Pharmacokinetic mechanisms for reduced toxicity of irinotecan by coadministered Thalidomide

The clinical use of irinotecan (CPT-11) is hindered by dose-limiting diarrhea and myelosuppression. Recent clinical studies indicate that thalidomide, a known tumor necrosis factor-alpha inhibitor, ameliorated the toxicities induced by CPT-11. However, the mechanisms for this are unknown. This study aimed to investigate whether combination of thalidomide modulated the toxicities of CPT-11 using a rat model and the possible role of the altered pharmacokinetic component in the toxicity modulation using in vitro models. The toxicity model was constructed by treatment of healthy rats with CPT-11 at 60 mg/kg per day by intravenous (i.v.) injection. Body weight, acute and delayed-onset diarrhea, blood cell counts, and macroscopic and microscopic intestinal damages were monitored in rats treated with CPT-11 alone or combined therapy with thalidomide at 100 mg/kg administered by intraperitoneal (i.p.) injection. Single dose and 5-day multiple-dose studies were conducted in rats to examine the effects of concomitant thalidomide on the plasma pharmacokinetics of CPT-11 and its major metabolites SN-38 and SN-38 glucuronide (SN-38G). The effect of CPT-11 on thalidomide's pharmacokinetics was also checked. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were used to study the in vitro metabolic interactions between these two drugs. H4-II-E cells were also used to investigate the effect of thalidomide and its hydrolytic products on the transport of CPT-11 and SN-38. In addition, the effect of thalidomide and its hydrolytic products on rat plasma protein binding of CPT-11 and SN-38 was examined. Administration of CPT-11 by i.v. for 4 consecutive days to rats induced significant body weight loss, decrease in neutrophil and lymphocyte counts, severe acute- and delayed-onset diarrhea, and intestinal damages. These toxicities were alleviated when CPT-11 was combined with thalidomide. In both single-dose and 5-day multiple-dose pharmacokinetic study, coadministered thalidomide significantly increased the area under the plasma concentration-time curve (AUC) of CPT-11, but the AUC and elimination half-life (t(1/2)) of SN-38 were significantly decreased. However, CPT-11 did not significantly alter the pharmacokinetics of thalidomide. Thalidomide at 25 and 250 microM and its hydrolytic products at a total concentration of 10 microM had no significant effect on the plasma protein binding of CPT-11 and SN-38, except for that thalidomide at 250 microM caused a significant increase in the unbound fraction (f(u)) of CPT-11 by 6.7% (P < 0.05). The hydrolytic products of thalidomide (total concentration of 10 microM), but not thalidomide, significantly decreased CPT-11 hydrolysis by 16% in rat liver microsomes (P < 0.01). The formation of both SN-38 and SN-38G from CPT-11, SN-38 glucuronidation, or intracellular accumulation of both CPT-11 and SN-38 in H4-II-E cells followed Michaelis-Menten kinetics with the one-binding site model being the best fit for the kinetic data. Coincubation or 2-hr preincubation of thalidomide at 25 microM and 250 microM and its hydrolytic products at 10 microM did not show any significant effects on CPT-11 hydrolysis and SN-38 glucuronidation. However, preincubation of H4-II-E cells with thalidomide (250 microM), its hydrolytic products (total concentration of 10 microM), or phthaloyl glutamic acid (one major thalidomide hydrolytic product, 10 microM) significantly increased the intracellular accumulation of SN-38, but not CPT-11 (P < 0.01). The dose-limiting toxicities of CPT-11 were alleviated by combination with thalidomide in rats and the pharmacokinetic modulation by thalidomide may partially explain its antagonizing effects on the toxicities of CPT-11. The hydrolytic products of thalidomide, instead of the parental drug, modulated the hepatic hydrolysis of CPT-11 and intracellular accumulation of SN-38, probably contributing to the altered plasma pharmacokinetics of CPT-11 and SN-38. Further studies are needed to explore the role of both pharmacokinetics and pharmacodynamic components in the protective effect of thalidomide against the toxicities of CPT-11.

Reduced ankle dorsiflexion range may increase the risk of patellar tendon injury among volleyball players

Patellar tendon injury, a chronic overuse injury characterised by pain during tendon loading, is common in volleyball players and may profoundly restrict their ability to compete. This cross-sectional study investigated the association between performance factors and the presence of patellar tendon injury. These performance factors (sit and reach flexibility, ankle dorsiflexion range, jump height, ankle plantarflexor strength, years of volleyball competition and activity level) were measured in 113 male and female volleyball players. Patellar tendon health was determined by measures of pain and ultrasound imaging. The association between these performance factors and patellar tendon health (normal tendon, abnormal imaging without pain, abnormal imaging with pain) was investigated using analysis of variance. Only reduced ankle dorsiflexion range was associated with patellar tendinopathy (p < 0.05). As coupling between ankle dorsiflexion and eccentric contraction of the calf muscle is important in absorbing lower limb force when landing from a jump, reduced ankle dorsiflexion range may increase the risk of patellar tendinopathy.

Reduced Skeletal Muscle Uncoupling Protein-3 Content in Prediabetic Subjects and Type 2 Diabetic Patients: Restoration by Rosiglitazone Treatment

Context: The mitochondrial uncoupling protein-3 (UCP3) has been implicated in the protection of the mitochondrial matrix against lipid-induced mitochondrial damage. Recent evidence points toward mitochondrial aberrations as a major contributor to the development of insulin resistance and diabetes, and UCP3 is reduced in diabetes.
Objective: We compared skeletal muscle UCP3 protein levels in prediabetic subjects [i.e. impaired glucose tolerance (IGT)], diabetic patients, and healthy controls and examined whether rosiglitazone treatment was able to restore UCP3.
Patients, Design, Intervention: Ten middle-aged obese men with type 2 diabetes mellitus [age, 61.4 ± 3.1 yr; body mass index (BMI), 29.8 ± 2.9 kg/m2], nine IGT subjects (age, 59.0 ± 6.6 yr; BMI, 29.7 ± 3.0 kg/m2), and 10 age- and BMI-matched healthy controls (age, 57.3 ± 7.4 yr; BMI, 30.1 ± 3.9 kg/m2) participated in this study. After baseline comparisons, diabetic patients received rosiglitazone (2 x 4 mg/d) for 8 wk.
Main Outcome Measures: Muscle biopsies were sampled to determine UCP3 and mitochondrial protein (complex I–V) content.
Results: UCP3 protein content was significantly lower in prediabetic IGT subjects and in diabetic patients compared with healthy controls (39.0 ± 28.5, 47.2 ± 24.7, and 72.0 ± 23.7 arbitrary units, respectively; P < 0.05), whereas the levels of the mitochondrial protein complex I–V were similar between groups. Rosiglitazone treatment for 8 wk significantly increased insulin sensitivity and muscle UCP3 content (from 53.2 ± 29.9 to 66.3 ± 30.9 arbitrary units; P < 0.05).
Conclusion: We show that UCP3 protein content is reduced in prediabetic subjects and type 2 diabetic patients. Eight weeks of rosiglitazone treatment restores skeletal muscle UCP3 protein in diabetic patients.

Design of reduced-order state/unknown input observers: a descriptor system approach

This paper addresses the problem of estimating simultaneously a linear function of both the state and unknown input of linear system with unknown inputs. By adopting the descriptor system approach, the problem can be conveniently solved. Observers proposed in this paper are of low-order and do not include the derivatives of the outputs. New conditions for the existence of reduced-order observers are derived. A design procedure for the determination of the observer parameters can also be easily derived based on the derived existence conditions

Design of reduced-order observers for neutral time-delay systems

This paper presents a method for the design of reduced-order observers for a class of linear time-delay systems of the neutral-type. Conditions for the existence of reduced-order observers that are capable of asymptotically estimating any given function of the state vector are derived. A step-by-step design procedure is given for the determination of the observer parameters. A numerical example is given to illustrate the design procedure.

Human sarcopenia reveals an increase in SOCS-3 and myostatin and a reduced efficiency of Akt phosphorylation

Age-related skeletal muscle sarcopenia is linked with increases in falls, fractures, and death and therefore has important socioeconomic consequences. The molecular mechanisms controlling age-related muscle loss in humans are not well understood, but are likely to involve multiple signaling pathways. This study investigated the regulation of several genes and proteins involved in the activation of key signaling pathways promoting muscle hypertrophy, including GH/STAT5, IGF-1/Akt/GSK-3β/4E-BP1, and muscle atrophy, including TNFα/SOCS-3 and Akt/FKHR/atrogene, in muscle biopsies from 13 young (20 ± 0.2 years) and 16 older (70 ± 0.3 years) males. In the older males compared to the young subjects, muscle fiber cross-sectional area was reduced by 40–45% in the type II muscle fibers. TNFα and SOCS-3 were increased by 2.8 and 1.5 fold, respectively. Growth hormone receptor protein (GHR) and IGF-1 mRNA were decreased by 45%. Total Akt, but not phosphorylated Akt, was increased by 2.5 fold, which corresponded to a 30% reduction in the efficiency of Akt phosphorylation in the older subjects. Phosphorylated and total GSK-3β were increased by 1.5 and 1.8 fold, respectively, while 4E-BP1 levels were not changed. Nuclear FKHR and FKHRL1 were decreased by 73 and 50%, respectively, with no changes in their atrophy target genes, atrogin-1 and MuRF1. Myostatin mRNA and protein levels were significantly elevated by 2 and 1.4 fold. Human sarcopenia may be linked to a reduction in the activity or sensitivity of anabolic signaling proteins such as GHR, IGF-1, and Akt. TNFα, SOCS-3, and myostatin are potential candidates influencing this anabolic perturbation.

The effect of training in reduced energy density eating and food self-monitoring accuracy on weight loss maintenance

Background:
Failure to maintain weight losses in lifestyle change programs continues to be a major problem and warrants investigation of innovative approaches to weight control.
Objective:
The goal of this study was to compare two novel group interventions, both aimed at improving weight loss maintenance, with a control group.
Methods and Procedures:
A total of 103 women lost weight on a meal replacement–supplemented diet and were then randomized to one of three conditions for the 14-week maintenance phase: cognitive-behavioral treatment (CBT); CBT with an enhanced food monitoring accuracy (EFMA) program; or these two interventions plus a reduced energy density eating (REDE) program. Assessments were conducted periodically through an 18-month postintervention. Outcome measures included weight and self-reported dietary intake. Data were analyzed using completers only as well as baseline-carried-forward imputation.
Results:
Participants lost an average of 7.6 plusminus 2.6 kg during the weight loss phase and 1.8 plusminus 2.3 kg during the maintenance phase. Results do not suggest that the EFMA intervention was successful in improving food monitoring accuracy. The REDE group decreased the energy density (ED) of their diets more so than the other two groups. However, neither the REDE nor the EFMA condition showed any advantage in weight loss maintenance. All groups regained weight between 6- and 18-month follow-ups.
Discussion:
Although no incremental weight maintenance benefit was observed in the EFMA or EFMA + REDE groups, the improvement in the ED of the REDE group's diet, if shown to be sustainable in future studies, could have weight maintenance benefits.

Association of reduced riparian vegetation cover in agricultural landscapes with coarse detritus dynamics in lowland streams

Studies were conducted on streams flowing through agricultural floodplains in south-eastern Australia to quantify whether reductions in riparian canopy cover were associated with alterations to the input and benthic standing stocks of coarse allochthonous detritus. Comparisons were made among three farmland reaches and three reaches within reserves with intact cover of remnant overstorey trees. Detritus inputs to these reaches were measured monthly over 2 years using litter traps. Direct inputs to streams within the reserves were relatively high (550–617 g ash free dry weight (AFDW) m^–2 year^–1), but were lower at farmland reaches with the lowest canopy covers (83–117 gAFDW m^–2 year^–1). Only a minor fraction of the total allochthonous input (<10%) entered any of the study reaches laterally. The mean amounts of benthic detritus were lowest in the most open farmland reaches. Standing stocks of benthic detritus were found to be highly patchy across a large number of agricultural streams, but were consistently very low where the streamside canopy cover was below ~35%. Canopy cover should be restored along cleared agricultural streams because allochthonous detritus is a major source of food and habitat for aquatic ecosystems. Given the absence of pristine lowland streams in south-eastern Australia, those reaches with the most intact remnant overstorey canopies should be used to guide restoration.

Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance

In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE^-/-) and compared with wild-type littermates. Compared with wild-type littermates, ACE^-/- mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE^-/- mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE^-/- mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excrete in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE^-/- mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance.

Television viewing and abdominal obesity in young adults : is the association mediated by food and beverage consumption during viewing time or reduced leisure-time physical activity?

BACKGROUND:The behavioral pathways through which television (TV) viewing leads to increased adiposity in adults are unclear.

OBJECTIVE:We wanted to determine whether the association between TV viewing and abdominal obesity in young adults is mediated by food and beverage consumption during TV viewing time or by a reduction in overall leisure-time physical activity (LTPA).

DESIGN:This study involved a cross-sectional analysis of data from 2001 Australian adults aged 26–36 y. Waist circumference (WC) was measured at study clinics, and TV viewing time, frequency of food and beverage consumption during TV viewing, LTPA, and demographic characteristics were self-reported.

RESULTS:Women watching TV >3 h/d had a higher prevalence of severe abdominal obesity (WC: =88 cm) compared with women watching =1 h/d [prevalence ratio (PR): 1.89; 95% CI: 1.32, 2.71]. Moderate abdominal obesity (WC: 94–101.9 cm) was more prevalent in men watching TV >3 h/d than in men watching =1 h/d (PR: 2.16; 95% CI: 1.37, 3.41). Adjustment for LTPA made little difference, but adjustment for food and beverage consumption during TV viewing attenuated the associations (PR: 1.48; 95% CI: 1.01, 2.17 for women; PR: 1.73; 95% CI: 1.06, 2.83 for men).

CONCLUSIONS:The association between TV viewing and WC in young adults may be partially explained by food and beverage consumption during TV viewing but was not explained by a reduction in overall LTPA. Other behaviors likely contribute to the association between TV viewing and obesity.