Rapid changes in functional responsiveness of the 5-HT system after single-dose and multiple-dose treatment with antidepressants: effects of maprotiline and oxaprotiline and its enantiomers

Abstract Background: Despite the existence of a population-based control program using single dose albendazole or mebendazole as a preventive chemotherapy, hookworm transmission remains high. It causes a negative impact on the growth and school performance of children. In connection to this preventive chemotherapy, different studies produced conflicting results. This study aimed at evaluating the efficacy of single (500mg) versus multiple doses (100mg twice a day during three consecutive days) of mebendazole against hookworm infections among school-aged children. Methods: This randomized open-label clinical trial took place among school-aged children (6-14 years old) in Burie and Debre Elias towns, Northwest Ethiopia. Using simple randomization, eligible hookworm-positive children were allocated (1:1) to either a single or multiple dose treatment arms. Stool samples were collected and processed using McMaster method at baseline and follow-up period (14-21 days after treatment). Only laboratory technicians were blinded. The cure and egg reduction rates which were assessed after 14-21 days of treatment were the primary and secondary therapeutic outcome measures against hookworm infections, respectively. An independent t-test was used to compare group means, and logistic regression was used to calculate odds ratio (OR). P-value < 0.05 at 95% CI was considered statistically significant. Result: 108 children, 54 in each treatment arm had completed baseline data and received allocated treatment. 103 children had completed follow-up data records and included for the final efficacy analysis. Cure rate against hookworm was significantly higher in the multiple dose (96.1%) than in the single dose (30.8%) with OR=55.125; 95% CI: 11.92-254.9; P < 0.001. The egg reduction rate in the multiple dose treatment arm (99.5%) was also significantly higher than in the single dose arm (68.9%) with difference t (101) =5.38; 95% CI 230.95-505.36; P < 0.001. Conclusion: The single dose regimen of mebendazole for the treatment of hookworm infections showed poor cure and egg reduction rates, while the multiple dose revealed satisfactory. Although multiple dose regimen administration is a bit more complex than the single dose, we strongly encourage replacing it with multiple dose regimen during deworming programs in hookworm endemic areas. Trial registration: This trial is registered in www.pactr.org, # PACTR201911466695052.

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Pharmacokinetics of Sativex® in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders

Biomolecules ◽

10.3390/biom10020279 ◽

2020 ◽

Vol 10 (2) ◽

pp. 279

Author(s):

María Fernández-Trapero ◽

Carmen Pérez-Díaz ◽

Francisco Espejo-Porras ◽

Eva de Lago ◽

Javier Fernández-Ruiz

Keyword(s):

Veterinary Medicine ◽

Single Dose ◽

Multiple Dose ◽

Plasma Concentrations ◽

Beagle Dogs ◽

Blood Samples ◽

Dose Treatment ◽

Pathological Conditions ◽

Sublingual Delivery ◽

Progressive Accumulation

The phytocannabinoid-based medicine Sativex® is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathologies, including human-like pathological conditions. With the purpose of assessing different dosing paradigms for using Sativex in Veterinary Medicine, we investigated its pharmacokinetics when administered to naïve dogs via sublingual delivery. In the single dose arm of the study, adult Beagle dogs were treated with 3 consecutive sprays of Sativex, and blood samples were collected at 12 intervals up to 24 h later. In the multiple dose arm of the study, Beagle dogs received 3 sprays daily for 14 days, and blood samples were collected for 24 h post final dose. Blood was used to obtain plasma samples and to determine the levels of cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC) and its metabolite 11-hydroxy-Δ9-THC. Maximal plasma concentrations of both Δ9-THC (Cmax = 18.5 ng/mL) and CBD (Cmax = 10.5 ng/mL) were achieved 2 h after administration in the single dose condition and at 1 h in the multiple dose treatment (Δ9-THC: Cmax = 24.5 ng/mL; CBD: Cmax = 15.2 ng/mL). 11-hydroxy-Δ9-THC, which is mainly formed in the liver from Δ9-THC, was almost undetected, which is consistent with the use of sublingual delivery. A potential progressive accumulation of both CBD and Δ9-THC was detected following repeated exposure, with maximum plasma concentrations for both cannabinoids being achieved following multiple dose. Neurological status, body temperature, respiratory rate and some hemodynamic parameters were also recorded in both conditions, but in general, no changes were observed. In conclusion, this study demonstrates that single or multiple dose sublingual administration of Sativex to naïve dogs results in the expected pharmacokinetic profile, with maximal levels of phytocannabinoids detected at 1–2 h and suggested progressive accumulation after the multiple dose treatment.

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Oxytocin treatment attenuates amygdala activity in autism: a treatment-mechanism study with long-term follow-up

Translational Psychiatry ◽

10.1038/s41398-020-01069-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sylvie Bernaerts ◽

Bart Boets ◽

Jean Steyaert ◽

Nicole Wenderoth ◽

Kaat Alaerts

Keyword(s):

Single Dose ◽

Multiple Dose ◽

Biological Motion ◽

Brain Activity ◽

Neural Substrates ◽

Emotional States ◽

Dose Treatment ◽

Amygdala Activity ◽

Point Light

Abstract Intranasal administration of the neuropeptide oxytocin (IN-OT) is increasingly considered as a potential treatment for targeting the core symptoms of autism spectrum disorder (ASD), but the effects of continual use on neural substrates are fairly unexplored and long-term effects are unknown. In this double-blind, randomized, placebo-controlled study, we investigated the effects of single-dose and multiple-dose IN-OT treatment (4 weeks of daily (24 IU) administrations) on brain activity related to processing emotional states. Thirty-eight adult men with ASD (aged between 18 and 35 years) underwent functional magnetic resonance imaging of the posterior superior temporal gyrus (pSTS) and amygdala regions while processing emotional states from point-light biological motion. In line with prior research, a single dose of IN-OT induced a reliable increase in pSTS brain activity during the processing of point-light biological motion, but no consistent long-term changes in pSTS activity were induced after the multiple-dose treatment. In terms of bilateral amygdala, the multiple-dose treatment induced a consistent attenuation in brain activity, which outlasted the period of actual administrations until four weeks and one year post-treatment. Critically, participants with stronger attenuations in amygdala-activity showed greater behavioral improvements, particularly in terms of self-reported feelings of avoidant attachment and social functioning. Together, these observations provide initial insights into the long-lasting neural consequences of chronic IN-OT use on amygdala functioning and provide first indications that the acute versus chronic effects of IN-OT administration may be qualitatively different. Larger studies are however warranted to further elucidate the long-term impact of IN-OT treatment on human neural substrates and its behavioral consequences.

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Effect Of Multiple Dose PF-06700841 On The Pharmacokinetics Of Single Dose Oral Contraceptive Steroids

Case Medical Research ◽

10.31525/ct1-nct04267250 ◽

2020 ◽

Author(s):

Keyword(s):

Single Dose ◽

Oral Contraceptive ◽

Multiple Dose ◽

Contraceptive Steroids ◽

Dose Oral ◽

Dose Oral Contraceptive

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Faculty Opinions recommendation of Multiple-dose versus single-dose ivermectin for Strongyloides stercoralis infection (Strong Treat 1 to 4): a multicentre, open-label, phase 3, randomised controlled superiority trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736675072.793566801 ◽

2019 ◽

Author(s):

Pedro Legua Leiva

Keyword(s):

Single Dose ◽

Multiple Dose ◽

Strongyloides Stercoralis ◽

Open Label ◽

Phase 3 ◽

Open Label Phase ◽

Superiority Trial ◽

Randomised Controlled

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Activation of GLP-1 and Glucagon Receptors Regulates Bile Homeostasis Independent of Thyroid Hormone

Current Molecular Pharmacology ◽

10.2174/1874467212666190212112402 ◽

2019 ◽

Vol 12 (2) ◽

pp. 139-146

Author(s):

Vishal J. Patel ◽

Amit A. Joharapurkar ◽

Samadhan G. Kshirsagar ◽

Brijesh K. Sutariya ◽

Maulik S. Patel ◽

...

Keyword(s):

Single Dose ◽

Lipid Metabolism ◽

Thyroid Hormone ◽

Fibroblast Growth Factor 21 ◽

Dose Treatment ◽

Obesity And Diabetes ◽

Serum T3 ◽

Serum T4 ◽

Glucagon Like Peptide 1 ◽

Glucagon Receptors

Background: Balanced coagonists of glucagon-like peptide-1 (GLP-1) and glucagon receptors are emerging therapies for the treatment of obesity and diabetes. Such coagonists also regulate lipid metabolism, independent of their body weight lowering effects. Many actions of the coagonists are partly mediated by fibroblast growth factor 21 (FGF21) signaling, with the major exception of bile homeostasis. Since thyroid hormone is an important regulator of bile homeostasis, we studied the involvement of thyroid hormone in coagonist-induced changes in lipid and bile metabolism. Methods: We evaluated the effect of a single dose of coagonist Aib2 C24 chimera2 at 150 to 10000 µg/kg on tetraiodothyronine (T4) and triiodothyronine (T3) in high-fat diet-induced obese (DIO) mice and chow-fed mice. Repeated dose treatment of coagonist (150 µg/kg, subcutaneously) was assessed in four mice models namely, on lipid and bile homeostasis in DIO mice, propylthiouracil (PTU)-treated DIO mice, methimazole (MTM)-treated DIO mice and choline-deficient, L-amino acid-defined, highfat diet (CDAHFD)-induced nonalcoholic steatohepatitis (NASH). Results: Single dose treatment of coagonist did not alter serum T3 and T4 in chow-fed mice and DIO mice. Coagonist treatment improved lipid metabolism and biliary cholesterol excretion. Chronic treatment of GLP-1 and glucagon coagonist did not alter serum T3 in hypothyroid DIO mice and CDAHFDinduced NASH. Coagonist increased serum T4 in DIO mice after 4 and 40 weeks of treatment, though no change in T4 levels was observed in hypothyroid mice or mice with NASH. Conclusion: Our data demonstrate that coagonist of GLP-1 and glucagon receptors does not modulate bile homeostasis via thyroid signaling.

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