Triennial Lactation Symposium: Mammary metabolism of amino acids in dairy cows.

Although in dairy cows the mammary gland (MG) is the major net user of essential AA (EAA) supply, milk protein synthesis from absorbed EAA is not a straightforward process. Early studies identified 2 groups of EAA based on different pattern of mammary utilization: group 1 [Met, Phe (+Tyr), Trp], where MG uptake was similar to secretion in milk protein, and group 2 (Arg, Ile, Leu, Lys, Thr, and Val), where uptake exceeded milk protein output. This review examines the validity of this classification under variable protein supply through a meta-analysis, with the outcomes then explained with studies in which the fates of individual EAA were monitored using isotope approaches. For the meta-analysis, the Fick principle, based on stoichiometric transfer of Phe+Tyr uptake to milk protein, was used to estimate mammary plasma flow across all studies. This approach was judged acceptable because doubling Phe supply did not result in mammary oxidation of Phe+Tyr and either limited or no contribution of peptides to Phe and Tyr mammary supply could be detected. The AA content of proteins synthesized by the MG was estimated from milk protein composition, and the uptake-to-output ratio (U:O) for individual AA was re-calculated based on these assumptions. Analysis of individual samples by isotopic dilution resulted in reduced variance compared with analysis on pooled samples performed with an AA analyzer. Globally, the U:O of His and Met is maintained close to unity under variable protein supply. The group 2 AA could be subdivided. First, the U:O for group "2v" AA (Ile, Leu, Val, and Lys) is greater than 1 and varied with protein supply. Accordingly, the increased U:O of Leu, induced by duodenal casein infusion, led to extra-mammary Leu oxidation. Decreasing Lys supply decreased Lys U:O and the associated transfer of N to non-EAA, mainly to Glx, Asx, Ser, and Ala. Second, the U:O of group "2nv" AA, Arg and Thr, does not vary with protein supply. The Arg U:O averages 2.5, whereas the Thr U:O, albeit averaging 1.2, does not differ from unity. Excess of both these AA is probably directed toward the synthesis of non-EAA rather than energy supply. Overall, the ability of the MG to use excess EAA-N supply offers alternative sources of N and C for energy provision, lactose synthesis and non-EAA synthesis. The latter function spares dietary non-EAA for other necessary processes, such as gluconeogenesis and energy supply, in other tissues to support lactation.

Whole-body glucose metabolism and mammary energetic nutrient metabolism in lactating dairy cows receiving digestive infusions of casein and propionic acid.

This study analyzed the effect of propionate (C3) and casein (CN) on whole-body and mammary metabolism of energetic nutrients. Three multiparous Holstein cows fitted with both duodenal and ruminal cannulas were used in 2 replicated Youden squares with 14-d periods. Effects of CN (743 g/d in the duodenum) and C3 (1,042 g/d in the rumen) infusions, either separately or in combination as supplements to a grass silage diet, were tested in a factorial arrangement. The control diet provided 97% of energy and protein requirements. Within each period, blood samples were taken (d 11) from the carotid artery and the right mammary vein to determine net uptake of energetic nutrients. Plasma blood flow was calculated using the Fick principle (based on Phe and Tyr). On d 13, [6,6-(2)H(2)]glucose was infused in the jugular vein to determine whole-body glucose rate of appearance (Ra) based on enrichments in arterial plasma. Both C3 and CN treatments increased whole-body Ra (17% and 13%, respectively) but only CN increased milk (18%) and lactose (14%) yields, suggesting no direct link between whole-body Ra and milk yield. When CN was infused alone, the apparent ratio of conversion of CN carbon into glucose carbon was 0.31 but, when allowance was made for the CN required to support the extra milk protein output, the ratio increased to 0.40, closer to the theoretical ratio (0.48). This may relate to the observed increases in arterial glucagon concentrations for CN alone. Conversely, the apparent conversion of infused C3 carbon alone to glucose was low (0.31). With C3, mammary plasma flow increased as did uptakes of lactate, Ala, and Glu whereas the uptake for beta-hydroxybutyrate (BHBA) decreased. Mammary net carbon balance suggested an increase with C3 treatment in glucose, lactate, Ala, and Glu oxidation within the mammary gland. Mammary glucose uptake did not increase with CN treatment, despite an increase in glucose arteriovenous difference and extraction rate, because plasma flow decreased (-17%). Whereas CN, alone or in combination with C3, increased both lactose and protein yields, only mammary AA (and BHBA in CN alone) uptake increased because plasma flow decreased (-17%). These data suggest that the observed variations of milk lactose yield (and other milk components) are linked to metabolic interchanges between several energetic nutrients at both the whole-body and mammary levels and are not explained by increases in whole-body glucose availability.

Hepatic arterial infusion plus systemic irinotecan in patients with unresectable hepatic metastases from colorectal cancer previously treated with systemic oxaliplatin: a retrospective analysis.

BACKGROUND: Response rates to systemic chemotherapy are low after tumor progression on oxaliplatin regimens. Hepatic arterial infusion (HAI) therapy in patients with tumor progression is a viable alternative. PATIENTS AND METHODS: Thirty-nine heavily pre-treated patients (all receiving prior oxaliplatin) with unresectable colorectal hepatic metastases were treated with systemic CPT-11 and concurrent HAI floxuridine (FUDR) and dexamethasone (DEX). RESULTS: Partial responses were seen in 44% of patients. Median time to hepatic progression was 8.6 months, and median time to overall progression was 6.5 months. Median survival from time of initiation of HAI was 20.1 months [95% confidence interval (CI) 16.9-21.4] and from the initiation of treatment of metastatic disease, 32.01 months (95% CI 29.1-34.6). After a median follow-up of 19.1 months, seven patients (18%) proceeded to potentially curative surgery. Grade 3/4 toxic effects included neutropenia (13%), diarrhea (15%), intra-abdominal hemorrhage (2%), and bleeding duodenal ulcer (2%). Elevated liver function tests were seen, including bilirubin concentration >3 mg/dl (7%), alkaline phosphatase 2X baseline (20%), and aspartate aminotransferase >3X baseline (26%). CONCLUSIONS: HAI FUDR/DEX plus systemic CPT-11 achieves a response rate of 44% and a median overall survival of 20 months in heavily pre-treated patients with colorectal hepatic metastases all receiving previous oxaliplatin; 18% of patients proceeded to surgical resection or ablation.

Effect of protein supply on hepatic synthesis of plasma and constitutive proteins in lactating dairy cows.

The effects of metabolizable protein (MP) supply on the synthesis of plasma total proteins and albumin, as well as total hepatic protein synthesis, were determined in 6 multicatheterized lactating Holstein cows. Three TMR formulated to supply the same amount of energy but different amounts of MP, 1,922 (low), 2,264 (medium), and 2,517 g of MP/d (high), were fed every 2 h according to a double 3 x 3 Latin square design. For the low and high MP treatments, the cows were continuously infused with [(2)H(5)]Phe (d5-Phe) into a jugular vein for 8 h (1.3 mmol/h) on d 21 of each period. Concentration and isotopic enrichment of d5-Phe were measured for free plasma Phe, plasma total proteins, and albumin on hourly samples collected between 3 and 8 h. Low MP decreased the plasma albumin concentration (32.3 vs. 33.7 +/- 0.11 g/L) but the plasma total protein concentration was unchanged (74.1 vs. 75.6 +/- 1.13 g/L). Incorporation of d5-Phe over time into both plasma total proteins and albumin was linear (R(2) > 0.98). Neither fractional nor absolute synthesis rates of plasma total proteins (6.8 vs. 6.5 +/- 0.65%/d; 168 vs. 154 +/- 19.9 g/d) or albumin (3.4 vs. 3.4 +/- 0.10%/d; 36.3 vs. 36.5 +/- 1.11 g/d) were affected by the MP supply. Net hepatic removal of Phe was lower with the low-MP diet (-12.3 vs. -20.2 +/- 1.98 mmol/h). As a result, net hepatic Phe removal used for total export protein synthesis (17.9 vs. 11.1 +/- 1.83%) and albumin synthesis (4.6 vs. 2.9 +/- 0.54%) tended to be greater at low MP. These results suggest that hepatic synthesis of plasma proteins, including albumin, is maintained in lactating dairy cows even when the protein supply is reduced.

Comparison of net portal absorption with predicted flow of digestible amino acids: scope for improving current models?

This study was undertaken to determine the relationship between measured net portal absorptions (NPA) and flows of digestible essential amino acids (EAA) predicted with the National Research Council model (NRC, 2001) or the Cornell Net Carbohydrate and Protein System model (CNCPS, version 5.0.34). Net portal absorption data were obtained from 33 measurements of portal-arterial plasma EAA concentration differences among 8 treatments in lactating dairy cows, with plasma flow estimated from downstream dilution of para amino-hippurate. The predicted digestible flows from NRC (2001) related better than CNCPS to NPA observed in our studies, as shown by the lower standard errors on the slopes for all EAA and lower root mean prediction errors for all EAA except Met and Phe. However, the partitioning of the prediction error indicated a systematic underprediction (mean bias) for the NRC model (2001), with the exception of Ile. It is important to note that a relationship of unity was not expected, as discussed in the paper, because of losses of EAA through portal-drained viscera metabolism. A revised set of predictive equations for digestible EAA was obtained using a subset of data from NRC (2001) limited to trials conducted with dairy cows. This increased the predicted flows of digestible EAA by only 2%. Flows of digestible EAA were also estimated using a factorial approach, assuming an AA composition for each fraction of the duodenal flow estimated by NRC (undegradable, microbial, and endogenous proteins). This resulted in a slight improvement in the slope of the regression between predicted flows and measured NPA, but still yielded predicted digestive flows that were too low to support observed NPA. Finally, on the basis of literature values, increment of the digestibility of the undegradable fraction of forages and of microbial protein is suggested to improve the relationship between predicted digestible flows and NPA. Overall, this study indirectly confirms, across EAA, smaller losses through gut metabolism for His, Met, and Lys, intermediate losses for the branched-chain AA with the higher losses for Thr.

Effect of casein and propionate supply on mammary protein metabolism in lactating dairy cows.

The effects of casein (CN) and propionate (C3) on mammary AA metabolism were determined in 3 multiparous Holstein cows fitted with both duodenal and ruminal cannulas and used in a replicated Youden square with six 14-d periods. Casein (743 g/d in the duodenum) and C3 (1,041 g/d in the rumen) infusions were tested in a factorial arrangement. For each period, L-[1-(13)C]Leu (d 11) and NaH[13C]O3 (d 13) were infused into a jugular vein, and blood samples were taken from the carotid artery and the mammary vein to determine Leu kinetics and net uptake of AA. Both CN and C3 treatments separately increased milk protein concentration and yield. With CN there was a general response in mammary protein metabolism, involving increases in Leu net uptake (30%), the uptake:output ratio (8%), protein synthesis (11%), secretion in milk protein (21%), and oxidation (259%). In contrast, C3 treatments tended to increase only Leu in milk protein (7%) and, when in combination with CN, to reduce Leu used for protein synthesis (5%). Across all treatments, most Leu uptake by the mammary gland was accounted for as Leu in milk or oxidized, and the Leu balance was therefore achieved without involvement of either net peptide use or production. Mammary uptake of group 1 AA increased to match milk output with all infusions. In contrast, mammary uptake of group 2 AA exceeded output to a greater extent with CN than with C3 infusions, whereas the increment in uptake of group 3 AA increased with C3 treatments. Overall, these data suggest that different mechanisms operate to improve milk protein production when either protein or energy is supplied.

Effect of level of metabolizable protein on splanchnic flux of amino acids in lactating dairy cows.

The response of splanchnic tissue metabolism to different levels of metabolizable protein (MP) was measured in 6 catheterized multiparous lactating Holstein cows. Three diets, balanced to provide similar energy intakes and increasing amounts of MP (g/d)-1922 (low), 2264 (medium), and 2517 (high)-were fed during 21-d experimental periods according to a replicated Latin square. On d 18, 19, or 20, six hourly blood samples were collected simultaneously from the portal and hepatic veins plus an artery to determine net fluxes of nutrients across the portal-drained viscera and the liver. Yields of milk and protein increased, as did urinary N excretion with increasing MP. Portal absorption of essential amino acids (EAA) increased linearly with increasing MP supply, as did liver removal of His, Met, and Phe. In contrast, liver removal of the branched-chain AA (BCAA) and lysine was unaffected by diets. With increasing MP, the ratio of milk output to postliver supply of BCAA, Thr, and Lys decreased linearly, indicating oxidation of these AA in the peripheral tissues. Concomitant to a decreased catabolism of EAA in the liver (His, Met, Phe, and Thr) and/or in peripheral tissues (BCAA, Lys, and Thr), the efficiency of transfer of absorbed EAA into milk protein decreases markedly as protein supply increases. The efficiency of transfer of absorbed AA into milk also varies greatly between AA. These 2 important factors should be taken into account when building predictive schemes for milk protein output.

Assessment of health economics in Alzheimer's disease (AHEAD) based on need for full-time care.

OBJECTIVE: To develop a framework for estimating the long-term health and economic consequences of AD based on patient characteristics at a given point in time. METHODS: A pharmacoeconomic model (Assessment of Health Economics in Alzheimer's Disease, AHEAD) was developed based on equations that relate the probability of needing full-time care (FTC) over time to patient characteristics summarized in index scores. These equations were developed from published data on interquartile times until FTC is needed and until death, using nonlinear regressions of the resulting index-specific hazards. These equations were then incorporated into a hidden Markov framework that allows for calculation of expected time to FTC and to death, as well as of the economic consequences of disease progression. There are three major states in the model: not requiring FTC ("pre-FTC"), requiring FTC, and death. RESULTS: Outcomes for five sample patients are derived to illustrate application of the AHEAD model. The impact of altering disease markers in these patients is also considered. CONCLUSION: The need for a generally applicable tool to forecast long-term outcomes based on relatively short-term data is becoming increasingly acute with the advent of new therapies for AD. The AHEAD model provides a relatively simple framework for the prediction of time to FTC requirement based on short-term observed data such as those from clinical trials. Although subject to the uncertainties inherent in modeling, the model nevertheless provides a standard estimation technique that may facilitate comparisons between existing and emerging therapies.

Treatment of migraine in Canada with naratriptan: a cost-effectiveness analysis.

OBJECTIVE: To evaluate the cost-effectiveness of naratriptan for the treatment of migraine in Canada. BACKGROUND: The substantial disability brought on by migraine, coupled with the high prevalence of this disorder, leads to substantial costs. Naratriptan is a newly developed triptan shown to be effective in the treatment of migraine. METHODS: Monte Carlo modeling techniques were used to simulate the experience of Canadian migraineurs over the course of 1 year. Data from a multinational study comparing oral naratriptan 2.5 mg to customary therapies were used in the cost-effectiveness analysis. RESULTS: Naratriptan leads to an annual reduction in symptom duration of 225 hours compared to customary therapy not including other triptans. Reductions in lost productivity yield savings of Can $390 (1998 Canadian dollars) relative to customary therapy, which exceed the increase in drug costs resulting in overall savings of Can $109 per year. CONCLUSIONS: The use of naratriptan in the treatment of migraine is an economically attractive option, leading to savings in overall costs. Increases in drug costs seem acceptable in light of reductions in symptom duration.

Sumatriptan: economic evidence for its use in the treatment of migraine, the Canadian comparative economic analysis.

The objective of this study was to evaluate economic and health effects of sumatriptan relative to customary therapy in Canada. The relationship between treatment and functionality was established based on analysis of existing data from a multinational study. A Monte Carlo model was developed to simulate 1 year for each of customary therapy and six sumatriptan formulations. Costs are expressed in 1998 Canadian dollars. Sumatriptan is expected to reduce the time spent with migraine symptoms and resulting time lost. Under customary therapy, the annual cost of lost time is estimated at pound908 ($1973). With sumatriptan, these costs ranged from pound406 ($882) with subcutaneous sumatriptan to pound577 ($1254) with nasal sumatriptan 10 mg, saving pound331-502 ($719-1091) in the annual cost of time lost. All these benefits are expected to be obtained at an additional drug cost ranging from pound869 ($1889) for subcutaneous sumatriptan to pound278 ($605) for sumatriptan suppository. The cost of sumatriptan treatment is significantly offset by a substantial reduction of costs associated with time lost due to migraine symptoms.

Economic analysis of initial HIV treatment. Efavirenz- versus indinavir-containing triple therapy.

OBJECTIVE: To compare the clinical and economic outcomes associated with triple therapy containing efavirenz or indinavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs; zidovudine and lamivudine) in HIV-positive patients. DESIGN AND SETTING: An economic model based on viral load and CD4+ cell counts to predict long term outcomes such as progression to AIDS and AIDS-related death was developed and then analysed using data from a randomised clinical trial. Cost estimates from the healthcare system perspective were based on data from 6 state, all-payor databases, the AIDS Cost and Services Utilisation Study, and other literature. Analyses were carried out for time horizons between 5 and 15 years. PATIENTS AND INTERVENTIONS: HIV-positive patients with limited exposure to NRTIs. Initial regimens consisted of efavirenz or indinavir, each combined with 2 NRTIs. A maximum of 2 switches to other regimens was permitted. MAIN OUTCOME MEASURES AND RESULTS: The efavirenz-containing triple therapy regimen was predicted to prolong survival at a savings of up to 10,923 US dollars (1998 values) relative to initial therapy with the indinavir-containing regimen. Patients who receive efavirenz are expected to have 11% greater survival at 5 years and fewer treatment failures (28 vs 52%, at 2 years). Overall, the economic and health benefits predicted for the efavirenz-containing regimen were robust to reasonable variation in key parameters. CONCLUSIONS: The superior clinical trial outcomes for efavirenz-containing regimens should translate into substantial economic and health benefits.

The migraine ACE model: evaluating the impact on time lost and medical resource Use.

OBJECTIVE: To describe the Migraine Adaptive Cost-Effectiveness Model in the context of an analysis of a simulated population of Canadian patients with migraine. BACKGROUND: The high prevalence of migraine and its substantial impact on patients' ability to function normally present a significant economic burden to society. In light of the recent availability of improved pharmaceutical treatments, a model was developed to assess their economic impact. METHODS: The Migraine Adaptive Cost-Effectiveness Model incorporates the costs of time lost from both work and nonwork activities, as well as medical resource and medication use. Using Monte Carlo techniques, the model simulates the experience of a population of patients with migraine over the course of 1 year. As an example, analyses of a Canadian population were carried out using data from a multinational trial, surveys, national statistics, and the available literature. RESULTS: Using customary therapy, mean productivity losses (amounting to 84 hours of paid work time, 48 hours of unpaid work time, and 113 hours of leisure time lost) were estimated to cost $1949 (in 1997 Canadian dollars) per patient, with medical expenditures adding an average of $280 to the cost of illness. CONCLUSIONS: With customary treatment patterns, the costs of migraine associated with reduced functional capacity are substantial. The migraine model represents a flexible tool for the economic evaluation of different migraine treatments in various populations.

Economic assessment of troglitazone as an adjunct to sulfonylurea therapy in the treatment of type 2 diabetes.

OBJECTIVE: To assess the economic efficiency of adding troglitazone to sulfonylurea therapy to improve glycemic control. BACKGROUND: Despite the high prevalence of type 2 diabetes, existing treatment strategies often fail. New oral agents give a wider segment of the population with type 2 diabetes hope of achieving near-normal blood-glucose levels. Troglitazone, a novel chemical entity, is one promising new agent. METHODS: We conducted an economic analysis based on glycemic-control data from a randomized clinical trial comparing troglitazone with placebo, each added to glyburide. A patient simulation model was used to translate these data to long-term outcomes associated with diabetes. Patients had poorly controlled type 2 diabetes mellitus despite glyburide therapy. Risk functions of developing and progressing through nephropathy, retinopathy, neuropathy, hypoglycemia, and macrovascular disease were developed from the Diabetes Control and Complications Trial and large epidemiologic studies. Cost estimates were based on data from 5 states, all payor databases, surveys, and literature. The main outcomes of the model were cost-consequences, number of patients developing each type of complication, mean time to development of the complication, cost per life-year gained (LYG), and cost per quality-adjusted life-year. RESULTS: The model predicts that for every 1000 patients treated with troglitazone, the improved glycemic control could mean that 95 to 140 fewer patients would experience one of the most severe diabetic complications (eg, blindness, end-stage renal disease, amputation), which may increase life expectancy by 2.0 years. These benefits are obtained at an additional $2100 per LYG (undiscounted). The ratio remains <$50,000 per LYG for most variations in input. CONCLUSIONS: The clinical trial demonstrated that troglitazone + glyburide improves glycemic control compared with glyburide alone. Based on these results, the model estimates fewer diabetic complications at a cost well below accepted cost-effective thresholds.

Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data.

BACKGROUND: Rational medical decisions should be based on the best possible evidence. Clinical trial results, however, may not reflect conditions in actual practice. In hypertension, for example, trials indicate equivalent antihypertensive efficacy and safety for many medications, yet blood pressure frequently remains uncontrolled, perhaps owing to poor compliance. This paper examines the effect of initial choice of treatment on persistence with therapy in actual practice. METHODS: The authors examined all outpatient prescriptions for antihypertensive medications filled in Saskatchewan between 1989 and 1994 by over 22,000 patients with newly diagnosed hypertension whose initial treatment was with a diuretic, beta-blocker, calcium-channel blocker or angiotensin-converting-enzyme (ACE) inhibitor. Rates of persistence over the first year of treatment were compared. RESULTS: After 6 months, persistence with therapy was poor and differed according to the class of initial therapeutic agent: 80% for diuretics, 85% for beta-blockers, 86% for calcium-channel blockers and 89% for ACE inhibitors (p < 0.001). These differences remained significant when age, sex and health status in the previous year were controlled for. Changes in the therapeutic regimen were also associated with lack of persistence. INTERPRETATION: A relation not seen in clinical trials--between persistence with treatment and initial antihypertensive medication prescribed--was found in actual practice. This relation also indicates the importance of real-world studies for evidence-based medicine.

Persistence with treatment for hypertension in actual practice.

BACKGROUND: Despite the existence of efficacious medications, many patients in actual practice remain with uncontrolled hypertension. Randomized clinical trials, cannot address this issue well given their highly restricted environment. This paper examines persistence with antihypertensive therapy among patients in actual practice. METHODS: Cohort study of patients who received a diagnosis of hypertension and were treated between 1989 and 1994 identified through the Saskatchewan Health databases. Patients with concurrent diagnoses likely to affect initial treatment choice were excluded. The resulting population of 79,591 subjects was grouped into those with established hypertension (52,227 [66%]) and those with newly diagnosed hypertension (27,364 [34%]). The initial antihypertensive prescription, subsequent changes in treatment and persistence with antihypertensive therapy were analysed. RESULTS: Persistence with antihypertensive therapy decreased in the first 6 months after treatment was started and continued to decline over the next 4 years. Of the patients with newly diagnosed hypertension, only 78% persisted with therapy at the end of 1 year, as compared with 97% of the patients with established hypertension (p < 0.001). Among those with newly diagnosed hypertension, older patients were more likely than younger ones to persist, and women were more likely than men to persist (p < 0.001). INTERPRETATION: This analysis of actual practice data indicates that barriers to persistence occur early in the therapeutic course and that achieving successful therapy when treatment is started is important to maintaining long-term persistence.

Direct medical costs of complications resulting from type 2 diabetes in the U.S.

OBJECTIVE: To estimate direct medical costs of managing the complications of type 2 diabetes. RESEARCH DESIGN AND METHODS: Costs were estimated for 15 diabetic complications by applying unit costs to typical resource-use profiles. Resource used and unit costs were estimated from many sources, including acute care discharge databases, clinical guidelines, government reports, fee schedules, and peer-reviewed literature. For each complication, the event costs are those associated with resource use that is specific to the acute episode and any subsequent care occurring in the 1st year. State costs are the annual costs of continued management. All costs are expressed in 1996 U.S. dollars. RESULTS: As expected, the more severe or debilitating events, such as acute myocardial infarction ($27,630 event cost; $2,185 state cost), generate a greater financial burden than do early-stage complications, such as microalbuminuria ($62 event cost; $14 state cost). Yet, complications that are initially relatively low in cost (e.g., microalbuminuria) can progress to more costly advanced stages (e.g., end-stage renal disease, $53,659 state cost); therefore, minor complications should also be considered in any economic analysis of diabetes. CONCLUSIONS: The recent literature has lacked cost estimates that may be readily translated into patient-level cost inputs for an economic model. Emerging therapies that may reduce the incidence of some diabetic complications will need to be scrutinized economically in today's cost-conscious environment. The cost estimates from this study provide one piece of the economic analysis needed to evaluate these new interventional therapies.