Constant Daily Dose Research Articles

Investigation of Diffusion Characteristics through Microfluidic Channels for Passive Drug Delivery Applications.

Microfluidics has many drug delivery applications due to the ability to easily create complex device designs with feature sizes reaching down to the 10s of microns. In this work, three different microchannel designs for an implantable device are investigated for treatment of ocular diseases such as glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy. Devices were fabricated using polydimethylsiloxane (PDMS) and soft lithography techniques, where surface chemistry of the channels was altered using 2-[methoxy(polyethyleneoxy)propyl]trimethoxysilane (PEG-silane). An estimated delivery rate for a number of common drugs was approximated for each device through the ratio of the diffusion coefficients for the dye and the respective drug. The delivery rate of the model drugs was maintained at a physiological condition and the effects of channel design and surface chemistry on the delivery rate of the model drugs were recorded over a two-week period. Results showed that the surface chemistry of the device had no significant effect on the delivery rate of the model drugs. All designs were successful in delivering a constant daily dose for each model drug.

Chronic exposure to low doses of lipopolysaccharide and high-fat feeding increases body mass without affecting glucose tolerance in female rats.

Obesity-related inflammation may have a causal role in the development of diabetes and insulin resistance, and studies using animal models of chronic experimental endotoxemia have shown the link. However, many studies use only males, and much less is known about the role of obesity-related inflammation in females. Therefore, we addressed how experimentally induced chronic inflammation affects body mass, energy intake, and glucose metabolism in female rats. Adult female Sprague Dawley rats were instrumented with slow release pellets that delivered a constant daily dose of 53 or 207 μg of lipopolysaccharide (LPS) per rat for 60 days. Control rats were instrumented with vehicle pellets. Due to inflammatory nature of high-fat diet (HFD) half of the rats received HFD (60% of calories from lard), while the other half remained on control diet to detect possible interactions between two modes of induced inflammation. Our results showed that chronic LPS administration increased female rat body mass and calorie intake in a dose-dependent manner, and that HFD further exacerbated these effects. Despite these effects, no effects of LPS and HFD were evident on female rat glucose metabolism. Only LPS elevated expression of inflammatory markers in the hypothalamus. To conclude, female rats respond to experimentally induced chronic inflammation by increasing body mass, but do not develop glucose intolerance in the given period of time.

Have nonsteroidal anti-inflammatory drugs a pathogenetic action?

It is pointed out that there is weighty evidence that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in osteoarthrosis (OA) and ankylosing spondyloarthritis (AS) can achieve not only symptomatic improvement, but also slower progression of the underlying pathological process. This effect is confirmed not only theoretically, but also experimentally and clinically. The information given in the review may serve as a ground for more active use of NSAIDs when there are direct indications for their use. It is stated that it is reasonable to switch from the purely symptomatic use of these drugs (only when pain occurs) to the practice of regular intake in their constant daily dose if pain in the joints and/or spine is present for most time.

Insulin glargine improves glycemic control and quality of life in type 2 diabetic patients on hemodialysis

Diabetic patients on hemodialysis often experience severe hypoglycemia during intensive insulin therapy using conventional neutral protamine hagedorn (NPH) or nonintensive therapy with premixed insulin. Insulin glargine can simulate normal basal insulin secretion. We investigated the efficacy and safety of switching from NPH to glargine in type 2 diabetes patients on hemodialysis. Hemodialysis patients who were being treated with NPH-based basal-bolus insulin therapy, regular insulin, NPH insulin or premixed insulin were switched to glargine. The target early morning fasting blood glucose (FBG) level was 110 mg/dL. Any increase in glargine dose was coupled with a reduction in the dose of any regular or rapid-acting insulin analogue as far as possible while maintaining a constant daily insulin dose. FBG, HbA(1c), daily insulin dosage, percentage of basal insulin dose in total daily insulin dose, body weight and incidence of hypoglycemic events were evaluated during the study period. Quality of life (QOL) was measured with a short questionnaire. HbA(1c) improved significantly during the observation period after switching. The daily insulin dose was reduced from 20.1 ± 15.2 to 18.1 ± 15.1 U/day, although the change was not statistically significant. FBG decreased significantly from 174.4 ± 58.7 to 126.2 ± 27.7 mg/dL. Body weight measured after dialysis did not change, and there were no changes in hemoglobin or hematocrit. The frequency of hypoglycemic episodes decreased significantly. QOL reports with switching to glargine were improved compared with those before switching. The results suggest that glargine is useful, can improve QOL of diabetic patients on hemodialysis, and achieve better glycemic control than NPH.

Effects of Flow Rate Modifications on Reported Analgesia and Quality of Life in Chronic Pain Patients Treated with Continuous Intrathecal Drug Therapy

We compared the analgesia and the quality of life of a constant daily dose of intrathecal drug administered at different flow rates in patients treated for chronic pain. We postulate that the quality of the analgesia, at the same daily dose, will show an infusion rate dependent pattern with decreased pain at higher flow rates. Twenty consecutive patients on stable intrathecal treatment were included in a double-blind three-period crossover study where the same daily dose was administered at single, double, and quadruple flow rates in a randomized sequence. The mean daily pain score and the quality of life (EuroQol measure of health outcome [EQ-5D]) were measured following each flow rate change, after 1 week of stabilization. Results. Visual analog scale (VAS) scores remained unchanged with all flow rates. Compared with the lowest flow rate, the EQ-5D index decreased with double and even more with quadruple flow rate, suggesting a clinically relevant worsening of the health state with higher flow rates. Adverse events were equally distributed in all groups. Pain VAS did not significantly change with flow rate. This is consistent with preclinical data showing very limited increase in drug distribution in the cerebrospinal fluid with much larger flow rate augmentation. However, the quality of life decreased consistently as the flow rate increased. This was entirely due to a worsening of the pain and anxiety dimension of the EQ-5D questionnaire, caused presumably by a slight increase in pain rather than adverse events. We suggest that at higher flow rates increased drug dilution results in a decreased effect at the receptor site.

Possible Dose Adjustment of Hydroxyurea In Young Patients with Sickle Cell Disease and Followed In the Belgian Registry

AbstractAbstract 4823Hydroxyurea (HU) is used to treat patients with severe forms of sickle cell disease (SCD) for more than 15 years. In 2007 the European Medicines Agency approved 1,000 mg coated breakable tablets (Siklos®, Addmedica) for the treatment of SCD in both adults and children from 2 years of age onwards. In Belgium these tablets are not yet available and SCD patients are prescribed 500 mg capsules (Hydrea®, Bristol Myers Squibb Laboratories; off-label use). Because the added value of a body weight-adapted dose has not been studied, we assessed whether dose adjustment with 250mg steps, compared to 500mg steps, can be of benefit in term of daily intake at constant dose. As a 100mg tablet is expected to be available soon, we also included it in our calculations. Patients and methods:In August 2009, 138/230 patients included in the Belgian Registry of SCD were on HU. The criteria for HU treatment were mainly recurrent ACS or > 2 hospitalisations/year for vaso-occlusive crisis. Based upon patient's age and mean weight, we calculated theoretically the possibilities of giving the adequate HU daily dose by prescribing either 500 mg capsules or the new formulation with the possibility of adjustment by increment of 250 mg or 100 mg. Dose regimens were defined as starting dose (15-20 mg/kg/day), normal dose (20-25 mg/kg/day), increased dose (25-30 mg/kg/day), high dose (30-35 mg/kg/day) and very high dose (>35 mg/kg/day). “Daily intake” is defined as HU administration during 7 days per week with a constant daily posology, “daily alternating intake” is defined as a different posology for at least one day per week. When a daily dose is judged outside the chosen posology with the available formulations, a weekly dose is calculated and given few days per week (weekly regimen) at the fixed available formulation. Neuman-Keuls Multiple Comparison Test was used; p < 0.05 is statistically significant. Results:Median age at start of HU therapy was 4.9 years (range, 0.7 – 35.8) and the median age in August 2009 was 11.3 years (range, 3.3–36.2). Comparison of the posology with the three HU formulations (500 mg capsules,1,000 mg breakable tablets alone or in combination with 100 mg tablets) according to the dose options at initiation of HU therapy is shown on Table1. At initiation of HU using the 500 mg capsules, the treatment is administered as weekly, daily alternating regimen and at constant daily posology for 70%, 19% and 11% of the patients, respectively. At initiation of HU treatment, using the 100 mg combination option, 96% of the patients had a constant daily posology, versus 41% and 11% with the with 250 mg alone and 500 mg formulations, respectively. Data on other dose regimens are detailed in Table1. It shows that for starting and increasing dosage a significantly higher percentage of patients can benefit of a daily constant intake when using the breakable 1,000 mg tablets (and 100 mg tablets) rather than if using the 500 mg capsules.According to the patient's age and weight in August 2009, with the 500mg capsules, 41% and 78% can receive HU at constant daily dose if treated at starting and normal dose respectively, while the proportion increases up to 72% and 92% with the 1,000 mg breakable tablets. Conclusion:Among SCD patients of the Belgian Registry, 60% are under HU therapy. Starting HU doses are generally within the range of 15–20 mg/kg/day, and escalated up to the maximum tolerated dose if judged appropriate. Both the 100 mg and 250 mg formulations allow a daily treatment at constant dose for a majority of young patients and to avoid high or very high doses of HU. With these formulations, an increased tolerance and safety is expected. In addition, a daily standard medication is probably also a factor of improved adherence to therapy. These data emphasize the need of appropriate HU formulation to treat children with SCD. Disclosures:No relevant conflicts of interest to declare.

Combination therapy with mitiglinide and voglibose improves glycemic control in type 2 diabetic patients on hemodialysis

Objective: Mitiglinide, a rapid- and short-acting insulinotropic sulfonylurea receptor ligand, exhibits hypoglycemic action unlike other sulfonylureas. The efficacy of the combination of mitiglinide and α-glucosidase inhibitors for diabetic patients on hemodialysis (HD) has not been prospectively evaluated; therefore, we evaluated the efficacy and safety of mitiglinide in these patients.Research design and methods: We performed an open-label randomized study with 36 type 2 diabetics with poor glycemic control on HD and receiving daily doses of voglibose (0.9 mg). The patients were randomly assigned to two groups: a combination-therapy group (mitiglinide group), mitiglinide initial dose 7.5 – 15 mg titrated to 30 mg daily and constant daily dose 0.9 mg of voglibose, and a monotherapy group (control group), constant daily dose 0.9 mg of voglibose alone. The efficacy of the treatment was determined by monitoring plasma glucose, hemoglobin A1c (HbA1c), and glycated albumin (GA) levels and using homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerance were determined by monitoring clinical and laboratory parameters.Results: The final dose of mitiglinide was 22.9 ± 8.9 (mean ± s.d.) mg (0.41 mg/kg) daily. Mitiglinide reduced fasting plasma glucose and GA levels after 4 weeks and HbA1c levels after 8 weeks. Triglyceride levels and HOMA-IR values also decreased significantly after mitiglinide treatment. No significant changes in blood pressure levels or serious adverse effects such as hypoglycemia or liver impairment were observed.Conclusions: This study suggests a combination therapy of mitiglinide and voglibose may have potential for the treatment of diabetics on HD. Due to the small sample size used, further studies should be performed, particularly to assess the safety of mitiglinide treatment.

Repeatability of the low‐dose ACTH test in asthmatic children on inhaled corticosteroids

To assess the repeatability of low-dose Synacthen test (LDST) in asthmatic children receiving high-dose fluticasone propionate (FP). Low-dose Synacthen test was performed on 18 children with stable chronic asthma treated with FP at a constant daily dose of > or =500 microg and repeated 1 month later. Repeatability was assessed using the Kappa statistic for categorical variables. Fifteen patients had consistent results (either two normal or two abnormal responses) and three patients had inconsistent results (one normal and one abnormal response). The Kappa statistic was 0.56 indicating fair to good agreement between the tests. The results of adrenal function testing in patients on inhaled steroids can have major implications for patient management, making it important to use a test with excellent repeatability. The LDST conducted using our protocol does not fulfil this criterion.

Linear response of mutans streptococci to increasing frequency of xylitol chewing gum use: a randomized controlled trial [ISRCTN43479664

BackgroundXylitol is a naturally occurring sugar substitute that has been shown to reduce the level of mutans streptococci in plaque and saliva and to reduce tooth decay. It has been suggested that the degree of reduction is dependent on both the amount and the frequency of xylitol consumption. For xylitol to be successfully and cost-effectively used in public health prevention strategies dosing and frequency guidelines should be established. This study determined the reduction in mutans streptococci levels in plaque and unstimulated saliva to increasing frequency of xylitol gum use at a fixed total daily dose of 10.32 g over five weeks.MethodsParticipants (n = 132) were randomized to either active groups (10.32 g xylitol/day) or a placebo control (9.828 g sorbitol and 0.7 g maltitol/day). All groups chewed 12 pieces of gum per day. The control group chewed 4 times/day and active groups chewed xylitol gum at a frequency of 2 times/day, 3 times/day, or 4 times/day. The 12 gum pieces were evenly divided into the frequency assigned to each group. Plaque and unstimulated saliva samples were taken at baseline and five-weeks and were cultured on modified Mitis Salivarius agar for mutans streptococci enumeration.ResultsThere were no significant differences in mutans streptococci level among the groups at baseline. At five-weeks, mutans streptococci levels in plaque and unstimulated saliva showed a linear reduction with increasing frequency of xylitol chewing gum use at the constant daily dose. Although the difference observed for the group that chewed xylitol 2 times/day was consistent with the linear model, the difference was not significant.ConclusionThere was a linear reduction in mutans streptococci levels in plaque and saliva with increasing frequency of xylitol gum use at a constant daily dose. Reduction at a consumption frequency of 2 times per day was small and consistent with the linear-response line but was not statistically significant.

Enteral Administration of a Simulated Amniotic Fluid to Very Low Birth Weight Neonates

To reduce feeding intolerance among very low birth weight neonates. A total of 10 neonates with birth weights of 750 to 1250 g were given oral-gastric boluses (2.5 ml/kg every 3 hours) of a solution patterned after amniotic fluid. When milk feedings were begun the milk was mixed with the test solution. The solution was given at a constant daily dose of 20 ml/kg/day while the volumes of milk feedings were gradually increased. When milk feedings reached 80 ml/kg/day the test solution was discontinued. A comparison group consisted of neonates who met study criteria but were cared for during the period immediately preceding the study. The outcome was the number of calories taken enterally over the first 21 days of life. The test solution was begun an average of 27 hours after birth (range, 4 to 45). In the test group the first milk feedings were introduced 74 hours after birth (range, 18 to 144), which was similar to the time milk was introduced in the comparison subjects (79 hours; range, 18 to 168). After milk feedings were started, the test patients had a total of four NPO days (0.4 NPO days per patient) during their first 21 days, while the comparison group had 34 NPO days (3.4 NPO days per patient). During the first 14 days of life the test solution recipients had a median of 26.5 enteral cal/kg/day (range, 4.3 to 68.9), while the comparison neonates had 8.5 (range, 0.2 to 25; p < 0.05). During the first 21 days of life the test solution recipients had a median of 56.9 enteral cal/kg/day (range, 11.5 to 89.4), while the comparison neonates had 19.2 (range, 0.9 to 52.8; p < 0.05). In all, 10 VLBW infants tolerated the test solution for periods up to 14 days with no significant adverse effects. A randomized trial to determine whether this solution reduces feeding intolerance among VLBW neonates should be conducted.

Effect of Angiotensin-Converting Enzyme Inhibitors on Response to Erythropoietin Therapy in Chronic Dialysis Patients

Background: Erythropoietin (EPO) therapy is a common and effective treatment for the correction of anemia in patients with end-stage renal disease. Simultaneous treatment with angiotensin-converting enzyme (ACE) inhibitors for the control of hypertension and/or heart failure is often necessary. Recent reports in the literature have raised concern about a potential interaction between these drugs, with a resultant decreased EPO efficacy. Methods: To investigate whether this interaction occurs in chronic dialysis patients, we retrospectively reviewed the records of 175 patients receiving chronic dialysis. All study patients were treated with EPO for at least 3 months, and had normal iron indices. Patients were treated with ACE inhibitors for at least 3 months, at a constant daily dose for at least 1 month (group 1, n = 32), or did not receive ACE inhibitors (group 2, n = 143). Patients with infections or overt iron deficiency were excluded. Total weekly EPO doses and hematocrit (Hct)/hemoglobin (Hgb) values in the two groups were compared. Variables known to affect response to EPO were compared, including ferritin, transferrin saturation, dialysis dose and serum aluminum. Results: Total weekly EPO dose was 17,358 ± 6,871 units in group 1 and 17,612 ± 7,744 units in group 2 (p = 0.854). The achieved Hct was 32.1 ± 4.4% (group 1) and 30.5 ± 4.0% (group 2) (p = 0.079). Similarly, Hgb, ferritin, transferrin saturation, Kt/V, and serum aluminum were not different. The dose or duration of ACE inhibitor therapy did not affect Hgb or Hct. Thus, ACE inhibitor therapy does not appear to affect response to EPO in chronic dialysis patients.

PGD10 Bambuterol is A More Cost-Effective Treatment than Salmeterol in Asthma Patients with Nocturnal Symptoms

OBJECTIVE:To compare the cost-effectiveness of oral bambuterol (B) 20 mg once daily with that of salmeterol (S) pMDI 50 mg twice daily for treatment of asthma patients with nocturnal symptoms. METHODS:126 patients, aged 18–70 years and using inhaled corticosteroids at a constant daily dose and with an FEV1 40–85% of predicted normal value, were included in this double-blind, randomized, parallel-group study (2 weeks of run-in and 6 weeks of treatment) in the UK, Italy, and Norway. During run-in, they had to show a nocturnal awakening or early awakening due to asthma symptoms that required rescue medication at least once, and a 15% fall in overnight PEF on 3 out of the last 7 days. Morning and everning PEF were measured and tremor was scored. The effectiveness variables in the cost-effectiveness analysis were symptom-free days and number of nights with no awakenings. Costs for both study and rescue medication were calculated. RESULTS:There were no statistically significant differences between B and S regarding morning and evening PEF (change from baseline), tremor, and the effectiveness variables. Mean number of symptom-free days were 20–25%, and mean number of nights with no awakenings were 69–77%. Costs (study + rescue medication) were lower during bambuterol treatment in all three countries. UK Italy Norway Daily cost Bamb Salm Bamb Salm Bamb Salm US$ 0.71 1.35 0.67 0.92 0.74 1.19 CONCLUSION:Treatment with bambuterol is more cost-effective than treatment with salmeterol in asthma patients with nocturnal symptoms.

Efficient designs for animal carcinogenicity experiments

In a typical carcinogenicity study, animals, usually rats or mice. are divided into a control and two to three dose groups of 50 or more by randomization. A chemical is administered at a constant daily dose rate for a major portion of the lifetime of the test animals, for example, two years. In general, such an experiment is expensive and time consuming In this paper, we propose an efficient design with reduced sample size and/or shortened study duration. An equal number of animals per dose group is considered in this study. A power study of the age-adjusted trend test, for the turnor incidence rate for single-sacrifice experiments proposed by Kodell et al. (Drug Information Journal, 1997) is conducted. A Monte Carlo simulation study is performed to compare the performance of the trend test for the standard design and various reduced designs. Based on the Kodell et al. test, the 21-month study duration with sample size 50 per group is recommended as the best, reduced design over the traditional 2-year study design with the same sample size.

Effects of Increasing Maintenance Dose of Digoxin on Left Ventricular Function and Neurohormones in Patients With Chronic Heart Failure Treated With Diuretics and Angiotensin-Converting Enzyme Inhibitors

Despite almost three centuries of use, the appropriate dosage of digitalis in patients with chronic heart failure and normal sinus rhythm has not been well studied. We studied 22 patients with heart failure who were receiving constant daily doses of digoxin, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. In 18 patients, the oral daily dose of digoxin was increased from a mean of 0.20 +/- 0.07 to 0.39 +/- 0.11 mg/day corresponding to an increase in the serum digoxin concentration from 0.67 +/- 0.22 to 1.22 +/- 0.35 ng/mL. Radionuclide and echocardiographic left ventricular ejection fraction; maximal treadmill time; heart failure score; serum concentrations of norepinephrine, aldosterone, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity were obtained before and after the increase in digoxin dose. Subsequently, 9 patients were randomized to receive digoxin and 9 to receive placebo and radionuclide ejection fraction measured after 12 weeks. With the higher dose of digoxin compared with the lower dose, there was a significant increase in radionuclide ejection fraction from 23.7 +/- 9.6% to 27.1 +/- 11.8% (P = .007). No significant changes were noted in heart failure score; exercise tolerance; serum concentrations of norepinephrine, atrial natriuretic factor, and antidiuretic hormone; and plasma renin activity. There was, however, an increase in serum aldosterone concentration. Twelve weeks after the patients were randomized to receive digoxin or placebo, there was a significant decrease in ejection fraction (from 29.4 +/- 10.4% to 23.7 +/- 8.9%) in the placebo group but not in patients who continued to receive digoxin (P = .002). The increase in maintenance digoxin dose, while maintaining serum concentrations within therapeutic range, resulted in a significant increase in left ventricular ejection fraction that was not associated with significant changes in heart failure score, exercise tolerance, and neurohumoral profile.

Ratios of transfer coefficients for radiocesium transport in ruminants.

A corollary of the multiple-compartment model for the transport of trace elements through animals was tested for cows, goats, and sheep. According to this corollary, for a given body "compartment" k of the animal (soft tissue, lung, liver, etc.), the ratio a(k) = f(k)/f(blood) of the transfer coefficients f, should exhibit similar values for physiologically similar animals. In order to verify this prediction, two experiments were performed at the Agricultural Research Station of Ioannina and at the facilities of Ria Pripyat in Pripyat, Ukraine. Eight animals in the first experiment and eighteen in the second were housed in individual pens and were artificially contaminated with a constant daily dose of radiocesium until equilibrium was reached. The animals were then sacrificed and transfer coefficients f(k) to twelve body "compartments" k were measured. These data were used to calculate the ratios a(k). The results were in accordance with predictions of the model and average values of a(k) were extracted for ruminants. It is concluded that these values may be employed for the prediction of animal contamination in any body compartment through the measurement of blood samples.

Efficacy of tianeptine in the treatment of major depression and depressed bipolar disorders. Illustration of the interest of surveillance of a European multicentre double-blind study in progress: tianeptine versus placebo and imipramine

SummaryIn the course of the international development of tianeptine (T), depressed patients were recruited by 15 centres from Belgium, Italy, Portugal, Spain and Switzerland in a double-blind parallel group study versus placebo (P) and imipramine (I). Efficacy and safety of tianeptine are evaluated in the treatment of major depressions (single episode or recurrent) and depressed bipolar disorders. The initial severity of the depression is controlled by a MADRS score equal to or greater than 25. Rapid placebo responded are excluded during a placebo pre-inclusion period (duration: 1 week). After an increasing daily dose period (3 days), depressed patients are treated, until the 14th day (D14), at a constant daily dose (T: 37.5 mg; I: 150 mg; P: 3 capsules). After D14 and until the end of the 6th week, a flexible dosage can be used in accordance with the therapeutic efficacy and/or the potential adverse events (T: 25–50 mg; I: 100–200 mg; P: 2–4 capsules). The antidepressant efficacy is regularly evaluated by rating scales (MADRS, HSCL). Anxiety linked to depression is evaluated by the Hamilton Anxiety Rating Scale. The safety is controlled by clinical examination, laboratory parameters and a check-list of side-effects. Preliminary results are presented and discussed showing the interest of surveillance of trials in progress.

Tissue concentrations of 2,3,7,8-TCDD in rats and offspring after continuous exposure during the late fetal and postnatal period

If animal experiments are designed to investigate the possible influence of a perinatal exposure to “dioxins”, dose regimens should be applied which lead to rather constant tissue concentrations in the dams and thereby to a relatively constant exposure of the offspring. This prerequisite is not at all fulfilled with a constant daily dose given to the dam, and considerable fluctuations in the body burden result. In an attempt to achieve rather constant body burdens we treated Wistar rats subcutaneously on day 19 of pregnancy with 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD): a loading-dose of 1000 or 300 ng TCDD/kg body wt, followed by weekly maintenance-doses of 400 or 120 ng/kg body wt, respectively. Treatment of the dam was continued up to week 7 postnatally. Until weaning the offspring were exposed via milk, after weaning they were treated by subcutaneous injections with the maintenance-dose up to week 11 postnatally. TCDD tissue concentrations were determined in dams (liver, abdominal fat, thymus) and offspring (liver, thymus) at different time points during the postnatal period. It was found that fluctuations in body burden were reduced, but the dosing regimen used was still suboptimal for achieving quite constant tissue concentrations in the dams and their offspring. If more constant tissue levels are required, further adaptations of the dosing regimen are necessary.

A longitudinal, five year survey of urea kinetic parameters in CAPD patients

This study reports on the five years' evolution of the KT/V urea index and protein catabolic rate (PCR) in 16 CAPD patients who were treated with a constant daily dialysis dose. Total KT/V urea index decreased with time from a value of 0.96 +/- 0.06 at the start to 0.55 +/- 0.05 at five years of treatment. This decline was due to the opposite changes of two important parameters affecting the index. First, the contribution of the residual urinary KT/V gradually decreased from 28.6% at the start to 8 to 9% after four years. Second, the distribution volume of urea calculated as a constant fraction of body weight gradually increased. The body weight increased from 58.2 +/- 2.79 kg at start to 70.6 +/- 3.33 kg at five years. Peritoneal urea clearances and ultrafiltration rates remained stable. In 12 patients with stable body weight between 24 and 48 months, PCR decreased from 0.98 +/- 0.05 to 0.87 +/- 0.05 g/kg/day. A positive correlation between KT/V urea and PCR and a negative correlation between KT/V urea and number of hospitalization days, peritonitis rates and peripheral nerve conductivity was found. The same negative correlation was found when only the KT/V urea index obtained during the first year of treatment was considered. In conclusion, the KT/V urea index decreases in CAPD patients primarily because residual renal function decreases and body weight increases, while the peritoneal clearing for urea is maintained. The index correlates with some clinical parameters, and may have some prognostic value.

Effects of decreasing exogenous GnRH pulse frequency on FSH and inhibin secretion in men with idiopathic hypogonadotropic hypogonadism

The potential importance of GnRH pulse frequency modulation and steroid or inhibin negative feedback in the selective control of pituitary FSH secretion was investigated in 5 adult men with idiopathic hypogonadotropic hypogonadism in whom plasma testosterone has been previously normalized by pulsatile GnRH therapy. The effects of decreasing frequency of pulsatile iv GnRH administration from 2- to 4-hourly for 7 days were examined at constant GnRH bolus dose or constant daily dose and also with interrupted gonadal steroid feedback using a combination of an anti-androgen (flutamide 250 mg t.i.d.) and an aromatase inhibitor (aminogluthetimide 125 mg b.d.) orally for a further 7 days. Slowing GnRH pulse frequency from 2- to 4-hourly did not alter mean plasma FSH at constant bolus dose or constant total daily doses of GnRH. In two subjects with subnormal but not in another two with normal testicular volumes, FSH rise was observed when the 4-hourly GnRH pulse frequency was combined with the interruption of steroid feedback. These results are not compatible with a major role for GnRH pulse frequency modulation in the regulation of pituitary FSH secretion in the presence of normal gonadal steroid feedback. Irrespective of FSH concentrations, plasma inhibin immunoactivity did not change significantly with the alteration in GnRH pulse frequency. The role of inhibin in the control of FSH therefore remains undefined in men.

Influence of radiation and CO2 enrichment on whole plant net CO2 exchange in roses

At three stages of flowering shoot development, varying the irradiance and CO2 levels had a similar effect on the whole-plant net CO2 exchange rate (NCER) of Samantha rose plants. At 22 °C, the NCER was saturated at 1000 μmol m−2 s−1 photosynthetically active radiation (PAR). The duration of the light period was also important in determining daily carbon (C) gain. When roses were exposed to a constant daily radiant energy dose of 17.6 μmol m−2 provided either as a 12-h irradiation interval at 410 μmol m−2 s−1 PAR or 24 h of irradiation at 204 μmol m−2 s−1 PAR, the plants exposed to 24 h of continuous irradiation at the lower photon flux density retained 80% more C. Under saturating irradiance, the net photosynthetic rate at an enriched (1000 μL L−1) CO2 level was almost double that at ambient (350 μL L−1) CO2. However, plants grown at ambient and enriched CO2 levels had similar whole-plant NCERs when compared at the same assay CO2 level. Under CO2 enrichment the flower stem was longer and thicker but the flower bud size at harvest was not significantly different to that of roses grown at the ambient CO2 level. Key words: CO2 enrichment, daily carbon gain, net CO2 exchange rate, radiation, Rosa hybrida