[Respiratory stimulants].
Explore the source record for details and available documents.
Acetazolamide↗
Biomedical subjects
C A van Ginneken
Publications and source records attributed to C A van Ginneken.
Effect of substituted benzoates on p-aminohippurate transport in dog renal membrane vesicles.
The effect of substituted benzoates on the transport of p-aminohippurate (PAH) was studied in basolateral (BLMV) and brush border membrane vesicles (BBMV) isolated from dog kidney cortex. For both membranes, kinetic analysis of [3H]PAH transport in the presence of a fixed concentration of two different benzoates, respectively, revealed an increase in the apparent Km for PAH, while the transport capacity (Vmax) was unaffected. This is compatible with competitive inhibition of a common transport pathway. A range of 19 monosubstituted benzoates were then tested as potential inhibitors by measuring the probenecid-sensitive fraction of 100 mumol/l PAH uptake into BLMV and BBMV in the presence of 5 mmol/l benzoate, and apparent inhibition constants (Ki) were calculated. For all benzoates the inhibitory potency in BBMV was lower than in BLMV, but the pattern of inhibition was similar; the most pronounced inhibition was found for 3-Cl- and 4-Cl-benzoate, while the least pronounced inhibition was found for the 3-NH2 and 4-NH2 substitutes. The inhibitory potency, expressed as logKi, correlated significantly with the relative hydrophobicity of the benzoates determined by reversed phase HPLC, whereas a poor correlation was found between pKa and logKi. This indicates that hydrophobic and electronic parameters are the main determinants of affinity for the PAH transport system. It is suggested that the PAH transport system present in the proximal tubules is responsible for the active secretion of benzoates by the mammalian kidney.
Animals↗
Alterations of muscarinic acetylcholine receptors in the nasal mucosa of allergic patients in comparison with nonallergic individuals.
Cholinergic nasal hyperresponsiveness in nasal allergy may be due to changes of the characteristics in muscarinic cholinergic receptors. Radioligand receptor binding and in vitro autoradiographic studies of nasal mucosa in nonallergic (NA) and allergic patients were performed to investigate this hypothesis. The heterogeneous NA group was subdivided into control individuals and patients with chronic sinusitis and vasomotor rhinitis. The 3H-(-)-Quinuclidinylbenzilate binding to muscarinic receptors in human nasal mucosa membranes was saturable and of high affinity in all groups. No significant differences could be demonstrated between the subgroups of the NA patients. In allergic patients the dissociation constants and receptor densities were significantly decreased in comparison with those of NA and with those of control individuals. No differences in agonist binding or coupling of the muscarinic receptor to the effector system via the G protein could be observed in allergic patients. In vitro autoradiographic experiments demonstrated specific 3H-(-)-Quinuclidinylbenzilate labeling of the glandular acini in NA and allergic patients. No specific labeling could be observed in the epithelium, blood vessels, or connective tissue. In conclusion, the increased sensitivity and decreased muscarinic receptor number may reflect the cholinergic-induced hypersecretion in nasal allergy but are probably too small to explain the complex allergic reaction.
Acetylcholine↗
Alterations of adrenoceptors in the nasal mucosa of allergic patients in comparison with nonallergic individuals.
Nasal hyperreactivity in nasal allergy may be due to changes of the characteristics in adrenergic receptors. Radioligand receptor-binding studies with the antagonists, 3H-prazosin (alpha 1-adrenoceptor), 3H-rauwolscine (alpha 2-adrenoceptor), and 125I-(-)-Cyanopindolol (beta-adrenoceptor) were performed in homogenates of nasal mucosa of allergic and nonallergic (NA) patients to investigate this hypothesis. The heterogeneous NA group was subdivided into control individuals and patients with chronic sinusitis and vasomotor rhinitis. No significant differences in affinities or densities of alpha 1- and alpha 2-adrenoceptors could be demonstrated in allergic patients in comparison with NA and control individuals. The beta-adrenoceptor density was significantly reduced in allergic patients in comparison with that of control individuals. Neither changes in agonist binding or in the effect of Gpp(NH)p on the agonist binding to beta-adrenoceptors could be observed in allergic patients. The subtype selective antagonist, LK203-030, demonstrated the presence of a homogeneous population of beta 2-adrenoceptors in human nasal mucosa of both NA and allergic patients. In vitro, autoradiography demonstrated specific 125I-(-)-Cyanopindolol labeling of the epithelium in NA and allergic patients. In conclusion, no changes in characteristics of alpha 1- or alpha 2-adrenoceptors in the nasal mucosa could be demonstrated in nasal allergy. However, a decreased number of beta-adrenoceptors may reflect a beta-adrenergic abnormality in nasal allergy.
Autoradiography↗
Renal handling and effects of S(+)-ibuprofen and R(-)-ibuprofen in the rat isolated perfused kidney.
1. The renal handling and effects of S(+)- and R(-)-ibuprofen have been studied in the isolated perfused kidney (IPK) of the rat. 2. Both ibuprofen enantiomers were extensively reabsorbed and accumulated in the kidney in a concentration-dependent manner. No pharmacokinetic differences were observed between the two enantiomers. 3. S(+)-ibuprofen concentrations ranging from 0.25 to 25 micrograms ml-1 (1.2 to 120 microM) caused a decrease in urinary flow, glomerular filtration rate (GFR) and electrolyte excretion. Urinary pH and excretion of glucose were not influenced. R(-)-ibuprofen concentrations ranging from 2.5 to 25 micrograms ml-1 (12 to 120 microM) also decreased urinary flow and electrolyte excretion. This decrease, however, was less than observed with S(+)-ibuprofen. GFR, urinary pH and glucose excretion were not affected by R(-)-ibuprofen. Prostaglandin E2 (PGE2) concentrations of 133 ng ml-1 reversed the effects on renal function of both enantiomers. 4. Very high S(+)- and R(-)-ibuprofen concentrations (greater than 400 micrograms ml-1) resulted in an increase in urinary flow and fractional excretion of sodium, chloride, potassium, glucose and calcium. 5. It is concluded that the pharmacokinetic behaviour of ibuprofen in the kidney is not stereoselective. Relatively high concentrations of both enantiomers increased the urinary flow and electrolyte excretion in a nonstereoselective manner. Lower concentrations of S(+)-ibuprofen decreased urinary flow and electrolyte excretion. The pharmacologically inactive R(-)-ibuprofen was also able to affect renal function in a similar way, but at different concentrations. These effects on renal function are probably caused by inhibition of PGE2 synthesis.
Animals↗
Renal handling and effects of salicylic acid in the isolated perfused rat kidney.
The renal handling of salicylic acid (SA) and its effects on renal function were studied in the isolated perfused rat kidney (IPK). The renal handling of SA is dominated by reabsorption and only a small fraction of the filtered SA is excreted into the urine. Reabsorption is a passive process and is dependent on urinary pH. Because of the extensive reabsorption, no decrease in perfusate concentration can be observed in the course of the IPK experiment. SA accumulated slightly in the IPK and this accumulation is concentration dependent. Small amounts of SA were converted to salicyluric acid (SU), the glycine conjugate of SA. SA concentrations higher than 100 micrograms/ml caused an immediate increase in urinary flow and in fractional excretion of sodium, potassium, chloride and calcium. Fractional excretion of glucose increased gradually. Glomerular filtration rate, renal perfusion flow, renal pressure and fractional excretion of magnesium were not affected by SA. The effects were dependent on the SA concentration. Although SA is a classical non-steroidal antiinflammatory drug (NSAID), its influence on renal function appears to be different from other NSAIDs which are usually associated with a reduction in urinary flow and salt excretion.
Animals↗
Indometacin: renal handling and effects in the isolated perfused rat kidney.
We investigated renal handling and effects of indometacin on renal function in the isolated perfused rat kidney (IPK). Indometacin concentrations less than 2.5 ng/ml did not influence renal function, while higher concentrations caused a decrease in urinary flow and electrolyte excretion. The presence of 133 ng/ml prostaglandin E2 (PGE2) in the perfusate fully opposed these effects on kidney function. Only a small fraction of the filtered indometacin is excreted into the urine, indicating extensive reabsorption of the compound. This is probably a passive process, dependent on the tubular load, urinary pH and urinary flow. Indometacin accumulates extensively in the IPK, causing a kidney to perfusate ratio between 5 and 9. Accumulation decreased with increasing perfusate concentration. This can be explained by active secretion: increasing the perfusate concentration leads to a saturation of the active secretion and a decrease in the relative accumulation. We conclude that indometacin accumulates extensively in the IPK, that it affects kidney function and that this influence is probably caused by the inhibition of PGE2 synthesis.
Animals↗
Pharmacokinetic properties of the antimuscarinic drug [3H]-hexahydro-sila-difenidol in the rat.
The pharmacokinetics of tritiated hexahydro-sila-difenidol [( 3H]-HHSiD) were examined in rats. Furthermore, the distribution of radioactivity was studied by means of whole body autoradiography. After i.v. administration of 2.9 mg/kg HHSiD plus [3H]-HHSiD to anaesthetized rats bearing a catheter implanted in the ductus choledochus and receiving a mannitol infusion, HHSiD was rapidly distributed and metabolized. Only 5% of the radioactivity was recovered in blood after 23 s and 0.4% after 2.5 h. 64% of the plasma radioactivity could be extracted with hexane from the samples taken 23 s after administration. 52% of the radioactivity was eliminated within 2.5 h, 13% by urinary and 39% by biliary excretion. Following oral administration of 8.6 mg/kg HHSiD plus [3H]-HHSiD there was an absorption of approximately one fourth of the administered radioactivity within 4 h. By means of whole body autoradiography (i.v. injection) as well as by tissue distribution measurement the highest levels of radioactivity were found in bile, urine, lung, kidney, adrenals, liver and pancreas. Thus, after i.v. administration to rats HHSiD is rather quickly distributed, metabolized and excreted. This explains its low antimuscarinic potency in vivo.
Administration, Oral↗
Comparison of the diuretic effect and absorption of a single dose of furosemide and free and the fixed combinations of furosemide and triamterene in healthy male adults.
The absorption and diuretic effect of furosemide 40 mg alone (F), and of the free (F + T) and the fixed (FT) combinations of furosemide 40 mg and triamterene 50 mg have been compared in 12 healthy young men. A slight reduction in the area under the concentration-time curve (AUC) of plasma furosemide was found for the fixed combination (AUC480) F2.58 micrograms.h.ml-1; F + T 2.46 micrograms.h.ml-1; FT 1.97 micrograms.h.ml-1. There was a significant reduction in the AUC480 of plasma triamterene (F + T 204.9 micrograms.h.l-1; FT 130.2 micrograms.h.l-1). Sodium excretion after F + T and FT was more pronounced than after F (F + T 302 mmol; FT 311 mmol; F259 mmol). When compared to F alone, there was a reduction in the 24-hour potassium excretion after F + T as well as after FT (F 121 mmol; F + T 104 mmol; FT 107 mmol). It is concluded that the absorption of triamterene was significantly reduced after ingestion of the fixed combination tablet. However, in healthy male adults this had no influence on its natriuretic and potassium-sparing effect as compared to the free combination.
Absorption↗
Isolated perfused rat kidney as a tool in the investigation of renal handling and effects of nonsteroidal antiinflammatory drugs.
An isolated perfused rat kidney (IPK) preparation is described in which renal perfusion flow, perfusion pressure, urinary flow, urinary pH, and glomerular filtration rate (GFR) are recorded continuously during the perfusion experiment. The usefulness of this IPK system in studying the renal handling and the effects of non-steroidal antiinflammatory drugs (NSAIDs) is shown using salicyluric acid (SU), salicylic acid (SA), and naproxen (NA). Excretion of SU involves glomerular filtration, active secretion, and passive reabsorption. The excretion rates of SA and NA were both much lower than their filtration rate, indicating extensive reabsorption. All three drugs accumulate in the IPK but at different levels. SU accumulates much more than either SA or NA. The effects on renal function were different for the three drugs studied. SU had no effect on kidney function. SA perfusate concentrations greater than 100 micrograms/mL caused diuresis and natriuresis, while SA concentrations less than 100 micrograms/mL did not influence kidney function. NA perfusate concentrations ranging from 0.16 to 25 micrograms/mL caused a decrease in urinary flow and sodium excretion. Very high NA concentrations (greater than 500 micrograms/mL) caused an increase in urinary flow and sodium excretion. We conclude that the IPK is a suitable preparation for characterizing and comparing renal handling and effects of NSAIDs.
Animals↗
Naproxen and indomethacin: disposition and effects in the isolated perfused rat kidney.
Explore the source record for details and available documents.
Animals↗
Age-dependent pharmacokinetics of phenylbutazone in calves.
The pharmacokinetics of phenylbutazone (PBZ) in relation to age was studied in calves. The drug was applied intravenously to calves (dose 22 mg/kg), which were divided, depending on age, into three groups. Heparinised blood samples were taken in defined intervals. The concentrations of phenylbutazone and two of its metabolites were determined in plasma by high performance liquid chromatography. The pharmacokinetic data derived from 1-month-old calves revealed a longer persistence (elimination half-lives twice as long, total body clearance 40-50% lower) of PBZ in the body than in the other two groups of calves aged 3-6 months. With respect to the long elimination half-lives (mean values 39-94 h), caution is needed in case of repeated doses (accumulation).
Aging↗
Binding characteristics of the muscarinic receptor subtype in rabbit pancreas.
The muscarinic receptor in the rabbit pancreas was characterized with the use of the labeled ligand (3H)-(-)-quinuclidinyl-benzylate ((3H)-(-)-QNB). Specific binding of (3H)-(-)-QNB to pancreatic acini was found to be reversible and of high affinity, with an equilibrium dissociation constant (KD) of 68 pmol/l and a receptor density (RT) of 170 fmol/mg protein. Agonist binding behaviour was investigated by displacement of (3H)-(-)-QNB binding by eight agonists like arecoline, arecaïdine-propargylester (APE) and carbachol, yielding only low affinity binding sites. The inhibition of (3H)-(-)-QNB binding by the selective antagonists pirenzepine, hexahydrosiladifenidol (HHSiD) and (11-[2-[diethyl-amino)-methyl)-1-piperidinyl]acetyl)-5,11-dihydro-6H-pyr ido (2,3-b) (1,4) benzodiazepin-6-one) (AF-DX 116) confirmed the M3 nature of the rabbit pancreatic receptor.
Animals↗
Renal disposition and effects of naproxen and its l-enantiomer in the isolated perfused rat kidney.
Renal handling, metabolism and effects on kidney function of naproxen and its l-enantiomer were examined in the isolated perfused rat kidney (IPK). Urinary excretion rate of naproxen was much lower than the filtration rate, indicating extensive reabsorption. Naproxen is accumulated considerably in the IPK. This accumulation is concentration-dependent and is probably the result of active secretion of naproxen. Considerable amounts of desmethyl-naproxen were formed in the IPK. The kinetic behavior of the l-enantiomer of naproxen did not differ from naproxen. Addition of 37.5 to 3750 micrograms naproxen caused a decrease in urinary flow, glomerular filtration rate and fractional excretion of sodium, chloride, potassium, magnesium and calcium. The presence of prostaglandin E2 in the perfusate fully opposed the effects of naproxen on kidney function. Addition of 375 micrograms l-enantiomer of naproxen did not influence kidney function. Addition of very high doses (1 x 10(5) micrograms) of naproxen and its l-enantiomer to the IPK caused diuresis and increased the fractional excretion of sodium, chloride, potassium, glucose and calcium. We conclude that the pharmacokinetic behavior and the metabolism of naproxen in the IPK is probably not stereoselective; that relatively low doses of naproxen exert a specific, stereoselective effect on kidney function caused by inhibition of the prostaglandin E2 synthesis and that high doses of naproxen exert a nonstereoselective effect on kidney function.
Animals↗
Muscarinic receptor binding in central airway musculature in chronic airflow obstruction.
The hypothesis of an increased muscarinic receptor sensitivity in airway musculature of patients with chronic airflow obstruction (CAO) has been investigated by in vitro radioligand binding studies. The receptor binding profiles were determined in membrane homogenates of tracheal and main bronchial smooth muscle, as well as in segmental bronchial tissue preparations. The number of receptors was measured by binding of the radioactive muscarinic antagonist [3H]-(-)-quinuclidinyl benzilate ([3H]-(-)-QNB). The affinity for agonists was investigated by studying the inhibition of [3H]-(-)-QNB binding by the full muscarinic agonist methylfurtrethonium. Binding characteristics were determined (1) in tracheal smooth muscle from 7 patients with chronic airflow obstruction (2) in main bronchial smooth muscle of 5 patients with CAO and (3) in segmental bronchial tissue of 10 patients with CAO. The receptor binding properties were compared with values obtained on airway tissue from 31 subjects without CAO. Muscarinic receptors in smooth muscle preparations of trachea and main bronchus were present in normal density, and showed normal [3H]-(-)-QNB binding affinity and methylfurtrethonium binding properties. In segmental bronchial tissue preparations which contain smooth muscle and glandular tissue, also normal receptor numbers and [3H]-(-)-QNB affinity values were found. Morphometric examination of these preparations revealed normal amounts of smooth muscle and submucosal glands. This suggests that the excessive mucus production of CAO is not accompanied by an increased muscarinic receptor density in submucosal glands. These observations suggest unaltered muscarinic receptor characteristics in central airway smooth muscle of patients with chronic airflow obstruction.
Aged↗
Beta adrenoceptor binding and induced relaxation in airway smooth muscle from patients with chronic airflow obstruction.
Beta adrenoceptor function in central airway smooth muscle of patients with chronic airflow obstruction was investigated by radioligand binding studies and isoprenaline relaxation experiments. Receptor characteristics were determined in tracheal smooth muscle preparations obtained at necropsy from 12 patients and in bronchial tissue obtained at thoracototomy from 21 patients with chronic airflow obstruction. Receptor characteristics were compared with those obtained in airway tissue preparations from 65 control subjects without chronic airflow obstruction. The number of beta adrenoceptors, their binding affinity for the radioligand [125I]-(-)-cyanopindolol, and the tissue binding characteristics of isoprenaline were similar in tissue from patients with chronic airflow obstruction and from control subjects. Isoprenaline induced relaxation of tracheal smooth muscle without precontraction by methacholine showed slightly (though not significantly) less sensitivity to isoprenaline in patients with chronic airflow obstruction than in control subjects (mean (SEM) pD2--the negative logarithm of the concentration producing 50% relaxation--6.32 (0.16) v 6.62 (0.15)). The same pattern of pD2 values was found in segmental bronchial strips without precontraction by methacholine (chronic airflow obstruction 6.55 (0.27), control 7.14 (0.12)). Isoprenaline relaxation in segmental bronchial strips when contracted maximally was significantly less in the patients with airflow obstruction than in the control subjects (pD2 value 5.99 (0.18) v 6.45 (0.07)). These results suggest that beta adrenoceptors in airway smooth muscle of patients with chronic airflow obstruction are not abnormal in number or in binding affinity but that there is less effective coupling between components of the relaxant system distal to the beta adrenoceptor. The possibility that the reduced isoprenaline sensitivity is a consequence of previous bronchodilator treatment cannot be excluded.
Airway Resistance↗
Modes of association of indometacin with human polymorphonuclear leucocytes.
The basic transport properties of indometacin (INDO) were investigated in human blood polymorphonuclear leucocytes (PMNs) of healthy volunteers. The silicone oil cushion centrifugation method was used as ligand-binding assay for both the measurements of the cellular association of INDO and the intracellular volume. This assay enabled us to calculate the intracellular INDO concentrations. A considerable amount of INDO accumulates in the PMNs to cause cell/medium ratios between 20 and 90. At low INDO levels (1-10 nmol/l) the cell/medium ratio appeared to be higher than at high INDO levels (greater than 2 mumol/l). This finding suggests that the cell accumulation of INDO comprises saturable binding and/or transport components. Scatchard analysis of the association isotherm of INDO after incubation for 60 min at 37 degrees C reveals apparent KD values of 3.7 mumol/l (low affinity) and 1.2 nmol/l (high affinity). The number of high-affinity association sites (60 fmol/3 X 10(6) PMNs) was 1,000-2,000 times lower than the number of low-affinity association sites (103 pmol/3 X 10(6) PMNs). INDO cell association is suggested to be a net result of diffusive and mediated influx and efflux mechanisms, and of binding to (plasma) membranes. The capacity of the PMN to accumulate INDO is enhanced upon (1) establishment of an inward gradient of [H+], and (2) activation of the Na(+)-H+ antiport by chemotactic peptide. The possible mechanisms of incorporation of INDO in the PMN are discussed in the scope of the proposed PMN-related anti-inflammatory action of INDO.
Biological Transport↗
Saturable pharmacokinetics in the renal excretion of drugs.
The renal excretion of drugs is the result of different mechanisms: glomerular filtration, passive back diffusion, tubular secretion and tubular reabsorption. Of these mechanisms the last 2 are saturable, as they involve carrier transport. This also implies that both tubular secretion and tubular reabsorption are susceptible to competition between similar substrates for a common carrier site. Furthermore, transport via these mechanisms is energy-dependent, so-called active transport, able to concentrate a drug. Tubular secretion takes place in the proximal tubule of the nephron. Many organic compounds are actively secreted, but there are separate carrier systems for anions and cations. Anions appear to be transported actively over the basolateral membrane and by a less efficient non-active carrier-mediated process (facilitated diffusion) over the brush border membrane. As a result of these mechanisms, anions tend to accumulate in proximal tubular cells. For cations, however, the active transport step operates over the brush border membrane, whereas the uptake of the cation in the cell occurs via facilitated diffusion over the basolateral membrane. Active reabsorption is most prominent for many nutrients and endogenous substrates (amino acids, glucose, vitamins), but various exogenous compounds also have a certain affinity for the reabsorptive carrier systems. Uricosuric drugs, for instance, interfere with carrier-mediated reabsorption of urate. The occurrence of saturable excretion routes causes dose-dependent, non-linear pharmacokinetics. In clinical pharmacokinetics, tubular secretion can adequately be described with the use of a Michaelis-Menten equation. This implies that a compound undergoing tubular secretion exhibits a concentration-dependent renal clearance. At low plasma concentrations the clearance will be maximal, and for several drugs may be as high as the effective renal plasma flow. Increasing concentrations cause decreasing renal clearance, until eventually the secretion mechanism becomes fully saturated. Then the excretion of the drug in urine will depend primarily on its net rate of filtration. It is important to realise that the non-linear kinetics will be evident from the plasma kinetics only when the saturable pathway contributes to at least some 20% of the total body clearance. Interactions with other substrates, however, are likely to occur even when only a very small amount of drug is transported by the carrier system. Non-linear kinetics inevitably lead to disproportionate accumulation.(ABSTRACT TRUNCATED AT 400 WORDS)
Drug Interactions↗