Enantioselective pharmacokinetic and pharmacodynamic properties of carvedilol in spontaneously hypertensive rats: focus on blood pressure variability

The cardiovascular effects and pharmacokinetics of carvedilol were assessed in spontaneously hypertensive (SH) and Wistar Kyoto (WKY) animals with special focus on short-term blood pressure variability (BPV). Male SH and WKY rats were acutely treated with vehicle or carvedilol 1 or 5 mg kg⁻¹ (i.v.), and effects on blood pressure (BP), heart rate (HR) and BPV were recorded. Plasma pharmacokinetics of R- and S-carvedilol was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by pharmacokinetic–pharmacodynamic (PK–PD) modelling. Short-term BPV was assessed by standard deviation of BP recording. Vascular sympatholytic activity of carvedilol was studied by estimation of drug effects on ratio between low frequency (LF) and high frequency (HF) BPV (LF/HF ratio). Although pharmacokinetic properties of carvedilol remained mainly unaffected in SH rats with regard to WKY rats, hypertensive animals showed a reduction in drug clearance of R- and S-carvedilol after administration of 1 mg kg⁻¹ compared with WKY rats. PK–PD analysis of HR changes induced by S-carvedilol showed a greater maximal bradycardic response to carvedilol in SH rats (E _max, −27.6 ± 3.9%; p < 0.05) compared with WKY group (E _max, −13.4 ± 2.5%). SH rats showed a greater hypotensive effect of racemic carvedilol (E _max, −45.5 ± 5.0%; p < 0.05) with regard to WKY group (E _max, −17.9 ± 4.5%). Carvedilol induced a greater reduction of LF/HF ratio in SH rats compared with WKY rats. Short-term BPV was markedly reduced by carvedilol in WKY and SH rats. In conclusion, as a consequence of an enhanced bradycardic response and a greater vascular sympatholytic activity, carvedilol exerts a greater hypotensive response in SH rats compared with WKY animals and dramatically reduces short-term BPV.     

Constriction of rat extra-splenic veins to lipopolysaccharide involves endothelin-1

The spleen has an important role in blood volume regulation and increased resistance of post-capillary hilar veins (in mesentery adjoining the spleen) can regulate this. This study investigated whether venular constriction to lipopolysaccharide (LPS) involved endothelin-1 (ET-1). Pressure myography was used to study isolated extra-splenic (hilar) vessels from male Wistar rats (n = 111). Arteries and veins were treated with LPS (50 μg ml⁻¹) for 4 h. Extra-splenic veins constricted to LPS (p < 0.05), but there was no effect on arteries. Denudation did not abolish venular constriction to LPS, indicating an endothelial independent mechanism. However, the dual ET-1 receptor antagonist bosentan (10⁻⁵ M) and specific ET_A and ET_B antagonists ABT-627 (atrasentan, 6.3 × 10⁻⁶ M) and A-192621(1.45 × 10⁻⁶ M) completely abolished constriction of LPS-treated veins. ET-1 alone also constricted the extra-splenic arteries and veins (p < 0.05), with a greater response observed in veins (p < 0.05). ELISA also confirmed that serum and spleen levels of ET-1 increased in response to LPS (p < 0.05). That LPS-induced constriction of extra-splenic veins is mediated by ET-1. Greater constriction of post- versus pre-capillary extra-splenic vessels to LPS would result in increased intra-splenic fluid extravasation and hypovolaemia in vivo.     

Purification and Characterisation of a Newly Isolated Stable Long-Life Tannase produced by F. subglutinans (Wollenweber and Reinking) Nelson et al.

A stable long-life tannase was synthesised by Fusarium subglutinans and the fermentation processing parameters were optimised. Maximum enzyme production (9.38 U/ml) was recorded after 96 h of incubation at 35°C, initial pH 5, in submerged culture (200 rpm) utilising 2% (w/v) tannic acid as a sole carbon source. The tannase produced was purified to electrophoretic homogeneity through two-step column chromatography and the purified form remained stable in a pH range of 6–8. Its midpoint of thermal inactivation (T _m) was recorded at 70°C after 60 min of exposure. Maximum tannase activity was enabled at pH 6 and 40°C. Ca²⁺, K⁺, Mg²⁺ and Mn⁺ showed a stimulatory effect while Ba²⁺, Co²⁺, Cu²⁺, Fe³⁺ and Zn⁺ showed a competitive inhibitory effect on enzyme activity. Values of K _m, V _max, K _cat and the molecular mass of the purified enzyme were 0.116 μM ml⁻¹ min⁻¹, 3.57 mM, 1.16 μM ml⁻¹ min⁻¹ and 150 kDa, respectively. The participation of the SH group and carbohydrates in the enzyme structure was also suggested by the results. The stability of the purified and partially purified enzyme at −15°C extended to 13 months.     

The bioavailability of bromazepam, omeprazole and paracetamol given by nasogastric feeding tube

Aims

To characterize and compare the pharmacokinetic profiles of bromazepam, omeprazole and paracetamol when administered by the oral and nasogastric routes to the same healthy cohort of volunteers.

Methods

In a prospective, monocentric, randomized crossover study, eight healthy volunteers received the three drugs by the oral (OR) and nasogastric routes (NT). Sequential plasma samples were analyzed by high-performance liquid chromatography–UV, pharmacokinetic parameters (C_max, ${\text{AUC}}_{0 - \infty } Aims  To characterize and compare the pharmacokinetic profiles of bromazepam, omeprazole and paracetamol when administered by the oral and nasogastric routes to the same healthy cohort of volunteers. Methods  In a prospective, monocentric, randomized crossover study, eight healthy volunteers received the three drugs by the oral (OR) and nasogastric routes (NT). Sequential plasma samples were analyzed by high-performance liquid chromatography–UV, pharmacokinetic parameters (C_max, , t_?, k_e, t_max) were compared statistically, and C_max, and t_max were analyzed for bioequivalence. Results  A statistically significant difference was seen in the of bromazepam, with nasogastric administration decreasing availability by about 25%: AUC_OR = 2501 ng mL⁻¹ h; AUC_NT = 1855 ng mL⁻¹ h (p < 0.05); ratio (geometric mean) = 0.74 [90% confidence interval (CI) 0.64–0.87]. However, this does not appear to be clinically relevant given the usual dosage range and the drug’s half-life (approx. 30 h). A large interindividual variability in omeprazole parameters prevented any statistical conclusion from being drawn in terms of both modes of administration despite their similar average profile: AUC_OR = 579 ng mL⁻¹ h; AUC_NT = 587 ng mL⁻¹ h (p > 0.05); ratio (geometric mean) = 1.01 (90% CI 0.64–1.61). An extended study with a larger number of subjects may possibly provide clearer answers. The narrow 90% confidence limits of paracetamol indicate bioequivalence: AUC_OR = 37 μg mL⁻¹ h; AUC_NT = 41 μg mL⁻¹ h(p > 0.05); ratio (geometric mean) = 1.12 (90% CI 0.98–1.28). Conclusion  The results of this study show that the nasogastric route of administration does not appear to cause marked, clinically unsuitable alterations in the bioavailability of the tested drugs.     

Effect of nitroxyalkyl derivatives of fullerenylproline on the activity of CA<Superscript>3+</Superscript>-ATPase of sarcoplasmic reticulum

The effect of nitroxyalkyl derivatives of fullerenylproline methyl ester on the enzymatic activity of Ca²⁺-ATPase of sarcoplasmic reticulum (SR) has been studied. It is shown that hybrid derivatives of C₆₀ fullerene are capable of inhibiting the activity of Ca²⁺-ATPase of SR. The mononitrate inhibits the hydrolytic activity of the enzyme with K _i = 1.92 × 10⁻⁶ M; active Ca²⁺ transport, with K _i = 3.79 × 10⁻⁶ M. The dinitrate inhibits ATP hydrolysis with K _i = 2.38 × 10⁻⁸ M; Ca²⁺ transport, with K _i  = 3.08 × 10⁻⁸ M. Fullerenylproline methyl ester does not affect the enzymatic activity of Ca²⁺-ATPase. Based on these data it is possible to predict the possible fields of application for hybrid fullerene derivatives as potential drugs.     

The effect of long-term repeated exposure to 3,4-methylenedioxymethamphetamine on cardiovascular and thermoregulatory changes

Rationale  3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) disrupts thermoregulation in rats and can lead to life-threatening hyperthermia in humans. MDMA administration can also lead to long-term neurotoxicity in animals and possibly humans. Objectives  The purpose of the current study was to extend previous results on the acute effects of MDMA on behavioral thermoregulation to a repeated dosing regime, simulating regular weekend use of ecstasy, on measures of thermoregulation and heart rate (HR). Materials and methods  Sprague–Dawley rats with telemetry implants were administered 40 μmol/kg MDMA on three consecutive days each week for 1 or 6 weeks before being confined to an elevated ambient temperature (T _A) (HOT; 30 ± 1°C) or an area at room temperature (ROOM; 21.5 ± 1.5°C) for 30 min. After the final drug administration, rats were placed in a thermal gradient for 4 h to allow behavioral thermoregulation. Results  HOT rats showed higher core temperature (T _C), HR, and locomotor activity than ROOM rats during confinement to a set T _A (P < 0.001). HR responses to MDMA over 6 weeks at both T _As progressively decreased with repeated dosing (P < 0.05). T _C was significantly higher in both 6-week groups compared to the 1-week groups (P < 0.05) at the end of time in the gradient. Cortical concentrations of dihydroxyphenylacetic acid (DOPAC; P < 0.05) and 5-hydroxyindole acetic acid (5-HIAA; P < 0.001) decreased significantly irrespective of T _A, while concentrations of dopamine and 5-HT did not change. Conclusion  Long-term treatment with MDMA resulted in apparent tolerance to the effects of the drug on HR, dysregulation of T _C in thermal gradient, and depletion of cortical DOPAC and 5-HIAA.     

Comparative pharmacokinetics and pharmacodynamics of the novel rapid-acting insulin analogue, insulin aspart, in healthy volunteers

Objective: The pharmacokinetics of a new insulin analogue, insulin aspart, were compared with unmodified human insulin in a double-blind crossover study of 25 fasting healthy men following a single subcutaneous dose. Methods: Either insulin aspart or human insulin, 0.1 U · kg-body-weight⁻¹, was injected subcutaneously and followed by determination of 8-h profiles of serum insulin and plasma glucose concentrations. Results: The absorption of insulin aspart was, on average, more than twice as fast and reached levels more than twice as high compared with human insulin [t_max(ins) of 52 (23) vs 145 (93) min, P < 0.0001; and C_max(ins) of 41 (11) vs 18 (4) mU · l⁻¹, P < 0.0001; mean with (SD)]. However, total bioavailability did not differ between the insulins, and thus the mean residence time was significantly shorter for insulin aspart [MRT_(ins) of 149 (26) vs 217 (30) min, P < 0.0001]. Plasma glucose (PG) fell more than twice as rapidly [t_min(PG) of 94 (45) vs 226 (120) min, P < 0.0001], to a greater extent [C_min(PG) 2.1 (0.6) vs 1.4 (0.4) mmol · l⁻¹, P < 0.0001], and for a shorter duration with insulin aspart than with human insulin. Conclusion: With improved subcutaneous absorption characteristics, the insulin aspart concentration–time profile resembles physiological meal-stimulated insulin release more closely than that of unmodified human insulin. This significantly alters the pharmacodynamic response in an advantageous manner in the meal-related treatment of diabetes mellitus. Received: 26 October 1998 / Accepted in revised form: 23 January 1999     

Changes in urinary PGE<Subscript>2</Subscript> after ibuprofen treatment in preterm infants with patent ductus arteriosus

Purpose  To investigate changes in urinary PGE₂ after ibuprofen treatment in preterm infants with patent ductus arteriosus (PDA). Methods  Twenty preterm infants with a hemodynamically significant PDA (gestational age, 28.6 ± 2.3 weeks) and 20 controls (gestational age, 30.4 ± 1.5 weeks) were prospectively enrolled at 48–72 h of life. After enrollment, the former underwent conventional ibuprofen-lysine treatment. At 48–72 h (T₀) and 108–144 h of life (T₁), urine samples were noninvasively collected in both groups to measure urinary PGE₂ concentrations (enzyme immunoassay method), and renal function was investigated. Results  Urinary PGE₂ decreased significantly both in ibuprofen-treated patients (66.95 ± 16.78 vs. 27.15 ± 17.92 pg/mL, P < 0.001) and in controls (71.7 ± 16.2 vs. 53.2 ± 18.4 pg/mL, P < 0.001) from T₀ to T₁. However, urinary PGE₂ at T₁ was significantly lower (P < 0.001) in the ibuprofen group compared to the control group. Acute renal failure occurred in three ibuprofen-treated patients (15%). Conclusions  Ibuprofen markedly reduces (59.4%) urinary PGE₂ and may alter renal function in the newborn.     

Bayesian pharmacokinetic estimation of vinorelbine in non-small-cell lung cancer patients

Objective: To develop a population pharmacokinetics of vinorelbine in a population of non-small-cell lung cancer (NSCLC) patients using a Bayesian estimation in order to calculate for any further patient, individual pharmacokinetic parameters from few blood samples. Methods: Vinorelbine was given by a 15-min infusion (30 mg · m⁻²) to eight patients with NSCLC. Its serum concentration was determined by HPLC and its pharmacokinetics was described by a three-compartment open model with elimination from the central compartment. Volume of the central compartment (V₁) and rate constants (k₁₀, k₁₂, k₂₁, k₁₃, k₃₁) were selected as population pharmacokinetic parameters and computed by non-linear regression (two-step approach) from 14 to 18 concentration measurements per course. Subsequently, these parameters were used by the Bayesian estimator to calculate individual pharmacokinetics from only 2 or 3 measured concentrations. Results: The population mean values (CV%) of V₁, k₁₀, k₁₂, k₂₁, k₁₃, k₃₁, CL, t _1/2 were respectively 21 l (55%), 3.2 h⁻¹ (29%), 7.7 h⁻¹ (74%), 1.3 h⁻¹ (67%), 4.7 h⁻¹ (53%), 0.04 h⁻¹ (20%), 57 l · h⁻¹ (31%) and 43 h (36%). The comparison of results obtained from the Bayesian estimator and from the three-compartment model showed that CL and t _1/2 were well predicted (relative deviation: ±12 to 22%) by the Bayesian method using only two blood samples. Conclusion: We demonstrated that Bayesian estimation allows, at minimal cost and minimal disturbance for the patient, the determination of several vinorelbine pharmacokinetic parameters and therefore dose adaptation from as few as two drug concentrations, measured at 6 h and 24 h after infusion. Received: 4 July 1997 / Accepted in revised form: 15 November 1997     

Phosphodiesterases PDE3 and PDE4 jointly control the inotropic effects but not chronotropic effects of (−)-CGP12177 despite PDE4-evoked sinoatrial bradycardia in rat atrium

Acting through a low-affinity site of the β₁-adrenoceptor (β_1LAR), CGP12177 causes sinoatrial tachycardia and positive inotropic effects in left atrium but not in the ventricle of the rat. However, inhibition of either PDE3 or PDE4 also uncovers positive inotropic effects of CGP12177 in ventricle, but whether these phosphodiesterases also control the atrial agonist effects of CGP12177 was unknown. We, therefore, investigated the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4 inhibitor rolipram (1 μM) on the (−)-CGP12177-evoked increases of sinoatrial beating rate and force of paced left atria of the rat. Rolipram (n = 8) increased basal sinoatrial rate by 27 ± 5 bpm but cilostamide (n = 8) had no effect. The chronotropic potency of (−)-CGP12177 (−logEC₅₀M = 7.5) was not changed by rolipram and cilostamide or their combination. (-)-CGP12177 increased left atrial force with intrinsic activity 0.25 compared to (-)-isoprenaline. Rolipram (n = 8) and cilostamide (n = 8) did not change basal force of left atria but concurrent rolipram + cilostamide (n = 8) increased force by 52 ± 9% of the effect of 200 μM (−)-isoprenaline. Neither rolipram nor cilostamide affected the inotropic potency of (−)-CGP12177 (−logEC₅₀M = 7.4) but concurrent rolipram + cilostamide caused potentiation (−logEC₅₀M = 8.2) and converted (-)-CGP12177 into a full agonist compared to (-)-isoprenaline. Cyclic AMP appears to maintain sinoatrial rate and PDE4 elicits bradycardia through hydrolysis of cAMP in a compartment distinct from the β_1LAR-induced cAMP compartment through which (−)-CGP12177 causes tachycardia. In contrast to the (−)-CGP12177-evoked tachycardia, not controlled by PDE3 and PDE4, these isoenzymes jointly reduce (−)-CGP12177-evoked increases of left atrial contractility through β_1LAR.     

Pharmacokinetics of lidocaine and its metabolite in peridural anesthesia administered to pregnant women with gestational diabetes mellitus

Background  Peridural blockade with lidocaine, bupivacaine, and fentanyl is an anesthetic procedure extensively used in obstetrics, justifying the pharmacokinetic study of these drugs during labor. Objective  To investigate the influence of the physiopathological changes of gestational diabetes mellitus (GDM) on the pharmacokinetics of lidocaine and its metabolite monoethylglycinexylidide (MEGX) in pregnant women subjected to peridural anesthesia. Patients and methods  Ten normal pregnant women (group 1) and six pregnant women with GDM (group 2) were studied, all of them at term. The patients received 200 mg 2% lidocaine hydrochloride without a vasoconstrictor by the peridural locoregional route. Maternal blood samples were collected at predetermined times for the analysis of lidocaine and MEGX by chromatography and pharmacokinetic analysis. Results  The median pharmacokinetic parameters of lidocaine for groups 1 and 2 (P ≤ 0.05), respectively, were as follows: for Cmax 879.11 and 1,145.58 ng/ml, AUC_0–∞ 256.01 and 455.95 μg min⁻¹ ml⁻¹, Cl/f/kg 10.61 and 5.64 ml min⁻¹ kg⁻¹, and Vd/f/kg 3.26 and 2.19 L/kg. The median pharmacokinetic parameters of MEGX for groups 1 and 2 (P ≤ 0.05), respectively, were as follows: for Cmax 82.71 and 141.38 ng/ml, Tmax 44.71 and 193.14 min, t_1/2α 7.64 and 59.77 min, α 0.097 and 0.012/min, and AUC_0–∞ 29.91 and 108.23 μg min⁻¹ ml⁻¹. Conclusion  The present data permit us to conclude that the apparent clearance of lidocaine and MEGX was reduced in diabetic patients compared to normal women, suggesting that GDM inhibits the CYP1A2/CYP3A4 isoforms responsible for the metabolism of this drug and its metabolite.     

<Emphasis Type="BoldItalic">In Vitro</Emphasis> Effects on MCF-7 Breast Cancer Cells Of Signal Transduction Inhibitor/Tamoxifen/Eicosapentaenoic Acid Combinations and their Simultaneous Delivery Across Skin

Purpose  To determine the in vitro effects of simultaneously administered LY29400, PD98059, tamoxifen and eicosapentaenoic acid (EPA) on breast cancer cells, and determine their transcutaneous delivery. Methods  Growth assays were performed on MCF-7 cells challenged with IC₅₀ and permeated concentrations of PD98059, LY294002 and tamoxifen firstly in isolation then combined. Permeation studies were performed using PD98059 and LY294002 (singly or simultaneously) in DMSO then fish oil, with enhancers. Immunocytochemical detection of phospho-MAPK, phospho-Akt, total COX-2 and Ki-67 was performed. Results  When applied singly, fluxes of PD98059 and LY294002 were 0.09 ± 0.008 and 0.14 ± 0.045 μg cm⁻² h⁻¹, respectively; applied simultaneously, 0.18 ± 0.045 and 0.49 ± 0.051 μg cm⁻² h⁻¹. Permeated concentrations of PD98059 and LY294002 reduced growth to 13.78 ± 0.63%. Fish oil plus 2.5% DMSO/ethanol allowed 5.96 ± 0.9 and 7.7 ± 1.2 μg cm⁻² of PD98059 and LY294002 to permeate after 48 h. Conclusions  PD98059 and LY294002 permeate excised skin at therapeutically useful rates, and also demonstrate growth inhibitory effects on MCF-7 cancer cells. Synergism was noted in co-transport across skin and activity against cancer cells. A formulation based on fish oil is potentially skin friendly; simultaneous permeation of EPA provides further anti-cancer action.     

Lack of pharmacokinetic interaction between ropinirole and theophylline in patients with Parkinson's disease

Objective: Ropinirole and theophylline have the potential to interact, because they use the same hepatic cytochrome P450 (CYP1A2) as their major metabolic pathway. The present study investigated the effect of steady-state oral theophylline on the pharmacokinetics of ropinirole at steady state and the effect of steady-state ropinirole on the pharmacokinetics of a single intravenous (i.v.) dose of theophylline, both in patients with idiopathic Parkinson's disease (PD). Methods: Pharmacokinetic parameters (AUC and C_max) for i.v. theophylline were compared before and after a 4-week period of oral treatment with ropinirole (2 mg t.i.d.) in 12 patients with PD. Patients were then maintained at this dose of ropinirole, and oral theophylline was co-administered at doses of up to 300 mg b.i.d. The parameters AUC, C_max and t_max for ropinirole were compared before, during and after oral theophylline co-treatment. Results: Co-administration of ropinirole did not significantly change the pharmacokinetics of i.v. theophylline (mean AUC with and without ropinirole: 68.6 μg · h⁻¹ · ml⁻¹ and 70.0 μ· h⁻¹ · ml⁻¹, respectively; mean C_max with and without ropinirole: 11.07 μ g · ml⁻¹ and 11.83 μg · ml⁻¹, respectively). Similarly, there were no significant changes in ropinirole pharmacokinetics when the drug was co-administered with oral theophylline (mean AUC for ropinirole with and without theophylline: 21.91 ng · h⁻¹ · ml⁻¹ and 22.09 ng · h⁻¹ · ml⁻¹, respectively; mean C_max for ropinirole with and without theophylline: 5.65 ng · ml⁻¹ and 5.54 ng · ml⁻¹, respectively; median t_max for ropinirole with and without theophylline: 2.0 h and 1.5 h, respectively). Conclusion: These results suggest a lack of significant pharmacokinetic interaction between the two drugs at current therapeutic doses. Received: 10 August 1998 / Accepted in revised form: 27 January 1999     

The effect of the menstrual cycle on the pharmacokinetics of caffeine in normal, healthy eumenorrheic females

  Objective: Hormonal fluctuations of estrogen and progesterone in eumenorrheic women may be capable of altering the pharmacokinetics of certain agents. The objective of this study was to determine the effect of the luteal, ovulatory and follicular phases of the menstrual cycle on the pharmacokinetics of caffeine, a low clearance, flow-independent drug. Methods: Subjects were ten healthy, non-smoking, eumenorrheic females who were not pregnant and had not used oral contraceptives for a minimum of 3 months prior to the study. Blood samples were collected during one menstrual cycle for the determination of estradiol and progesterone concentrations during the follicular (days 2–6 post-onset of menses), ovulatory (days 13–16 post-onset of menses) and luteal (days 22–26 post-onset of menses) phases. Caffeine was administered over a single menstrual cycle during the follicular, ovulatory and luteal phases. Each subject was administered a single oral dose of caffeine (300 mg) in 100 ml of lemonade during each phase of the menstrual cycle. A venous catheter was used to collect blood samples at pre-dose and at the following time points: 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 and 24 h. Plasma caffeine concentrations were determined using a validated ultraviolet high-performance liquid chromatography method. Results: There were no significant (P < 0.05) differences in the pharmacokinetic parameters of caffeine across the menstrual cycle phases. The average area under the plasma concentration–time curve (AUC_inf) was 93.01 mg l^−1.h and the absorption rate constant (k _a) was 2.88 h⁻¹ during the ovulatory phase, 83.0 mg l⁻¹ h and 2.06 h⁻¹, respectively, during the luteal phase and 84.7 mg l^−1.h and 1.84 h⁻¹, respectively, during the follicular phase. Conclusions: These findings suggest that the menstrual cycle does not significantly alter the pharmacokinetics of caffeine. Received: 16 November 1998 / Accepted in revised form: 19 April 1999     

Comparative pharmacokinetics of dirithromycin and erythromycin in normal volunteers with special regard to accumulation in polymorphonuclear leukocytes and in saliva

Objective: In a randomized cross-over study, we assessed pharmacokinetics and intracellular concentrations in polymorphonuclear leukocytes (PMN) and saliva of erythromycin and erythromycylamine, the active metabolite of dirithromycin. Methods: Ten healthy volunteers received 1 g erythromycin b.i.d. or 500 mg dirithromycin qd for 5 days (wash out period, 35 days). Concentrations of erythromycin and erythromycylamine were measured in serum, urine, saliva, and granulocytes by bioassay and high-performance liquid chromatography (HPLC) on days 1, 3, and 5 of each study period, respectively. Results: While maximal serum concentrations (C_max) and the area under the data (AUD_tot) of erythromycin were significantly higher (C_max 1.44 mg · l⁻¹, AUD_tot 5.66 mg · h · l⁻¹) than those of erythromycylamine (C_max 0.29 mg · l⁻¹, AUD_tot 1.96 mg · h · l⁻¹), erythromycylamine had a significantly higher mean residence time (21 h) than erythromycin (5.5 h). Erythromycylamine accumulated significantly more in PMN than erythromycin;␣the accumulation factor of erythromycylamine was 100 with a maximal intracellular concentration of 13.4 mg · l⁻¹, whereas the maximal accumulation factor of erythromycin was 4 with a maximal intracellular concentration of 6.1 mg · l⁻¹. There were no significant differences in maximal saliva concentrations (erythromycin 0.35 mg · l⁻¹, erythromycylamine 0.31 mg · l⁻¹). Received: 16 September 1996 / Accepted in revised form: 12 February 1997     

Acute and chronic effects of sodium and potassium on the tropical freshwater cladoceran <Emphasis Type="Italic">Pseudosida ramosa</Emphasis>

In this study, the toxicities of sodium and potassium to the tropical freshwater cladoceran Pseudosida ramosa were assessed. Acute toxicity tests on this species showed that the 48-h LC₅₀ of Na⁺ was 556 mg l⁻¹, while that of K⁺ was 17.7 mg l⁻¹. Long-term exposure of female P. ramosa to sodium reduced the total number of survivors from 10 to 6 at a concentration of 249 mg l⁻¹, 21-day fecundity from 20.4 to 14.3 eggs female⁻¹ at concentrations ranging from 72 to 249 mg l⁻¹, 21-day fertility from 20.1 to 6.5 neonates female⁻¹ at concentrations ranging from 25 to 249 mg l⁻¹. Furthermore, fecundity of each brood from the second to the fifth was significantly lower at 249 mg l⁻¹ and fertility of each brood from the first to the fifth at concentrations ranging from 25 to 249 mg l⁻¹. A significant decrease in fertility was associated with an increase in the number of aborted eggs. Long-term exposure to potassium decreased the 21-day fecundity of P. ramosa from 14.2 to 10.8 eggs female⁻¹ at a concentration of 11 mg l⁻¹ and fertility (fourth brood only) at 6.2 and 11 mg l⁻¹. Tropical reservoirs located near areas where the soil is overloaded with fertilizers and ferti-irrigation with vinasse already show concentrations of Na⁺ and K⁺ very close to those producing sub-lethal long-term effects on P. ramosa. A possible consequence is that organisms of the aquatic biota cannot adapt and freshwater taxa may become locally extinct, transferring dominance to salt-tolerant taxa.     

Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation

Inward rectifier potassium currents I_K1 and acetylcholine activated I_K,ACh are implicated in atrial fibrillation (AF) pathophysiology. In chronic AF (cAF), I_K,ACh develops a receptor-independent, constitutively active component that together with increased I_K1 is considered to support maintenance of AF. Here, we tested whether class I (propafenone, flecainide) and class III (dofetilide, AVE0118) antiarrhythmic drugs inhibit atrial I_K1 and I_K,ACh in patients with and without cAF. I_K1 and I_K,ACh were measured with voltage clamp technique in atrial myocytes from 58 sinus rhythm (SR) and 35 cAF patients. The M-receptor agonist carbachol (CCh; 2 μM) was employed to activate I_K,ACh. In SR, basal current was not affected by either drug indicating no effect of these compounds on I_K1. In contrast, all tested drugs inhibited CCh-activated I_K,ACh in a concentration-dependent manner. In cAF, basal current was confirmed to be larger than in SR (at −80 mV, −15.2 ± 1.2 pA/pF, n = 88/35 vs. −6.5 ± 0.4 pA/pF, n = 194/58 [myocytes/patients]; P < 0.05), whereas CCh-activated I_K,ACh was smaller (−4.1 ± 0.5 pA/pF vs. −9.5 ± 0.6 pA/pF; P < 0.05). In cAF, receptor-independent constitutive I_K,ACh contributes to increased basal current, which was reduced by flecainide and AVE0118 only. This may be due to inhibition of constitutively active I_K,ACh channels. In cAF, all tested drugs reduced CCh-activated I_K,ACh. We conclude that in cAF, flecainide and AVE0118 reduce receptor-independent, constitutively active I_K,ACh, suggesting that they may block I_K,ACh channels, whereas propafenone and dofetilide likely inhibit M-receptors. The efficacy of flecainide to terminate AF may in part result from blockade of I_K,ACh.     

Helicobacter pylori clearance and serum gastrin and pepsinogen I concentrations in omeprazole treatment of duodenal ulcer patients

Objective: To determine which demographic factors may influence serum gastrin and pepsinogen I (PGI) levels in duodenal ulcer patients undergoing omeprazole treatment. Methods: We conducted an outpatient-based prospective study in the Veterans General Hospital, Taipei, to investigate the pharmacological effects on patients with duodenal ulcers receiving omeprazole treatment for 4 weeks. Sixty-eight patients (61 males/7 females, aged 25–73 years) with endoscopically confirmed duodenal ulcer were included. Gastrin and pepsinogen I levels were measured before and after treatment. Demographic factors including age, sex, smoking, ulcer healing and antral Helicobacter pylori colonization/clearance were analyzed, in order to measure their probable influences on serum gastrin and pepsinogen I levels. Results: Ulcer healing was seen in 92.6% of patients while 48 (70.6%) antral clearances were seen in 66 H. pylori colonized patients at the end of trial. Omeprazole monotherapy led to a marked elevation of serum gastrin (85.8 pg · ml⁻¹, SD 32.0 pg · ml⁻¹ vs 133.9 pg · ml⁻¹, SD 71.6 pg · ml⁻¹, P < 0.01), and pepsinogen I (111.0 ng · ml⁻¹, SD 36.7 ng · ml⁻¹ vs 253.6 ng · ml⁻¹, SD 64.8 ng · ml⁻¹, P < 0.01) levels when measured on day 29. Only patients showing antral H. pylori clearance exhibited an influence on the magnitude of pepsinogen I elevation following omeprazole monotherapy (143.9%, SD 67.3% vs 78.6%, SD 51.2%, P < 0.01). Moreover, the sensitivity and specificity of serum pepsinogen I variations were plotted on a receiving operating characteristic (ROC) curve. The 140% increased pepsinogen I level yielded a maximum accuracy of 80% specificity or 50% sensitivity to predict antral H. pylori clearance. Conclusion: Antral H. pylori clearance is at least partially responsible for the omeprzaole-induced hyperpepsinogenemia I. The magnitude of hyperpepsinogenemia I probably provides a non-invasive alternative for predicting H. pylori clearance. Received: 22 August 1996 / Accepted in revised form: 1 October 1998     

Pharmacokinetics and pharmacodynamics of ranitidine in renal impairment

Objective: The pharmacodynamics and pharmacokinetics of ranitidine were examined in subjects with varying degrees of renal function to determine the effect of this condition on acid-antisecretory activity. Methods: Subjects with creatinine clearances (C_Cr) ranging from 0 to 213 ml · min⁻¹ received single 50-mg and 25-mg i.v. doses of ranitidine. This was followed by determination of serum and urine ranitidine concentrations, and continuous gastric pH monitoring for 24 h. Results: Serum ranitidine concentrations were described by a two-compartment model linked to a sigmoidal E_max model describing gastric pH. Ranitidine renal clearance, ranging from 0 to 1003 ml · min⁻¹, correlated with C_PAH (r ² = 0.707), while non-renal clearance was unaltered. Steady-state volume of distribution decreased by half in severe renal impairment. No changes in the effective concentration at half-maximal response (EC₅₀), maximal response (E_max), or basal response (E₀) were observed. Thus, renal elimination of ranitidine declined in parallel with renal function, while sensitivity to the pharmacologic effect (gastric pH elevation) was unaltered. Ranitidine was well tolerated in these renally impaired subjects. Conclusion: These data indicate that the current recommendation for renal impairment dose reduction (by two-thirds when C_Cr<50 ml · min⁻¹) might result in under-treating moderately impaired patients, and suggests a less conservative dose reduction (by half when C_Cr<10 ml · min⁻¹) to avoid therapeutic failure while remaining within the wide margin of safety for this drug. Received: 10 September 1996 / Accepted in revised form: 7 December 1996     

Food increases the bioavailability of mefloquine

Objectives: To assess the effect of food on the pharmacokinetics of the antimalarial mefloquine and its major plasma metabolite in healthy volunteers. Methods: In an open, two-way cross-over study, 20 healthy male volunteers who had fasted overnight were randomised to receive a single oral dose of 750 mg mefloquine in the absence or presence of a standardised, high-fat breakfast, administered 30 min before drug administration. Blood samples were taken at specific times over an 8-week period. Plasma concentrations of mefloquine and its carboxylic acid metabolite were determined by high-performance liquid chromatography for pharmacokinetic evaluation. Results: The parameters C_max and AUC of both mefloquine and its metabolite were significantly (P < 0.05) higher under post-prandial conditions than under fasting conditions (mefloquine: mean C_max 1500 vs 868 μg · l⁻¹, mean AUC 645 vs 461 mg l⁻¹ · h; metabolite: C_max 1662 vs 1231 μg · l⁻¹, AUC 1740 vs 1310 mg l⁻¹ · h). The intersubject variability in C_max and AUC of mefloquine was less than 30% (coefficient of variation). The time to peak plasma concentration of mefloquine was significantly shorter after food intake (17 vs 36 h). Compared with absorption in volunteers who had fasted, food did not alter t_1/2 (mefloquine and its metabolite) and t_max (metabolite). Conclusion: Under the conditions of this study, food increases the rate and the extent of mefloquine absorption. It is reasonable to recommend that mefloquine be administered with food in travellers receiving chemoprophylaxis and in patients on recovery receiving curative treatment. In acutely ill patients, mefloquine should be taken as soon as possible and administration with or shortly after meals should be attempted as soon as feasible. Received: 10 February 1997 / Accepted in revised form: 16 June 1997