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

Biomolecules ◽  
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.

Efficacy of a Single Dose versus a Multiple Dose Regimen of Mebendazole against Hookworm Infections among School Children: a Randomized Open-label Trial

2020 ◽  
Author(s):  
Tegegne Eshetu ◽  
Mulugeta Aemero ◽  
Ayalew Jejaw
Keyword(s):  
Single Dose ◽  
Dose Regimen ◽  
Multiple Dose ◽  
Open Label ◽  
Preventive Chemotherapy ◽  
Dose Treatment ◽  
School Aged Children ◽  
Multiple Dose Regimen ◽  
Hookworm Infections

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.

Preclinical toxicology of a novel polymeric antitumour agent: HPMA copolymerdoxorubicin (PK1)

1998 ◽  
Vol 17 (2) ◽  
pp. 93-104 ◽  
Author(s):  
R Duncan ◽  
J K Coatsworth ◽  
S Burtles
Keyword(s):  
Single Dose ◽  
Multiple Dose ◽  
Clinical Chemistry ◽  
Testicular Atrophy ◽  
Phase I Clinical Trials ◽  
Polymer Backbone ◽  
Single Dose Study ◽  
Blood Samples ◽  
Multiple Dose Study ◽  
Dose Study

N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1) is a novel polymeric anticancer agent containing doxorubicin (approximately 8 wt%) bound to the polymer backbone via a Gly-Phe-Leu-Gly peptidyl linker. The approximate LD50 of PK1 in MF1 mice after a single i.v. injection was 63 mg/kg (doxorubicin-equivalent). Single doses of PK1 were administered to MF1 mice at 22.5 or 45 mg/kg and blood samples taken on days 3, 7 and 14 for haematological examination and clinical chemistry. At day 14 all animals were sacrificed for necropsy. In a multiple dose study, PK1 was administered i.v. to MF1 mice or Wistar rats (20 animals per group) weekly for five consecutive weeks at doses of 12.0 or 22.5 mg/kg (mice) or 3 and 5 mg/kg (rats). After 31 days 10 animals from each group were sacrificed for necropsy and the remainder were sacrificed after 59 days. Blood samples were taken 3 days after administration of each dose and at the end of the experiment, and urine samples were collectedonthe day prior to sacrifice.Mortality inthe single dose mouse and multiple dose rat studies was low. In the multiple dose mouse study 4/10 animals were killed in extremis before the scheduled day 31 and all animals died before day 37. PK1 induced a reduction in WBC and platelets in rats and mice shortly after treatment and RBC at later times, and in the single dose study alanine and aspartate aminotransferase levels were elevated at higher doses. Liver damage was seen only in rat tissue during histological examination. Other histological changes induced by PK1 include thymic and testicular atrophy, bone marrow depletion gastrointestinal tract changes and in the multiple dose study an increase in nuclear size in the proximal tubules of the kidney (although no changes in urine were seen). Recovery from these effects was seen in rats at 59 days. A PK1 dose of 20 mg/m2 (doxorubicin equivalent) was recommended as a safe dose for the start of Phase I clinical trials.

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

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.

scholarly journals Effect of the African Traditional Medicine,Sutherlandia frutescens, on the Bioavailability of the Antiretroviral Protease Inhibitor, Atazanavir

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Adrienne C. Müller ◽  
Michael F. Skinner ◽  
Isadore Kanfer
Keyword(s):  
Single Dose ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Time Profile ◽  
Blood Samples ◽  
Concentration Time ◽  
The Mean ◽  
Male Subjects ◽  
Anti Hiv ◽  
Sutherlandia Frutescens

The objective of this study was to investigate the effect ofSutherlandia frutescens(SF) on the bioavailability of atazanavir (ATV) in twelve healthy male subjects. During Phase I (Day 1), subjects ingested a single dose of ATV and blood samples were drawn before dose and at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 9.0, 12, 18, and 24 hours after dose. From Day 3 to Day 14, a single dose of milled SF was administered twice daily to each subject. During Phase II, Day 15, subjects ingested single doses of ATV and SF. Blood samples were drawn as previously described. Plasma was harvested from blood samples and the concentration of ATV therein was determined. For each phase, the mean ATV plasma concentration-time profile was plotted and the means ofAUC0–24andCmaxfor ATV were computed. The geometric mean ratios and confidence intervals (CIs) forCmaxandAUC0–24 hrwere 0.783 (0.609–1.00) and 0.801 (0.634–1.01), respectively. The CIs for both PK parameters fell below the limits of the “no-effect” boundary, set at 0.8–1.25, indicating that SF significantly reduced the bioavailability of ATV. This may potentially result in subtherapeutic plasma concentrations and thus reduced anti-HIV efficacy of ATV.

Pharmacokinetics of meropenem after intravenous, intramuscular and subcutaneous administration to cats

2016 ◽  
Vol 18 (12) ◽  
pp. 976-980 ◽  
Author(s):  
Gabriela A Albarellos ◽  
Laura Montoya ◽  
Sabrina M Passini ◽  
Martín P Lupi ◽  
Paula M Lorenzini ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Single Dose ◽  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Plasma Concentrations ◽  
Computer Software ◽  
Subcutaneous Administration ◽  
Maximum Plasma ◽  
Blood Samples ◽  
Elimination Half

Objectives The aim of the study was to describe the pharmacokinetics and predicted efficacy of meropenem after intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration to cats at a single dose of 10 mg/kg. Methods Five adult healthy cats were used. Blood samples were withdrawn at predetermined times over a 12 h period. Meropenem concentrations were determined by microbiological assay. Pharmacokinetic analyses were performed with computer software. Initial estimates were determined using the residual method and refitted by non-linear regression. The time that plasma concentrations were greater than the minimum inhibitory concentration (T >MIC) was estimated by applying bibliographic MIC values and meropenem MIC breakpoint. Results Maximum plasma concentrations of meropenem were 101.02 µg/ml (Cp(0), IV), 27.21 µg/ml (Cmax, IM) and 15.57 µg/ml (Cmax, SC). Bioavailability was 99.69% (IM) and 96.52 % (SC). Elimination half-lives for the IV, IM and SC administration were 1.35, 2.10 and 2.26 h, respectively. Conclusions and relevance Meropenem, when administered to cats at a dose of 10 mg/kg q12h,, is effective against bacteria with MIC values of 6 μg/ml, 7 μg/ml and 10 μg/ml for IV, IM and SC administration, respectively. However, clinical trials are necessary to confirm clinical efficacy of the proposed dosage regimen.

Reduction of enantioselectivity in the kinetic disposition and metabolism of verapamil in rats exposed to toluene

2008 ◽  
Vol 86 (5) ◽  
pp. 232-239 ◽  
Author(s):  
F.H. Mateus ◽  
J.S. Lepera ◽  
M.P. Marques ◽  
V.B. Boralli ◽  
V.L. Lanchote
Keyword(s):  
Single Dose ◽  
Oxidative Metabolism ◽  
Wistar Rats ◽  
Plasma Concentrations ◽  
Wilcoxon Test ◽  
Control Group ◽  
Chiral Drugs ◽  
Blood Samples ◽  
Male Wistar Rats ◽  
Air Control

Toluene and verapamil are subject to extensive oxidative metabolism mediated by CYP enzymes, and their interaction can be stereoselective. In the present study we investigated the influence of toluene inhalation on the enantioselective kinetic disposition of verapamil and its metabolite, norverapamil, in rats. Male Wistar rats (n = 6 per group) received a single dose of racemic verapamil (10 mg/kg) orally at the fifth day of nose-only toluene or air (control group) inhalation for 6 h/day (25, 50, and 100 ppm). Serial blood samples were collected from the tail up to 6 h after verapamil administration. The plasma concentrations of verapamil and norverapamil enantiomers were analyzed by LC-MS/MS by using a Chiralpak AD column. Toluene inhalation did not influence the kinetic disposition of verapamil or norverapamil enantiomers (p > 0.05, Kruskal–Wallis test) in rats. The pharmacokinetics of verapamil was enantioselective in the control group, with a higher plasma proportion of the S-verapamil (AUC 250.8 versus 120.4 ng·h·mL–1; p ≤ 0.05, Wilcoxon test) and S-norverapamil (AUC 72.3 versus 52.3 ng·h·mL–1; p ≤ 0.05, Wilcoxon test). Nose-only exposure to toluene at 25, 50, or 100 ppm resulted in a lack of enantioselectivity for both verapamil and norverapamil. The study demonstrates the importance of the application of enantioselective methods in studies on the interaction between solvents and chiral drugs.

scholarly journals Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers

Pituitary ◽  
2022 ◽  
Author(s):  
Ajay Madan ◽  
Stacy Markison ◽  
Stephen F. Betz ◽  
Alan Krasner ◽  
Rosa Luo ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Single Dose ◽  
Neuroendocrine Tumors ◽  
Multiple Dose ◽  
Phase 1 ◽  
Somatostatin Receptor ◽  
Plasma Concentrations ◽  
Receptor Subtype ◽  
Once Daily ◽  
Orally Bioavailable

Abstract Purpose Evaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors. Methods A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability. Results Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo. Conclusions Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors. Trial registration NCT03276858, registered September 8, 2017, retrospectively registered.

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