Endogenous versus Exogenous Lithium Clearance for Evaluation of Dopamine-Induced Changes in Renal Tubular Function

1. The present randomized, double-blind cross-over study compared endogenous and exogenous lithium clearance (CLi) for estimation of the effect of dopamine on tubular sodium reabsorption. Twelve normal, salt-repleted male subjects were investigated on three different occasions with either placebo or 450 mg or 600 mg of lithium given in random order at 22.00 hours. After an overnight fast, renal clearance studies were performed during a 1 h baseline period and subsequently during the second hour of an infusion of 3 μg min−1 kg−1 of dopamine. 2. Baseline values of endogenous CLi and fractional excretion of lithium (FELi) [27.0 (23.5–30.5) ml/min and 24.2 (203–28.2)% (means with 95% confidence interval)] were lower than exogenous values [lithium, 450 mg: 32.7 (29.9–35.4) ml/min (P < 0.05) and 27.4 (25.2–29.6)% (P < 0.05); lithium, 600 mg: 33.4 (29.2–37.6) ml/min (P < 0.05) and 28.6 (26.3–31.0)% (P < 0.01)]. Both test doses of lithium increased the baseline sodium clearance (CNa), but glomerular filtration rate and urine flow rate remained unchanged. 3. Dopamine increased CNa to similar values on the three study days. CLi increased to 40.9 (35.5–46.5) ml/min (endogenous lithium, P < 0.001), 43.2 (40.8–45.6) ml/min (450 mg of lithium, P < 0.01) and 44.9 (41.3–48.4) ml/min (600 mg of lithium, P < 0.001), respectively. FELi increased to 32.2 (27.5–37.0)% (P < 0.01), 35.4 (33.0–37.7)% (P < 0.01) and 35.9 (32.8–38.9)% (P < 0.01), respectively. Values during dopamine infusion did not differ significantly. 4. The lower baseline values of endogenous CLi and FELi compared with exogenous values suggest that CLi in humans depends on the plasma concentrations of lithium. However, the effect of dopamine on CLi and FELi was expressed to the same extent with endogenous and exogenous lithium, indicating that the two methods are interchangeable for estimation of dopamine-induced changes in tubular function.

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Renal effects of oral prostaglandin supplementation after ibuprofen in diabetic subjects: a double-blind, placebo-controlled, multicenter trial.

Journal of the American Society of Nephrology ◽

10.1681/asn.v591684 ◽

1995 ◽

Vol 5 (9) ◽

pp. 1684-1688

Author(s):

G L Bakris ◽

U Starke ◽

M Heifets ◽

D Polack ◽

M Smith ◽

...

Keyword(s):

Blood Pressure ◽

Renal Insufficiency ◽

Fractional Excretion ◽

Multicenter Trial ◽

Common Side Effect ◽

Double Blind ◽

Entire Study ◽

Fractional Excretion Of Sodium ◽

Induced Changes

Prostaglandins of the E series (PGE) are known to contribute to the maintenance of renal hemodynamics in subjects with chronic renal insufficiency. Agents that block PGE synthesis, nonsteroidal anti-inflammatory agents (NSAID), are widely used by people with renal insufficiency. This study was undertaken in subjects with renal insufficiency secondary to diabetes to evaluate the acute effects of a PGE1 analog, misoprostol, on NSAID-induced changes in RBF, as calculated by para-aminohippurate clearance, and GFR, as calculated by inulin clearance. Sodium excretion was also assessed. Twenty-five fasting subjects with a mean age of 56 +/- 4 yr received 800 mg of ibuprofen orally. A concomitant dose of either a placebo (PL) or 200 micrograms of misoprostol was also given. This was followed in 1 h by either a placebo or an additional 200-micrograms dose of misoprostol. Measurements for the determination of RBF, GFR, blood pressure, and fractional excretion of sodium were performed every 30 min for the next 5 h. The greatest reduction in both GFR (-25 +/- 7 mL/min per 1.73 m2 PL versus -10 +/- 4 mL/min per 1.73 m2, misoprostol delta GFR; P < 0.05) and RBF (-48 +/- 21 mL/min per 1.73 m2 PL versus -15 +/- 8 mL/min per 1.73 m2, M delta RBF; P < 0.05) occurred approximately 2 h after the NSAID dose. No significant differences were noted in blood pressure, fractional excretion of sodium, or other measured parameters between groups during the entire study. Gastrointestinal upset was the most common side effect observed in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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Natriuretic effect of caffeine: assessment of segmental sodium reabsorption in humans

Clinical Science ◽

10.1042/cs1030461 ◽

2002 ◽

Vol 103 (5) ◽

pp. 461-466 ◽

Cited By ~ 21

Author(s):

D.G. SHIRLEY ◽

S.J. WALTER ◽

F.H. NOORMOHAMED

Keyword(s):

Control Period ◽

Fractional Excretion ◽

Experimental Period ◽

Caffeine Intake ◽

Sodium Reabsorption ◽

Lithium Clearance ◽

Distal Nephron ◽

Clearance Ratio ◽

Fractional Excretion Of Sodium ◽

Natriuretic Effect

In order to assess the intrarenal mechanisms responsible for the natriuretic action of caffeine, the renal clearances of 51Cr-EDTA [used as a measure of glomerular filtration rate (GFR)] and lithium (used as an index of end-proximal fluid delivery) were measured in eight healthy males before (control period) and immediately after (experimental period) a 400mg oral dose of caffeine (given over 90min) or placebo. In caffeine-treated subjects, the fractional excretion of sodium rose from 1.00±0.25% in the control period to 1.47±0.18% in the experimental period, while corresponding values on the placebo day were 1.04±0.16% and 0.70±0.07% respectively. GFR was unchanged following either caffeine or placebo. When compared with the placebo day, caffeine caused increases in lithium clearance (experimental period values: caffeine, 37±1ml/min; placebo, 28±2ml/min; P<0.001), the fractional excretion of lithium (caffeine, 34±1%; placebo, 26±2%; P<0.001) and the sodium/lithium clearance ratio (used as an index of the fraction of sodium delivered to the distal nephron that escapes reabsorption therein: caffeine, 4.4±0.3%; placebo, 2.8±0.2%; P<0.001). These results suggest that reduced fractional sodium reabsorption in both the proximal tubule and the distal nephron contributes to the acute natriuretic effect of caffeine. The data also confirm the importance of controlling caffeine intake when investigating renal function using lithium clearance.

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Renal effects of a urodilatin infusion in patients with liver cirrhosis, with and without ascites.

Journal of the American Society of Nephrology ◽

10.1681/asn.v981489 ◽

1998 ◽

Vol 9 (8) ◽

pp. 1489-1498

Author(s):

J Carstens ◽

J Greisen ◽

K T Jensen ◽

H Vilstrup ◽

E B Pedersen

Keyword(s):

Liver Cirrhosis ◽

Fractional Excretion ◽

Controlled Study ◽

Sodium Reabsorption ◽

Lithium Clearance ◽

Renal Effects ◽

Fluid Delivery ◽

Tubular Sodium Reabsorption ◽

Proximal Tubular ◽

Cirrhotic Patients

This study reports the effects of a short-term (60 min) low-dose (20 ng x kg(-1) x min(-1)) infusion of synthetic urodilatin (URO) in patients with liver cirrhosis. URO is a natriuretic peptide. A total of 15 cirrhotic patients with ascites and nine without ascites participated in a randomized, double-blind, placebo-controlled study in a crossover design. Renal hemodynamics were estimated by a clearance technique using radioactive tracers, and tubular handling of sodium was evaluated by the lithium clearance method. The renal effects of URO were characterized by a significant increase in urine sodium excretion rate (UNa) and urine flow rate (V) in the cirrhotic patients without ascites (UNa: 173%; V: 94%) and with ascites (UNa: 219%, P < 0.01; V: 42%, P < 0.01) when compared with placebo infusions. Fractional excretion of sodium increased significantly, indicating a tubular effect of URO on sodium handling. Filtration fraction, lithium clearance (a marker of end-proximal fluid delivery), and fractional excretion of lithium increased, fractional proximal tubular sodium reabsorption decreased, and absolute proximal tubular sodium reabsorption remained unchanged, suggesting increased delivery of isotonic fluid from the proximal tubule during URO infusion. In addition, a significant decrease in fractional distal tubular sodium reabsorption contributed to the natriuresis. In conclusion, URO improved sodium and urine output in cirrhotic patients with and without ascites by enhancing fluid delivery from the proximal tubules in addition to inhibiting fractional sodium reabsorption in the distal nephron.

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Cimetidine administration and tubular creatinine secretion in patients with compensated cirrhosis

Clinical Science ◽

10.1042/cs1020091 ◽

2001 ◽

Vol 102 (1) ◽

pp. 91-98 ◽

Cited By ~ 14

Author(s):

Giovanni SANSOÈ ◽

Alberto FERRARI ◽

Carmen Nives CASTELLANA ◽

Lorenzo BONARDI ◽

Erica VILLA ◽

...

Keyword(s):

Oral Administration ◽

Fractional Excretion ◽

Tubular Secretion ◽

Inulin Clearance ◽

Sodium Reabsorption ◽

Lithium Clearance ◽

Clearance Ratio ◽

Compensated Cirrhosis ◽

Tubular Sodium Reabsorption ◽

Sodium Load

Cimetidine inhibits the tubular secretion of creatinine, without altering the glomerular filtration rate (GFR). During cimetidine administration the creatinine/inulin clearance ratio approaches unity in patients with renal failure. We determined the clearance of lithium (an index of fluid delivery to the distal nephron), inulin (a measure of the actual GFR) and creatinine during cimetidine administration to investigate the occurrence of tubular creatinine secretion in patients with compensated cirrhosis. A total of 12 patients with Child-Pugh A cirrhosis were studied initially. The subjects consumed a stable diet containing 100mmol of sodium. On successive days, 9h creatinine clearances were measured, first without and then with the oral administration of cimetidine (400mg as a priming dose, followed by 200mg every 3h). During the first study day, 4h renal lithium clearance was also calculated. A further group of five patients with fully compensated cirrhosis underwent the measurement (on successive days) of plasma inulin clearance, first without and then with the oral administration of cimetidine (same schedule of drug administration). Cimetidine administration unmasked a marked overestimation of GFR when calculated as creatinine clearance (baseline, 138±20ml/min; +cimetidine, 89±13ml/min; P < 0.01). Consequently, during cimetidine administration the calculated lithium fractional excretion (a measure of the fraction of filtered sodium load that is delivered to the loop of Henle) rose from 21.4±13.2% to 32.3±18.9% (P < 0.05), and the ratio between absolute distal tubular sodium reabsorption and filtered sodium load rose from 20.6±13.1% to 31.6±19.3% (P < 0.01). Cimetidine caused no significant decrease in the actual GFR (i.e. inulin clearance) when administered to the second group of patients with compensated cirrhosis. Our data demonstrate significant tubular secretion of creatinine in patients with compensated cirrhosis and, consequently, a marked overestimation of GFR and filtered sodium load and an underestimation of the fractional distal tubular sodium reabsorption when these parameters are calculated by means of the traditional creatinine and lithium clearance computation. The true GFR (measured as inulin clearance) is unaffected by cimetidine administration.

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

10.31234/osf.io/su2kw ◽

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.

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Tonabersat, a Gap-Junction Modulator: Efficacy and Safety in Two Randomized, Placebo-Controlled, Dose-Ranging Studies of Acute Migraineceph

Cephalalgia ◽

10.1111/j.1468-2982.2009.01974.x ◽

2009 ◽

Vol 29 (2_suppl) ◽

pp. 17-27 ◽

Cited By ~ 31

Author(s):

SD Silberstein ◽

J Schoenen ◽

H Göbel ◽

HC Diener ◽

AH Elkind ◽

...

Keyword(s):

Adverse Events ◽

North American ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Plasma Concentrations ◽

International Study ◽

Maximum Plasma ◽

Serious Adverse Events ◽

Double Blind ◽

Dose Ranging

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.

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Some Recent Controversies in Intensive Care

Asian Cardiovascular and Thoracic Annals ◽

10.1177/021849239500300102 ◽

1995 ◽

Vol 3 (1) ◽

pp. 4-7

Author(s):

Colin J McArthur

Keyword(s):

Intensive Care ◽

Ventilatory Support ◽

Selective Decontamination ◽

Experimental Therapy ◽

Sodium Reabsorption ◽

Double Blind ◽

Patients At Risk ◽

Bacteria And Fungi ◽

Tract Infections ◽

Upper Gastrointestinal

The ability of dopamine to reverse oliguria has led to its ubiquitous renal protective use in patients at risk of acute renal failure. However, this diuresis is due primarily to inhibition of distal tubular sodium reabsorption and not renal vasodilation. Recent controlled clinical studies have been unable to demonstrate a renal protective effect independent of changes in cardiac output. Selective decontamination of the digestive tract (SDD) has the appealing theoretical ability to minimize upper gastrointestinal colonization with gram-negative bacteria and fungi, and subsequently reduce nosocomial infection and mortality. Such modification of flora does occur, but the initial studies showing a reduction in lower respiratory tract infections have not been supported by recent large double-blind randomized controlled trials. A reduction in mortality or length of stay of general intensive care patients given SDD has never been demonstrated, and it remains an experimental therapy with possible application for some patient subgroups. Upper gastrointestinal hemorrhage (UGH) in the critically ill is associated with prolonged ventilatory support and coagulopathy, but clinically important bleeding is now uncommon. Prophylaxis with agents that increase gastric pH is effective in reducing UGH, but may be associated with a higher incidence of nosocomial pneumonia than occurs with alternatives such as sucralfate. Prophylaxis does not alter mortality, and it is now controversial which patients, if any, should routinely receive such treatment.

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Disposition of MDMA and Metabolites in Human Sweat Following Controlled MDMA Administration

Clinical Chemistry ◽

10.1373/clinchem.2008.117093 ◽

2009 ◽

Vol 55 (3) ◽

pp. 454-462 ◽

Cited By ~ 21

Author(s):

Allan J Barnes ◽

Bruno S De Martinis ◽

David A Gorelick ◽

Robert S Goodwin ◽

Erin A Kolbrich ◽

...

Keyword(s):

Solid Phase ◽

Random Order ◽

Research Unit ◽

Sweat Test ◽

Test Results ◽

Double Blind ◽

Scientific Database ◽

Sweat Testing ◽

Clinical Research Unit ◽

Sweat Tests

Abstract Background: Understanding the excretion of 3,4-methylenedioxymethamphetamine (MDMA) and metabolites in sweat is vital for interpretation of sweat tests in drug treatment, criminal justice, and workplace programs. Methods: Placebo, low (1.0 mg/kg), and high (1.6 mg/kg) doses of oral MDMA were given double-blind in random order to healthy volunteers (n = 15) with histories of MDMA use. Participants resided on the closed clinical research unit for up to 7 days after each dose. Volunteers wore PharmChek® sweat patches (n = 640) before, during, and after controlled dosing. Patches were analyzed by solid phase extraction and GC-MS for MDMA, methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxyamphetamine (HMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA). Limits of quantification (LOQ) were 2.5 ng/patch for MDMA and 5 ng/patch for HMA, HMMA, and MDA. Results: MDMA was the primary analyte detected in 382 patches (59.7%), with concentrations up to 3007 ng/patch. MDA was detected in 188 patches (29.4%) at <172 ng/patch, whereas no HMMA or HMA was detected; 224 patches (35.0%) and 60 patches (9.4%) were positive for MDMA and MDA, respectively, at the 25-ng/patch threshold proposed by the Substance Abuse and Mental Health Services Administration. Conclusions: Sweat testing was shown to be an effective and reliable method for monitoring MDMA use in this controlled MDMA administration study. However, variability in sweat excretion suggests that results should be interpreted qualitatively rather than quantitatively. These data provide a scientific database for interpretation of MDMA sweat test results.

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Analysis of acute naproxen administration on memory in young adults: A randomized, double-blind, placebo-controlled study

Journal of Psychopharmacology ◽

10.1177/0269881117724406 ◽

2017 ◽

Vol 31 (10) ◽

pp. 1374-1376

Author(s):

Jack H Wilson ◽

Amy H Criss ◽

Sean A Spangler ◽

Katherine Walukevich ◽

Sandra Hewett

Keyword(s):

Young Adults ◽

Healthy Adult ◽

Adult Population ◽

Critical Role ◽

Random Order ◽

Controlled Study ◽

High Dose ◽

Short Term ◽

Double Blind ◽

Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs work by non-selectively inhibiting cyclooxygenase enzymes. Evidence indicates that metabolites of the cyclooxygenase pathway play a critical role in the process of learning and memory. We evaluated whether acute naproxen treatment impairs short-term working memory, episodic memory, or semantic memory in a young, healthy adult population. Participants received a single dose of placebo or naproxen (750 mg) in random order separated by 7–10 days. Two hours following administration, participants completed five memory tasks. The administration of acute high-dose naproxen had no effect on memory in healthy young adults.

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Exercise-induced changes in immune function: effects of zinc supplementation

Journal of Applied Physiology ◽

10.1152/jappl.1994.76.6.2298 ◽

1994 ◽

Vol 76 (6) ◽

pp. 2298-2303 ◽

Cited By ~ 65

Author(s):

A. Singh ◽

M. L. Failla ◽

P. A. Deuster

Keyword(s):

Immune Function ◽

Zinc Supplementation ◽

Thymidine Incorporation ◽

Phase 1 ◽

Antioxidant Effect ◽

Oxygen Species ◽

Respiratory Burst Activity ◽

Double Blind ◽

Exercise Induced ◽

Induced Changes

To examine the effect of zinc (Zn) supplementation on exercise-induced changes in immune function, five male runners were randomly assigned in a double-blind crossover design to take a supplement (S; 25 mg of Zn and 1.5 mg of copper) or placebo (P) twice daily for 6 days. On morning 4 of each phase, 1 h after taking S or P, subjects ran on a treadmill at 70–75% of maximal oxygen uptake until exhaustion (approximately 2 h). Blood samples were obtained before (Pre), immediately after (Post), and 1 (Rec1) and 2 (Rec2) days after the run. [3H]thymidine incorporation by mitogen-treated mononuclear cell cultures was significantly lower (P < 0.05) Post than Pre, Rec1, or Rec2 for both S and P. Respiratory burst activity of isolated neutrophils was enhanced after exercise with P but not with S (P: Pre 12.0 +/- 1.1 vs. Post 17.6 +/- 2.3 nmol O2-/10(6) cells; S: Pre 11.7 +/- 0.3 vs. Post 12.1 +/- 1.2 nmol O2-/10(6) cells). Thus supplemental Zn blocked the exercise-induced increase in reactive oxygen species. Whether this antioxidant effect of Zn will benefit individuals exposed to chronic physical stress remains to be determined.

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