Increased peritoneal permeability in patients with peritonitis undergoing continuous ambulatory peritoneal dialysis

Summary The distribution of cefuroxime (250 mg) was studied in patients with renal failure undergoing continuous ambulatory peritoneal dialysis (CAPD). 10 uninfected patients received the drug intravenously and intraperitoneally, while 9 patients with peritonitis were randomly allocated to intravenous or intraperitoneal administration. Samples were taken over the first 6 hour dialysis period. In the infected patients, more drug (p<0.01) crossed into the peritoneal cavity following intravenous injection and reached the systemic circulation following intraperitoneal administration than in the uninfected group. This increased permeability of the peritoneal membrane during infection may result in unexpected systemic toxicity in patients treated with intraperitoneal antibiotics.     

Clinical efficacy of controlled-release oxycodone 20 mg administered on a 12-h dosing schedule on the management of postoperative pain after breast surgery for cancer

SUMMARY

Objective: To assess clinical efficacy of controlled-release oxycodone (CRO) 20?mg on a 12-h dosing schedule in this prospective, randomised, placebo-controlled, double-blinded study of 40 ASA physical status I-III women undergoing breast surgery for cancer.

Research design and methods: General anaesthesia using remifentanil and propofol was performed for surgery. Both groups received premedication with oral midazolam 7.5?mg 1?h before surgery. In the controlled-release oxycodone group, one tablet of 20?mg CRO was administered with the premedication, and 12?h after the premedication another 20?mg CRO. In the placebo (PL) group, a placebo tablet was administered with the premedication, and 12?h later another placebo tablet. All patients had access to opioid rescue medication via an IV patient-controlled analgesia (PCA) device.

Main outcome measures: Area under the curve (AUC), based on IV opioid rescue consumption over 24?h postoperatively.

Results: The AUC for IV PCA opioid consumption was significantly lower in the CRO group than in the PL group (p?=?0.01). The CRO group required less IV opioid loading dose (p?<?0.001), and consumed less opioid rescue medication 4h (p?=?0.036), 16h (p?=?0.01), and 24?h (p?=?0.005) postoperatively. AUC for VAS scores at rest was significantly lower in the CRO group than in the PL group (p?=?0.05). VAS scores at rest were lower in the CRO group 16?h (p?=?0.04) and 24h (p?=?0.03) postoperatively. There was no difference in AUC for pain scores on movement (p?=?0.103) and for quality of analgesia (p?=?0.139). There was no difference in nausea between groups (p?=?0.34). Pruritus, arterial hypotension or hypertension, bradycardia, and tachycardia were not observed in either treatment group. None of the patients showed signs of confusion, agitation, or respiratory depression.

Conclusion: The administration of CRO 20?mg on a 12-h dosing schedule halves postoperative IV PCA opioid consumption. CRO 20mg is effective in preventing pain after breast surgery for cancer with only mild side-effects.     

Effects of Ginkgo biloba extracts on pharmacokinetics and efficacy of atorvastatin based on plasma indices

1. Ginkgo biloba extract (GBE) is one of the most widely used herbal medicines in the world. It is often administered in combination with statins to treat diseases, especially some nervous system disorders. We aimed to investigate the influences of GBE on pharmacokinetics and efficacy of atorvastatin, which are currently unclear.

2. Sixteen volunteers received a single oral dose of 40 mg atorvastatin, followed by a wash-out period of at least 5 days. Then the volunteers took 360 mg GBE daily for 14 days, followed by a single dose of 40 mg atorvastatin. Serial blood samples obtained over a period of 48 h after atorvastatin ingestion were subjected to determination of atorvastatin plasma concentrations and markers of cholesterol synthesis (lathosterol) and cholesterol absorption (sitosterol).

3. With GBE administration, AUC_0–48, AUC_0–∞ and C_max of atorvastatin were reduced by 14.27% (p = 0.005), 10.00% (p = 0.03) and 28.93% (p = 0.002), respectively; Vd/F and CL/F of atorvastatin were increased by 31.95% (p = 0.017) and 6.48% (p = 0.044). After 14 days of treatment, GBE has no significant effects on cholesterol-lowering efficacy of atorvastatin.

4. This study suggests that GBE slightly decreases the plasma atorvastatin concentrations, but has no meaningful effect on the cholesterol-lowering efficacy of atorvastatin.

     

Plasma pharmacokinetics and gastrointestinal transit of a new Propionyl-l-Carnitine controlled release formulation

1. Propionyl-l-carnitine is a naturally occurring analogue of l-carnitine (LC) produced in the body. PLC administration has shown beneficial effects in cardiovascular pathologies. In ulcerative colitis (UC), oral PLC treatment increased clinical presentation and positively influenced colon histology. In the present study, the MMX Multi Matrix System^® (MMX?) was used as drug delivery strategy for targeted PLC colon delivery.

2. A pharmacoscintigraphic study (n?=?6 healthy volunteers) described release characteristics of two MMX-PLC-HCl controlled release 500?mg tablets. A pharmacokinetic (PK) parallel group study (n?=?24) determined safety, plasma PLC concentrations and PK parameters after single and multiple doses.

3. Gastrointestinal transit was slow and variable. The colon was the main site of PLC release and absorption. After single 500 or 1000?mg PLC doses plasma PLC and LC increased up to 2.6 and 1.2–1.3-fold compared to baseline. Multiple doses of 500 and 1000?mg twice a day over 7 days did not significantly increase maximum plasma concentrations of PLC or LC with respect to concentrations achieved after single dose administration.

4. The colon is the main site of PLC release and absorption from MMX-PLC tablets. A daily dose of 500?mg to 1000?mg PLC twice a day was well tolerated, justifying further studies in patients with pathologies of the distal gastrointestinal tract to evaluate the efficacy of the MMX-PLC formulation.

     

Influence of CYP2C19 and ABCB1 polymorphisms on plasma concentrations of lansoprazole enantiomers after enteral administration

1. An intraoral annihilation enteric-coated preparation of lansoprazole is often administered via intestinal fistula. The purpose of this study was to determine the plasma concentrations of lansoprazole enantiomers after enteral administration in subjects with cytochrome P4502C19 (CYP2C19) and ABCB1 C3435T genotypes.

2. Fifty-one patients who underwent a curative oesophagectomy for oesophageal cancer were enrolled in this study. After a single enteral dose of racemic lansoprazole (30?mg), plasma concentrations of lansoprazole enantiomers were measured 4?h post-dose (C_4h).

3. There were significant differences in the C_4h of (R)- and (S)-lansoprazole and the R/S-enantiomer ratio for three CYP2C19 genotype groups (*1/*1, *1/*2 ± *1/*3, and *2/*2 ± *2/*3 ± *3/*3 (poor metabolizers (PMs)), but not the ABCB1 C3435T genotypes. In a stepwise forward selection multiple regression analysis, the C_4h of (R)- and (S)-lansoprazole were associated with CYP2C19 PMs (p?=?0.0005 and < 0.0001 respectively) and age (p?=?0.0040 and 0.0121 respectively), while the R/S-enantiomer ratio was associated with CYP2C19*1/*1 (p?=?0.0191) and CYP2C19 PMs (p?=?0.0426).

4. Direct administration to the jejunum is unaffected by residence time in the stomach and the gastric emptying rate. With enteral administration, CYP2C19 phenotyping of patients using the lansoprazole R/S enantiomer index at C_4h could be possible.

     

Effect of ursodeoxycholic acid on the pharmacokinetics of midazolam and CYP3A in the liver and intestine of rats

1. The elimination half-life of midazolam administered intravenously (5 mg kg^?1) or orally (15 mg kg^?1) was significantly decreased by 70% and 73%, respectively, 24 h after a single oral administration of ursodeoxycholic acid (UDCA, 300 mg kg^?1) in rats. In the liver there was a significant enhancement of the hydroxylation of midazolam in the microsomes and expression of cytochrome P450 (CYP) 3A1 messenger RNA (mRNA) and CYP3A2 mRNA.

2. The C_max and area under the curve (AUC)_0–∞ of midazolam were significantly (1.8–2.3 fold) increased by the single oral treatment with UDCA (100 and 300 mg kg^?1). Thus, the oral bioavailability, estimated from the AUC_0–∞, of midazolam administered intravenously and orally was significantly (1.8- and 2.3-fold, respectively) increased by the treatment with UDCA.

3. Repeated administration of UDCA (300 mg kg^?1 day^?1) for 7 days did not alter the pharmacokinetics of midazolam administered intravenously or orally, and the expression of mRNA for CYP3As in the rat liver.

4. The study has shown that a single administration of UDCA in rats induces significant hepatic CYP3A activity and increases significantly the oral bioavailability of midazolam. Such effects on the pharmacokinetics of midazolam were little observed on the repeated administration of UDCA.

     

The estimation of the plasma free fraction of cyclosporine in rabbits and heart transplant patients: The application of a physiological model of renal clearance

We estimated the free fraction (f_u) of cyclosporine (CyA) in the plasma from concentrations of CyA in urine (C_u) and plasma (C_p), urine flow rate (UF), and glomerular filtration rate in rabbits and in heart transplant patients. Following intravenous administration of CyA (5–30 mg kg^?1) in ten NZW rabbits and oral administration of CyA (4.8–12.1 mg kg^?1) in nine heart transplant patients, CyA concentrations in urine and plasma were measured by HPLC. The ratios of C_u to C_p and UF data were fitted to a physiological model of renal clearance using NONMEM. The free fraction of cyclosporine in the rabbits and the heart transplant patients was 0.0122 and 0.14, respectively. Because of the relatively low permeability of CyA across the tubular epithelium, no apparent equilibrium between C_u and C_p at any urine flow rate was reached and, therefore, the C_u to C_p ratio will not be equal to f_u.     

β-1,3-Glucan given orally modulates immunomyelopoietic activity and enhances the resistance of tumour-bearing mice

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The effects of topical everolimus and sunitinib on corneal neovascularization

Purpose: To evaluate the effects of topical everolimus and sunitinib on corneal neovascularization (CNV).

Methods: CNV was induced by application of silver nitrate to the cornea for all groups. Rats were divided into four groups of 10 rats each, and two corneas were obtained from each rat. Group I received 1?mg/ml everolimus, Group II received 0.5?mg/ml sunitinib, Group IV received no treatment (control group) and Group IV received 1% Dimethylsulfoxide (DMSO). All treatments were administrated twice daily for 2 weeks. The right corneas were used for extracellular signal-regulated kinase 1/2 (ERK 1/2) protein analysis by western blot analysis and the left corneas were used for ERK 1/2 and vascular endothelial growth factor-receptor (VEGFR-2) gene expression analysis by quantitative real-time PCR.

Results: VEGFR-2 mRNA expression levels (ΔCt, median, min-max) were reduced in the everolimus 1.0 (0.25–1.81) and sunitinib 1.06 (0.24–2.68) treated groups compared with the control 4.74 (1.02–14.74) and DMSO groups 7.41 (0.72–13.10). The expression of ERK 1/2 protein and mRNA levels were reduced in everolimus group compared with the control group (p?<?0.05). These differences were not seen between the sunitinib and control groups.

Conclus?on: Topical administration of both everolimus and sunitinib reduced VEGFR-2 levels and inhibited CNV. In additon, everolimus reduced ERK 1/2 levels and seems to be more effective than sunitinib on CNV.     

Dose proportionality and pharmacokinetics of dronedarone following intravenous and oral administration to rat

1. The aim of this study was to investigate the pharmacokinetic properties of dronedarone by using noncompartmental analysis and modeling approaches after intravenous and oral administration of dronedarone to rats.

2. Twenty-eight male Sprague-Dawley rats were randomly divided into four groups, and dronedarone was administered intravenously (1?mg/kg) and orally (5, 10 and 40?mg/kg) based on a parallel design. Blood samples were collected before and 0.083 (intravenous administration only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24?h after drug administration. The plasma concentration of dronedarone was determined by using LC-MS/MS.

3. The oral bioavailability of dronedarone was evaluated as approximately 16% in rats, similar to that in humans. The assessment of dose proportionality by using the power model showed that AUC_inf increased in a dose-proportional manner, whereas AUC_24h and C_max exhibited a lack of dose proportionality over the dose range between 5 and 40?mg/kg. The two-compartment model, with first-order absorption and elimination rate constants, was sufficient to explain the pharmacokinetics of dronedarone with biexponential decay.

4. These findings will help to understand the pharmacology of dronedarone to develop the new formulation and therapeutics optimization linked to pharmacokinetic/pharmacodynamic study.

     

Treatment with alendronate plus calcium,alendronate alone,or calcium alone for postmenopausal low bone mineral density

ABSTRACT

Objective: Bisphosphonates such as alendronate are widely used for postmenopausal osteoporosis. Supplemental calcium is also generally recommended. This trial directly compares alendronate to supplemental calcium and examines the effect of calcium supplementa­tion on alendronate treatment.

Methods: This 2-year, randomized, double-blind, multicenter trial enrolled healthy, postmenopausal women with low bone mineral density (BMD). Patients with a dietary calcium intake ≥?800?mg/day received daily vitamin D 400?IU and alendronate 10?mg/calcium-placebo, alendronate 10?mg/elemental calcium 1000?mg, or alendronate-placebo/calcium 1000?mg (2:2:1). Endpoints included BMD, bone turnover markers (BTMs), and adverse events.

Results: Randomized patients (N = 701) were an average of 20.4 years postmenopausal. After 24 months, increases in lumbar spine BMD differed significantly between patients receiving calcium alone (0.8%) and either alendronate alone (5.6%) or alendronate + calcium (6.0%) (?p < 0.001). Significant differences were also seen at the trochanter and femoral neck (?p < 0.001). BTMs were significantly lower with alendronate-containing treatments than calcium alone (?p < 0.001). Addition of calcium supplementation to alendronate did not signif­icantly increase BMD compared to alendronate alone (?p = 0.29 to 0.97), but did result in a statistically significant, though small, additional reduction in urinary NTx. Adverse events were similar among treatment groups. Limitations include no assessment of vitamin D levels and a discontinuation rate of approximately 30%, although discontinuation rates were similar among treatment groups.

Conclusions: In postmenopausal women with a daily intake of ≥?800?mg calcium and 400?IU vitamin D, 24-month treatment with alendronate 10?mg daily with or without calcium 1000?mg resulted in significantly greater increases in BMD and reduction of bone turnover than supplemental calcium alone. Addition of supplemental calcium to alendronate treatment had no effect on BMD and resulted in a small, though statistically significant, additional reduction in NTx.     

Frequency of pharmacological target attainment with flucloxacillin and cefazolin in invasive methicillin-susceptible Staphylococcus aureus infection: a prospective cohort study in hospitalized patients

BackgroundThe proportion of patients with invasive methicillin-susceptible Staphylococcus aureus (MSSA) infection who achieve target concentrations of flucloxacillin or cefazolin with standard dosing regimens is uncertain. This study measured drug concentrations in a prospective cohort of patients with invasive S. aureus infections to determine the frequency of target concentration attainment, and risk factors for failure to achieve target concentrations.Patients and methodsUnbound flucloxacillin and cefazolin plasma concentrations were measured at the midpoint between intravenous doses. Adequate and optimal targets were defined as an unbound plasma concentration of ≥1 and ≥2 times the minimum inhibitory concentration (MIC) (flucloxacillin 0.5 mg/L, cefazolin 2 mg/L), respectively (50%fT_≥1MIC, 50%fT_≥2MIC).ResultsThere were 50 patients in each of the flucloxacillin and cefazolin groups. Eighty-five (85%) patients met the target of 50%fT_≥2MIC and 95 (95%) patients met the target of 50%fT_≥1MIC. The median unbound flucloxacillin concentration was 2.6 mg/L [interquartile range (IQR) 1.0–8.1]. The median unbound cefazolin concentration was 15.4 mg/L (IQR 8.8–28.2). A higher proportion of patients in the flucloxacillin group failed to achieve the optimal target compared with the cefazolin group [13 (26%) vs 2 (4%); P=0.002]. Younger age and higher creatinine clearance were associated with lower plasma concentrations.ConclusionsStandard dosing of flucloxacillin and cefazolin in the treatment of invasive MSSA infections may not achieve target plasma concentrations for a subgroup of patients. Measuring drug concentrations identifies this subgroup and facilitates dose individualization.     

Levels of cefuroxime in bronchial secretion

Summary

Levels of cefuroxime in bronchial secretion were measured in 49 patients requiring bronchoscopy for diagnostic purposes. Patients were randomly allocated to one of 4 groups which differed with respect to the size (750?mg or 1.5 g) and number (1 or 7) of intravenous doses of cefuroxime given approximately 1 hour prior to sampling. Levels of cefuroxime achieved after administration of all 4 dosages were sufficient to exceed the MIC values for the major chest pathogens. Penetration of cefuroxime into bronchial secretion was also found to be dose-related.     

Effect of amphetamines on tryptophan concentrations in mice and rats

(±)-Amphetamine and some of its analogues were administered intraperitoneally to mice and rats and the concentrations of tryptophan in tissues were analysed by fluorimetric and microbiologic techniques. The concentration of tryptophan in brain was markedly increased by (±)-amphetamine and reached a maximum about 80 min after drug administration. The effect was dose-dependent with a threshold dose below 1 mg/kg. (+)-Amphetamine was significantly more potent than p-chloroamphetamine and p-hydroxyamphetamine, indicating that the changes in tryptophan concentrations might be related to the central stimulating effect of the drugs. (±)-Amphetamine delayed the disappearance from brain of intravenously administered [³H]tryptophan. Inhibition of monoamine oxidase by nialamide (100 mg/kg) and tryptophan hydroxylase by H 22/54 (500 mg/kg) had no effect on the tryptophan concentration in brain.     

Pharmacokinetics of free and total flucloxacilin in newborn infants

Summary Flucloxacillin 50 mg/kg b.w. was administered intravenously (in combination with ampicillin/gentamicin) and orally (with amoxicillin) to 9 newborn infants (gestational age 33–41 weeks) to treat bacterial infections. The concentrations of flucloxaxillin in plasma and urine after i.v. injection were analysed according to an open two-compartment model, and the plasma protein binding of flucloxacillin and its distribution to blood cells and plasma water in whole blood were determined. Considerable differences were found from values reported in adults. The terminal half-life averaged 4 h 38 min and was significantly correlated with gestational age. Plasma clearance was low (0.744 ml·min^–1·kg^–1), due to the small renal clearance (0.182 ml·min^–1·kg^–1), whilst non-renal clearance (0.563 ml·min^–1·kg^–1) was approximately the same as in adults. The mean apparent volume of distribution of total drug (V_z) was 0.280 l/kg. The corresponding volume of distribution of unbound drug (V ₁ ^u + V ₂ ^u ) was 1.74 l/kg, which indicates considerable extravascular drug binding. The plasma protein binding of flucloxacillin (mean 86.3%) was significantly correlated with gestational age and the bilirubin/albumin concentration ratio. Bioavailability after oral administration, when corrected for changes in terminal half-life, was 47.7%, which is only slightly lower than that reported in adults. Since the plasma concentrations after both i.v. and oral administration were well above the MIC-values generally reported for Staphylococcus aureus, and since few side-effects were observed, intravenous injection or, in selected cases, oral administration of flucloxacillin appears to be a reliable therapy for the treatment of infections due to sensitive strains of S. aureus in premature newborn infants.     

Pharmacokinetics of antofloxacin hydrochloride,a novel fluoroquinolone,after single-dose intravenous administration in healthy Chinese male volunteers

1. The purpose of the study was to evaluate the pharmacokinetic characteristics of a single, intravenous dose of antofloxacin hydrochloride in healthy Chinese male volunteers.

2. Twelve subjects were randomly assigned to groups that received a single, intravenous dose of 200, 300, or 400?mg antofloxacin hydrochloride in a three-way crossover design study. The serum and urine concentrations of antofloxacin were then assayed with high-performance liquid chromatography (HPLC). Major pharmacokinetic parameters and urine excretion were obtained up to 96?h after administration.

3. All three dosages were well tolerated. No clinically adverse reactions or abnormal laboratory results were detected.

4. After single-dose intravenous administration, antofloxacin hydrochloride exhibited linear pharmacokinetic characteristics with increasing dosages. The C_max for groups treated with 200, 300, or 400?mg dosages were 2.05?±?0.38, 3.01?±?0.60, and 3.80?±?0.78?mg l^?1, respectively; the areas under the curve from zero to infinity (AUC_0–∞) were 25.14?±?2.95, 37.63?±?5.42, and 53.87?±?9.48?mg l^?1·h, respectively. The t_1/2β was around 20?h; and the urinary excretion was measured as being from 58% to 60% within 96?h.

5. Based on these results, 300?mg of antofloxacin hydrochloride administered once daily is the dose suggested for further investigation in multiple-dose administration studies.

     

Exogenous Methemoglobin as a Cyanide Antidote in Rats

The effects of the administration of methemoglobin (MetHb) prepared in vitro were evaluated in Sprague–Dawley rats given increasing doses of potassium cyanide (KCN). Median lethal dose (LD50) studies were conducted by giving intraperitoneal injections of KCN (in 0.3- to 0.5-ml volumes), then 2 min later administering intravenous (iv) doses of 1000, 1500, or 2500 mg/kg of MetHb through the tail vein. Control rats received an equivalent volume of saline. The resulting LD50 values for KCN were 7.4 ± 1.1, 11.7 ± 1.1, 13.9 ± 1.0, and 14.2 ± 1.0 mg/kg (mean ± SD) for the control (no MetHb) and 1000-, 1500-, and 2500-mg/kg dose groups, respectively. Additional groups of rats were given 1000, 1500, or 2500 mg/kg MetHb and submitted for necropsy. The gross finding of darkened kidneys was present in both dose groups, but became consistent and more prominent in the 2500-mg/kg dose group. Evidence of pathologic changes was not present in other organs. Single-dose pharmacokinetic studies were conducted using iv doses of 1600 and 2500 mg/kg MetHb. The elimination half-life was similar in both doses (62.6 min), but the volume of distribution (95.3 ± 7.2 and 126.3 ± 5.2 ml/kg, mean ± SE) and clearance (1.1 ± 0.1 and 1.5 ± 0.1 ml/min/kg) were significantly different (P < 0.05) for the 1600-and 2500-mg/kg dose groups, respectively. From these data we conclude that although MetHb is cleared from the vascular system rapidly, it may be an effective and nontoxic antidote for doses of cyanide up to twice that of the control LD50.     

Serum concentrations of cis(Z)-flupentixol and prolactin in chronic schizophrenic patients treated with flupentixol and cis(Z)-flupentixol decanoate

Nine chronic schizophrenic patients selected from three hospital departments were treated with flupentixol (orally and IV) and cis(Z)-flupentixol decanoate in Viscoleo (IM) in a three-phase pharmacokinetic study. Oral administration (single and repeated dosage) showed a relatively slow absorption with maximum serum concentration around 4 h after administration. Intravenous injection indicated multicompartment kinetics for cis(Z)-flupentixol. The biological half-lives calculated after the different doses were the same, indicating that the pharmacokinetics of cis(Z)-flupentixol does not differ between single and repeated administration and does not change when moderately higher doses are given. The bioavailability of orally administered cis(Z)-flupentixol was calculated to be about 40% with IV injection as reference. After IM administration maximum serum concentration was seen between 4 and 10 days in most patients. Calculation of a disappearance half-life gave very variable results, indicating that the release of the drug from the oil depot is not a monoexponential process. The intramuscular depot had a much lower bioavailability than IV injection, which means that steady state has not been obtained after 8 weeks of depot treatment. Serum prolactin concentrations were elevated during neuroleptic treatment, but no correlation was found between prolactin concentrations and the serum concentrations of cis(Z)-flupentixol. A correlation between the changes in clinical ratings and concentrations of cis(Z)-flupentixol or prolactin was not found.     

Disposition of tris(4-chlorophenyl)methanol and tris(4-chlorophenyl)methane in male and female Harlan Sprague Dawley rats and B6C3F1/N mice following oral and intravenous administration

1. Tris(4-chlorophenyl)methane (TCPME) and tris(4-chlorophenyl)methanol (TCPMOH) have been detected in various biota and human tissues.

2. The current studies were undertaken to investigate the disposition and metabolism of TCPME and TCPMOH in rats and mice.

3. [¹⁴C]TCPME was well absorbed (≥66%) in male rats and mice following a single oral administration of 1, 10, or 100?mg/kg. The excretion of [¹⁴C]TCPME-derived radioactivity in urine (≤2.5%) and feces (≤18%) was low. The administered dose was retained in tissues (≥?64%) with adipose containing the highest concentrations. The metabolism of TCPME was minimal. The disposition and metabolism of [¹⁴C]TCPME in females was similar to males.

4. The time to reach maximum concentration was ≤7?h, the plasma elimination half-life was ≥31?h, and the bioavailability was ≥82% following a 10?mg/kg oral dose of [¹⁴C]TCPME in male rats and mice.

5. The disposition of [¹⁴C]TCPMOH was similar to that of [¹⁴C]TCPME.

6. Following an intravenous administration of [¹⁴C]TCPME or [¹⁴C]TCPMOH in male rats and mice, the pattern of disposition was similar to that of oral administration.

7. In conclusion, both TCPME and TCPMOH are readily absorbed and highly bioavailable following a single oral administration pointing to importance of assessing the toxicity of these chemicals.

     

Effects of pioglitazone on metabolic control and blood pressure: a randomised study in patients with type 2 diabetes mellitus

SUMMARY

Aim: This Swiss multicentre study examined the efficacy and safety of oral pioglitazone in patients with type 2 diabetes.

Methods: Patients were randomised to pioglitazone at once-daily doses of 30mg for 20 weeks (n?=?76), 30?mg for 12 weeks followed by 45?mg for 8 weeks (n?=?74), or 45?mg for 20 weeks (n?=?84); 94.9% of patients completed 12 weeks and 88.9% completed all 20 weeks. Almost all (96.6%) patients received pioglitazone in combination with other anti-diabetic treatments.

Results: Mean HbA1c at baseline was 8.8?±?1.2%, and changes to endpoint were ?1.1?±?1.1%, ?1.1?±?1.4% and ?0.9?±?1.6%, respectively for the three dose groups (p?<?0.001 for each group). Triglyceride concentrations decreased in each group and the overall mean change during the study was ?0.58?mmol/l (p?<?0.001 versus baseline). HDL-cholesterol increased, with an overall mean change of 0.10?mmol?l^?1 (p?<?0.001 versus baseline). Blood pressure decreased from baseline, particularly for hypertensive patients with mean changes: systolic -10mmHg, p?<?0.001, diastolic-8mmHg, p?<?0.001 versus baseline. Serum alanine aminotransferase and γ-glutamyl transferase concentrations were significantly (p?<?0.001 for each) reduced during the study.

Conclusions: The study demonstrates the efficacy of pioglitazone 30?mg?day^?1 and 45?mg?day^?1 in the treatment of type 2 diabetes, with an improved lipid profile and decreased blood pressure in addition to improved glycaemic control.