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.

St Johns wort modulates the toxicities and parmacokinetics of CPT-11 (Irontecan) in rats

CPT-11 is a DNA topoisomerase I inhibitor for the therapy of colorectal cancer, whereas St. Johnrsquos Wort (Hypericum perforatum, SJW) is a widely used herbal anti-depressant. This study aimed to investigate the effects of co-administered SJW on the toxicities and pharmacokinetics of CPT-11 and the underlying mechanisms. The body weight loss, gastrointestinal and hematological toxicities induced by CPT-11, and the pharmacokinetic parameters of CPT-11 were evaluated in rats pretreated with SJW or vehicle. Rats treated with CPT-11 alone experienced rapid decrease in body weight, whereas co-administration of SJW with CPT-11 resulted in lesser body weight loss. The gastrointestinal and hematological toxicities following CPT-11 injection were both alleviated in the presence of SJW. The rat pharmacokinetics of both CPT-11 and its metabolite SN-38 were significantly altered in presence of SJW. In conclusion, co-administered SJW significantly ameliorated the toxicities induced by CPT-11. The protective effect of SJW may be partially due to pharmacokinetic interaction between CPT-11 and SJW.

The ultimate food energy guide

This is the third book in Garry Egger's new series of books based on his 'Professor Trim's Medically Supervised Weight Loss Program', a unique medically-based program being endorsed by GPs throughout Australia.In the same vein as Garry Egger and Rosemary Stanton's previously published fat and fibre counters, The Ultimate Energy Guide will provide a comprehensive listing of hundreds of Australian food products broken down by 'energy density', the hottest new topic in weight control research. Regulating the energy density of food that is consumed has begun to supersede previous medical arguments about fat or carbohydrate content as the pivotal factor in weight loss. This will be a quick reference listing which can be used in conjunction with the Becoming Gutless or Becoming Slim weight loss books for men and women respectively.

Effects of high-intensity progressive resistance training on self-reported health status in older persons with type 2 diabetes

Purpose: To evaluate the influence of high-intensity progressive resistance training (PRT) on self-reported physical and mental health in older persons with type 2 diabetes.

Methods: We performed a 12-month RCT with 36 overweight men and women with type 2 diabetes (aged 60-80 years) who were randomly assigned to a moderate weight-loss diet plus PRT (PRT&WL) or a moderate weight-loss diet plus a control (stretching) program (WL). Gymnasium-based training for 6 months was followed by an additional 6 months of home-based training. The SF-36 (v1) questionnaire was used to obtain physical (PCS) and mental (MCS) health component summary scores at baseline, 6 and 12 months.

Results: Subject retention was 81% and 72% after 6 and 12 months respectively. Exercise adherence during gymnasium- and home-based training was 88% and 73% for the PRT&WL group, and 85% and 78.1% for the WL group respectively. In a regression model adjusted for age and sex, PCS improved in the PRT&WL group compared to the WL group after 6 months of gymnasium-based training (2.3 versus -2.0, p = 0.05), which persisted after 12 months training (0.7 versus -4.1, p = 0.03). There were no between-group differences at 6 or 12 months for the MCS.

Conclusion: High-intensity PRT was effective in improving self-reported physical health, but not mental health. PRT provides an effective exercise alternative in lifestyle management for older adults with type 2 diabetes.

Biometric, nutritional and organoleptic changes in intensively farmed Murray Cod (Maccullochella peelii peelii) purged for different time periods

A period of purging before harvesting is common practice in intensive aquaculture to eliminate any possible off flavours from the fish. The present study was conducted to evaluate the biometrical, nutritional and sensory changes in intensively farmed Murray cod (Maccullochella peelii peelii) after 0, 2 and 4 weeks of purging. After the main biometric parameters were recorded, fish were analysed for proximate, fatty acid composition and flavour volatile compounds. A consumer preference test (triangle test) was also conducted to identify sensorial differences that may affect the consumer acceptability of the product.

Fish purged for 2 and 4 weeks had a significant weight loss of 4.1% and 9.1%, respectively, compared to unpurged fish, whilst perivisceral fat content did not change. The concentration of saturated (SFA), monounsaturated (MUFA) and highly unsaturated (HUFA) fatty acids were not significantly affected by purging time, while polyunsaturated fatty acids (PUFA), n − 3 and n − 3 HUFA were significantly higher (P < 0.05) in purged fish compared to unpurged fish. Consumers were able to detect differences between the purged and unpurged fish (P < 0.05) preferring the taste of the purged fish. However, consumers were unable to distinguish between fish purged for 2 and 4 weeks.

This study showed that a 2 weeks purging period was necessary and sufficient to ameliorate the final organoleptic quality of farmed Murray cod. With such a strategy the nutritional qualities of edible flesh are improved while the unavoidable body weight loss is limited.

Nutrient intake and plate waste from an Australian residential care facility

Objective: To determine the plate waste, energy and selected-nutrient intake, from elderly residents living in a high-level care (HLC) and low-level care (LLC) facility.

Design: Three, single, whole day assessments of plate waste, energy, and selected nutrients, using a visual rating plate waste scale.

Setting: Long-term residential care establishment.

Subjects: One hundred and sixty-nine (93 HLC and 76 LLC) individual daily intakes.

Main findings: The mean energy wasted throughout the whole day was 17%. The energy wasted from main meals (16%) was significantly less than the energy wasted at mid-meals (22%, P=0.049). The lowest mean energy wastage occurred at breakfast (8%) compared to lunch (22%) and dinner (25%, P<0.001). The mean (s.d.) daily energy served and consumed was 8.1 (2.0) and 6.6 (2.2) MJ, respectively. There was no difference in energy served or consumed between HLC and LLC residents. On the observation day, 60% of residents consumed less than their estimated energy requirement. The mean calcium intake was 796 (346) mg, and the median (inter-quartile range) vitamin D intake was 1.78 (2.05) μg.

Conclusion: On 1 day, more than half the residents surveyed were at risk of consuming an inadequate energy intake, which over-time, may result in body weight loss. Although wastage was not excessive and energy served was adequate, the amount of food eaten was insufficient to meet energy and calcium requirements for a significant number of residents and it is not possible to consume sufficient vitamin D through food sources.

Biometric, nutritional and sensory changes in intensively farmed Murray cod (Maccullochella peelii peelii, Mitchell) following different purging times

A period of purging before harvesting is common practice in intensive aquaculture to eliminate any possible off flavours from the fish. The present study was conducted to evaluate the biometrical, nutritional and sensory changes in intensively farmed Murray cod (Maccullochella peelii peelii) after 0, 2 and 4 weeks of purging. After the main biometric parameters were recorded, fish were analysed for proximate, fatty acid composition and flavour volatile compounds. A consumer preference test (triangle test) was also conducted to identify sensorial differences that may affect the consumer acceptability of the product.

Fish purged for 2 and 4 weeks had a significant weight loss of 4.1% and 9.1%, respectively, compared to unpurged fish, whilst perivisceral fat content did not change. The concentration of saturated (SFA), monounsaturated (MUFA) and highly unsaturated (HUFA) fatty acids were not significantly affected by purging time, while polyunsaturated fatty acids (PUFA), n − 3 and n − 3 HUFA were significantly higher (P < 0.05) in purged fish compared to unpurged fish. Consumers were able to detect differences between the purged and unpurged fish (P < 0.05) preferring the taste of the purged fish. However, consumers were unable to distinguish between fish purged for 2 and 4 weeks.

This study showed that a 2 weeks purging period was necessary and sufficient to ameliorate the final organoleptic quality of farmed Murray cod. With such a strategy the nutritional qualities of edible flesh are improved while the unavoidable body weight loss is limited.

Annetocin and TCTP expressions in the earthworm Eisenia fetida exposed to PAHs in artificial soil

The toxicity of sublethal polycyclic aromatic hydrocarbons (PAHs) levels in soils was assessed by testing their impact on expression of annetocin, a reproduction regulating gene, and translationally controlled tumor protein (TCTP), a tumorigenic response gene, in the earthworm Eisenia fetida cultured in artificial soil spiked with, phenanthrene (Phe), pyrene (Pyr), fluoranthene (Flu), or benzo(a)pyrene (Bap). Annetocin and TCTP were both up-regulated by 0.1 and 1.0 mg kg−1 benzo(a)pyrene and TCTP was down-regulated by 10.0 mg kg−1 phenanthrene. Weight loss and cocoon production of the worms were also analyzed. Only 10.0 mg kg−1 phenanthrene impacted earthworm weight loss significantly and no significant differences on cocoon production were observed. Our study indicated that the potential ecotoxicity of sublethal PAHs in soil should not be neglected and mRNA transcription level in earthworms was a more sensitive indicator of PAHs exposure than traditional indexes using cocoon production as endpoints and/or using the whole-organism as the test materials.

Effects of starvation and water quality on the purging process of farmed Murray cod ( Maccullochella peelii peelii )

The aim of this study was to determine the effects of starvation and water quality during the purging process on the biometric parameters, fatty acids, and flavor volatiles of Murray cod farmed in a recirculation system. Market size Murray cod, at the end of the grow-out stage, were divided into eight treatments. The treatments were either fed/starved (F or S) and kept in clean water (CW: CWF2, CWS2, CWF4, and CWS4) or fed/starved and kept in recycled water (RW: RWF2, RWS2, RWF4, and RWS4) for either 2 or 4 weeks. Fish were sampled at 0, 2, and 4 week intervals. Food deprivation was responsible for a significant (P < 0.05) weight loss compared to that of fed treatments. The same was observed for the condition factor (K), hepatosomatic index (HSI), and dress-out percentage (DP). No significant changes were, however, observed in the visceral fat index (VFI). Saturated fatty acids (SFA) were highest in RWF4 and lowest in CWS4 (P < 0.05), while monounsaturated fatty acids (MUFA) were lowest in CWF4 (P < 0.05). Starvation did not affect the flavor volatile compounds, which were mainly affected by changes in water quality. Specifically, total aldehyde (% w/w) content was significantly (P < 0.05) affected by water quality, but the time of purging was not responsible for any noteworthy differences. This study was able to separate the effects of starvation and water quality, in the purging process, on the final eating quality of farmed market size Murray cod. It is concluded that because of the inevitable weight loss during starvation, Murray cod should be fed during the purging stage but kept in clean water and deprived of food only for the time necessary to empty the gastro-intestinal tract.

Cost-effectiveness of a family-based GP-mediated intervention targeting overweight and moderately obese children

Objective
 To assess from a societal perspective the incremental cost-effectiveness of a family-based GP-mediated intervention targeting overweight and moderately obese children. The intervention was modelled on the LEAP (live, eat and play) trial, a randomised controlled trial conducted by the Centre for Community Child Health, Melbourne, Australia in 2002–2003. This study was undertaken as part of the assessing cost-effectiveness (ACE) in obesity project which evaluated, using consistent methods, 13 interventions targeting unhealthy weight gain in children and adolescents.
Method
A logic pathway was used to model the effects of the intervention compared to no intervention on body mass index (BMI) and health outcomes (disability-adjusted life years—DALYs). Disease costs and health benefits were tracked until the cohort of eligible children reached the age of 100 years or death. Simulation-modelling techniques were used to present a 95% uncertainty interval around the cost-effectiveness ratio. The intervention was also assessed against a series of filters (‘equity’, ‘strength of evidence’, ‘acceptability’, ‘feasibility’, sustainability’ and ‘side-effects’) to incorporate additional factors that impact on resource allocation decisions.
Results
The intervention, as modelled, reached 9685 children aged 5–9 years with a BMI z-score of ≥3.0, and cost $AUD6.3M (or $AUD4.8M excluding time costs). It resulted in an incremental saving of 2300 BMI units which translated to 511 DALYs. The cost-offsets stemming from the intervention totalled $AUD3.6M, resulting in a net cost per DALY saved of $AUD4670 (dominated; $0.1M) (dominated means intervention costs more for less effect).
Conclusion
Compared to a ‘no intervention’ control group, the intervention was cost-effective under current assumptions, although the uncertainty intervals were wide. A key question related to the long-term sustainability of the small incremental weight loss reported, based on the 9-month follow-up results for LEAP.

Body dissatisfaction and body change behaviors in Chile : the role of sociocultural factors

With interest in body image and body change behaviors growing around the world, there has been surprisingly little research conducted in Latin America on these issues. In order to gain some understanding of them in this context, this study investigated body image and body change behaviors, and the sociocultural factors that may influence them, among 337 Chilean adolescents aged 12–18 years. Participants completed a questionnaire that assessed BMI, body dissatisfaction, strategies to lose weight and strategies to increase muscle bulk. In addition, perceived pressure from family, peers, and the media to change body shape was evaluated. Results were partially consistent with those reported in Western nations. Girls were found to report greater body dissatisfaction than boys, but no difference was found between males and females in perceived pressure from adults in the family or from older siblings/cousins to lose weight. However, girls experienced higher levels of perceived pressure to lose weight from the media than boys, and boys reported greater perceived pressure from peers to lose weight than girls, and more pressure than girls from all sources to increase muscle bulk. These findings are discussed in relation to research conducted in other contexts, and it is concluded that findings from other locations may not be applied universally.

Nutrition screening in long-term care facilities : an evaluation of the methodological quality of available instruments

A variety of nutrition screening instruments have been developed and implemented for identifying the risk of undernutrition among community and hospitalized older adults. Despite the high prevalence of undernutrition amongst older adults in long-term care, few screening instruments have been developed or evaluated in this setting. This review aims to evaluate the validity, reproducibility and feasibility of nutrition screening instruments developed for use, or described as being used, with older adults in long-term care. Ten publications encompassing nine independent nutrition screening tools were identified using electronic databases and manual searches of reference lists. The Mini Nutritional Assessment-Short Form (MNA-SF) was the most widely evaluated nutrition screening instrument and met the requirements for a valid instrument (sensitivity and specificity >0.9) for use in the long-term care setting. Modified versions of the MNA for use in China and South Africa also demonstrated acceptable levels of sensitivity and specificity. Other nutrition screening instruments were found to have variable levels of sensitivity and specificity and while some demonstrated levels consistent with the MNA-SF, only two were evaluated across more than one study population, Body Mass Index (BMI)+weight loss and BMI+albumin. These same instruments reported the highest levels of inter-rater and test-retest reproducibility, although this was only tested in one other instrument (Chinese Nutrition Screen -modified MNA). In conclusion, it is evident from this review that further work in this area is needed. Based on validity, reproducibility and feasibility it appears that BMI+weight loss is the most suitable nutrition screening instrument for use in the long-term care setting at this time. MNA-SF is promising; however, there is currently no data for inter-rater or test-retest reproducibility in the long-term care setting.

Nutrition therapy in the prevention and treatment of pressure ulcers

Pressure ulcers are serious problems within hospital and aged care settings and are associated with adverse health outcomes and high treatment costs. Because of a high incidence of pressure ulcers in the health system, attention is now being directed to not just preventing, but also more effectively treating them. Nutrition plays a fundamental part in wound healing, with malnutrition, dehydration and recent weight loss identified as independent risk factors for the development of pressure ulcers. While the optimal nutrient intake to promote wound healing is unknown, increased needs for energy, protein, zinc and vitamins A, C and E have been documented. There is reasonable evidence to show that nutritional support, mostly by high-protein oral nutritional supplements, is effective in significantly reducing the incidence of pressure ulcers in at-risk patients by 25%. Intervention studies using high-protein or specialised disease-specific nutritional supplements support a trend to increased healing of established pressure ulcers. Such specialised supplements are typically based on defined amounts of arginine, vitamin C and zinc. Mechanisms by which nutritional support can aid in pressure ulcer prevention and healing are likely related to addressing macro- and/or micro-nutrient deficiencies arising from either poor oral intake or increased nutrient requirements related to the wound healing process. With much more research still to be done in this area, nutrition support appears an efficacious and costeffective adjunct to current medical and nursing approaches in the prevention and treatment of pressure ulcers.

Biometric, nutritional and sensory characteristic modifications in farmed Murray cod (Maccullochella peelii peelii) during the purging process

Intensively farmed, market-size Murray cod (~ 600 g), were purged (transferred into a clean water system and starved) and sampled at three day intervals for a total of 18 days (D0, D3, D6, D9, D12, D15 and D18). Purged fish lost from 6% (D3) to 14% (D18) body weight, and the weight loss was highly correlated to the number of days of purging/starvation. Condition factor and Hepatosomatic Index decreased significantly (P < 0.05) only after 18 days of purging compared to the control (D0). Fillet lipid content (%) did not vary during the trial. Eicosapentaenoic acid (EPA: 20:5 n−3) decreased and docosapentaenoic acid (DPA: 22:5 n−3) increased (P < 0.05) during the trial, while docosahexaenoic acid (DHA: 22:6 n−3) did not show any significant variation. Purging contributed positively to the improvement of the volatile flavour compound composition, with a significant (P < 0.05) reduction in total volatile aldehydes and an increase in total volatile hydrocarbons. Since no major differences were found between samples during the last stages of the purging process (D12, D15 and D 18), it is possible to conclude that, under these experimental conditions, 12 days is the minimum duration to obtain an improvement in the volatile compound profile of intensively farmed Murray cod whilst keeping body weight loss to a minimum.

The effectiveness of physical activity interventions for the treatment of overweight and obesity and type 2 diabetes

This review summarises current evidence relating to the effectiveness of physical activity (PA) interventions for treating overweight and obesity and type 2 diabetes. Interventions to increase PA for the treatment of overweight and obesity in both children and adults have primarily consisted of health education and behaviour modification strategies in clinical settings or with selected families or individuals. Although evidence is limited, strategies to reduce sedentary behaviours appear to have potential for reducing obesity among children and adolescents. Among adults, strategies that combine diet and PA are more effective than PA strategies alone. Combined lifestyle strategies are most successful for maintained weight loss, although most programs are unsuccessful in producing long-term changes. There is little evidence about compliance to prescribed behaviour changes or the factors that promote or hinder compliance to lifestyle changes. Limited evidence suggests that continued professional contact and self-help groups can help sustain weight loss. Most of the interventions for the treatment of type 2 diabetes have been conducted in clinical settings and have typically required the use of extensive resources. Evidence suggests that interventions can lead to small but clinically meaningful improvements in glycaemic control, even in the absence of weight loss. A recent study demonstrated that a multifactorial intervention (diet, PA and pharmaceutical) can reduce the risk of diabetes complications in individuals with type 2 diabetes. Nevertheless, there is little evidence about the effectiveness of community-based interventions in producing long-term changes in glycaemic control and reduced mortality in people with type 2 diabetes.