Browsing Posts published in April, 2011

    Medium-chain triglycerides (MCT) have unique characteristics relating to energy density and metabolism giving them advantages over more common long-chain triglycerides (LCT). Human consumption of MCT oils is low since naturally occurring sources of MCTs are rare; however, those sources include milk fat, palm kernel oil and coconut oil.

    MCTs are less energy dense and highly ketogenic compared to LCTs. First, the energy density of MCTs is less than that of LCTs due to their shorter chain length. MCTs provide about ten percent fewer calories than LCTs; 8.3 Cal per gram for MCTs versus 9 Cal per gram for LCTs. MCTs also differ from LCTs in their metabolic pathway because they are easily oxidized and utilized as energy, with little tendency to deposit as body fat. Consequently, the intake of MCTs can decrease caloric intake and potentially decrease body weight and body fat in the long term.
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    The literature supports that MCT oil increases energy expenditure and decreases body fat in the majority of studies in both animals and humans. In addition, MCTs may have a greater effect in overweight subjects as opposed to normal weight or obese subjects. Overall, short-term intakes of MCT oil have been shown to promote weight loss; however, chronic intakes of MCTs have shown various effects on energy expenditure, body weight, and fat mass. Yet, appetite control may play a bigger role in weight loss in long-term feedings of MCTs. The exact mechanism for the satiating effects of MCT is unknown, but may perhaps be explained by the distinctive energy density of MCT or the increase in fat oxidation. These studies suggest that replacing LCT with MCT oil could generate body fat loss over long periods of time, with or without reduced energy intake.

    Studies provide varying results concerning the influence of MCT on lipid metabolism such as increased TG concentrations. In addition, several studies have reported that MCTs do not affect blood cholesterol levels; however, others have reported hypercholesterolemic effects of MCTs due to their high saturated fat content. Therefore, the incorporation of other functional foods, such as conventional oils, essential fatty acids or plant sterol may minimize the risk of negative effects of MCT on blood lipids while optimizing decreases in body weight and body fat accumulation. In addition, the ingestion of MCT incorporated into the diet does not appear to cause any adverse symptoms.

    MCTs are easily included in food products without negatively affecting their taste or producing undesirable effects. MCT production is cost-effective compared to other oil-based functional foods. The short-term efficacy of MCT is proven; however, long-term effects of MCT still need to be examined more carefully. Overall, MCT shows a good AECES model and demonstrates the greatest potential for use as a functional fat for weight control.

    All cooking oils naturally contain small quantities of diacylglycerols (DAG), ranging from 0.8% in rapeseed oil to 9.5% in cottonseed oil.39 In addition, DAG is produced in the digestive tract as a metabolic intermediate, as 1,2-diacyl-sn-glycerol (1,2-DAG) or 2,3-diacyl-sn-glycerol (2,3-DAG), after the ingestion of TG.40 In recent years manufacturers have developed an enzymatic process to produce 1,3-diacyl-sn-glycerol (1,3-DAG) by migration of the acyl group with the reverse reaction of the 1,3-specific lipase. DAG oil can be easily incorporated into food products since it is similar in taste, appearance, and fatty acid composition to other oils.

    It is the specific structural differences of DAG isomers and not the fatty acid composition of DAG or TG that appear to explain the different action on lipid metabolism and body weight. The main end products of lipase action on 1,3-DAG are glycerol and free fatty acids, which may be less readily re-synthesized to chylomicron TG. Moreover, larger amounts of fatty acids from digested DAG may be released into the portal circulation rather than being incorporated into chylomicrons, compared with TG oils. In addition to producing lower TG content of chylomicrons, lower serum TG levels in a fasted state and in the postprandial state occur after DAG ingestion. This hepatic exposure to fatty acids by increasing DAG intake may lead to greater fat oxidation by the liver than following TG intake. Enhanced fat oxidation may lead to increased satiety. Thus, decreasing caloric intake may induce a decrease in weight and fat loss in long-term DAG feedings.

    While certain studies indicate that 1,3-DAG has a positive outcome in animal and human trials, other studies show no effect on body weight63-67 or TG levels. This lack of effect may be due to insufficient doses used (10% in the diet) or the heterogeneity across subjects used including overweight or obese versus normal weight individuals. Overweight and obese subjects could have defective fat oxidation; thus, higher fat oxidation may produce greater weight loss. Although the use of DAG oils for weight control is promising, much remains to be clarified regarding the mechanism of dietary DAG.

    DAG oil studies do not indicate any severe adverse health effects related to its consumption. However, it still remains to be seen how DAG oil intake will affect humans on a long-term basis as well as synergistically with other nutrients.

    Overall, DAG oils are easily incorporated into foods without affecting palatability, but have slightly higher costs than conventional oils. The AECES model for DAG shows it being a generally appropriate functional food for weight control; however, DAG oil has not yet been a huge success with consumer acceptance due to conflicting studies on the efficacy of the product. Overall, DAG oil demonstrates potential as a weight loss agent, but future research is needed to elucidate mechanisms responsible for its action on weight loss.

    Conjugated linoleic acid (CLA) is a collective term for a group of positional and geometrical conjugated dienoic isomers of linoleic acid that are found in dairy products and meat. The cis-9, trans-11 CLA is the principal dietary CLA form, but lower levels of the other isomers (trans-10, cis-12 CLA, trans-9, trans-11 CLA, and trans-10, trans-12-CLA) are present in food CLA sources. Naturally, CLA is produced in the rumen of ruminant animals by the fermentative bacteria that isomerize linoleic acid into CLA.

    Mechanisms of action of CLA include: enhanced thermogenesis, increased satiety, augmented fat oxidation, reduced fat cell size as well as fat deposition, increased apoptosis of adipocytes and altered preadipocyte differentiation. Potentially, the combination or additive effects of all these mechanisms of action of CLA may lead to changes in weight and body fat, as no single mechanism fully explains CLA action.

    Studies have shown that CLA, specifically the trans-10, cis-12 isomer, can reduce body weight and fat mass. Most animal studies associated with feeding CLA have shown that CLA lowers body fat and energy retention as well as increases energy expenditure, thereby decreasing weight; yet, others have shown no effects on weight. This may be due to the dose or the CLA isomers used in animal studies. Results demonstrate that body weight and/or fat mass of animals were not affected when they were supplemented with low amounts of CLA mixture (0.5% in the diet), which contained about equal amounts of the trans-10, cis-12 isomer and cis-9, trans-11 isomer. Yet, weight gain was similar to control when high amounts of CLA mixture with mostly the cis-9, trans-11 isomer were given. However, most human studies have not been able to replicate the magnitude of weight lost. Only a few human studies suggest that CLA supplementation has reduced body fat and other studies did not show any effect. The variety of species used in studies may also explain the discrepancy of results obtained.

    In animals, CLA supplements appear to have some undesirable side effects such as induced insulin resistance as well as fatty liver and spleen. These animal studies also demonstrate that CLA may have detrimental effects on plasma lipids. Human studies also show evidence that CLA may adversely influence health, in particular insulin sensitivity and blood lipids, but the results are conflicting. CLA is widely available in capsule form that improves its oxidative stability, therefore having an appropriate matrix, cost, and sensory quality for consumers. However, the efficacy of CLA is questionable because the animal evidence is more convincing than the human data. The lack of clarity on the mechanism of action can explain the inconsistencies in the research results. In addition, human studies should be carried out to determine the long-term effects of CLA and whether any adverse outcomes occur. In summary, the data available from literature demonstrates a poor AECES model. More research is needed to investigate the efficacy and the safety aspects before CLA will have optimal consumer acceptance.

    Numerous functional foods have been examined for their potential as weight-loss agents. To evaluate the future of functional foods, the AECES model has been developed to verify the following: Acceptability, Ease of formatting, Cost-effectiveness, Efficacy and Safety. The goal of this review is to assess three oil-based weightloss functional foods, including: conjugated linoleic acid (CLA), diacylglycerols (DAG) and medium-chain triglycerides (MCT), in terms of the AECES model for consumer acceptability. First, CLA is an overall poor AECES model due to its weaknesses in the efficacy and safety aspects since most of the evidence of CLA is based on animal studies. Secondly, oils rich in DAG, specifically the 1,3-isoform, have an appropriate AECES model. Although, the efficacy still needs more research to determine the exact mechanisms of action for DAG-rich oils. Thirdly, MCT oils exhibit a good AECES model; nevertheless, the long-term efficacy of MCT needs to be further explored. The capability of these three functional oils as effective anti-obesity agents is substantial, yet further investigation should be conducted to determine the missing gaps in research and to accomplish satisfactory AECES model for market acceptance.

    Obesity is at the forefront of global health issues as it directly contributes to many chronic illnesses. Excess weight is the result of an imbalance between energy intake (EI) and energy expenditure (EE), by which surplus EI is stored as triacylglycerol (TG) in adipose tissue. Overweight and obese consumers often turn to natural health products to help support and maintain their weightloss program. Although the weight management industry is large, most of the weight-loss supplements on the market have not been scientifically proven to be effective.(1) Recently, several natural health products have shown promise in the treatment of obesity, some of which are oil rich in conjugated linoleic acid (CLA), diacylglycerols (DAG) and mediumchain triglycerides (MCT).

    The AECES model has been developed by experts in the nutrition field to determine the future of functional foods in the marketplace. Five criteria can be used to evaluate the potential of functional foods and nutraceuticals, including: acceptability, ease of formatting, cost-effectiveness, efficacy and safety.(2) This is known as the AECES model (Figure 1). A “good” AECES model includes the following characteristics (Table 1): easily incorporated into a suitable matrix and diet, acceptable cost to manufacturer and consumer, ability to produce a desired effect and lack of major side effects. All the components of the AECES model are closely interrelated sharing the same final goal: consumer acceptability of the functional food. The range of “appropriate” to “poor” in the AECES model would be assigned to functional foods that either lack data or provide some negative research results in one or more of the model criteria, which would lead to decreased consumer acceptance of the functional food. The purpose of this review is to examine the role of functional foods in health promotion, in relation to body weight and circulating lipid levels, such as oils rich in CLA, DAG and MCT oils. Particularly, this review is intended to evaluate these functional oils in terms of the AECES model for consumer suitability.

    Recommended Lycopene Intakes

    Average daily intake levels of lycopene range from 0.70 to 25.20 mg/day but 50% of North Americans consume < 1.86 mg/day of lycopene. Based on human research, recent recommendations for the daily intake of lycopene suggest 7 mg/day. At this level of intake, circulatory lycopene concentration is maintained at a level consistent with that shown to reduce lipid peroxidation and to result in other beneficial effects of lycopene.
    Health Claims Associated with Lycopene

    Emphasizing consumption of fruits and vegetables is part of the dietary guidelines recommended for the prevention of chronic diseases.33 Dietary benefits generally associated with increased plant food consumption include lower intakes of energy and fat, and higher intakes of fiber and micronutrients including phytochemicals such as lycopene but also phytosterols, flavonoids, indoles, isoflavones, isothiocyanates, lignans, phytates, soluble and insoluble fibers, terpenoids (saponins) and other carotenoids. The FDA has approved Generally Recognized as Safe (GRAS) status to lycopene. Recently, the FDA has also given a limited health claim declaration for lycopene, stating “Very limited and preliminary scientific research suggests that eating one-half to one cup of tomatoes and/or tomato sauce a week may reduce the risk of prostate cancer.” However, FDA concludes that the evidence in support of lycopene in prostate cancer risk reduction is still not very strong and needs further research.

    Conclusion

    There is convincing evidence to suggest a causal link between oxidative stress and human chronic diseases. Antioxidants have been suggested as playing an important role in protecting cells and cellular components against oxidative damage. Lycopene is a potent antioxidant carotenoid present in tomatoes, tomato products and other fruits. However, it is not synthesized by animals and humans. Dietary sources and nutritional supplements constitute the major source of lycopene intake. The evidence in support of the role of lycopene in the prevention of chronic diseases is primarily epidemiological in nature up to this stage. However, tissue culture, animal experiments and more recently human intervention studies are providing convincing evidence in support of the epidemiological observations. Although the antioxidant properties of lycopene are considered to drive the major mechanism by which lycopene provides beneficial effects, other mechanisms are also being suggested. A daily intake of 7 mg of lycopene is currently recommended to maintain the circulatory levels of lycopene consistent with reduction in lipid peroxidation. Recent studies also suggest synergistic interactions between lycopene and other phytonutrients in tomatoes and tomato products leading to its beneficial effects. Future research addressing the bioavailability of lycopene, its mechanisms of action and its role in other important human chronic diseases is needed to fully understand the role of lycopene in human health and to take advantage of this important ‘nutraceutical’ product in the management of chronic diseases.

    In a large multicenter case-control study (EURAMIC), the relationship between adipose tissue antioxidant status (alpha- and beta-carotene and lycopene) and acute myocardial infarction were evaluated in 662 cases and 717 controls. Subjects in this trial were recruited from 10 European countries to maximize the variability in exposure within the study. Adipose antioxidant levels were measured because they are considered to be a better marker of long-term exposure than serum lycopene. After adjusting for a range of dietary variables, higher lycopene but not alpha- or beta-carotene adipose tissue levels were found to be protective against myocardial infarction risk in non-smokers (OR=0.52, P=0.005; OR=0.91, P=0.66; and OR=1.01, P=0.96; respectively). Also related to cardiovascular disease, mildly hypercholesterolemic men and women with grade-1 hypertension taking 15 mg/day of lycopene from tomato oleoresin antioxidant-rich tomato extract had significantly decreased systolic and diastolic blood pressure compared toplacebo.

    Lycopene and Bone Health
    Recently, lycopene research has begun to explore the potential for this antioxidant carotenoid to work against the onset of bone disease. Although not fully understood, there is evidence that oxidative stress caused by ROS is associated with the pathogenesis of osteoporosis. In a recent in vitro study of bone marrow prepared from rat femurs, it was demonstrated that lycopene, in the absence or presence of parathyroid hormone (PTH), inhibited osteoclastic mineral resorption and formation of tartrate-resistant acid phosphatase (TRAP) positive multinucleated osteoclasts, as well as the ROS produced by osteoclasts.30 The authors suggested that this finding may be important in the pathogenesis, treatment and prevention of osteoporosis. Clinical studies are now being conducted to study the role of lycopene in osteoporosis. Researchers have studied the relationship between lycopene and bone resorption as measured by serum N-telopeptides of type I collagen (NTx) in postmenopausal women. They found higher lycopene intake and higher serum lycopene to be associated with lower bone resorption (p<0.005). Based on the results from this study, the researchers are now conducting a lycopene intervention study with postmenopausal females to evaluate the relationship between lycopene and the risk of osteoporosis.

    Lycopene and Male Infertility
    An area of concern for many men is that of infertility. Infertile men genetically tend to produce higher levels of free radicals. Ongoing research in India is exploring this relationship and the influence of supplementing with lycopene. In one study of 50 volunteers with low active sperm counts, 35 volunteers (70%) experienced an improvement in sperm count, 30 (60%) had improved functional sperm concentrations, 27 (54%) had improved sperm motility, 23 (46%) had improved sperm motility index, and 19 (38%) had improved sperm morphology following consumption of 8 mg/day of lycopene supplementation from tomato oleoresin extract. Further studies are now being undertaken to confirm these preliminary observations and to gain further understanding into the role of lycopene in male infertility.

    Oxidative stress induced by highly reactive oxygen species (hROS) is recognized as an important mechanism in the causation of chronic diseases such as cancer, cardiovascular disease, osteoporosis and diabetes. Fruits and vegetables are good sources of several antioxidants including lycopene, of recent interest and available in the diet primarily from tomatoes and tomato products. Popular for its role in prostate health, lycopene also improves markers for and risk of multiple cancers, cardiovascular disease, osteoporosis, diabetes, hypertension, male infertility and macular degeneration. Epidemiological, tissue culture, animal and human studies show a beneficial role for lycopene in the prevention and possibly treatment of chronic diseases. Generally, lycopene intake of North Americans is low (≤1.86 mg/day) compared to 7 mg/day now recommended to maintain circulatory lycopene at levels consistent with providing beneficial effects. Ongoing and future research is warranted to increase our understanding of lycopene’s role in human diseases, its mechanisms of action and its use in the management of public health.

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    Lycopene has attracted attention for nearly 50 years for its biochemical and physiochemical properties. Since that time, epidemiological, in vitro, and in vivo animal and human experiments have provided support for lycopene’s antioxidant health benefits and its potential to reduce the risk of several cancers and cardiovascular disease (CVD). Lycopene is a natural pigment synthesized by plants and microorganisms, and the diet constitutes the primary source of lycopene for humans. The attractive red color of tomatoes is due to the presence of lycopene; this antioxidant carotenoid can also be found in watermelon, pink grapefruit, apricots and pink guava. Lycopene is an acyclic, highly unsaturated, straight chain hydrocarbon containing 13 double bonds. Lycopene is an isomer of beta-carotene but does not have provitamin A activity. Oxygen-derived free radicals known as reactive oxygen species (ROS) are generated endogenously through normal metabolic activity, lifestyle activities, and diet. ROS-related oxidative stress results in the damage of cellular components including lipids, proteins and DNA. Cellular damage and oxidation of cellular biomolecules has been implicated in the early stages and pathogenesis of various human chronic diseases. In contrast, lycopene is a potent antioxidant that provides protection against cellular damage caused by ROS13 and, therefore, may play an important role in disease prevention. More specifically, because of its high number of conjugated double bonds, lycopene exhibits higher (two and ten times) singlet oxygen quenching ability compared with beta-carotene and alphatocopherol, respectively.

    Lycopene: Bioavailability and Isomerization

    In human dietary intervention research, serum lycopene levels significantly increase after consuming tomato foods or lycopene supplementation. However, not all sources of lycopene are equally bioavailable. Ingested in its natural trans form, such as is prominent in tomatoes, lycopene is poorly absorbed whereas heat processing of tomatoes and tomato products induces isomerization of lycopene from all-trans to cis configuration in turn increasing its bioavailability. Remaining to be determined, however, is whether or not cisisomers are biologically more effective than trans-isomers once in the body.

    Study Limitations

    Our study has limitations. We evaluated a commercially insured population; rates of dispense as written requests and prescription reversals may differ for uninsured patients. Our measure of reversal was linked to the specific prescription that was adjudicated by the pharmacy. Some of the unfilled prescriptions may not represent clinically significant medication non-adherence, because patients may have requested new prescriptions for different medications to treat the same condition. However, previous studies indicate that patients who are initially prescribed branded medications are less likely to subsequently adhere to any medication in the class when compared with patients prescribed generics. We recruited during a 1-month period in the winter. We did not account for seasonality; patient medication use and prescription requests may vary by season. We also are unsure of the extent of misclassification in this data set, because pharmacies may not accurately capture all patient dispense as written requests in administrative data sets, which may have led to conservative estimates of dispense as written rates.

    Conclusions

    Overall, we found that both patients and physicians commonly make dispense as written requests, totaling approximately 5% of all prescriptions. Advocates of dispense as written may argue that providing physicians and patients with greater discretion offers greater choice, opportunities for communication, and adherence to therapy. However, our results indicate that dispense as written requests are associated with excess costs, and that patients are less likely to fill prescriptions with dispense as written designations. Some private health plans have implemented financial penalties to reduce the rates of dispense as written designation. The cost savings and clinical effects of these policies should be studied to better understand what policies best encourage cost-effective medication use and adherence to chronic therapy.

    Physicians and patients should be aware that dispense as written designations not only increase costs to the patient but also adversely affect rates that patients purchase those prescriptions. Educational efforts to encourage generic acceptability should target those most likely to express concern about generics. Our findings indicate that specialists, older physicians, and patients aged 55 to 74 years are more likely to request dispense as written and may represent targets for educational outreach. These efforts should focus on initiation of chronic medications, because patients disproportionately fail to purchase these prescriptions when either physicians or patients request dispense as written.

    Prescriptions for certain classes of medications were far more likely to be accompanied by a dispense as written request. In particular, classes with narrow therapeutic indices, such as thyroid medications, anticoagulants, and anticonvulsants, were commonly delivered with a dispense as written request. There has been substantial debate in the scientific literature as to the equivalency of these products; although the literature may not corroborate these clinical concerns, it is likely that patients and physicians have a clinical rationale for these requests. The high rates of dispense as written requests for migraine products, ulcer agents, and hypnotics are more surprising, and may be related to effective marketing campaigns to patients and physicians.

    It is interesting to observe that physicians request dispense as written frequently for single-source branded products, medications for which no generics could be automatically substituted. Physicians with a strong preference for branded medications may not be aware of whether a generic is available and may request the branded agent as a preventive measure. Alternatively, physicians may request the branded medication to ensure that pharmacists do not substitute a different medication in the class for the prescribed medication (eg, substitution of simvastatin for atorvastatin [Lipitor, Pfizer Inc, New York, NY]); this so-called therapeutic substitution is generally not permitted without first contacting the physician. It is unclear whether these requests ultimately exert any influence on the medication that is delivered to the patient.

    Substantial geographic variation in dispense as written requests was seen. This variation may reflect patterns of marketing or the culture of medical education and prescribing that pervade different regions. These also may reflect habit, reflex, or consequences of automatically checked boxes in electronic prescribing systems or on standardized prescription pads. In addition, these variations may be related to geographic differences in pharmacy practice that influence communication with patients and physicians.

    Among multi-source brands, physician dispense as written requests were associated with increased rates of prescription reversals (OR 1.16, P<;.001), indicating that patients did not fill these prescriptions. New prescriptions (ie, the first maintenance prescriptions filled in a chronic medication class) had greater odds of reversal than subsequent maintenance prescriptions (OR 2.07, P<;.001). Rates of reversal also were higher for acute medications compared with maintenance medications (OR 1.37 P<;.001). Strong relationships were seen when we tested the interactions of dispense as written requests and initial maintenance or acute prescriptions. Among initial maintenance prescriptions, physician dispense as written (OR 1.50, P<;.001) and patient dispense as written (OR 1.60, P<;.001) were associated with greater odds of reversal. Similar trends were seen for acute medications; physician dispense as written was associated with 1.42 greater odds and patient dispense as written was associated with 1.61 greater odds of reversal compared with those filling subsequent maintenance medications, indicating higher rates of patient failure to fill these prescriptions.

    Among single-source brand medications, the neutral control where dispense as written designations should have no effect on which medication is actually filled, we found little effect of dispense as written designation on reversal rates. Overall, physician dispense as written was associated with a small reduction in reversal rates (OR 0.89, P<;.001). Acute medications and new prescriptions for maintenance medications were more likely to be reversed (OR 2.2 and 2.9, respectively; P<;.001 for both), although the odds of reversal was not influenced by dispense as written status.

    Discussion

    In this national sample of prescriptions written for patients receiving drug coverage administered by a large pharmacy benefits manager, approximately 5% of all prescriptions included a dispense as written designation requesting dispensing of a brand product. Dispense as written requests were made by prescribers (2.7% of prescriptions) and patients (2.0% of prescriptions). Prescriptions written with dispense as written designations were more likely to be reversed, indicating that they were less likely to be purchased by patients and went unfilled. In particular, when chronic therapy was initiated, physician and patient dispense as written requests led to more than 50% greater odds of non-filling.

    By substituting the generic alternative for each multi-source brand that was filled after both physician and patient dispense as written designation, the patient population in this sample could have reduced their charges by more than $1.7 million and the health plans could have experienced more than a $10.6 million reduction in costs in the 1-month study period. By assuming a similar rate of dispense as written requests in uninsured patients, patients covered by state or federal governments, and other commercially insured beneficiaries, we can estimate the savings potential of a policy that eliminates the dispense as written option. With more than 3.6 billion prescriptions filled in the United States annually,14 patient charges could be reduced by as much as $1.2 billion annually and health system costs could be reduced by as much as $7.7 billion by eliminating dispense as written opportunities. We are unable to estimate the implications of specifying dispense as written for single-source brands because these designations likely have minimal effect on the actual prescriptions delivered.