Valve movement response of the freshwater clam Corbicula fluminea following exposure to waterborne arsenic

We developed an inductance-based valvometry technique as a detection system to measure the valve daily activity in freshwater clam Corbicula fluminea in response to waterborne arsenic. Our findings reveal that C. fluminea experiences a valve opening in the absence of arsenic predominantly in the morning hours (03:00–08:00) with a mean daily opening/closing period of 21.32 (95% CI: 20.58–22.05) h. Amplification of daily activity occurred in the presence of arsenic. Behavioral toxicity assays revealed arsenic detection thresholds of 0.60 (95% CI: 0.53–0.66) mg l⁻¹ and 0.35 (95% CI: 0.30–0.40) mg l⁻¹ for response times of 60 and 300 min, respectively. The proposed valve daily activity model was linked with response time-specific Hill dose-response functions to predict valve opening/closing behavior in response to arsenic. The predictive capabilities were verified satisfactory with the measurements. Our results implicate a biomonitoring system by valve daily activity in C. fluminea to identify safe water uses in areas with elevated arsenic.     

Bioaccumulation and degradation of pesticide fluroxypyr are associated with toxic tolerance in green alga <Emphasis Type="Italic">Chlamydomonas reinhardtii</Emphasis>

The herbicide fluroxypyr is widely used for controlling weeds and insects but intensive use of fluroxypyr has resulted in its widespread contamination in soils and aquatic ecosystems. To evaluate the eco-toxicity of fluroxypyr to green algae, bioaccumulation and degradation of fluroxypyr in Chlamydomonas reinhardtii, a model unicellular alga, along with its biological adaptation to fluroxypyr toxicity were investigated. The microalgae were treated with fluroxypyr at 0.05–1.00 mg l⁻¹ for 2 days or 0.50 mg l⁻¹ for 1–5 days. The growth of C. reinhardtii was stimulated at low levels of fluroxypyr (0.05–0.5 mg l⁻¹) but inhibited at high concentrations (0.75–1.00 mg l⁻¹). Fluroxypyr was significantly accumulated by C. reinhardtii. Interestingly, the accumulated fluroxypyr could be rapidly degraded in the cells. On day 5 more than 57% of cellular fluroxypyr was degraded. Our results indicated that accumulation and degradation of fluroxypyr occurred simultaneously. Treatment with 0.05–1.00 mg l⁻¹ fluroxypyr for 30 min induced significant production of reactive oxygen species and as a consequence resulted in accumulation of peroxides and DNA degradation. Additionally, activities of several major antioxidant enzymes were activated in C. reinhardtii exposed to high levels of fluroxypyr. Overall, the present studies represent the initial comprehensive analyses of the green alga C. reinhardtii in adaptation to the fluroxypyr-contaminated aquatic ecosystems.     

The effect of hypoxaemia on drug disposition in chronic respiratory failure

Objective: The influence of hypoxaemia on the disposition of two common drugs has been examined in ten adults with stable chronic respiratory failure. Methods: There were two experimental periods in this cross-over study: during these periods supplemental oxygen was either withheld or administered to impose clinical hypoxaemia or maintain normoxaemia, respectively. Each participant received either oral (40 mg) or intravenous (20 mg) frusemide combined with oral paracetamol (500 mg) on consecutive days of the two experimental periods. Results: The total (bound plus unbound) plasma clearance of frusemide during hypoxaemia (arterial oxygen tension, PaO₂ ≤ 50 Torr) was not significantly different from the value during normoxaemia (PaO₂ ≥ 60 Torr) [76.9 and 62.4 ml ⋅ min⁻¹]. The volume of distribution was not affected by acute hypoxaemia (121 ml ⋅ kg⁻¹ without and 109 ml ⋅ kg⁻¹ with oxygen; P > 0.05). Renal and non-renal clearances of frusemide were similar during the period of hypoxaemia (31 and 38 ml ⋅ min⁻¹, respectively) compared to respective values during supplemental oxygen delivery (29 and 32 ml ⋅ min⁻¹). The absolute bioavailability of frusemide during hypoxaemia (0.62) was not different to that obtained during normoxaemia (0.56). The combined sodium and potassium excretion rate (expressed as a function of the frusemide excretion rate) was not altered by changing the oxygen tension. The pharmacokinetics of paracetamol were unaffected by hypoxaemia.     

Pharmacokinetics of cloxacillin in patients undergoing hip or knee replacement

Objective: The pharmacokinetics of cloxacillin was investigated in 14 men and 24 women undergoing cemented hip (n = 19; age range 56–90) or knee replacement surgery (n = 19; age range 51–84) for osteoarthritis. Cloxacillin 1 g was given intravenously as a bolus dose at the induction of anesthesia, and plasma samples and urine were collected for 6 h. Drug levels were determined using HPLC. Results: Preoperative serum creatinine levels were 84 μmol · l⁻¹ in hip patients and 72 μmol · l⁻¹ in knee patients. The calculated values for creatinine clearance were 63 and 85 ml · min⁻¹ · 1.73 m⁻², respectively. Total clearance of cloxacillin was 134 ml · min⁻¹ · 1.73 m⁻² in eighteen evaluated patients undergoing hip replacement, and 162 ml · min⁻¹ · 1.73 m⁻² in eighteen patients undergoing knee surgery. Renal clearance was 72 and 79 ml · min⁻¹ · 1.73 m⁻², respectively. Non-renal clearance was 57 ml · min⁻¹ · 1.73 m⁻² in hip patients and 77 ml · min⁻¹ · 1.73 m⁻² in knee patients. Renal clearance of cloxacillin correlated with the estimated creatinine clearance (r = 0.652). Although women received higher doses than men (median 2.02 vs 2.32 mmol · 1.73 m⁻²), there were no sex differences in clearance corrected for body surface area. Conclusion: Total clearance of cloxacillin was lower in patients undergoing hip replacement than in patients undergoing replacement of the knee, but there was no difference between men and women. Received: 7 May 1996 / Accepted in revised form: 15 October 1996     

Assessment of the potential toxicity of a linear alkylbenzene sulfonate (LAS) to freshwater animal life by means of cladoceran bioassays

The acute and chronic toxic effects of LAS on the cladocerans Daphnia similis, Ceriodaphnia dubia and Ceriodaphnia silvestrii were tested. Both types of toxicity bioassays and the methods of culture and stock maintenance of the test organisms conformed to the recommendations of ABNT (Brazilian Society of Technical Standards), which closely follow the standard methods of USEPA. The results obtained for EC₅₀ (48 h) were: 14.17 mg L⁻¹ for D. similis, 11.84 mg L⁻¹ for C. dubia and 13.52 mg L⁻¹ for C. silvestrii. In the chronic toxicity tests performed on C. dubia and C. silvestrii, there was a significant decrease in the fecundity of the exposed animals; the value of NOEC for C. dubia and C. silvestrii were 1.00 mg L⁻¹ and 2.50 mg L⁻¹, respectively. Cladoceran bioassays provided evidence that LAS concentration as low as 1.00 mg L⁻¹ can damage invertebrate animal life in freshwaters, concentrations that can be found in many eutrophic rivers and reservoirs.     

Clearance of ceftriaxone during haemodialysis using cuprophane, haemophane and polysulfone dialysers

Objective: The purpose of the present study was to investigate whether the clearance of ceftriaxone during haemodialysis is influenced by the type of membrane used (cuprophane, haemophane or polysulphone). Methods: After administration of a single 2-g dose of ceftriaxone, the half-life of the drug during haemodialysis and the clearance of the dialyser were measured. Results: The mean dialysis clearance normalised for square metre of membrane surface was significantly different for the three dialysers (haemophane 24  ml · min⁻¹ · m⁻²; cuprophane 32 ml · min⁻¹ · m⁻²; polysul phone 42 ml · min⁻¹· m⁻²). Conclusions: Polysulphone membranes are more permeable and increase the extraction of ceftriaxone more than the other dialysers studied (haemophane and cuprophane membranes). These results, taken together with previous data, show that an increase of the dose in dialysis patients treated with large surface (>0.8 m²) and high permeability membranes might be necessary. Received: 18 November 1996 / Accepted in revised form: 12 May 1997     

Hypoxia-induced oxidative DNA damage links with higher level biological effects including specific growth rate in common carp, Cyprinus carpio L

Both hypoxia and hyperoxia, albeit in different magnitude, are known stressors in the aquatic environment. Adopting an integrated approach, mirror carp (Cyprinus carpio L.), were exposed chronically (i.e. 30 days) to hypoxic (1.8 ± 1.1 mg O₂ l⁻¹) and hyperoxic (12.3 ± 0.5 mg O₂ l⁻¹) conditions and resultant biological responses or biomarkers were compared between these two treatments as well as with fish held under normoxic conditions (7.1 ± 1.04 mg O₂ l⁻¹). The biomarkers determined included the activities of glutathione peroxidase (GPx), measurement of oxidative DNA damage (using modified Comet assay employing bacterial enzymes: Fpg and Endo-III), haematological parameters, histopathological and ultrastructural examination of liver and gills. Specific growth rate (SGR) of the fish, as an important ecotoxicological parameter was also determined over the exposure period. The study suggested that while the levels of hepatic GPx were unaffected, there was a significant difference in activity in the blood plasma under different exposure conditions; the hyperoxic group showed increased GPx activity by approximately 37% compared to normoxic group and the hypoxic group showed a decrease by approximately 38% than the normoxic group. Interestingly, oxidative DNA damage was significantly higher in both hypoxic and hyperoxic by approximately 25% compared to normoxic conditions, Fpg showing enhanced level of damage compared to the Endo-III treatment (P < 0.001). The haematological parameters showed enhanced values under hypoxic conditions. Transmission electron microscopic (TEM) studies revealed damage to liver and gill tissues for both the treatments. Interestingly, SGR of fish was significantly lowered in hypoxic by approx. 30% compared to normoxic condition and this was found to be correlated with DNA damage (R = −0.82; P = 0.02). Taken together, these results indicate that prolonged exposure to both hypoxic and hyperoxic conditions induce oxidative stress responses at both DNA and tissue levels, and hypoxia can result in compensatory changes in haematological and growth parameters which could influence Darwinian fitness of the biota with wider ecological implications.     

<Emphasis Type="Italic">CYP2C9</Emphasis> genotype and pharmacodynamic responses to losartan in patients with primary and secondary kidney diseases

Background  Losartan is used for anti-proteinuric as well as blood pressure effects in chronic kidney disease (CKD). It is metabolized by cytochrome P450 (CYP) 2C9 to active E-3174. Single nucleotide polymorphisms in CYP2C9 that reduce catalytic activity could reduce clinical benefits. Aim  The study aims were to determine whether CYP2C9 variant alleles (*2 and *3) altered urinary protein excretion, glomerular filtration rate, and blood pressure in Caucasian patients prescribed losartan. Methods  Differences between baseline and 6-month follow-up outcomes were compared by CYP2C9 genotypes in 59 patients using unpaired t test or Mann–Whitney U test. Results  Primary renal disease patients had a trend toward less favorable antiproteinuric response (−31.7 ± 156 vs. −125 ± 323%;  p = 0.123) when carrying variant alleles. Patients with secondary renal diseases had less favorable diastolic blood pressure (9.8 ± 16.0 vs. −3.2 ± 10.6 mmHg; p = 0.043) and systolic blood pressure (16.2 ± 27.1 vs. −5.5 ± 17.5 mmHg; p = 0.044) with CYP2C9 variants. Conclusion  These preliminary results suggest a possible influence of CYP2C9 genotype on proteinuria and blood pressure in Caucasian CKD patients treated with losartan.     

Pharmacokinetics and antidiuretic effect of a new vasopressin analogue (F992) in overhydrated male volunteers

Objective: The aim of the present study was to study the pharmacokinetics, the antidiuretic effects and the safety of [D-Phe², Thi³, α-Me-Abu⁴, Hyp⁷, D-Arg⁸]-dC¹-vasopressin, a new antidiuretic peptide (F992, Ferring, Sweden), administered as intravenous infusion to orally overhydrated male volunteers. Methods: Eight healthy male volunteers participated in this open study consisting of two parts: a dose titration study and a safety study. In the dose titration study ascending doses of F992 were administered to volunteers in pairs in order to find a dose that within 1 h after the infusion, in both subjects, caused a reduction of the urine flow rate to below 5 ml · min⁻¹ (target dose). Subsequently, this target dose was administered to all volunteers. In the safety study the target dose was doubled and given to all volunteers. On each study occasion, in both study parts, the subjects were orally overhydrated with water. F992 was administered as i.v. infusion approximately 1.5 h after the start of the hydration procedure. Throughout the study days, blood was sampled for determination of plasma concentrations of F992 and for safety evaluation. Urine was collected at intervals in order to estimate flow rate and osmolality. Results: The target dose was found to be 4.0 μg as this dose fulfilled the criteria regarding antidiuretic effect, consequently 8.0 μg was administered to all subjects in the safety study. After infusion of 4.0 and 8.0 μg, the median half-lives of elimination were 4.72 (range 3.99–6.53) h and 3.85 (range 3.04–11.08) h, respectively. The plasma clearance and the volume of distribution at steady state were estimated to be 0.88 (SD 0.24) ml · min⁻¹ · kg⁻¹ and 326 (SD 68) ml · kg⁻¹ after infusion of 4 μg. After the highest dose (8 μg), the corresponding estimates were 0.86 (SD 0.32) ml · min⁻¹ · kg⁻¹ and 299 (SD 81) ml · kg⁻¹, respectively. Significantly (P = 0.033) different maximum mean urine osmolalities were produced after infusion of 4.0 and 8.0 μg of F992 (534 (SD 318) vs 732 (SD 189) mOsmol · kg⁻¹). The median times to reach these values showed some tendency to be longer for the highest dose, however statistical significance was not reached. No serious adverse events were observed during the study. Conclusion: We found it safe to administer F992 as infusion to overhydrated male volunteers. The results suggest that F992 has a longer half-life and a lower potency than the widely used peptide desmopressin. Received: 10 August 1998 / Accepted in revised form: 30 December 1998     

Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose and during steady state in patients with chronic renal failure

Objective: An open study on the single dose and steady-state pharmacokinetics of imidapril, a novel prodrug-type angiotensin-converting enzyme (ACE) inhibitor, and its active metabolite imidaprilat was conducted in eight patients with moderate chronic renal failure [mean creatinine clearance (CL_CR) 64 ml · min⁻¹; range 42–77 ml · min⁻¹], eight patients with severe chronic renal failure (mean CL_CR, 18 ml · min⁻¹; range 11–29 ml · min⁻¹) and eight healthy volunteers with normal renal function. Subjects received an oral dose of 10 mg imidapril once per day for 7 days. Results: No statistical differences of either maximum concentration (C_max) or the area under the curve (AUC) were found between patients with moderate renal failure and healthy subjects. However, C_max and AUC for both imidapril and imidaprilat were significantly higher in patients with severe renal impairment than in healthy volunteers. There were no clinically relevant differences among the three subject groups with regard to total urinary excretion of both imidapril and imidaprilat. Conclusion: The smallest imidapril dose which is clinically effective should be used in patients with severe renal insufficiency. Received : 11 July 1997 / Accepted in revised form : 6 October 1997     

Solubility,Stability, Physicochemical Characteristics and <Emphasis Type="BoldItalic">In Vitro</Emphasis> Ocular Tissue Permeability of Hesperidin: A Natural Bioflavonoid

Purpose  Hesperidin holds potential in treating age-related macular degeneration, cataract and diabetic retinopathy. The aim of this study, constituting the first step towards efficient ocular delivery of hesperidin, was to determine its physicochemical properties and in vitro ocular tissue permeability. Methods  pH dependent aqueous solubility and stability were investigated following standard protocols. Permeability of hesperidin across excised rabbit cornea, sclera, and sclera plus retinal pigmented epithelium (RPE) was determined using a side-bi-side diffusion apparatus. Results  Hesperidin demonstrated poor, pH independent, aqueous solubility. Solubility improved dramatically in the presence of 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) and the results supported 1:1 complex formation. Solutions were stable in the pH and temperature (25, 40°C) conditions tested, except for samples stored at pH 9. Transcorneal permeability in the apical-basal and basal-apical directions was 1.11 ± 0.86 × 10⁻⁶ and 1.16 ± 0.05 × 10⁻⁶ cm/s, respectively. The scleral tissue was more permeable (10.2 ± 2.1 × 10⁻⁶ cm/s). However, permeability across sclera/choroid/RPE in the sclera to retina and retina to sclera direction was 0.82 ± 0.69 × 10⁻⁶, 1.52 ± 0.78 × 10⁻⁶ cm/s, respectively, demonstrating the barrier properties of the RPE. Conclusion  Our results suggest that stable ophthalmic solutions of hesperidin can be prepared and that hesperidin can efficiently permeate across the corneal tissue. Further investigation into its penetration into the back-of-the eye ocular tissues is warranted.     

Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function

Objective: We studied the pharmacokinetics and pharmacodynamics of single and multiple doses of candesartan cilexetil 8 mg per day in hypertensive patients with different degrees of renal function impairment. Candesartan is an angiotensin II subtype 1 (AT1) receptor antagonist that is administered orally as candesartan cilexetil which is converted in the active compound. Methods: Twenty-three patients were included, divided into groups according to creatinine clearance (cr cl. group A >60 nl · min⁻¹ · 1.73 m⁻², group B 30–60 ml · min⁻¹ · 1.73 m⁻² and group C 15–30 ml · min⁻¹ · 1.73 m⁻²). Results: Trough serum concentrations of candesartan were higher in group C compared with group A. The values did not increase after multiple dosing, indicating absence of accumulation. There was a significant negative correlation between the area under the concentration-time curve extrapolated to time infinity (AUC_inf) and the glomerular filtration rate (GFR) indicating a lower renal clearance of candesartan in patients with impaired renal function. The onset of haemodynamic and hormonal effects was gradual. During the single-dose study blood pressure as well as plasma renin activity (PRA) and angiotensin II were unchanged at peak. At day 5 of the multiple-dose study blood pressure was lower and both PRA and angiotensin II were higher compared with baseline. Conclusion: Although serum trough levels increased during repeated administration and half-life was higher in patients with impaired renal function, candesartan cilexetil at a dose of 8 mg per day does not lead to drug accumulation in these patients. This dose is effective in lowering blood pressure and appears to be suitable for patients with renal function impairment. Received: 3 August 1998 / Accepted in revised form: 19 October 1998     

Evaluation of genotoxicity and effects on reproduction of nonylphenol in <Emphasis Type="Italic">Oreochromis niloticus</Emphasis> (Pisces: cichlidae)

Nonylphenol ethoxylate (NPE) is widely used as a component of detergents, paints, pesticides, and many other products. In the aquatic environment NPE breakdown to 4-nonylphenol (NP), which is more stable and persistent. NP is estrogenic in fish, avian, and mammals and is described as an environmental pollutant with endocrine disruptor characteristics. The genotoxicity of NP was evaluated through micronuclei assay and single cell gel electrophoresis (Comet assay) in peripheral erythrocytes of Oreochromis niloticus exposed in vivo. The study on reproductive development was also carried out in male and female gonads of O. niloticus. Lethal concentration (LC 50%) of 0.032 ml l⁻¹ was previously determined. We ran assays with O. niloticus exposed to concentrations of 1.0, 10.0, and 16.0 μl l⁻¹ of NP diluted in water. Our results showed that NP was not genotoxic. However, 3-day exposure to NP in concentrations of 1.0, 10.0, and 16.0 μl l⁻¹ of water increased the frequency of reproductive stages in males and females. The histology of the reproductive tract of the treated fish was significantly altered in females treated with 16.0 μl l⁻¹ of water when compared to controls. Analogous estrogenic effects were observed, such as accelerated maturation of oocytes and spermatogenesis. These results showed that the O. niloticus reproductive system is sensitive to NP estrogenicity.     

Change in life cycle parameters and feeding rate of <Emphasis Type="Italic">Ceriodaphnia silvestrii</Emphasis> Daday (Crustacea,Cladocera) exposure to dietary copper

Changes in life cycle parameters (survival, growth, reproduction) and feeding rate of the tropical cladoceran Ceriodaphnia silvestrii as affected by Cu contaminated algae Pseudokirchneriella subcapitata were investigated. The dietary copper exposure ranged from 3 × 10⁻¹⁵ to 68 × 10⁻¹⁵ g Cu algal cell⁻¹. Low waterborne copper exposure (around 10⁻¹⁰ mol l⁻¹ free Cu²⁺ ions) was kept in the experiments. The results show an increasing toxic effect on C. silvestrii with copper increase in algal cells; at the highest copper exposure, all life cycle parameters were significantly affected. A concentration of 38 × 10⁻¹⁵ g Cu algal cell⁻¹ reduced egg hatching percentile and the number of neonates produced per female, but did not cause any statistically significant effect on animals survival nor to the number of eggs produced per female. The following sequence of events was observed from the lowest to the highest copper contamination: reproduction, feeding rate, body length and, at last, survival was affected. We conclude that algal cells are an important route of copper exposure and toxicity to cladocerans.     

RP-HPLC method for the quantitative determination of fexofenadine hydrochloride in coated tablets and human serum

Fexofenadine is a non-sedative and selective peripheral H₁ receptor antagonist prescribed for allergic rhinitis and chronic urticaria. This article deals with a simple, feasible, and sensitive isocratic reverse-phase high-performance liquid chromatographic method for the determination of fexofenadine hydrochloride in bulk drug, pharmaceutical dosage forms and in human serum. The chromatography was carried out at 20 ± 2°C using two different chromatographs and five different stationary phases. The isocratic mobile phase was phosphate buffer pH 7.4 and methanol (methanol–phosphate buffer, 35:65, v/v), detection was made at 218 nm and the mobile phase flowed at 1 ml min⁻¹. Validation parameters included linearity, accuracy, precision, specificity, limit of detection (LOD), limit of quantification (LOQ), and robustness over a linearity range 5–15 μg ml⁻¹ according to the ICH guidelines (r > 0.9999), the inter- and intra-day precisions were relative standard deviation (RSD) < 0.8%. The system suitability was scrutinized by capacity factor, tailing factor, and number of theoretical plates (capacity factor > 2.0, tailing factor ≤ 2.0, and theoretical plates > 2000). The retention time for five different stationary phases ranged from 3.78 to 4.15 min. The LOD and LOQ for the procedure were executed on samples containing very low concentrations of analytes on two different commercial brands of detectors.     

Chloroquine blood concentrations and malaria prophylaxis in Tanzanian women during the second and third trimesters of pregnancy

Objective: Routine malaria prophylaxis with chloroquine (CQ) is recommended to pregnant semi-immune women in several countries in Africa. The dosage is empirically based. We investigated whether blood CQ concentrations and apparent oral blood clearance (CL/F) change during the course of pregnancy. We also studied whether malaria parasites could be detected together with low CQ blood levels. Methods: Forty nine semi-immune Tanzanian women were recruited in the 16th week of pregnancy. They were given 310 mg oral CQ base once per week as prophylaxis during the whole pregnancy. Capillary blood samples were taken for analysis of CQ before treatment and at weeks 26 and 36. Blood samples were dried on filter paper and analysed by HPLC. Blood was also drawn to detect occurrence of malaria parasites. Results: A total of 25 women fulfilled the sampling schedule. CL/F increased significantly from 160 ml ·  min⁻¹ at week 26 to 180 ml · min⁻¹ at week 36. In 7 of 25 women, CL/F increased >20%. Trough blood CQ concentrations, determined on four occasions at week 26 and at week 36 varied between 200 and 900 nmol · l⁻¹. No statistically significant differences between occasions were seen. Malaria parasites were seen in two individuals early in pregnancy. Conclusion: Blood CQ CL/F showed a small increase during the course of pregnancy. The estimated mean blood CL/F values of 160 and 180 ml · min⁻¹ (week 26 and 36, respectively) were higher than the mean CL/F of 125 ml · min⁻¹ in non-pregnant individuals, published previously. Efficacy of higher dosages of CQ in malaria prophylaxis in pregnant women could, therefore, be evaluated in controlled trials in high-risk malaria areas. Received: 3 July 1996 / Accepted in revised form: 5 November 1996     

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     

Effects of cadmium hyperaccumulation on the concentrations of four trace elements in <Emphasis Type="Italic">Lonicera japonica</Emphasis> Thunb.

Hyperaccumulators are important in the phytoremediation of cadmium (Cd)-contaminated soil. In this study, Cd accumulation and the interactions between Cd and four other trace elements (Fe, Mn, Cu, and Zn) in Lonicera japonica Thunb. were investigated. As a result of exposure to soil containing 50 mg kg⁻¹ Cd, stem and shoot Cd concentrations reached 344.49 ± 0.71 and 286.12 ± 9.38 μg g⁻¹ DW respectively, without showing symptoms of visible damage to the plants. This suggests that L. japonica has a strong tolerance to Cd. It is proposed that trace metal elements are involved in the Cd-detoxification mechanisms shown by hyperaccumulators. There is a synergistic interaction in accumulation and translocation between Cd and Fe and a significantly negative correlation between Cd and Cu or Zn concentrations in L. japonica plant tissues. The imbalanced trace element concentrations influences detoxification processes to Cd, therefore, L. japonica could be considered as a new Cd-hyperaccumulator model to investigate the metal tolerance strategies of plants.     

Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate

Purpose  Methotrexate (MTX) causes dose-limiting gastrointestinal toxicity due to exposure of intestinal tissues, and is a substrate of the multidrug resistance-associated protein (MRP) 1. Here we examine the involvement of MRP1, which is reported to be highly expressed in the proliferative crypt compartment of the small intestine, in the gastrointestinal toxicity of MTX. Methods  MTX was intraperitonealy administered to mrp1 gene knockout (mrp1 ^(−/−)) and wild-type (mrp1 ^(+/+)) mice. Body weight, food and water intake were monitored, intestinal histological studies and pharmacokinetics of MTX were examined. Results   mrp1 ^(−/−) mice more severely decreased body weight, food and water intake than mrp1 ^(+/+) mice. Almost complete loss of villi throughout the small intestine in mrp1 ^(−/−) mice was observed, whereas the damage was only partial in mrp1 ^(+/+) mice. Plasma concentration and biliary excretion profiles of MTX were similar in mrp1 ^(−/−) and mrp1 ^(+/+) mice, though accumulation of MTX in immature proliferative cells isolated from mrp1 ^(−/−) mice was much higher compared to mrp1 ^(+/+) mice. Immunostaining revealed localization of Mrp1 in plasma membrane of the intestinal crypt compartment in mrp1 ^(+/+) mice, but not in mrp1 ^(−/−) mice. Conclusion  Mrp1 determines the exposure of proliferative cells in the small intestine to MTX, followed by gastrointestinal toxicity. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Pharmacokinetics of oxypolygelatine in healthy volunteers

Objective/methods: The pharmacokinetics of the plasma substitute oxypolygelatine (OPG) were studied in 12 healthy volunteers after single-dose administration of 27 ml · kg⁻¹ body weight, with a maximum of 2000 ml. OPG was determined in plasma and urine over 48 h after the infusion. Peak plasma OPG concentrations at the end of the infusion were determined to 4.600 (623) μg · ml⁻¹, the area under the plasma concentration/time curve (AUC_0∞) was calculated to 70.135 (15.861) μg · h · ml⁻¹. Results: The model-independently calculated volume of distribution came to 23.1 (4.8) l with a clearance total is (Cl_tot) of 24.6 (6.8) ml · min⁻¹. The initial half-life according to a three-compartment model came to 0.3 (0.2) h, followed by a distribution half-life of 3.1 (2.6) h and a terminal elimination half-life of 13.4 (2.2) h. Cumulative urinary excretion of OPG was 64% after 48 h. Conclusion: This low recovery rate may be explained by the distribution of OPG into the extravascular space and subsequent degradation in tissue sites. Received: 9 June 1998 / Accepted in revised form: 23 November 1998