HOT TOPICS is a review of the medical literature on a topic of current interest. The articles are taken from the MEDLINE online database produced by the National Library of Medicine, as well as many other online sources of information. This listing is NOT a complete review, but represents a selection. Further information may be obtained from campus libraries (including the Biomedical Library), or from your local library. Many of the articles will be available in the Biomedical Library. We will be happy to assist you in locating them during our regular hours. If you have any questions please leave a message. I welcome any suggestions for further HOT TOPICS, and will be happy to answer any questions regarding this section. -- Steve Clancy, Biomedical Library, UCI. ******************************************************************************* KEY TO HOT TOPICS REFERENCES 3. France C; Ditto B. Cardiovascular responses to occupational stress and caffeine in telemarketing employees.
Psychosomatic Medicine, 1989 Mar-Apr, 51(2):145-51. More <[Y],N,C,A>! Abstract: Cardiovascular responses to the combination of caffeine and a challenging occupational activity were examined using a within-subject, double-blind design. Seventeen female and 11 male telemarketing employees received drinks that did and did not contain 250 mg of caffeine on two *************************************************************************** NUTRASWEET: ADVERSE EFFECTS 1. Dailey JW; Lasley SM; Mishra PK; Bettendorf AF; Burger RL; Jobe PC. Aspartame fails to facilitate pentylenetetrazol-induced convulsions in CD-1 mice. Toxicology and Applied Pharmacology, 1989 May, 98(3):475-86. Abstract: Concentrations of plasma amino acids and brain monoamines as well as pentylenetetrazol-induced seizures were monitored in CD-1 mice treated with aspartame in acute oral doses from 0 to 2500 mg/kg. One hour after administration aspartame produced increases in plasma concentrations of phenylalanine and tyrosine and modest reductions in concentrations of brain serotonin and 5-hydroxyindole acetic acid. However, these effects of the sweetener had no influence on the convulsive dose fifty (CD50) of pentylenetetrazol. Moreover, aspartame failed to alter the percentage of mice exhibiting seizures when exposed to an approximate CD50 of More <[Y],N,C,A>! pentylenetetrazol. Finally, aspartame had no effect on brain norepinephrine or dopamine concentrations. In sharp contrast to previously reported studies, these observations suggest that aspartame, given in heroic doses, does not alter the propensity to seizure activity in CD-1 mice. We conclude that changes in plasma amino acids and brain serotonin produced by large oral bolus doses of aspartame are insufficient to result in functional deficits which might have the capacity to facilitate pentylenetetrazol-induced seizures. 2. Lipton RB; Newman LC; Cohen JS; Solomon S. Aspartame as a dietary trigger of headache. Headache, 1989 Feb, 29(2):90-2. Abstract: Many dietary factors have been implicated as possible precipitants of headache. There have been recent differences of opinion with regard to the effect of the artificial sweetener aspartame as a precipitant of headache. To assess the importance of aspartame as a dietary factor in headache, 190 consecutive patients of the Montefiore Medical Center Headache Unit were questioned about the effect of alcohol, carbohydrates and aspartame in triggering their headaches. Of the 171 patients who fully completed the survey, 49.7 percent reported alcohol as a precipitating factor, compared to 8.2 percent reporting aspartame and 2.3 percent reporting carbohydrates. Patients with migraine were significantly more likely to report alcohol as a triggering factor and also reported aspartame as a precipitant three More <[Y],N,C,A>! times more often than those having other types of headache. The conflicting results of two recent placebo-control studies of aspartame and headache are discussed. We conclude that aspartame may be an important dietary trigger of headache in some people. 3. Yost DA. Clinical safety of aspartame. American Family Physician, 1989 Feb, 39(2):201-6. Abstract: Aspartame is a synthetic sweetener commonly used in soft drinks and many foods. Even with high doses, the metabolites of this sweetener do not accumulate in toxic amounts. To date, no definite symptom complex has been connected with aspartame, and it is considered safe for use in all populations, including diabetics, phenylketonuric heterozygotes and pregnant women. 4. Tollefson L. Monitoring adverse reactions to food additives in the U.S. Food and Drug Administration. Regulatory Toxicology and Pharmacology, 1988 Dec, 8(4):438-46. Abstract: Technological advances in food science have resulted in the development of numerous food additives, most of which require premarket approval by the Food and Drug Administration (FDA). Concomitant with the More <[Y],N,C,A>! benefits of these additives, such as extending the shelf life of certain food commodities, is the potential for various risks. These potential risks include the possibility of the consumer experiencing an adverse reaction to the additive. In order to ascertain the character and the gravity of alleged adverse reactions to food products which it regulates, the FDA's Center for Food Safety and Applied Nutrition has developed the Adverse Reaction Monitoring System (ARMS). This postmarketing surveillance system for food additives is designed to analyze consumer reports of adverse reactions in order to alert FDA officials about any potential public health hazard associated with an approved food additive, and to delineate specific syndromes which may lead to focused clinical investigations. To date, among the products routinely monitored in the ARMS, sulfiting agents and the artificial sweetener aspartame have generated the largest volume of consumer reports describing adverse reactions. An overview of the analyses of the sulfite and aspartame adverse reaction reports is presented, along with a description of the mechanics of the postmarketing surveillance system, and a detailed discussion of its limitations. 5. Fountain SB; Hennes SK; Teyler TJ. Aspartame exposure and in vitro hippocampal slice excitability and plasticity. Fundamental and Applied Toxicology, 1988 Aug, 11(2):221-8. Abstract: Aspartame (APM) is a low-calorie sweetener recently approved and More <[Y],N,C,A>! released for widespread use in the United States. However, concerns still exist that APM consumption may be responsible for adverse neurological and psychological effects in some people. In addition, recent reports indicate that APM exposure may alter regional brain neurotransmitter levels. The present study assessed the effects of APM and its amino acid moieties on rat hippocampal slice excitability and plasticity. Specifically, tests of excitatory systems, inhibitory systems, and synaptic plasticity (induction of long-term potentiation--LTP) were administered postexposure. Exposures of 0.01, 0.1, 1, and 10 mM APM potentiated the response of hippocampal CA1 pyramidal cells, but had no apparent effect on local inhibitory systems. APM exposure did not block the establishment of LTP at any dose despite the potentiation of pyramidal cell response observed postexposure. In addition, 0.1 mM phenylalanine (PHE) produced a greater increase in excitability than that produced by an equivalent dose of APM, 0.1 mM aspartic acid (ASP) and 0.1 mM phenylalanine methyl ester (PM) produced effects comparable to those produced a smaller, but reliable, change in hippocampal CA1 excitability relative to baseline. Like APM, none of the amino acids produced detectable changes in inhibitory systems or neuronal plasticity. 6. Stegink LD; Filer LJ Jr; Baker GL; Bell EF; Ziegler EE; Brummel MC; Krause WL. Repeated ingestion of aspartame-sweetened beverage: effect on plasma amino acid concentrations in individuals heterozygous for phenylketonuria. Metabolism: Clinical and Experimental, 1989 Jan, 38(1):78-84. More <[Y],N,C,A>! Abstract: It has been suggested that excessive use of aspartame (APM) (N-L-alpha-aspartyl-L-phenylalanine methyl ester) might grossly elevate plasma aspartate and phenylalanine concentrations in individuals heterozygous for phenylketonuria (PKUH). In study 1 six adult PKUH (three males; three females) ingested three successive 12-oz servings of beverage at 2-h intervals. The study was carried out in two parts in a randomized crossover design. In one arm the beverage was not sweetened. In the other the beverage provided 10 mg APM/kg body weight per serving. The addition of APM to the beverage did not significantly increase plasma aspartate concentration but did increase plasma phenylalanine levels 2.3 to 4.1 mumol/dL above baseline values 30 to 45 min after each dose. The high mean plasma phenylalanine level after repeated APM dosing (13.9 +/- 2.15 mumol/dL) was slightly, but not significantly, above the normal postprandial range for PKUH (12.6 +/- 2.11 mumol/dL). In study 2 six different adult PKUH ingested beverage providing 30 mg APM/kg body weight as a single bolus. The high mean plasma phenylalanine concentration and the phenylalanine to large neutral amino acid ratio were significantly higher when APM was ingested as a single bolus than when ingested as a divided dose. 7. Garriga MM; Metcalfe DD. Aspartame intolerance. Annals of Allergy, 1988 Dec, 61(6 Pt 2):63-9. More <[Y],N,C,A>! Abstract: Aspartame is a food additive marketed under the brand name Nutrasweet. Aspartame is a white, odorless, crystalline powder and consists of two amino acids, L-aspartic acid and L-phenylalanine. It is 180 times as sweet as sugar. The Food and Drug Administration (FDA) first allowed its use in dry foods in July 1981 and then approved its use in carbonated beverages in July 1983. It has subsequently been approved for use in a number of materials including multivitamins, fruit juices, stick-type confections, breath mints, and iced tea. The FDA requires the statement "phenylketonurics: contains phenylalanine" on labels of food products containing aspartame because individuals with phenylketonuria (PKU) must restrict their intake of phenylalanine. Aspartame is judged to be free of long-term cancer risks. Aspartame is not stable under certain conditions including baking and cooking, and prolonged exposure to acid conditions. In such situations it loses its sweetness. Products formed from aspartame include its component amino acids (phenylalanine and aspartic acid), methanol, and diketopiperazine (DKP). Animal studies show DKP to be nontoxic. Methanol occurs in small amounts and does not exceed that formed during consumption of many foods including fresh fruits and vegetables. FDA's Center for Food Safety and Applied Nutrition (CFSAN) monitors aspartame's safety in part through reports of adverse reactions. After aspartame was approved for use in carbonated beverages, the FDA received an increased number of reports concerning adverse reactions related to aspartame. The Centers for Disease Control (CDC) reviewed these reports, More <[Y],N,C,A>! which included complaints of neurologic, gastrointestinal, andallergic reactions.(ABSTRACT TRUNCATED AT 250 WORDS) 8. Guiso G; Caccia S; Vezzani A; Stasi MA; Salmona M; Romano M; Garattini S. Effect of aspartame on seizures in various models of experimental epilepsy. Toxicology and Applied Pharmacology, 1988 Dec, 96(3):485-93. Abstract: We investigated in rats whether aspartame intake affected the susceptibility to seizures induced chemically (metrazol, quinolinic acid) or electrically (electroshock). Aspartame (0.75-1.0 g/kg), given orally as a single bolus to 16-hr fasted animals 60 min before metrazol, significantly increased the number of animals showing clonic-tonic seizures. At 1.0 g/kg the ED50 for clonic-tonic convulsions was lowered by 23%. A similar increase in seizure susceptibility was observed with 0.25-0.5 g/kg of the aspartame's metabolite phenylalanine. When aspartame was administered to fasted rats in three divided doses (0.33 g/kg) over 120 min or to fed animals after a meal, or overnight with the diet, no significant changes in the incidence of animals showing seizures was observed. One gram per kilogram aspartame and 0.5 g/kg phenylalanine did not modify the CC50 (mA) for tonic hindlimb extension induced by electroshock and the electroencephalographic seizures caused by intrahippocampal injection of 120 nmol quinolinic acid. Plasma and brain levels of phenylalanine and tyrosine significantly raised after both 1 g/kg More <[Y],N,C,A>! aspartame as a single bolus (plasma: Phe 285%, Tyr 288%; brain: Phe 146%, Tyr 192%; above controls) or in three divided doses (plasma: Phe 207%, Tyr 315%; brain Phe 103%, Tyr 211%; above controls) and 0.5 g/kg phenylalanine (plasma: Phe 339%, Tyr 410%; brain: Phe 219%, Tyr 192%; above controls), but the ratio Phe/Tyr was not modified. Our data indicate that aspartame cannot be regarded as a general proconvulsant agent. The mechanisms of potentiation of seizures induced by metrazol after the administration of the sweetner in a single rapid intake will be discussed. 9. Nabors LO. Saccharin and aspartame: are they safe to consume during pregnancy? [latter]. Journal of Reproductive Medicine, 1988 Aug, 33(8):102. 10. Copestake P. Aspartame--a bit of a headache? Food and Chemical Toxicology, 1988 Jun, 26(6):571. 11. Janssen PJ; van der Heijden CA. Aspartame: review of recent experimental and observational data. Toxicology, 1988 Jun, 50(1):1-26. Abstract: In this report the neurotoxicity of aspartame and its constituent amino acids aspartic acid and phenylalanine is reviewed. The adverse More <[Y],N,C,A>! reactions ascribed to the consumption of aspartame-containing products, as reported in the U.S.A., are discussed and placed in perspective with the results of recent behavioural studies in humans and animals. The issue of common intake levels associated with proposed uses of aspartame is addressed. In brief, the following conclusions can be drawn: When aspartame is consumed at levels within the ADI-limit of 40 mg/kg body wt, there is no significant risk for an aspartate-induced neurotoxic effect in the brain. When aspartame is consumed at levels within the ADI-limit by normal subjects or persons heterozygous for phenylketonuria (PKU) the resultant plasma phenylalanine concentrations are practically always within the normal postprandial range; elevation to plasma concentrations commonly associated with adverse effects has not been observed. Persons suffering from phenylketonuria (PKU-homozygotes) on a phenylalanine-restricted diet should avoid consumption of aspartame. PKU-homozygotes on the (less strict) phenylalanine-liberalized diet should be made aware of the phenylalanine content of aspartame. In the available behavioural studies in humans with acute dosing, no adverse effects were observed. Long-term studies on behaviour and cognitive function in (sensitive) humans are lacking. Analyses of adverse reaction reports made by consumers in the U.S.A. have not yielded a specific constellation of symptoms clearly related to aspartame that would suggest a widespread public health hazard associated with aspartame use. Focussed clinical studies are now being carried out in the U.S.A.; the results should provide additional evidence concerning the interpretation of the reports on adverse reactions ascribed to aspartame. More <[Y],N,C,A>! In the regulation of admitted uses for aspartame the possibility of intake levels exceeding the ADI-limit in some groups of consumers should be a point of attention. 12. Schiffman SS. Aspartame and headache [letter]. Headache, 1988 Jun, 28(5):370-2. 13. Aspartame and headache [letter]. New England Journal of Medicine, 1988 May 5, 318(18):1200-2. 14. Koehler SM; Glaros A. The effect of aspartame on migraine headache. Headache, 1988 Feb, 28(1):10-4. 15. Edmeads J. Aspartame and headache. Headache, 1988 Feb, 28(1):64-5. 16. London RS. Saccharin and aspartame. Are they safe to consume during pregnancy? Journal of Reproductive Medicine, 1988 Jan, 33(1):17-21. Abstract: Saccharin and aspartame are commonly used artificial sweeteners. Some More <[Y],N,C,A>! of the currently available information on their safety in pregnancy was reviewed, with recommendations formulated on their use in the periconceptional period and pregnancy. 17. Pinto JM; Maher TJ. Administration of aspartame potentiates pentylenetetrazole- and fluorothyl-induced seizures in mice. Neuropharmacology, 1988 Jan, 27(1):51-5. Abstract: An association has recently been proposed between the incidence of seizures and prolonged consumption of the phenylalanine-containing artificial sweetener, aspartame. Since consumption of aspartame, unlike dietary protein, can elevate phenylalanine in brain, and thereby inhibit the synthesis and release of neurotransmitters known to protect against seizure activity, the effect of oral doses of aspartame on the sensitivity of mice to the proconvulsant agents, pentylenetetrazole and fluorothyl was studied. Doses of aspartame were used which increased phenylalanine more than tyrosine in brain, as occurs in humans after the consumption of any dose of aspartame. Pretreatment with aspartame significantly increased the percentage of animals convulsing after administration of pentylenetetrazole and significantly lowered the CD50 for this convulsant. The average time to onset of seizures induced by fluorothyl in control mice was 510 sec; pretreatment with oral doses of 1000, 1500 and 2000 mg/kg of aspartame 1 hr earlier significantly reduced the time required to elicit seizures (394, More <[Y],N,C,A>! 381 and 339 sec, respectively). The seizure-promoting effect of aspartame could be demonstrated 30, 60 or 120 min after the 1000 mg/kg dose. The seizures induced by either convulsant were potentiated by equimolar amounts of phenylalanine, a major endogenous metabolite of aspartame, while the other metabolites, aspartic acid and methanol, were without effect. Administration together with aspartame of the large neutral amino acid valine, which competes with phenylalanine for entry into the brain, completely abolished the seizure-promoting effect of aspartame.(ABSTRACT TRUNCATED AT 250 WORDS) 18. Lout RK; Messer LB; Soberay A; Kajander K; Rudney J. Cariogenicity of frequent aspartame and sorbitol rinsing in laboratory rats. Caries Research, 1988, 22(4):237-41. Abstract: The cariogenicity of frequent rinsings with aspartame and sorbitol was studied in the rat caries model with animals randomly assigned to four oral rinse groups (16 rats/group): 0.05% aspartame, 20% sorbitol, deionized distilled water, and 20% sucrose; all solutions at pH 3.0. After rinsing five times daily for 21 days, mandibular molars were scored for caries. Smooth surface, proximal and morsal caries scores did not differ significantly between groups. Moderate dentinal sulcal caries for the sucrose group was significantly greater than in the aspartame, sorbitol, and water groups (p less than 0.05). Rinsing with 0.05% aspartame (similar in pH and concentration to that found in carbonated beverages) or sorbitol did not potentiate caries activity. 19. Position of the American Dietetic Association: appropriate use of nutritive and non-nutritive sweeteners. Journal of the American Dietetic Association, 1987 Dec, 87(12):1689-94. Abstract: Moderation in the consumption of nutritive and non-nutritive sweeteners appears to be prudent advice for persons who choose to use sweeteners. The major benefit from use of sweeteners is a perceived More <[Y],N,C,A>! c improvement in the quality of life. Some nutritive sweeteners also provide important textural properties to many foods. Sweeteners should be used in the context of an otherwise nutritious and well-balanced diet. Excessive intake of any sweetener requires nutrition counseling for basic nutrition reasons. An individual can minimize potential risks from any one sweetener by using a variety of available sweeteners, thus ingesting less of any specific sweetener. Research into possible risks of long-term uses of non-nutritive sweeteners, either alone or in combination, should continue. It is important that the public have a choice of various non-nutritive sweeteners, with safe and reasonable guidelines on how to use each. As new sweeteners become available, they must receive the same rigorous testing to which previously approved sweeteners have been subjected. 20. Schiffman SS; Buckley CE 3d; Sampson HA; Massey EW; Baraniuk JN; Follett JV; Warwick ZS. Aspartame and susceptibility to headache. New England Journal of Medicine, 1987 Nov 5, 317(19):1181-5. Abstract: We performed a double-blind crossover trial of challenges with 30 mg of aspartame per kilogram of body weight or placebo in 40 subjects who reported having headaches repeatedly after consuming products containing aspartame. The incidence rate of headache after aspartame (35 percent) was not significantly different from that after placebo (45 percent) (P less than 0.50). No serious reactions were observed, and the incidence of symptoms other than headache following aspartame was also equivalent to that after placebo. No treatment-related effects were detected in vital signs, blood pressure, or plasma concentrations of cortisol, insulin, glucagon, histamine, epinephrine, or norepinephrine. Most of the subjects were well educated and overweight and had a family or personal history of allergic reactions. The subjects who had headaches had lower plasma concentrations of norepinephrine (P less than 0.0002) and epinephrine (P less than 0.02) just before the development of headache. We conclude that in this population, aspartame is no more likely to produce headache than placebo. 21. Maher TJ; Wurtman RJ. Possible neurologic effects of aspartame, a widely used food additive. Environmental Health Perspectives, 1987 Nov, 75:53-7. Abstract: The artificial sweetener aspartame (L-aspartyl-L-phenylalanyl-methyl ester), is consumed, primarily in beverages, by a very large number of Americans, causing significant elevations in plasma and, probably, brain phenylalanine levels. Anecdotal reports suggest that some people suffer neurologic or behavioral reactions in association with aspartame consumption. Since phenylalanine can be neurotoxic and can affect the synthesis of inhibitory monoamine neurotransmitters, the phenylalanine in aspartame could conceiveably mediate neurologic effects. If mice are given aspartame in doses that elevate plasma phenylalanine levels more than those of tyrosine (which probably occurs after any aspartame dose in humans), the frequency of seizures following the administration of an epileptogenic drug, pentylenetetrazole, is enhanced. This effect is simulated by equimolar phenylalanine and blocked by concurrent administration of valine, which blocks phenylalanine's entry into the brain. Aspartame also potentiates the induction of seizures by inhaled fluorothyl or by electroconvulsive shock. Perhaps regulations concerning the sale of food additives should be modified to require the reporting of adverse reactions and the continuing conduct of mandated safety research. 22. Kruesi MJ; Rapoport JL; Cummings EM; Berg CJ; Ismond DR; Flament M; Yarrow M; Zahn-Waxler C. Effects of sugar and aspartame on aggression and activity in children. American Journal of Psychiatry, 1987 Nov, 144(11):1487-90. Abstract: Habitual sugar consumption and behavior following challenge by sugar and aspartame were studied in 30 preschool boys. The 18 subjects whose parents considered them sugar reactive had more disruptive behavior problems at baseline than the other 12 subjects. Habitual sugar consumption correlated only with duration of aggression against property in alleged responders. Double-blind crossover challenges with aspartame, saccharin, sucrose, and glucose produced no significant effect on aggression or observers' ratings of behavior. Lower actometer counts followed the trials of aspartame, but the difference was not apparent to observers. It is unlikely that sugar and aspartame are clinically significant causes of disruptive behavior. 23. Alfin-Slater RB; Pi-Sunyer FX. Sugar and sugar substitutes. Comparisons and indications. Postgraduate Medicine, 1987 Aug, 82(2):46-50, 53-6. Abstract: Public confusion and concern about the use of sugar and sugar substitutes are widespread. Physicians must be prepared to answer patients' inquiries about these substances. Some population groups should avoid certain sugar substitutes. In particular, pregnant women and young children should avoid saccharin, and phenylketonuric homozygous persons should avoid aspartame. In a varied, balanced diet, the use of aspartame and saccharin is one safe way for the general population to enjoy sweet foods with fewer calories and less cariogenic potential. Sugar substitutes may be helpful in dietary compliance for overweight and diabetic patients. 24. The safety of aspartame [letter]. Jama, 1987 Jul 10, 258(2):205-6. 25. Stegink LD. The aspartame story: a model for the clinical testing of a food additive. American Journal of Clinical Nutrition, 1987 Jul, 46(1 Suppl):204-15. Abstract: Toxicology is based on the premise that all compounds are toxic at some dose. Thus, it is not surprising that very large doses of aspartame (or its components--aspartate, phenylalanine, and methanol) produce deleterious effects in sensitive animal species. The critical question is whether aspartame ingestion is potentially harmful to humans at normal use and potential abuse levels. This paper reviews clinical studies testing the effects of various doses of aspartame upon blood levels of aspartate, phenylalanine, and methanol. These studies demonstrate that blood levels of these compounds are well below levels associated with adverse effects in sensitive animal species. 26. Dews PB. Summary report of an International Aspartame Workshop. Food and Chemical Toxicology, 1987 Jul, 25(7):549-52. 27. Zametkin AJ; Karoum F; Rapoport JL. Treatment of hyperactive children with D-phenylalanine. American Journal of Psychiatry, 1987 Jun, 144(6):792-4. Abstract: Eleven hyperactive boys were treated for 2 weeks with D-phenylalanine (20 mg/kg per day) and for 2 weeks with placebo in a double-blind crossover study. Tests included parent and teacher behavior ratings, cognitive measures, and blood and urine measures of norepinephrine, amino acids, and trace amines. No significant improvement or deterioration in behavior and no side effects were noted, and only serum phenylalanine was increased by the active treatment phase. This provides reassurance about the toxicity of aspartame, a food additive that contains phenylalanine, but argues against precursor loading treatment of hyperactivity. 28. Freedman M. Consumption of aspartame by heterozygotes for phenylketonuria [letter]. Journal of Pediatrics, 1987 Apr, 110(4):662-3. 29. Maher TJ. Natural food constituents and food additives: the pharmacologic connection. Journal of Allergy and Clinical Immunology, 1987 Mar, 79(3):413-22. itory monoamine neurotransmitters, the phenylalanine in aspartame could conceiveably mediate neurologic effects. If mice are given aspartame in doses that elevate plasma phenylalanine levels more than those of tyrosine (which probably occurs after any aspartame dose in humans), the frequency of seizures following the administration of an epileptogenic drug, pentylenetetrazole, is enhanced. This effect is simulated by equimolar phenylalanine and blocked by concurrent administration of valine, which blocks phenylalanine's entry int