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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.

We evaluated approximately 5.6 million prescriptions that were delivered to retail or mail-order pharmacies and adjudicated through Caremark during the 1-month period. These prescriptions were written for 2,047,124 patients by 315,379 specialist physicians, 126,430 generalists, and 39,128 non-physician prescribers (eg, nurse practitioners). Patients and their insurance plans, respectively, paid an average of $17.90 and $26.67 for generic medications, $49.50 and $158.25 for single-source brands, and $44.50 and $135.26 for multi-source brands.

Of the prescriptions we evaluated, 151,670 (2.7%) were designated as dispense as written by physicians and 112,243 (2.0%) were designated as dispense as written by patients. A majority of prescriptions designated as dispense as written by physicians were single-source brand products for which no generic alternatives were available. Most patient-assigned dispense as written prescriptions were for multi-source brands, which could have otherwise been substituted at the pharmacy without contacting the physician. Patient requests for dispense as written took place almost exclusively at retail pharmacies, whereas approximately one third of physician requests were filled at mail-order pharmacies.

Among multi-source brands used to treat chronic conditions (maintenance medications), patients failed to fill prescriptions more frequently when either patients or physicians requested dispense as written, compared with prescriptions with no dispense as written designation.

In multivariate analyses, older physicians were more likely to request dispense as written than younger ones, and patients age 55 to 74 years were most likely to receive physician dispense as written prescriptions. The odds of requesting dispense as written was 78.5% greater for specialists than generalists (P<;.001). Compared with rates of dispense as written request for oral antidiabetics (the referent class), a dispense as written was more likely to be written for anticonvulsants (odds ratio [OR] 2.2), estrogens (OR 2.2), migraine treatments (OR 2.4), thyroid medications (OR 9.8), and anticoagulants (OR 3.9). Physician dispense as written was more common in the northeast section of the country (OR 1.76 vs west, P<;.001) and when submitted to mail-order pharmacies.

The likelihood of patient dispense as written requests also varied by therapeutic class and region. Compared with oral antidiabetics, patient dispense as written requests were more common for ulcer agents (OR 6.1), hypnotics (OR 4.3), migraine medications (OR 14.4), contraceptives (OR 3.7), thyroid medications (OR 16.5), estrogens (OR 3.6), anticonvulsants (OR 4.8), anticoagulants (OR 4.5), and analgesics (OR 4.5). Patient dispense as written was requested most frequently in the west; there were 32.4% greater odds for having a patient-assigned dispense as written in the west than in the northeast (P<;.001). Dispense as written was most commonly requested by patients who were 55 to 74 years of age, for maintenance medications, and at retail pharmacies.

For each eligible prescription submitted, we constructed explanatory variables to assess the relationship between physician, patient, treatment, and pharmacy characteristics and dispense as written use and prescription filling. Physician variables included primary specialty, practice type (primary care, specialist, non-physician prescriber), and prescriber age. Patient characteristics included age (in years), gender, and US census region of residence. Treatment variables included the dispense as written assignment, GPI4/GPI2-designated therapeutic class, brand/generic status, and patient out-of-pocket cost (in dollars per 30-day equivalent prescription). Pharmacy characteristics included the type of dispensing pharmacy (retail or mail). Prescriptions were categorized as either acute or maintenance (chronic) using the First Data Bank designation. Maintenance medications were further categorized as either an “initiation” or “continuation” of therapy. Initiation prescriptions were defined on the basis of no paid pharmacy claims for a drug in the same therapeutic class in the 6 months before the index prescription claim. Maintenance continuation prescriptions were preceded by 1 or more paid claims in the previous 6 months, indicating recent use.
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Analysis Plan
We used descriptive statistics to evaluate patient, physician, pharmacy, and prescription characteristics. We described rates of dispense as written for both single-source brands and multi-source brands, despite the fact that dispense as written for single-source brands may not have any effect on prescription delivery. We also present rates of prescription reversals, prescription claims approved by a payer and then reversed by the pharmacy because they were not purchased by the patient and went unfilled, stratified by dispense as written designation and prescription type.

To assess the relationship between physician, patient, prescription, and pharmacy characteristics with physician and patient dispense as written requests, we used generalized estimating equations to adjust for clustering at the patient level. Our outcomes, at the submitted prescription level, were the presence or absence of physician dispense as written in one model and the presence or absence of patient dispense as written for the other. We studied whether physician, member, treatment, and pharmacy characteristics were associated with the submission of prescriptions with a dispense as written designation. When comparing rates of dispense as written requests by drug class, we selected oral diabetes medications as our referent category because they are essential medications, commonly prescribed, and include both generic and brand-name options.

Multivariate generalized estimating equation models were used to estimate the relationship between patient and physician dispense as written selection and whether the claim was reversed, indicating the medication was not purchased by the patient and went unfilled. In these models, we were interested in the relationship between dispense as written designation and rates of multi-source brand medication filling, because these are the medications for which dispense as written designations most clearly affect the medication received. Thus, in our primary model, we included only multi-source brand and generic medications. We ran a distinct model with single-source brands as a neutral control because we did not expect that dispense as written designation would have any effect on the medication that was delivered and, as a result, the likelihood of actual purchasing. In these models, we controlled for patient, physician, and pharmacy covariates and adjusted for clustering within patients. We included interactions between physician and patient dispense as written designations and prescription characteristics (initiation of a chronic medication, maintenance medication continuation, or acute medication), because we hypothesized that dispense as written designation may have the greatest effect on purchasing rates in new prescriptions or acute prescriptions, when patients first learn about the medication costs. Statistical evaluations were performed using SAS Version 9.1 with SAS/STAT(r) (SAS Institute Inc, Cary, NC) and Stata SE 9.1 for Windows (StataCorp LP, College Station, Tex).

Dispense as written requests may have important implications for patient adherence. Patients are more adherent when they are initiated on generic or lower-cost medications.9 Although dispense as written requests would seem to reflect a conscious decision by patients or their physicians to use a specific agent, the increased cost-sharing that results from a dispense as written designation may decrease the likelihood that patients actually fill their prescriptions.

Little is known about how frequently physicians or patients request dispense as written, the medications for which dispense as written is most commonly used, and the physician and patient characteristics associated with dispense as written requests. Previous descriptive analyses of this practice were conducted when generic use was far less common and have limited applicability to current practice.10, 11, 12 No prior studies have investigated the effect of dispense as written requests on patients’ likelihood to fill their prescriptions or on overall health system costs. By using transactional data from a large national pharmacy benefits manager, we assessed rates and correlates of dispense as written requests and the relationship between these requests and rates of filled prescriptions.

Materials and Methods

Sample
We identified all patients enrolled in employer-sponsored health plans who received pharmacy benefits from CVS Caremark in calendar years 2008 and 2009. From this sampling frame, we selected all members with a) continuous eligibility for pharmacy benefits between July 1, 2008, and January 31, 2009, and b) a valid entry for gender and date of birth in the administrative record. We limited our sample to patients who submitted a prescription claim from any retail or mail-order pharmacy for adjudication between January 1 and 31, 2009, the identification period. We excluded all clients who were enrolled in a plan that imposed penalties for dispense as written requests, because dispense as written requests in these settings may not reflect those in the general population.

For patients who submitted multiple eligible prescriptions within a class, we selected the prescription with the latest date during the identification period, which likely eliminates accidental or erroneous prescriptions that were delivered. If a member submitted prescriptions in multiple therapeutic classes, each was deemed eligible and included in the analysis. We included all therapeutic categories defined by MediSpan’s Generic Product Identifier (GPI-2).

We identified the dispense as written assignment and the brand status from the submitted claim record. We categorized claim records into 1 of 3 mutually exclusive categories: a physician-assigned dispense as written (Physician Dispense as Written); a member-assigned dispense as written (Patient Dispense as Written); or no Dispense as Written. Brands were listed as either single-source brand, indicating no generic equivalent was available at the time of the study, or multi-source brands, which are branded medications with a generic equivalent. For every eligible prescription, we also determined whether the prescription was purchased (“filled”) or reversed. Reversed prescriptions are those that the patient chose not to purchase, and therefore were not filled.