Investigating the KNDy hypothesis in humans by co-administration of kisspeptin, neurokinin B and naltrexone in men

Context: A subpopulation of hypothalamic neurons co-localise three neuropeptides namely kisspeptin, neurokinin B (NKB) and dynorphin collectively termed KNDy neurons. Animal studies suggest they interact to affect pulsatile GnRH release (KNDy hypothesis); kisspeptin stimulates, NKB modulates and dynorphin (an opioid) inhibits. Objective: To investigate the KNDy hypothesis in humans, we assessed for the first time the effects of co-administration of kisspeptin-54, NKB and an opioid receptor antagonist, naltrexone on LH pulsatility (surrogate marker for GnRH pulsatility) and gonadotropin release. Design, setting and participants: Ethically approved prospective, single-blinded placebo-controlled study. Healthy male volunteers (n=5/group) attended our research facility for 8 study visits. Intervention and main outcome measure: After 1h baseline blood sampling, participants received a different intervention at each visit: oral 50mg naltrexone (NAL), 8h intravenous infusions of vehicle, 2.56nmol/kg/h NKB (NKB), 0.1nmol/kg/h kissspeptin-54 (KP) alone and in combination. Frequent blood sampling to measure plasma gonadotropins and sex steroids was conducted and LH pulsatility was determined using blinded deconvolution analysis. Results: All kisspeptin and naltrexone containing groups potently increased LH and LH pulsatility (p<0.001 vs vehicle). NKB alone did not affect gonadotropins. NKB+KP had significantly lower increases in gonadotropins compared with kisspeptin alone (p<0.01). NAL+KP was the only group to significantly increase LH pulse amplitude (p<0.001 vs vehicle). Conclusions: Our results suggest significant interactions between the KNDy neuropeptides on LH pulsatility and gonadotropin release in humans. This has important implications for improving our understanding of GnRH pulse generation in humans

Pharmacokinetics of secnidazole in healthy volunteers after single oral dose

Introduction: Secnidazole is an anti infective agent which belongs to the 5-nitroimidazole class. Method: The objective of the trial was to characterize the pharmacokinetics of secnidazole after oral administration of a 2g dose, as microgranules formulation in healthy subjects. Blood samples were collected before, 1, 2, 3, 6, 9, 12, 24, 36, 48, 72, 96, 120, 168 and 240 h after dosing. Urines were collected in 24-h-fractions for the first five days and in 48 h-fraction for the last sample. The cumulative urinary excretion was captured for each subject from urine concentration (lg/L). Pharmacokinetic parameters were obtained by a non-compartmental approach (WinNonlin Pharsight). The assay was performed by ultra-performance liquid chromatography coupled with mass spectrometry detection (UPLC-MS/MS, Quattro Premier, Waters) after simple protein precipitation of 50 lL plasma sample. Chromatographic separation was done on a C18 Acquity column (50 mm · 2.1 mm, id 1.7 lm, Waters), in isocratic mode (80% water/0.1% formic acid and 20% acetonitrile). Ornidazole was used as internal standard. The detection was operated in positive mode and multiple reaction monitoring was used for quantification (186 &gt; 128 ion transition for secnidazole). The lower limit of quantification was 10 and 100 lg/L for plasma and urine samples respectively. Results: Sixteen subjects (8 female, 8 male) were included. Population characteristics such as: age ranged from 23 to 50 years (mean ± SD: 38 ± 9.2 years), weight ranged from 51 to 90 Kg (mean ± SD = 64.6 ± 10.1 Kg) and body mass index (BMI) ranged from 19.9 to 24.2 Kg/m 2 (mean ± SD = 21.9 ± 1.5 Kg/m 2 ;). Secnidazole exposure achieved a maximal concentration (Cmax) with a mean of 37.9 ± 8.5 mg/L (range 20–56 mg/L) and at a median time associated with the Cmax (Tmax) of 6 h (range 3–6 h). The area under the curve to the last measurable time (AUC0_t) and the total area under the curve (AUC0_¥) were 1281.9 ± 416.4 mg h/L and 1304.2 ± 444.1 mg h/L (mean ± SD) respectively. The Cl/F and V/F were 1.7 ± 0.5 L/h and 40.2 ± 9.2 L respectively and the elimination half-life (t1/2) was 17.5 ± 4.3 h (mean ± SD). The mean amount of secnidazole excreted in the 168-h urine collection was 310.47 mg (15.5% of the administered dose). For example, for the subject number 5, the observed parameters are: Cmax 37.3 mg/L, Tmax 3 h, AUC0_¥ 1029.5 mg h/L and t1/2 15.6 h. Conclusion: After a 2 g single oral dose, secnidazole presents a good absorption profile and relatively long elimination half life ensuring probable sufficient exposure with once a day administration

Pharmacokinetics of voriconazole and posaconazole administered in experimental models of disseminated scedosporiosis with cerebral involvement

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Pharmacokinetic analysis of pralidoxime after its intramuscular injection alone or in combination with atropine-avizafone in healthy volunteers

BACKGROUND AND PURPOSE Treatment of organophosphate poisoning with pralidoxime needs to be improved. Here we have studied the pharmacokinetics of pralidoxime after its intramuscular injection alone or in combination with avizafone and atropine using an auto-injector device. EXPERIMENTAL APPROACH The study was conducted in an open, randomized, single-dose, two-way, cross-over design. At each period, each subject received either intramuscular injections of pralidoxime (700 mg), or two injections of the combination: pralidoxime (350 mg), atropine (2 mg), avizafone (20 mg). Pralidoxime concentrations were quantified using a validated LC/MS-MS method. Two approaches were used to analyse these data: (i) a non-compartmental approach; and (ii) a compartmental modelling approach. KEY RESULTS The injection of pralidoxime combination with atropine and avizafone provided a higher pralidoxime maximal concentration than that obtained after the injection of pralidoxime alone (out of bioequivalence range), while pralidoxime AUC values were equivalent. Pralidoxime concentrations reached their maximal value earlier after the injection of the combination. According to Akaike and to goodness of fit criteria, the best model describing the pharmacokinetics of pralidoxime was a two-compartment with a zero-order absorption model. When avizafone and atropine were injected with pralidoxime, the best model describing pralidoxime pharmacokinetics becomes a two-compartment with a first-order absorption model. CONCLUSIONS AND IMPLICATIONS The two approaches, non-compartmental and compartmental, showed that the administration of avizafone and atropine with pralidoxime results in a faster absorption into the general circulation and higher maximal concentrations, compared with the administration of pralidoxime alone

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

Follicle size on day of trigger most likely to yield a mature oocyte

Funding: MRC, BBSRC and NIHR and supported by the NIHR/Wellcome Trust Imperial Clinical Research Facility and Imperial Biomedical Research Centre.Objective: To identify follicle sizes on the day of trigger most likely to yield a mature oocyte following hCG, GnRH agonist (GnRHa), or kisspeptin during IVF treatment. Design: Retrospective analysis to determine the size of follicles on day of trigger contributing most to the number of mature oocytes retrieved using generalized linear regression and random forest models applied to data from IVF cycles (2014–2017) in which either hCG, GnRHa, or kisspeptin trigger was used. Setting: HCG and GnRHa data were collected at My Duc Hospital, Ho Chi Minh City, Vietnam, and kisspeptin data were collected at Hammersmith Hospital, London, UK. Patients: Four hundred and forty nine women aged 18–38 years with antral follicle counts 4–87 were triggered with hCG (n = 161), GnRHa (n = 165), or kisspeptin (n = 173). Main outcome measure: Follicle sizes on the day of trigger most likely to yield a mature oocyte. Results: Follicles 12–19 mm on the day of trigger contributed the most to the number of oocytes and mature oocytes retrieved. Comparing the tertile of patients with the highest proportion of follicles on the day of trigger 12–19 mm, with the tertile of patients with the lowest proportion within this size range, revealed increases of 4.7 mature oocytes for hCG (P < 0.0001) and 4.9 mature oocytes for GnRHa triggering (P < 0.01). Using simulated follicle size profiles of patients with 20 follicles on the day of trigger, our model predicts that the number of oocytes retrieved would increase from a mean 9.8 (95% prediction limit 9.3–10.3) to 14.8 (95% prediction limit 13.3–16.3) oocytes due to the difference in follicle size profile alone. Conclusion: Follicles 12–19 mm on the morning of trigger administration were most likely to yield a mature oocyte following hCG, GnRHa, or kisspeptin.Publisher PDFPeer reviewe

Feasibility of aortic valve assessment with low dose prospectively triggered adaptive systolic (PTAS) cardiac computed tomography angiography

Background: Cardiac computed tomography angiography (CTA) is feasible for aortic valve evaluation, but retrospective gated protocols required high radiation doses for aortic valve assessment. A prospectively triggered adaptive systolic (PTAS) cardiac CT protocol was recently described in arrhythmia using second-generation dual-source CT. In this study, we sought to evaluate the feasibility of PTAS CTA to assess the aortic valve at a low radiation dose. Findings: A retrospective cohort of 29 consecutive patients whom underwent PTAS protocols for clinical indications other than aortic valve assessment and whom also received echocardiography within 2 months of CT, was identified. Images were reviewed for aortic valve morphology (tricuspid/bicuspid/prosthetic) and stenosis (AS) by experienced blinded readers. Accuracy versus echocardiography and radiation doses were assessed. All PTAS coronary CTAs were clinically diagnostic with 0 un-evaluable coronary segments. The accuracy of PTAS for aortic valve morphology was 92.6%, and for exclusion of severe AS was 93.1%. Two exams were un-evaluable for the aortic valve due to inadequate number of phases archived for interpretation. Total radiation dose was a median of 2.8 mSv (interquartile range 1.4–4.4 mSv). Conclusions: PTAS CTA protocols using second-generation dual-source CT for aortic valve evaluation are feasible at low doses. This protocol should be investigated further in larger cohorts

Clinical experiences of delayed contrast enhancement with cardiac computed tomography: case series

Background: Myocardial delayed enhancement (MDE) by gadolinium-enhanced cardiac MRI is well established for myocardial scar assessment in ischemic and non-ischemic heart disease. The role of MDE by cardiac CT (CT-MDE) is not yet defined. Findings: We reviewed all clinical cases of CT-MDE at a tertiary referral center to present the cases as a case series. All clinical cardiac CT exams which utilized CT-MDE imaging between January 1, 2005 and October 1, 2010 were collected as a series and their findings were also compared with available myocardial imaging to assess for myocardial abnormalities, including echocardiography (wall motion, morphology), cardiac MRI (delayed enhancement, morphology), SPECT MPI (perfusion defects). 5,860 clinical cardiac CT exams were performed during the study period. CT-MDE was obtained in 18 patients and was reported to be present in 9 patients. The indications for CT-MDE included ischemic and non-ischemic heart diseases. In segments positive for CT-MDE, there was excellent agreement of CT with other modalities: echocardiography (n=8) demonstrated abnormal morphology and wall motion (k=1.0 and k=0.82 respectively); prior MRI (n=2) demonstrated abnormal delayed enhancement (MR-MDE) (k=1.0); SPECT MPI (n=1) demonstrated fixed perfusion defects (k=1.0). In the subset of patients without CT-MDE, no abnormal segments were identified by echocardiography (n=8), MRI (n=1) and nuclear MPI (n=0). Conclusions: CT-MDE was performed in rare clinical situations. The indications included both ischemic and non-ischemic heart disease and there was an excellent agreement between CT-MDE and abnormal myocardium by echocardiography, cardiac MRI, and nuclear MPI