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Biomedical subjects

W W Stargel

Publications and source records attributed to W W Stargel.

At least 19 recordsLinked to original sources

Aspartame: scientific evaluation in the postmarketing period.

Prior to marketing, the safety of the high-intensity sweetener aspartame for its intended uses as a sweetener and flavor enhancer was demonstrated by the results of over 100 scientific studies in animals and humans. In the postmarketing period, the safety of aspartame was further evaluated through extensive monitoring of intake, postmarketing surveillance of anecdotal reports of alleged health effects, and additional research to evaluate these anecdotal reports and other scientific issues. The results of the extensive intake evaluation in the United States, which was done over an 8-year period, and the results of studies done in other countries demonstrated intakes which were well below the acceptable daily intakes set by the FDA and regulatory bodies in other countries, as well as the Joint FAO/WHO Expert Committee on Food Additives. Evaluation of the anecdotal reports of adverse health effects, the first such system for a food additive, revealed that the reported effects were generally mild and also common in the general population and that there was no consistent or unique pattern of symptoms that could be causally linked to consumption of aspartame. Finally, the results of the extensive scientific research done to evaluate these allegations did not show a causal relationship between aspartame and adverse effects. Thus, the weight of scientific evidence confirms that, even in amounts many times what people typically consume, aspartame is safe for its intended uses as a sweetener and flavor enhancer.

Animals↗

Evaluation of clinical and biochemical parameters in children after consumption of microparticulated protein fat substitute (Simplesse).

OBJECTIVE: The objective of this randomized, double-blind, two-way crossover study in healthy children was to evaluate whether microparticulated protein (MPP, Simplesse) fat substitute had any effects on various clinical and biochemical parameters when compared to super premium ice cream (approximately 16% butterfat). METHODS: Twenty-four children (12 males, 12 females), 7-10 years of age, received their normal diet plus two consecutive 7-day treatment regimens consisting of one serving (approximately 196 mL) per day of either ice cream or a frozen dessert made with MPP. Three-day food diaries, routine hematologies, clinical chemistries, urinalyses, fasting plasma lipids and amino acids, vital signs and adverse experiences were compared between treatments. RESULTS: There were no clinically significant effects on any of the parameters following either treatment, although there were statistically significant increases in fasting plasma cholesterol and high-density lipoprotein cholesterol following ice cream when compared to MPP. There were no statistically significant differences between the two treatments in regard to macronutrient consumption. The only adverse experience related to treatment was one episode of vomiting following the ice cream. The children ingested more than five times the amount of MPP than that found in the 90th percentile of frozen dessert consumption by this age group. The protein intake (5.5 g/day) from MPP at this level of consumption would only modestly increase the total daily protein intake. CONCLUSION: Children ingesting approximately 196 mL/day of frozen dessert made with MPP did not show any clinically significant changes in various clinical and biochemical parameters.

Amino Acids↗

Aspartame and sucrose produce a similar increase in the plasma phenylalanine to large neutral amino acid ratio in healthy subjects.

Aspartame (L-aspartyl-L-phenylalanine methyl ester) consumption has been postulated to increase brain phenylalanine levels by increasing the molar ratio of the plasma phenylalanine concentration to the sum of the plasma concentrations of the other large neutral amino acids (Phe/LNAA). Dietary manipulations with carbohydrate or protein can also produce changes in the Phe/LNAA value. To compare the effects of aspartame and carbohydrate on Phe/LNAA, beverages sweetened with aspartame, sucrose, and aspartame plus sucrose, and unsweetened beverage were ingested by 8 healthy, fasted subjects in a randomized, four-way crossover design. The beverages were sweetened with an amount of aspartame (500 mg) and/or sucrose (100 g) approximately equivalent to that used to sweeten 1 liter of soft drink. The baseline-corrected plasma Phe/LNAA values did not differ significantly following ingestion of aspartame or sucrose. Following aspartame alone, the high mean ratio increased 26% over baseline 1 h after ingestion. Following sucrose alone, the high mean ratio increased 19% at 2.5 h. Sucrose increased the Phe/LNAA value due to an insulin-mediated decrease in the plasma LNAA, while aspartame increased the ratio by increasing the plasma Phe concentration. These findings indicate that similar increases in plasma Phe/LNAA occur when healthy, fasting subjects ingest amounts of equivalent sweetness of sucrose or aspartame.

Adult↗

Bioavailability of phenylalanine and aspartate from aspartame (20 mg/kg) in capsules and solution.

Aspartame (L-aspartyl-L-phenylalanine methyl ester) was given in capsules or solution to compare the bioavailability of its constituent amino acids, aspartate and phenylalanine. Twenty healthy subjects received a single 20 mg/kg dose of aspartame in capsules or solution in a randomized, crossover design. Plasma amino acid concentrations and the phenylalanine to large neutral amino acid ratios (Phe/LNAA) were determined. Plasma aspartate concentrations did not increase with either treatment. For plasma phenylalanine following capsule ingestion, there was a smaller peak plasma concentration (Cmax; 103.3 v 126.6 mumol/L), a longer time to peak concentration (tmax; 108.6 v 36.6 minutes), but no significant difference in the area under the plasma concentration-time curve (AUC) (7,656 v 7,200 mumol.min/L) when compared with solution ingestion. The maximum plasma Phe/LNAA ratio was smaller (0.16 v 0.19) with capsules. The changes for plasma tyrosine were similar to those seen with phenylalanine. There were no significant differences in the plasma concentrations of the other LNAAs between capsule and solution ingestion. Thus, given the small effect on phenylalanine Cmax and Phe/LNAA and no effect on the extent of absorption of phenylalanine, aspartame ingested in capsules at doses up to 20 mg/kg is a suitable dosage form for blinded clinical studies, provided that the slower rate of absorption of phenylalanine from capsules is taken into account.

Adolescent↗

Factors affecting free (unbound) lignocaine concentration in suspected acute myocardial infarction.

1. Free plasma lignocaine concentrations were measured for up to 48 h after constant infusion of the drug in 41 subjects with suspected acute myocardial infarction. 2. The free plasma lignocaine clearance at 12 h was significantly and proportionately related to body weight and to the presence of mild (Killip Class II) heart failure, with an 18% reduction in free clearance in the latter condition. 3. The free plasma lignocaine was not related to sex, age or the presence of confirmed acute myocardial infarction, when corrected for the effects of body weight and presence of heart failure. 4. Free plasma lignocaine concentration 1 h after a fixed loading dose were also significantly related to body weight and presence of heart failure but not to sex, age or proven acute myocardial infarction. 5. The data indicate that correction of loading and maintenance infusion for body weight and presence of (even mild) heart failure should somewhat reduce variability in free (and presumably active) plasma lignocaine concentrations but that the free plasma lignocaine concentration at 12 h is most accurately predicted by measuring the free (and to a lesser extent total) plasma lignocaine concentration at 1 h.

Adult↗

A free lignocaine index as a guide to unbound drug concentration.

A free lignocaine index was developed on the basis of measurements of plasma lignocaine and its principle binding protein, alpha 1-acid glycoprotein (AAG) in 80 samples from 16 patients admitted to the coronary care unit and given prophylactic lignocaine therapy. The free drug fraction, fu, of lignocaine was determined by equilibrium dialysis and its relationship to AAG and total lignocaine concentration (T) defined by multiple linear regression analysis as l/fu = 1.45 + 0.023 (AAG) -0.129 (T) (multiple r = 0.872, P less than 0.001). This relationship was used to calculate the 'free lignocaine index' as fu X T and compared with the observed value obtained by equilibrium dialysis of 178 samples from 41 separate subjects who received lignocaine after suspected myocardial infarction. There was a highly significant relationship (r = 0.933, n = 178, P less than 0.001) between the observed and predicted values. We conclude that the free drug index may be useful in rapidly assessing the unbound (free) concentration of lignocaine in plasma.

Humans↗

In vitro stability of sodium nitroprusside solutions for intravenous administration.

A sensitive high-performance liquid chromatographic assay for nitroprusside using an ion-exchange column and UV detection was developed to evaluate the stability of aqueous solutions of sodium nitroprusside in light-protected glass and plastic containers and during simulated infusions. The results showed that sodium nitroprusside is stable in 5% dextrose, normal saline, and lactated Ringer's solutions in light-protected glass or plastic containers. In addition, there was no decrease in the delivered potency of sodium nitroprusside solutions during simulated infusions lasting up to 24 h.

Chromatography, High Pressure Liquid↗

Control of lidocaine therapy: new perspectives.

Although lidocaine has been available for clinical use for 30 years, it still retains an important place amongst antiarrhythmic drugs. It is still widely regarded as the first line of therapy in ventricular arrhythmias occurring after myocardial infarction or cardiac surgery. Recently, however, its use has been advocated in the prophylaxis of primary ventricular fibrillation occurring after myocardial infarction. This recommendation is based primarily on the well-designed and controlled study of Lie and co-workers (1). The results of this study have been reviewed and compared with the results of 11 other studies showing no significant effect of lidocaine in this situation (2). One other study did show that lidocaine gave protection against primary ventricular fibrillation (3). The authors concluded, however, that all the other studies had major defects in trial design, and were prepared to accept the conclusion that lidocaine was effective in preventing primary ventricular fibrillation after myocardial infraction. Similar conclusions were made by De Silva and co-workers (4). As a result, the drug is given in several centres in the U.S.A. to patients admitted with suspected acute myocardial infarction, particularly those aged less than 70 years who are seen within 6 h of the onset of chest pain (5,6).

Blood Proteins↗

Saliva concentrations of lidocaine and its metabolites in man.

The plasma concentrations of lidocaine and its two major active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX), were measured in simultaneously mixed saliva and plasma samples from 16 patients who had received the drug intravenously for at least 12 h. The concentrations of each compound in saliva tended to be greater than those in the corresponding plasma sample, so that the mean saliva-to-plasma ratio for lidocaine was 2.9 (median, 2.65); for GX, 4.7 (median 2.2); and for MEGX, 7.0 (median, 6.4). There was a statistically significant, although rather weak, relationship between the saliva and the total plasma lidocaine concentrations (r = 0.700; n = 16; p less than 0.01) and between the saliva and the free (unbound) plasma lidocaine concentrations (r = 0.509; n = 16; p less than 0.05). When the latter was corrected for the effect of pH, the relationship was significant but still weak (Spearman's P = 0.619; p less than 0.05). It appears that mixed salivary lidocaine concentrations are a relatively poor guide to free drug concentrations at steady state, even if correction is made for pH changes. Other rapid and convenient methods of estimating free plasma lidocaine concentrations are clearly needed.

Biotransformation↗

On the role of alpha 1-acid glycoprotein in lignocaine accumulation following myocardial infarction.

1 Blood plasma and free lignocaine concentrations have been measured 12 h after beginning a constant infusion of 2 mg/min and again at the end of the infusion (36-72 h) in five patients with myocardial infarction (MI) and compared with five control patients who did not develop objective evidence of MI. 2 In MI patients, total plasma concentration rose significantly between 12 h and the end of infusion. Because of an increase in alpha 1 acid glycoprotein (AAG) plasma binding increased, so that free drug concentration did not change. The rise in whole blood concentration was less than that in plasma as a result of drug redistribution out of red cells due to enhanced binding. 3 In control patients, neither blood nor plasma concentrations changed with time and plasma binding remained constant. Free drug concentrations, however, rose slightly. 4 The concentrations of GX and MEGX remained unchanged in all patients, but the ratio of lignocaine/MEGX concentrations fell in controls but rose in MI patients. 5 Pharmacokinetic modelling suggested that at least some of the rise in blood lignocaine concentration was due to reduced clearance resulting from enhanced plasma binding. 6 We conclude that the rise in AAG following MI is responsible for increased plasma binding and drug redistribution within blood. These changes, together with a reduction in lignocaine clearance, can explain much of the phenomenon of lignocaine accumulation in MI.

Adult↗

Clinical comparison of rapid infusion and multiple injection methods for lidocaine loading.

A rapid infusion regimen for lidocaine loading (150 mg infusion over 18 minutes following a 75 mg priming injection) was evaluated in 12 patients. This was compared with multiple injection loading method in six patients involving three 50 mg injections over 18 minutes following the same priming dose. Both loading regimens were followed by a maintenance infusion of 2 mg/min. Predictably, the multiple injection method produced wide variations in lidocaine concentrations compared to the rapid infusion method. Some evidence of lidocaine toxicity (drowsiness, tinnitus) was seen in 13 of the 18 patients after the priming injection. During multiple injection loading, all six patients experienced side effects (drowsiness, tinnitus, dysarthria, or paresthesias.) Only 1 of 12 patients experienced a side effect (drowsiness) during rapid infusion loading. The difference in incidence of adverse reactions was significantly greater with the multiple injection regimen (p less than 0.01) but was associated with measurably greater drug levels.

Adult↗

Relationship between alpha 1-acid glycoprotein and lidocaine disposition in myocardial infarction.

The effects of myocardial infarction (MI) on lidocaine disposition were investigated in eight patients during a constant infusion of 2 mg/min. Plasma lidocaine binding and total plasma and free lidocaine concentrations were measured 12, 24, 36, and 48 hr after beginning therapy and were related to alpha 1-acid glycoprotein (AAG) concentrations. By 48 hr total plasma lidocaine and AAG concentrations had risen, as had plasma lidocaine binding. Because of enhanced binding, free lidocaine concentrations did not change significantly over this time. There was a correlation between AAG and the binding ratio for lidocaine (r = 0.87) and between AAG and total plasma lidocaine concentrations (r = 0.81). The data suggest that the rise in AAG seen after MI is responsible for enhanced plasma lidocaine binding and may, at least in part, be related to lidocaine cumulation.

Adult↗

Sex-related differences in the plasma protein binding of lignocaine and diazepam.

1 The percentage of lignocaine free in the plasma of ten females receiving oral contraceptive medication was significantly greater than in 17 males of similar age (18--42 years). 2 In the same subjects the percentage of diazepam free in plasma was significantly greater in the contraceptive treated group than in 11 contraceptive-free females and significantly greater in contraceptive-free females than in males. 3 The differences in lignocaine binding were almost completely attributable to changes in alpha 1-acid glycoprotein concentration, which is reduced by oestrogens. The binding of diazepam was significantly related to albumin, alpha 1-acid glycoprotein and non-esterified fatty acid concentrations which together were related to 55% of the variation in the binding of this basic compound.

Adult↗

Lignocaine disposition in blood in epilepsy.

1 The plasma concentration of alpha 1-acid glycoprotein (AAG) was significantly greater in 27 epileptic subjects receiving anticonvulsants compared with 27 age- and sex-matched drug-free control subjects. 2 Increased AAG concentration was associated with enhanced lignocaine binding in the plasma of epileptics. 3 Increased AAG concentration was also associated with a redistribution of lignocaine out of red cells and into plasma thus lowering the blood to plasma concentration ratio. 4 Enhanced lignocaine binding in epileptics receiving anticonvulsant therapy may result in lower free (unbound) plasma concentrations of the drug compared to normal subjects with equivalent total plasma lignocaine concentrations.

Adult↗

Increased alpha-1-acid glycoprotein and lidocaine disposition in myocardial infarction.

In 15 patients with confirmed myocardial infarction, alpha-1-acid glycoprotein rose significantly from 117 mg/dL at admission to 140 mg/dL at 36 hours (p less than 0.01), but not in 15 age- and sex-matched patients with chest pain only. Twelve patients were given prolonged infusions of lidocaine (2 mg/min). In patients with myocardial infarction, the rise in plasma alpha 1-acid glycoprotein concentration was associated with increased lidocaine binding and a rise in total lidocaine concentrations between 12 and 48 hours (p less than 0.05). Because of the binding changes, however, the rise in free drug concentration (31.2%) was significantly less than the 56.3% rise in total drug level (p less than 0.05). No changes in alpha 1-acid glycoprotein or lidocaine disposition were seen between 12 and 48 hours in the control subjects. Our results show that the rise in alpha 1-acid glycoprotein after myocardial infarction is associated with lidocaine accumulation, but increased plasma binding attenuates the rise in free drug. This suggests that the toxicologic implications of lidocaine accumulation may have been exaggerated and therapeutic monitoring of total plasma levels may be misleading.

Adolescent↗