Glucophage SR

By W. Knut. Pfeiffer University.

Early management of risk fac- monounsaturated and polyunsaturated tors for coronary heart disease is a fat (fatty acids containing one or more major public health goal that can as- double bonds) purchase glucophage sr 500 mg fast delivery. Although the specific roles of ally purchase 500mg glucophage sr with visa, consuming diets high in fruits order 500 mg glucophage sr fast delivery, these plant foods are not yet fully un- vegetables generic 500 mg glucophage sr mastercard, and grain products, foods derstood, many studies have shown that contain soluble fiber, may be a that diets high in plant foods are asso- useful adjunct to a low saturated fat ciated with reduced risk of coronary and low cholesterol diet. I (4–1–10 Edition) (2) Other risk factors for coronary (C) The claim is limited to those heart disease include a family history fruits, vegetables, and grains that con- of heart disease, high blood pressure, tain fiber; diabetes, cigarette smoking, obesity (D) In specifying the dietary fiber, (body weight 30 percent greater than the claim uses the term "fiber," "die- ideal body weight), and lack of regular tary fiber," "some types of dietary physical exercise. Intakes of choles- (E) In specifying the fat component, terol are, on average, at or above rec- the claim uses the terms "saturated ommended levels. Intakes of fiber-con- fat" and "cholesterol;" and (F) The claim indicates that develop- taining fruits, vegetables, and grain ment of heart disease depends on many products are about half of rec- factors; and ommended intake levels. One of the (G) The claim does not attribute any major public health recommendations degree of risk reduction for coronary relative to coronary heart disease risk heart disease to diets low in saturated is to consume less than 10 percent of fat and cholesterol and high in fruits, calories from saturated fat, and an av- vegetables, and grain products that erage of 30 percent or less of total cal- contain fiber. Results of numerous studies be declared in the nutrition informa- have shown that fiber-containing tion panel, consistent with fruits, vegetables, and grain products §101. Cancer has many consistent with "Nutrition and Your causes and stages in its development. Health: Dietary Guidelines for Ameri- Both genetic and environmental risk cans," U. Persons con- The sources of this information shall suming these diets frequently have be identified, and it shall be current in- high intakes of these nutrients. The following diets rich in fruits and vegetables, in- model health claims may be used in cluding but not necessarily limited to food labeling to characterize the rela- dietary fiber, vitamin A (as beta-caro- tionship between diets low in saturated tene) and vitamin C, to displacement of fat and cholesterol and high in fruits, fat from such diets, or to intakes of vegetables, and grain products that other substances in these foods which contain soluble fiber: are not nutrients but may be protec- (1) Diets low in saturated fat and tive against cancer risk. The overall economic costs of cancer, (2) Development of heart disease de- including direct health care costs and pends on many factors. Eating a diet losses due to morbidity and mortality, low in saturated fat and cholesterol are very high. Stud- grain products that contain fiber may ies in various parts of the world indi- lower blood cholesterol levels and re- cate that populations who habitually duce your risk of heart disease. I (4–1–10 Edition) diets generally are low in fat and rich (J) The claim indicates that develop- in many nutrients, including, but not ment of cancer depends on many fac- limited to, dietary fiber, vitamin A (as tors. A health claim associating diets low in fat and high in fruits and substances in diets low in fat and high vegetables and some types of cancer in fruits and vegetables with reduced and the significance of the relation- risk of cancer may be made on the ship. Broccoli is results consistent with the conclusion high in vitamins A and C, and it is a that folate, at levels attainable in good source of dietary fiber. Eating a diet low in fat (b) Significance of folate—(1) Public and high in fruits and vegetables, foods health concern. Neural tube defects that are low in fat and may contain vi- occur in approximately 0. However, about 90 percent of in- ral tube defects are serious birth de- fants with a neural tube defect are fects of the brain or spinal cord that born to women who do not have a fam- can result in infant mortality or seri- ily history of these defects. The birth defects able evidence shows that diets ade- anencephaly and spina bifida are the quate in folate may reduce the risk of most common forms of neural tube de- neural tube defects but not of other fects and account for about 90 percent birth defects. Prevalence from failure of closure of the covering rates for neural tube defects have been of the brain or spinal cord during early reported to vary with a wide range of embryonic development. Because the factors including genetics, geography, neural tube forms and closes during socioeconomic status, maternal birth early pregnancy, the defect may occur cohort, month of conception, race, nu- before a woman realizes that she is trition, and maternal health, including pregnant. Rates for neural tube de- sumed a supplement containing 4 milli- fects vary within the United States, grams (mg)(4,000 micrograms (mcg)) with lower rates observed on the west folic acid daily before conception and coast than on the east coast. Based on a reduced risk of having a child with a synthesis of information from several neural tube defect. The claim shall neural tube defect incidence, ranges not attribute any specific degree of re- from none to substantial; a reasonable duction in risk of neural tube defects estimate of the expected reduction in from maintaining an adequate folate the United States is 50 percent. It is ex- intake throughout the childbearing pected that consumption of adequate years. The claim shall state that some folate will avert some, but not all, neu- women may reduce their risk of a neu- ral tube defects. The underlying causes ral tube defect pregnancy by maintain- of neural tube defects are not known. Optional of neural tube defects will be averted statements about population-based es- by adequate folate consumption. From timates of risk reduction may be made the available evidence, the Public in accordance with paragraph (c)(3)(vi) Health Service estimates that there is of this section. However, until further Claims on foods that contain more research is done, no firm estimate of than 100 percent of the Daily Value this proportion will be available. The label or labeling adults and children 4 or more years of of food may contain a folate/neural age, or 800 mcg when labeled for use by tube defect health claim provided that: pregnant or lactating women) shall (1) General requirements. The food shall meet or exceed adequate amounts of folate daily dur- the requirements for a "good source" ing their childbearing years may re- of folate as defined in §101. The nutrition anencephaly or spina bifida," "spina label shall include information about bifida and anencephaly, birth defects of the amount of folate in the food. This the brain or spinal cord," "birth de- information shall be declared after the fects of the brain or spinal cord;" or declaration for iron if only the levels of "brain or spinal cord birth defects. The claim iron are provided, or in accordance shall not imply that folate intake is with §101. The claim may specifically iden- tained in paragraph (b)(3) of this sec- tify risk factors for neural tube de- tion may be used. The with insulin-dependent diabetes claim may identify diets adequate in mellitus; those with seizure disorders folate by using phrases such as who are being treated with valproic "Sources of folate include fruits, vege- acid or carbamazepine) or from other tables, whole grain products, fortified parts of this paragraph (c)(3)(i). The claim may in- tained from diets rich in fruits, dark clude statements from paragraphs (a) green leafy vegetables, legumes, whole and (b) of this section that summarize grain products, fortified cereals, or die- the relationship between folate and tary supplements. The claim rice, and pasta, fortified cereals, or a may state that women with a history dietary supplement. The following should consult their physicians or are examples of model health claims health care providers before becoming that may be used in food labeling to de- pregnant. If such a statement is pro- scribe the relationship between folate vided, the claim shall also state that and neural tube defects: all women should consult a health care provider when planning a pregnancy. The claim may provide required elements: estimates, expressed on an annual (i) Healthful diets with adequate basis, of the number of neural tube de- folate may reduce a woman’s risk of fect-affected births among live births having a child with a brain or spinal in the United States. Model health claim ap- unless more current estimates from the propriate for foods containing 100 per- U. An estimate of tional information: Women who con- the reduction in the number of neural sume healthful diets with adequate tube defect-affected births that might folate throughout their childbearing occur in the United States if all women years may reduce their risk of having a consumed adequate folate throughout child with a birth defect of the brain or their childbearing years may be in- spinal cord. Frequent between-meal ucts, fortified cereals, and dietary sup- snacks that are high in sugars and plements. Model health claim ap- than eating such foods at meals and propriate for foods intended for use by then brushing. The noncariogenic (a) Relationship between dietary carbo- carbohydrate sweeteners listed in para- hydrates and dental caries. The rate and amount of acid mental and genetic factors can affect production is significantly less than the development of dental caries. Risk that from sucrose and other ferment- factors include tooth enamel crystal able carbohydrates and does not cause structure and mineral content, plaque the loss of important minerals from quantity and quality, saliva quantity tooth enamel. Sucrose, also known as sugar, is noncariogenic carbohydrate sweet- one of the most, but not the only, eners, compared to other carbo- cariogenic sugars in the diet. Bacteria hydrates, and the nonpromotion of den- found in the mouth are able to metabo- tal caries may be made on the label or lize most dietary carbohydrates, pro- labeling of a food described in para- ducing acid and forming dental plaque. Al- (B) The claim shall state that the though there has been a decline in the noncariogenic carbohydrate sweetener prevalence of dental caries among chil- present in the food "does not pro- dren in the United States, the disease mote," "may reduce the risk of," remains widespread throughout the "useful [or is useful] in not pro- population, imposing a substantial bur- moting," or "expressly [or is expressly] den on Americans. Box, Ch–4009 tal caries to the use of the Basel, Switzerland, or you may exam- noncariogenic carbohydrate sweetener- ine a copy at the Center for Food Safe- containing food. Wiley Federal Building, 5100 consuming noncariogenic carbohydrate Paint Branch Pkwy. The following those listed in paragraph (c)(2)(ii) of model health claims may be used in this section are present in the food, the food labeling to describe the relation- food shall not lower plaque pH below ship between noncariogenic carbo- 5. The sugar al- cholesterol levels of 240 milligrams per cohols in [name of food] do not pro- deciliter (mg/dL) (6. Border- sugars and starches as between-meal line high risk total cholesterol levels snacks can promote tooth decay.

The phenothiazine tranquilizers might be expected to produce a sufficient lack of concern in the subject to prevent his attempting to undo their effect discount glucophage sr 500mg overnight delivery, or glucophage sr 500 mg free shipping, more directly generic glucophage sr 500 mg on-line, preclude a state of arousal discount 500 mg glucophage sr otc. Summary and Conclusions Nature of Reviewed Studies A distinction has been made between interviews carried out for psychotherapy and those to obtain factual information. Although there has been considerable speculation regarding the possible use of drugs for the latter purposes, open publications of serious research dealing directly with such cases are scant. The paucity of reported studies on the matter has obliged the reviewer to include related published material of psychopharmacologic studies. When extrapolations are made from published material of this sort, they are presented as hypotheses, and in every instance require testing and validation. The interest of scientists in employing drugs in research transcends an interest in drug effects, per se. Drugs constitute valuable tools for experimentation directed toward developing basic physiologic and psychologic knowledge, such as the study of neurophysiologic correlates of symbolic and psychodynamic processes. Work by scientists in such areas is also likely to increase knowledge of drugs which may be applicable to interrogation. Methodologic Problems in Determining the Applicability of Drugs to Interrogation Procedures A large initial section of this report is devoted to a survey and discussion of the nonspecific effects of drugs and to the difficulties involved in discriminating these effects from the pharmacologic effects of the drugs used. The time spent in describing some of these nonspecific factors is needed to illustrate how the many variables involved complicate the problem of making a judgment regarding the present or potential usefulness of a drug for either therapeutic or intelligence purposes. This section has been included to point out some of the problems which require consideration in designing well-controlled studies in this area. The complexity inherent in psychopharmacologic research requires the integration of all levels of research on drug action: biochemical, neurophysiological and psychological. These problems are multiplied and prediction is lessened when the actions of drugs on living human beings are considered, rather than on isolated nerves, tissues, or animals of simpler neural structure. This reviewer has included only very few bibliographical references to work with animals, and yet a significant portion of excellent experimental, psychologic studies involve animals. This relative omission can be explained by the problem being one unique to human beings: the use of language symbols to communicate and interact with other human beings. A review of the literature illustrates a variety of effects produced by pharmacologically inert substances which simulate medication -129- (placebos). Depending on the personality of the subject and the circumstances under which the placebo is administered, 30 to 50 per cent of individuals show or experience a reaction. Well-designed studies can distinguish the pharmacologic effect of a drug from the placebo effect. The possibility is raised that an interrogator might exploit the "placebo phenomenon" with a susceptible subject, instead of employing a pharmacologically active drug. An examination of the literature demonstrates that the effects of drugs vary with the attitude and motivation of the person administering the medication and the person interviewing the informant. The sex and intelligence of the subject, the presence of mental or physical illness, the occurrence of biologic rhythms (e. The method of sampling the verbal behavior of an individual under the influence of a drug, directive, nondirective, free-associative, etc. For these reasons, it is recommended that a variety of sampling methods be used in experimental studies. The Efficacy of Drugs in Uncovering Information When one examines the literature for experimental and clinical studies that bear directly on the use of drugs in interrogation procedures, one finds relatively few studies. Reports dealing with the validity of material extracted from reluctant informants, whether criminal suspects or experimental subjects, indicate that there is no "truth serum" which can force every informant to report all the information he has. Experimental and clinical evidence indicate that not only the inveterate criminal psychopath may lie or distort under the influence of a drug, but the relatively normal individual may, with many drugs, successfully disguise factual data. Less well-adjusted individuals, plagued by guilt and depression, or suggestible individuals, who are compliant and easily swayed, are more likely to make slips revealing withheld information. Even they may, at times, unconsciously distort information and present fantasies as facts. The anesthetic action of the drug, as in narcosis with barbiturates, can interfere with cerebral functioning and promote the presentation of fantasy material as fact, or otherwise alter the form of verbalizations to render them relatively unintelligible. It would be very difficult under these circumstances for an interrogator to tell when the verbal -130- content was turning from fact to fantasy, when the informant was simulating deep narcosis but actually falsifying, which of contrary stories told under narcosis was true, and when a lack of crucial information coining from a subject under a drug meant the informant had none to offer. To derive useful information from an interrogation in which drugs are employed, an interrogator would have to consider and weigh many important factors: the personality of the subject, the milieu, other sources of evidence, the rapport obtained, and the skill of the questioning. These and other factors affect the validity of information obtained from an informant under sedation. Specific Effects of Drugs in Interrogation Situations Advantages and limitations of a number of different types of pharmacologic agents as adjuncts to interrogation can be examined by reviewing clinical and experimental data from the works of psychiatrists, neurologists, psychologists, physiologists, and pharmacologists. Barbiturates tend to increase contact and communication, decrease attention, decrease anxiety, decrease psychotic manifestations, and make the mood more appropriate and warmer. When combined with interview techniques that aim at arousing emotions, strong emotional reactions may be catalyzed for psychotherapeutic purposes. Barbiturates have been found helpful in detecting whether an individual is feigning knowledge of the English language and in getting mute catatonic schizophrenics and hysterical aphasics to talk. They are of no avail, however, in remedying the speech defects of true aphasics, even transiently. The use of barbiturates has helped to get more reliable estimates of intelligence and personality through psychological tests, particularly in emotionally upset individuals. The use of various stimulant and antidepressive drugs has been explored, for diagnostic and therapeutic purposes in psychiatric practice, but not to any extent for interrogation. Amphetamine, pipradrol, methylphenidylacetate have in common the capacity to produce an outpouring of ideas, emotions, and memories. An injection of amphetamine following an intravenous barbiturate is said to provoke a striking onrush of talking and activity from psychiatric patients. Without adequately controlling his study, one author claims that methamphetamine produces such a strong urge to talk that the criminal who feigns amnesia or withholds vital information cannot control himself and thus gives himself away. Iproniazid, an antidepressive drug which is relatively slow and sometimes dramatic in its thera- -131- peutic effect, should be considered for experimentation. This drug, and similar, less toxic analogs which are being developed, might be considered for use in special instances. For example, informants suffering from chronic depression, whether due primarily to emotional factors, situational stress, or physical debilitation, might become very responsive after using a medication of this type. As a class, the stimulants probably present the most obvious exploitative potential for an interrogator. The use of such drugs by an interrogator would tend to produce a state of anxiety or terror in most subjects, and promote perceptual distortions and psychotic disorientation. Their use could constitute a definite threat to most medically unsophisticated subjects, i. When the subject is not under the influence of such drugs, vital information might be extracted as a price for ceasing further medication. An enlightened informant would not have to feel threatened, for the effect of these hallucinogenic agents is transient in normal individuals. The information given during the psychotic drug state would be difficult to assess, for it may be unrealistic and bizarre. The introduction of new drugs like tranquilizers that sedate but do not impair intellectual functioning in moderate dosage (e. There is a possibility that these tranquilizers might be of use with selected informants who are highly agitated and disturbed, and who might give information they prefer to withhold in return for the tranquility they experience with such a sedative. Under the influence of this drug, the less emotionally upset informant might find that he can better master his anxieties and keep his resolve to remain silent. The ability of the subject to give information is not notably affected by a mainte- -132- nance dosage. The motivational effects of obtaining drug supplies, while extreme, are not of a different order for most subjects than those which the interrogator could produce by other more rapid means. The exploitation of addiction probably constitutes a threat to persons previously addicted, or to those who become addicted in the captivity situation as a sequel to other aspects of their treatment, rather than through the deliberate creation of addiction for exploitative purposes. Another use to which interrogators might put drugs and placebos would involve their ability to absolve the subject of responsibility for his acts. The popular meaning of being "drugged" or "doped" implies that an individual in this state has lost control over his actions and that society will not hold him responsible for them. When the transmittal of information is likely to induce guilt in the source, the interviewer can forestall some of this reaction by the administration of a placebo or drug. In some cases, this will be all that is require4l to remove the barrier to information transmittal.

Phenolphthalein did not induce sister chromatid exchange in Chinese hamster ovary cells in the presence or absence of exogenous metabolic activation buy glucophage sr 500mg amex, but it induced a dose-related response in chromosomal aberrations in these cells only in the presence of exogenous metabolic activation buy cheap glucophage sr 500mg on line. In experiments in which a number of end-points were studied in Syrian hamster embryo cells (a mixed population of cell types that retain some endogenous metabo- lizing enzymic activity discount glucophage sr 500mg with visa, including oxidation and peroxidation) purchase glucophage sr 500 mg with mastercard, phenolphthalein induced chromosomal aberrations and Hprt mutations, but not ouabain mutations or aneuploidy. Phenolphthalein caused cellular transformation in the same cell line, indicating that it is metabolized appropriately in this system. They found significant increases in the frequency of micronucleated ery- throcytes, most of which appeared to arise from whole chromosomes rather than chromosomal damage; these were observed at doses comparable to those to which humans are exposed. In phenolphthalein-induced thymic lymphomas in B6C3F1 mice, p53 protein accumulated in most tumour cell nuclei, but detectable p53 protein was not seen in control thymuses in this model (Dunnick et al. Other studies have shown that accumulation of p53 protein results from p53 gene alterations (Hegi et al. In p53+/– heterozygous mice, phenolphthalein induced atypical hyperplasia and malignant lymphomas of thymic origin within six months in 0% of controls, 5% of animals at 200 mg/kg, 5% at 375 mg/kg, 25% at 750 mg/kg, 100% at 3000 mg/kg and Table 5. Two of two thymic lymphomas examined from animals at 750 mg/kg, 13/13 from those at 3000 mg/kg and 6/6 from those at 12 000 mg/kg had lost the remaining p53 wild-type allele (Dunnick et al. No spontaneous thymic lymphomas were found in control mice in these studies, but in other studies in p53+/– mice of spontaneous tumours (which may occur in mice after one year of age), only 55% showed loss of the remaining functional p53 allele (Harvey et al. When this protein is absent, as is the case in phenolphthalein-induced thymic lym- phomas, regulation of cell cycle electrophoresis is lost and malignant progression may be enhanced. Generally available without prescription, it is now being withdrawn from the market in many countries because of recent toxicological concern. Phenolphthalein has also long been used in the laboratory as an indicator in acid–base titrations. In one experiment in mice, it induced histiocytic sarcomas and lymphomas in both males and females and benign ovarian tumours in females. In an experiment in mice lacking one allele of the p53 tumour suppressor gene, it increased the incidence of lymphomas. It induced benign renal tumours in male rats and benign phaeochromocytomas in males and females. As it passes through the small intestine, it is partially deconjugated and reabsorbed. Phenolphthalein and its glucuronide enhance oxygen radical production and cause oxidative damage in vitro. Phenolphthalein has also been shown to have low oestrogenic activity in some model systems. Phenolphthalein induced micronucleated erythrocytes in mice given multiple but not single treatments by gavage or in feed. Abnormal spermatozoa were induced in male mice but not male rats treated with phenolphthalein in the feed for 13 weeks. The malignant thymic lymphomas induced by phenolphthalein in female heterozygous p53-deficient mice showed loss of the normal p53 allele. Phenolphthalein induced chromosomal aberrations, Hprt gene mutations and morphological transformation but not aneuploidy or ouabain-resistant mutations or sister chromatid exchange in cultured mammalian cells. There is sufficient evidence in experimental animals for the carcinogenicity of phenolphthalein. Biphenyl, stilboestrol and phenolphthalein in the rat: Molecular weight, polarity and meta- bolism as factors in biliary excretion. The Metabolism and Detoxication of Drugs, Toxic Substances and Other Organic Compounds, 2nd Ed. The K vitamins all contain the 2-methyl-1,4-naphthoquinone (menadione) moiety, and the various naturally occurring forms differ in the alkyl substituent at the 3-position. Phylloquinone (vitamin K1) is 2-methyl-3-phytyl-1,4-naphthoquinone and is widely found in higher plants, including green leafy vegetables, and in green and blue algae. The menaquinones (formerly vitamin K2) have polyisoprenyl substituents at the 3-position and are produced by bacteria. The compound menadione (formerly vitamin K3) lacks an alkyl group at the 3-position but can be alkylated in vivo in some species. Several synthetic water-soluble derivatives, such as the sodium diphosphate ester of menadiol and the addition product of menadione with sodium bisulfite, also have commercial applications (National Research Council, 1989; Gennaro, 1995; Weber & Rüttimann, 1996). The United States Pharmaco- peia uses the name ‘phytonadione’; The European Pharmacopoeia uses the name ‘phytomenadione’, which is a synonym occasionally found in the pharmaceutical and pharmacological literature. In the biolo- gical literature, vitamin K2 is frequently referred to as menaquinone and is further designated by the number of isoprene units in the side-chain. For example, vitamin K2(20) is also called menaquinone-4 for the four isoprene units in the side-chain. The compound originally isolated from rotting fish meal and named vitamin K2 was later identified as menaquinone-7 (2-methyl-3-farnesylgeranyl-geranyl-1,4-naphthoquinone). In the older literature, the designation vitamin K2(35) is used for menaquinone-7, but this is no longer used. Menaquinones found in nature have side-chains of 4–13 isoprenoid residues and are usually in the all-trans configuration; however, menaquinones with the cis confi- guration and partially saturated side-chains also exist (Suttie, 1985, 1991; Weber & Rüttimann, 1996; Van Arnum, 1998). Phylloquinone occurs in nature only as the 2′,3′-trans-phylloquinone stereoisomer (Weber & Rüttimann, 1996; American Hospital Formulary Service, 1997; Council of Europe, 1997). Phylloquinone is available as a 5- and 10-mg tablet (chewable), a 2- and 10 mg/mL injection solution, a 10- and 20-mg/mL oral solution and a 20-mg/mL emulsion. The tablet may also contain carmellose, carob bean flour, carob gum, cocoa butter, cocoa powder, ethyl cellulose, ethyl vanillin, glucose, glycerol, gum arabic, hard and viscous paraffin, lactose, rice starch, sugar, silicic acid, silicon dioxide, skim- milk powder, sodium cyclamate, talc and titanium dioxide. The injection solution may also contain benzyl alcohol, dextrose, glacial acetic acid, glucose, glycocholic acid, hydrochloric acid, macrogol ricinoleate, phenol, phosphatidylcholine from soya beans, polyethoxylated fatty acid derivative (castor oil), polysorbate 80, propylene glycol, sodium acetate, sodium hydroxide and water. The oral solution may also contain benzoic acid, glycocholic acid, hydrochloric acid, lecithin, macrogol ricino- leate, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate, sodium hydroxide and water. Menaquinone-4 is available in Japan as 5- and 15-mg capsules and as a 2-mg/mL syrup. The syrup may also contain polyoxyethylene hydrogenated castor oil 60, propylene glycol, ethyl parahydroxybenzoate, sodium benzoate and flavouring (Japan Medical Products Trade Association, 1996). Trade names for menaquinone-4 include Glakay and Kaytwo (Japan Medical Products Trade Association, 1996). Menadione is available as a 2-, 5- and 10-mg tablet and as a 2- and 10-mg/mL injection (in oil). Menadione sodium bisulfite is available as a 10-mg tablet and as a 5- and 10-mg/mL and 72-mg/10 mL injection (Gennaro, 1985). Trade names for menadione sodium bisulfite include Austrovit-K, Golagen K, Hemoklot, Hetrogen K, Hetrogen K Premix, Hykinone, Ido-K, K-Thrombin, K- Trombina, Kalzon, Kareon, Kavitamin, Kavitan, Kavitol, Kawitan, Klotogen, Libavit K, Nuvit K, Vikaman, Vikasol, Vitaminum K and Zimema K (Swiss Pharmaceutical Society, 1999). Trade names for menadiol sodium phosphate hexahydrate include Kappadione, Kativ (injection), Kipca water soluble, Naphthidone, Procoagulo, Synkavit, Synka- Vit, Synkavite, Synkayvite and Thylokay (Swiss Pharmaceutical Society, 1999). Trade names for acetomenaphthone include Adaprin, Davitamon-K, Davitamon-K- oral, Kapathrom, Kapilin, Kapilon, Kappaxan, Kativ powder, Kayvite, Pafavit, Pro- kayvit Oral and Vitavel K. The limit of detection of phylloquinone is 25–500 pg, depending on the detection method used. Similar values, which vary according to the length of the side- chain, apply to the menaquinones. Alternative methods are thin-layer chromatography, high-performance thin-layer chromatography and gas chromatography. The stability of phylloquinone to heat made possible the use of commercially dehydrated alfalfa meal, for example, as a natural source (Hassan et al. The synthesis and spectral properties of all four stereoisomers of (E)-phylloquinone have been described and their biological potencies determined. When natural phylloquinone was used as a standard in bioassays, it was concluded that all four stereoisomers have essentially identical activity (Van Arnum, 1998). The first syntheses and structural elucidation of phylloquinone were published in 1939 almost simultaneously by four groups. The starting materials were menadione or menadiol as the aromatic component and natural phytol or one of its derivatives. A breakthrough in commercial synthesis was achieved in the 1950s, when it was found that monoacylated menadiols (e. In the Isler-Lindlar method, excess menadiol monobenzoate is condensed with iso- phytol in the presence of boron trifluoride etherate as a catalyst. The trans-enriched alkylation product (trans:cis 9:1) is saponified with potassium hydroxide and oxidized to phylloquinone with oxygen (Weber & Rüttimann, 1996). The industrial synthesis of menaquinones parallels that of phylloquinone and involves as a key step alkylation of monosubstituted menadione with an appropriate (all-trans) polyisoprenyl derivative.