Biomedical subjects

C G Ponte

Publications and source records attributed to C G Ponte.

6 recordsLinked to original sources

PubMed2001

WIN 17317-3 blocks Ca2+-activated K+ channels and enhances motility of guinea-pig detrusor muscle.

Patch-clamp experiments in both clonal GH3 cells and guinea-pig bladder myocytes reveal that 1-benzyl-7-chloro-4-(n-pentylimino)-1,4-dihydroquinoline hydrochloride (WIN 17317-3), a potent blocker of Kv1.3 channels and potential immunomodulator, reduces, in a reversible manner and at low micromolar concentrations, K+ currents through Ca2+-activated high conductance K+ channels (BK channels). Blockade of BK channels is thought to account for the stimulatory effect of WIN 17317-3 on the contractility of guinea-pig bladder. This effect is not modified by tetrodotoxin (1 microM), but is abolished by nifedipine (0.1 microM). In conclusion. WIN 17317-3 lacks selectivity for the Kv1.3 channels, its postulated target for immunosuppression.

Animals↗

PubMed2000

Modulation of the Ca(2+) release channel of sarcoplasmic reticulum by amiloride analogs.

Dichlorobenzamil, phenamil and other amiloride analogs (1-100 microM) elicit transient tension in rabbit skinned muscle fibers. Tension requires preloading of Ca(2+) into the sarcoplasmic reticulum, is facilitated by low-[Mg(2+)] solutions, abolished by ruthenium red or by functional disruption of the sarcoplasmic reticulum, and is followed by inhibition of the caffeine-evoked tension. Bilayer recording of Cs(+) currents through the sarcoplasmic reticulum Ca(2+) release channel reveals that phenamil (10-100 microM) increases the open channel probability, whereas dichlorobenzamil affects the channel activity in a complex concentration- and time-dependent manner: stimulation occurs throughout exposure to 10 microM, but is followed by channel blockade when 100 microM dichlorobenzamil is used. It is concluded that stimulation of the sarcoplasmic reticulum Ca(2+) release channel accounts for the dichlorobenzamil- or phenamil-induced tension in skinned fibers, whereas depletion of sarcoplasmic reticulum Ca(2+) stores and channel block (with dichlorobenzamil) explains the inhibition of the caffeine-evoked tension by amiloride analogs.

Amiloride↗

PubMed1999

Limited-sampling strategy models for estimating the area under the plasma concentration-time curve for amlodipine.

OBJECTIVE: Develop and validate limited-sampling strategy (LSS) models for estimating the area under the plasma concentration versus time curve (AUC) of amlodipine, using data from a bioequivalence study. METHODS: Sixteen healthy volunteers received single 5-mg oral doses of amlodipine, as reference or test formulation, at a 14-day interval, in a randomized, crossover protocol. Plasma concentrations of amlodipine (n = 288), measured by mass spectrometry, were used to develop LSS models. RESULTS: Linear regression analysis of the AUC0-72 and a "jack-knife" validation procedure revealed that LSS models based on two sampling times (12 h and 48 h) predict accurately (R2 = 0.99; bias < 0.01%; precision = 0.03%) the AUC0-72 of amlodipine for each formulation. Validation tests indicate that the 2-point LSS model developed for the reference formulation predicts accurately (R2 > 0.90): (a) the individual AUC0-72 for the test formulation in the same group of volunteers; (b) the individual AUC0-72 for the same reference formulation in another bioequivalence study in Brazilian volunteers; (c) the average AUC0-72 reported in seven additional international studies performed under protocols similar to the present investigation; (d) the individual AUC0-72 corresponding to concentration data points provided by a first-order compartmental pharmacokinetic model, when the relative values of either the absorption rate (Kabs) or the bioavailability (F) model parameters were set at 0.85 or 0.6, of their respective original values. CONCLUSIONS: The 2-point LSS models developed in the current study predict accurately the AUC of amlodipine under a variety of experimental conditions and, thus, may be valuable for exploring the relationships between the pharmacokinetics and pharmacodynamics of this calcium antagonist, at reduced costs of sample acquisition and analysis, and avoiding sampling at "unsociable" hours.

Administration, Oral↗

PubMed1999

Limited-sampling strategy models for itraconazole and hydroxy-itraconazole based on data from a bioequivalence study.

The extensive interindividual variability in oral bioavailability of itraconazole prompted an assessment of the bioequivalence of two formulations marketed in Brazil, namely, Sporanox (reference) and Traconal (test). Eighteen healthy volunteers received single 200-mg oral doses of each formulation at 2-week intervals in a randomized, crossover protocol. The concentrations of itraconazole and hydroxy-itraconazole in plasma were measured by high-performance liquid chromatography, and the datum points (n = 396) were subsequently used to develop limited-sampling strategy models for estimation of the areas under the curve (AUCs) for both compounds. The 90% confidence intervals for individual percent ratios (test/reference formulations) of the maximum concentration of drug in serum, the AUC from 0 to 48 h and the AUC from time zero to infinity (AUC0-infinity) for itraconazole and hydoxy-itraconazole were below the range of 80 to 125%, suggesting that these formulations are not bioequivalent. Linear regression analysis of the AUC0-infinity against time and a "jackknife" validation procedure revealed that models based on three sampling times accurately predict (R2, >0.98; bias, <3%; precision, 3 to 7%) the AUC0-infinity for each of the four formulation-compound pairs tested. Increasing the number of sampling points to more than three adds little to the accuracy of the estimates of AUC0-infinity. The three-point models developed for the reference formulation were validated retrospectively and were found to predict within 2% the AUC0-infinity reported in previous studies performed under similar protocols. In conclusion, the data in this study indicate (i) that the tested formulations are not bioequivalent when single doses are compared and (ii) that limited-sampling strategy models based on three points predict accurately the AUC0-infinitys for itraconazole and hydroxy-itraconazole and could be a valuable tool in pharmacokinetic and bioequivalence studies of single oral doses of itraconazole.

Adult↗

PubMed1997

Bovine serum albumin potentiates caffeine- or ATP-induced tension in human skinned skeletal muscle fibers.

Human skinned muscle fibers were used to investigate the effects of bovine serum albumin (BSA) on the tension/pCa relationship and on the functional properties of the Ca(2+)-release channel of the sarcoplasmic reticulum (SR). In both fast- and slow-type fibers, identified by their tension response to pSr 5.0, BSA (0.7-15 microM) had no effect on the Ca2+ affinity of the contractile proteins and elicited no tension per se in Ca(2+)-loaded fibers. In contrast, BSA (> 1.0 microM) potentiated the caffeine-induced tension in Ca(2+)-loaded fibers, this effect being more intense in slow-type fibers. Thus, BSA reduced the threshold caffeine concentration required for eliciting detectable tension, and increased the amplitude, the rate of rise and the area under the curve of caffeine-induced tension. BSA also potentiated the tension elicited in Ca(2+)-loaded fibers by low-Mg2+ solutions containing 1.0 mM free ATP. These results suggest that BSA modulates the response of the human skeletal muscle SR Ca(2+)-release channel to activators such as caffeine and ATP.

Adenosine Triphosphate↗

PubMed1995

Effects of uridine triphosphate on skinned skeletal muscle fibers of the rat.

Chemically skinned muscle fibers from rat extensor digitorum longus muscle were used to study the effects of uridine triphosphate (UTP) on Ca2+ uptake and release by the sarcoplasmic reticulum (SR) and on Ca2+-activated tensions. Total replacement (2.5 mM) of adenosine triphosphate (ATP) with UTP (i) increased submaximal Ca2+-induced tension (pCa 6.2-5.8) but diminished Po, the maximum tension elicited by pCa 4.2, by ca. 15%, (ii) markedly reduced Ca2+ uptake by the SR (evaluated by caffeine-elicited tension); and (iii) induced tension in Ca2+-loaded fibers. The UTP-induced tension averaged 55% of Po and its rates of development and decay were considerably slower than those of caffeine-evoked tension. The UTP-induced tension (i) depended on the Ca2+-loading conditions; (ii) was reversibly blocked by brief (15 s) exposures of Ca2+-loaded fibers to 5 mM EGTA or by pretreatment with caffeine; (iii) was abolished by functional disruption of the SR with the nonionic detergent Brij-58; and (iv) persisted after blockade of the SR Ca2+ release channels with ruthenium red. Exposure of Ca2+-loaded fibers to UTP depressed the tension elicited subsequently by caffeine, and enhanced the rate of depletion of caffeine-sensitive Ca2+ stores during soaking in relaxing solutions containing 5 mM EGTA. The UTP-induced tension is attributed to increased release of Ca2+ from the SR, via a ruthenium red insensitive pathway(s), combined with reduced Ca2+ uptake by the SR and increased Ca2+ affinity of the contractile proteins.

Adenosine Triphosphate↗