlled clinical trial.

PURPOSE: The aim of this study was to determine whether addition of plasma rich in growth factors (PRGF) improves functional and structural outcomes after arthroscopic repair of full-thickness rotator cuff tears. METHODS: The study design was independent (investigator-sponsored), randomized in parallel groups, double-blind, and controlled with a conventional surgical technique clinical trial. Sixty-nine patients with rotator cuff tears were included. Subsequently, 6 patients in whom less than 50% footprint coverage of the repair was possible were excluded. Before arthroscopic repair, patients were randomly assigned to receive PRGF at the end of arthroscopy (injected first in the repaired area and then spread over the tendon suture) or only conventional surgery. Efficacy was evaluated 1 year after surgery using functional (UCLA score) and structural (arthro-MRI) assessments. RESULTS: The baseline UCLA scores of the PRGF (14.9; 95% confidence interval [CI]: 13.7 to 16.12) and control (13.2; 95% CI: 13.3 to 16.3) groups were similar. After surgery, both groups showed an improvement in UCLA score, without significant differences between groups (23.2; CI 95%: 20.8 to 25.7, and 23.8; 95% CI: 21.0 to 26.7, respectively). Furthermore, no significant differences were observed in satisfaction 1 year after surgery. Tendon healing evaluated with arthro-magnetic resonance imaging showed total healing in 40% of cases, partial healing in 30%, and lack of healing in 30%, again with no significant differences between groups. No adverse events were recorded. CONCLUSIONS: The present clinical trial does not support the use of plasma rich in growth factors in the arthroscopic repair of rotator cuff tears because no differences in rotator cuff healing or improvements in function were observed in the 1-year postsurgical clinical and radiological follow-up assessments. LEVEL OF EVIDENCE: Level I, randomized, double-blind, controlled clinical trial.

Evaluation of the effect of pollution and fungal disease on Pinus radiata pollen allergenicity.

BACKGROUND: Pollutants and other stressing factors like mold infection might increase the production of pathogen-related proteins in plants. Since this is invoked as one of the causes for the high prevalence of allergic diseases in developed countries, we aimed to determine the potential effect of environmental pollution, with or without mold infection of the trees, on the allergenic potency of pine pollen (Pinus radiata). METHODS: Pine pollen samples were recovered from three selected areas: low polluted (A), highly polluted (B) and highly polluted and infected with fungi (Spheropsis sapinea) (C). The allergenic potency of pollen from areas A, B or C were compared in vivo in 35 pine pollen-allergic patients by skin prick test and specific IgE (sIgE) quantification. Pollen was also analyzed in vitro by SDS-PAGE immunoblotting, RAST inhibition and cDNA-AFLP (amplified fragment length polymorphism) to compare differences in proteins and mRNA expression. RESULTS: The allergenic potency measured by prick test, sIgE and RAST inhibition was greater in pollen A, which was exposed to smaller amounts of NO(x), PM(10) and SO(2) but greater amounts of O(3). No differences were found in IgE-binding bands in immunoblotting or densitometry of the bands. In cDNA-AFLP, three homologous transcript-derived fragments were expressed in samples B only, with an expressed sequence tag related with stress-regulated gene expression. CONCLUSIONS: A greater allergenic potency, in terms of skin tests and sIgE, is observed in pine pollen coming from unpolluted areas. We consider that this fact might be related to a higher exposure to ozone, resulting in a greater expression of allergenic proteins.

Population genetic data for 10 X-STR loci in autochthonous Basques from Navarre (Spain).

Ten X chromosome markers (DXS6789, DXS6809, DXS7132, DXS7133, DXS7423, DXS8378, DXS9898, DXS9902, GATA172D05, and GATA31E08) were analyzed in a sample of 185 unrelated autochthonous Basques from Navarre. Deviations from Hardy-Weinberg equilibrium and linkage disequilibrium between markers were not observed at any loci. Combined power of discrimination was 0.999999999 (females) and 0.999998764 (males). Mean exclusion chance was 0.99999463 (trios) and 0.999761591 (duos). Pairwise genetic distances (Fst) of X-STR frequencies indicate significant differences in the allele frequency distribution between the autochthonous Basques from Navarre and American and Iberian populations except with the Basque Country.