Stimulation of small intestinal burst activity in the postprandial state differentially affects lipid and glucose absorption in healthy adult humans

2004 ◽  
Vol 287 (5) ◽  
pp. G1028-G1034 ◽  
Author(s):  
L. K. Bryant ◽  
R. J. Fraser ◽  
R. Vozzo ◽  
B. Zacharakis ◽  
G. M. Matthews ◽  
...  
Keyword(s):  
Intravenous Infusion ◽  
Plasma Concentrations ◽  
Glucose Absorption ◽  
Burst Activity ◽  
Lipid Absorption ◽  
Healthy Human ◽  
Double Blind ◽  
Human Adults ◽  
Small Intestinal ◽  
Stimulation Of

Small intestinal motor activity is important for the optimal digestion and absorption of nutrients. These motor responses to feeding are frequently abnormal during critical illness, with the persistence of migrating bursts of contractions during enteral feeding. Whether this disturbance influences nutrient absorption is not known. In this study, the effects of small intestinal burst activity on lipid and glucose absorption were evaluated in 10 healthy human adults (6 males, 4 females, 19–47 yr). Upper gastrointestinal manometry was recorded for 6 h during and shortly after a 20-min intravenous infusion of either erythromycin (1 mg/kg), to stimulate burst activity, or saline (0.9%) in a double-blind randomized fashion. Simultaneously with the start of the intravenous infusion, 60 ml liquid feed mixed with 200 μl 13C-triolein and 2 g 3- O-methylglucose (3-OMG) was infused intraduodenally for 30 min. Absorption of lipid and glucose was assessed using the [13C]triolein breath test and plasma concentrations of 3-OMG, respectively. Infusion of erythromycin was followed by a more rapid onset of burst activity following commencement of the duodenal infusion compared with saline (30 ± 6.1 vs. 58 ± 10.7 min; P < 0.05). Erythromycin was associated with a slower recovery of 13CO2 ( P < 0.01). A positive correlation existed between the time to onset of burst activity and 13CO2 recovery ( P < 0.001). Erythromycin had no effect on 3-OMG absorption. In conclusion, stimulation of small intestinal burst activity reduces the rate of lipid absorption but not glucose absorption in healthy human adults.

Systemic and renal effect of intravenous infusion of endothelin-1 in healthy human volunteers

1994 ◽  
Vol 266 (3) ◽  
pp. F411-F418 ◽  
Author(s):  
S. S. Sorensen ◽  
J. K. Madsen ◽  
E. B. Pedersen
Keyword(s):  
Blood Pressure ◽  
Intravenous Infusion ◽  
Renal Plasma Flow ◽  
Plasma Concentrations ◽  
Urinary Sodium Excretion ◽  
Urinary Flow ◽  
Healthy Human ◽  
Water Excretion ◽  
Endothelin 1 ◽  
Human Volunteers

The effect of intravenous infusion of endothelin-1 (ET-1) at a rate of 1 pmol.min-1.kg-1 for 60 min (n = 9) or placebo (n = 9) was investigated in 18 healthy human volunteers with a mean age of 30 yr. In response to ET-1 infusion, concentration of ET-1 increased from 0.88 +/- 0.27 to 10.73 +/- 4.79 (SD) pmol/l. Diastolic blood pressure increased by 7.8% (P < 0.01) and heart rate decreased by 14.0% (P < 0.01), whereas systolic blood pressure did not change. Renal plasma flow decreased by 34.7%, glomerular filtration rate decreased by 16.1%, and renal vascular resistance increased by 66.0% (P < 0.01 all). Urinary sodium excretion decreased by 57.9% and urinary flow rate by 40.2% (P < 0.01 for both). As judged from the clearance of lithium, we found that ET-1 did not change absolute reabsorption of sodium and water in the proximal tubules, but in the distal tubules absolute reabsorption of both sodium and water decreased significantly. Plasma concentrations of angiotensin II, aldosterone, arginine vasopressin, and atrial natriuretic peptide did not change in response to ET-1 infusion. It is suggested that ET-1 at plasma concentrations found in certain pathophysiological conditions in humans may influence renal perfusion and renal sodium and water excretion.

scholarly journals SARS-CoV-2 Receptor ACE2 Gene Expression in Small Intestine correlates with Age

2020 ◽  
Author(s):  
Raphael N. Vuille-dit-Bille ◽  
Kenneth Liechty ◽  
François Verrey ◽  
Laura C. Guglielmetti
Keyword(s):  
Gene Expression ◽  
Older Patients ◽  
Entry Site ◽  
Healthy Human ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Adults ◽  
Small Intestinal ◽  
Ace2 Gene ◽  
Intestinal Enterocytes ◽  
Duodenal Biopsies

Abstract SARS-CoV-2 binds via its spikes to its receptor angiotensin-converting enzyme 2 (ACE2). ACE2 is also expressed in small intestinal enterocytes, making the intestine a possible entry site. We examined duodenal biopsies from 43 healthy human adults. ACE2 gene expression was directly correlated with age (Spearman’s r= 0.317, p=0.039. With each year duodenal ACE2 expression increased by 0.083 RU. The higher intestinal ACE2 mRNA expression in older patients might make them more susceptible to oral SARS-CoV-2 infection.

scholarly journals Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms

2013 ◽  
Vol 115 (7) ◽  
pp. 972-978 ◽  
Author(s):  
Anna E. Stanhewicz ◽  
Lacy M. Alexander ◽  
W. Larry Kenney
Keyword(s):  
Nitric Oxide ◽  
Human Skin ◽  
Human Subjects ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Healthy Human ◽  
Double Blind ◽  
Mean Body Temperature ◽  
Doppler Flowmetry ◽  
Aged Skin

Functional constitutive nitric oxide synthase (NOS) and its cofactor tetrahydrobiopterin (BH4) are required for full reflex cutaneous vasodilation and are attenuated in primary aging. Acute, locally administered BH4 increases reflex vasodilation through NO-dependent mechanisms in aged skin. We hypothesized that oral sapropterin (Kuvan, shelf-stable pharmaceutical formulation of BH4) would augment reflex vasodilation in aged human skin during hyperthermia. Nine healthy human subjects (76 ± 1 yr) ingested sapropterin (10 mg/kg) or placebo in a randomized double-blind crossover design. Venous blood samples were collected prior to, and 3 h following, ingestion of sapropterin for measurement of plasma BH4. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of 1) lactated Ringer's solution, 2) 10 mM BH4, and 3) 20 mM NG-nitro-l-arginine methyl ester (l-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced using a water-perfused suit. At 1°C rise in oral temperature, mean body temperature was clamped and 20 mM l-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC = LDF/MAP) and expressed as a percentage of maximum (%CVCmax 28 mM sodium nitroprusside and local heat 43°C). Plasma concentrations of BH4 were significantly elevated 3 h after ingestion of sapropterin (0 h: 19.1 ± 2 pmol/ml vs. 3 h: 43.8 ± 3 pmol/ml; P < 0.001). Sapropterin increased NO-dependent vasodilation at control site (placebo: 14 ± 1 %CVCmax vs. sapropterin: 25 ± 4 %CVCmax; P = 0.004). Local BH4 administration increased NO-dependent vasodilation compared with control in placebo trials only (control: 14 ± 1 %CVCmax vs. BH4-treated: 24 ± 3 %CVCmax; P = 0.02). These data suggest oral sapropterin increases bioavailable BH4 in aged skin microvasculature sufficiently to increase NO synthesis through NOS and that sapropterin may be a viable intervention to increase skin blood flow during hyperthermia in healthy aged humans.

Cranial parasympathetic activation induces autonomic symptoms but no cluster headache attacks

Cephalalgia ◽  
2017 ◽  
Vol 38 (8) ◽  
pp. 1418-1428 ◽  
Author(s):  
Song Guo ◽  
Anja Sofie Petersen ◽  
Henrik Winther Schytz ◽  
Mads Barløse ◽  
Anthony Caparso ◽  
...  
Keyword(s):  
Cluster Headache ◽  
Plasma Concentrations ◽  
Low Frequency ◽  
Double Blind ◽  
Pain Thresholds ◽  
Autonomic Symptoms ◽  
Sham Stimulation ◽  
Registration Number ◽  
Mechanical Detection ◽  
Stimulation Of

Background Low frequency (LF) stimulation of the sphenopalatine ganglion (SPG) may increase parasympathetic outflow and provoke cluster headache (CH) attacks in CH patients implanted with an SPG neurostimulator. Methods In a double-blind randomized sham-controlled crossover study, 20 CH patients received LF or sham stimulation for 30 min on two separate days. We recorded headache characteristics, cephalic autonomic symptoms (CAS), plasma levels of parasympathetic markers such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal peptide (VIP), and mechanical detection and pain thresholds as a marker of sensory modulation. Results In the immediate phase (0–60 min), 16 (80%) patients experienced CAS after LF stimulation, while nine patients (45%) reported CAS after sham ( p = 0.046). We found no difference in induction of cluster-like attacks between LF stimulation (n = 7) and sham stimulation (n = 5) ( p = 0.724). There was no difference in mechanical detection and pain thresholds, and in PACAP and VIP plasma concentrations between LF and sham stimulation ( p ≥ 0.162). Conclusion LF stimulation of the SPG induced autonomic symptoms, but no CH attacks. These data suggest that increased parasympathetic outflow is not sufficient to induce CH attacks in patients. Study protocol ClinicalTrials.gov registration number NCT02510729

scholarly journals Safety and Pharmacokinetics of the Antiorthopoxvirus Compound ST-246 following Repeat Oral Dosing in Healthy Adult Subjects

2010 ◽  
Vol 54 (6) ◽  
pp. 2560-2566 ◽  
Author(s):  
Robert Jordan ◽  
Jarasvech Chinsangaram ◽  
Tove' C. Bolken ◽  
Shanthakumar R. Tyavanagimatt ◽  
Deborah Tien ◽  
...  
Keyword(s):  
Multiple Dose ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Saturable Absorption ◽  
Healthy Human ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Elimination Half ◽  
Dose Study ◽  
Multiple Dose Pharmacokinetics

ABSTRACT ST-246, a novel compound that inhibits egress of orthopoxvirus from infected cells, is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. This phase I, double-blind, randomized, placebo-controlled, escalating multiple-dose study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 administered as a single daily oral dose of 250, 400, or 800 mg for 21 days to nonfasting healthy human volunteers. ST-246 appeared to be well tolerated, with no serious adverse events (AEs). Headache, for which one subject in the 800-mg group discontinued the study, was the most commonly reported AE in all treatment groups. The multiple-dose pharmacokinetics of ST-246 was well characterized. The day 21 mean elimination half-lives were calculated at 18.8, 19.8, and 20.7 h for each of the 250-, 400-, and 800-mg/day dose groups, respectively. Steady state was reached by day 6 (within 3 to 5 half-lives), saturable absorption was observed at the 800-mg dose level, and the fraction of parent drug excreted in the urine was very low. Based on these results, administration of 400 mg/day ST-246 can be expected to provide plasma concentrations above the efficacious concentration demonstrated in nonhuman primate models in earlier studies.

Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Ex Vivo ◽  
Oral Treatment ◽  
Plasma Concentrations ◽  
Vaginal Ring ◽  
Vaginal Fluid ◽  
Cervical Tissue ◽  
Double Blind ◽  
Group A ◽  
Group B ◽  
Anti Hiv

Objectives: Self-administered vaginal rings are a promising method for delivery of topical anti-HIV microbicidesand might offer an adherence advantage over daily or coitally-dependent dosage forms such as gels. This trialassessed the safety and pharmacokinetic aspects of the Dapivirine Vaginal Ring-004 when worn as multiple rings oversequential periods of ring use by healthy, sexually-active, HIV-negative women.Methods: This double-blind trial was conducted among 48 women (18-40 years). Participants were randomlyassigned to two groups (A or B) and received (3:1) either the dapivirine or a placebo vaginal ring. Group A used tworings over a 56-day period and Group B used three rings over a 57-day period. Safety evaluations were conductedthroughout the trial. Dapivirine concentrations were measured in plasma, vaginal fluid and cervical tissue samplescollected during and after the 56 days (Group A) or 57 days (Group B) of vaginal ring use.Results: Ring-004 was safe and well tolerated in all participants. The pharmacokinetic profile demonstrated arapid increase in plasma and vaginal fluid concentrations and achieved concentrations in vaginal fluids and cervicaltissue well above the in vitro IC99 in cervical tissue (3.3 ng/mL) that were sustained for a 28 to 35-day ring use period(approximately 3000 times higher in vaginal fluids and 14 -1000 times higher in cervical tissue). Drug levels wereassociated with significant inhibitory activity of genital secretions against HIV ex vivo, a biomarker of pharmacodynamics.Individual plasma dapivirine concentrations did not exceed 553 pg/mL and were well below plasma concentrations atthe maximum tolerated dose for oral treatment (mean Cmax 2286 ng/mL).Conclusions: The consecutive use of several rings over a period of up to 57 days was safe and well tolerated, andPK data indicate that a single Ring-004 is likely to be protective for at least 35 days.

Safety evaluation of an antimalarial herbal product from Andrographis paniculata (AS201-01) in healthy volunteers

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Aty Widyawaruyanti ◽  
Arijanto Jonosewojo ◽  
Hilkatul Ilmi ◽  
Lidya Tumewu ◽  
Ario Imandiri ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Healthy Volunteers ◽  
Day Treatment ◽  
Phase 1 ◽  
Andrographis Paniculata ◽  
Control Group ◽  
Healthy Human ◽  
Double Blind ◽  
Random Blood Glucose ◽  
Significant Difference

Abstract Objectives Andrographis paniculata tablets (AS201-01) have previously been shown to have potent bioactivity as an antimalarial and to produce no unwanted side effects in animal models. Here, we present the phase 1 clinical trial conducted to evaluate the safety of AS201-01 tablets in healthy volunteers. Methods The study was a randomized, double-blind controlled cross-over, a placebo-controlled design consisting of a 4-day treatment of AS201-01 tablets. A total of 30 healthy human volunteers (16 males and 14 females) were divided into two groups, and each group was given 4 tablets, twice daily for 4 days. Group 1 received AS201-01, while group 2 received placebo tablets. Volunteers were given a physical examination before the treatment. The effects of AS201-01 on random blood glucose, biochemical, and hematological as well as urine profiles were investigated. Results There were no changes in observed parameters as a result of AS201-01 being administered. Statistical analysis showed no significant difference (p>0.05) between the test and control group regarding hematology profile, biochemical profile, and random blood glucose. Increased appetite and better sleep, which categorized as grade 1 adverse event was reported after treatment with AS201-01 tablet Conclusions The outcome supports our previous observation that the AS201-01 tablet, given twice a day for 4 days, is safe and nontoxic.

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