Valmar

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Cap    Valmar
(Melatonin, 5-HTP, Pyridoxine & more)

Brand: Valmar
Generic: Melatonin, 5-HTP, Pyridoxine & more
Class: Medical Food Supplement
Route of administration: Oral
Dosage form: Capsule / Syrup
Dose: Capsule : Syrup
Contraindications: Pregnancy: Cat. C
Pack Size: 30 caps.
Price: Capsule: Rs. 410/- | Syrup: Rs. 170/-
Supplement facts:

Supplement Amount per serving
Melatonin 3mg
5-HTP 50mg
Pyridoxine 2mg
Valmar Blend (Valerian,GABA,L-Glycine,Passion flower, Lemon balm, L-theanine, English lavender) 519mg

1. Melatonin
Melatonin is an indoleamine with the chemical name N-acetyl-5-methoxytryptamine and is found in animals, plants, and bacteria. It has endocrine and antioxidant properties in both animals and plants. It is biosynthesized from the neurotransmitter serotonin, which in turn is made from the essential amino acid tryptophan. Because its normally charged amino group is acetylated and a methoxy rather than a hydroxyl group is present in the 5 position, melatonin is a relatively nonpolar compound that readily crosses the blood–brain barrier (BBB) and easily enters cells of all types. In mammals, melatonin has several roles; it is involved in circadian regulation and modulation of reproductive and immune responses, mood, and aging. It is produced by the pineal gland and several peripheral tissues, notably the gut [1]. Because it is liberated into the bloodstream from the pineal and acts through receptors located in a wide variety of body tissues, it can be considered a systemic hormone. Levels of melatonin vary diurnally, seasonally in some mammals, and throughout the life cycle. They are highest during hours of darkness and are lowest among the elderly. This chapter focuses on two areas: (i) recent findings suggesting a variety of therapeutic applications—ranging from improvement of disturbed sleep patterns and mood disorders to adjuvant cancer treatment and surgery and fertility enhancement and (ii) support for the safety of exogenously supplied melatonin. The potential molecular mechanisms underlying these potentially clinically beneficial uses are also discussed.

1.2. Range Of Conditions Where Melatonin May Have Clinical Utility
The evidence for the beneficial properties of melatonin in the derangements described is often derived from studies on animal models of disease, but any relevant human findings are also added to each section.

1.2.1. Disturbances of Sleep Patterns
Melatonin is perhaps most well-known for its ability to induce sleep. Plasma levels are highest during hours of darkness and decline rapidly at the onset of light. Thus, melatonin is widely used to reset normal circadian sleep patterns after disruption by jet lag. Sleep quality can be defined by tiredness upon waking, feeling rested, and the number of awakenings experienced during the night. This can be partly correlated with objective polygraphic measures to determine the extent of fragmentation of sleep. Melatonin has been found to improve sleep quality in patients with a variety of diseases. A dosage of 3 mg/day taken at bedtime for 24 days in a group of 2,062 patients with chronic cerebral ischemia improved multiple types of subjective sleep characteristics [2]. An analysis was made combining results from four clinical trials studying the effects in 401 hypertensive patients aged 55 years or older. The analysis determined that 2 mg/ day of prolonged-release melatonin taken 2 h before bedtime for 3 weeks improved quality of sleep and morning alertness [3]. The improvements in sleep quality were maintained during a follow-up period of 6 months; moreover, the rate of adverse events was lower in the patients using melatonin. Although melatonin had no significant effect on blood pressure in this study, a meta-analysis of seven other clinical trials demonstrated that 2–3 mg/day of controlled-release (but not fast-release) melatonin over periods of 28–90 days significantly reduced nocturnal blood pressure in a variety of subjects, including those with hypertension [4]. In a study of 36 type 2 diabetic individuals, a regimen of 2 mg/day of prolonged-release melatonin taken 2 h before bedtime for 3 weeks resulted in significant improvement in sleep efficiency, wake time after sleep onset, and reduced number of awakenings [5].
The melatonin receptor agonist ramelteon has been used to treat chronic insomnia clinically with success [6]. Some studies demonstrate that melatonin improves sleep quality more modestly. In a recent review of 35 randomized clinical trials, use of melatonin by healthy adults was found to show limited promise for preventing phase shifts from jet lag and for improving insomnia; both healthy adults and insomniacs benefited. However, available data could not confirm a positive benefit for either the initiation of sleep or sleep efficacy [7]. Aging is associated with an altered sleep profile; sleep time is shortened and sleep is more disrupted. Sleeplessness is often found with cardiovascular disease, obesity, type 2 diabetes, cancer, and a range of inflammatory disease states. There is evidence that melatonin can be of use in amelioration of the disrupted sleep associated with Alzheimer’s disease (AD) [8], but this is disputed [9].
Melatonin has also found utility in hypertensive patients in the treatment of sleep disruption caused by depression of intrinsic melatonin production by beta-blockers [10]. Reports of the add-on utility of melatonin to the treatment of several disorders, including epilepsy [11], may primarily be attributable to the improved quality of the sleep–wake cycle [12], but melatonin has also been shown to directly potentiate the anticonvulsant efficacy of phenobarbital [13]. Melatonin is effective as an adjuvant for improving cognitive function and sleep quality impaired by a number of disorders. A study group of 73 outpatients with mild to moderate AD took 2 mg prolonged-release melatonin or placebo daily 1–2 h before bedtime for with myofascial temporomandibular disorder (TMD) and pain [14].
1.2.2. Melatonin and Mood Disorders
The clinical applicability of melatonin and pharmacological agents active at its receptors to depressive and anxiety mood disorders has been reported. The principal antidepressant drug used is agomelatine, which acts as a melatonin MT1 and MT2 receptor agonist. However, agomelatine also acts as a serotonergic 5-HT(2C) receptor antagonist, and this could also contribute its antidepressant activity [15]. Ramelteon, another MT1/MT2 agonist, has no serotonergic antagonistic activity but retains antidepressant properties [16].
The mechanism of action may involve both restoration of a normal sleep cycle and the intrinsic anxiolytic and analgesic properties of melatonin, which has opioid activity [17]. Ramelteon has also been reported to protect against delirium [18]. The biochemical and behavioral deficits found in animal models of several neurodegenerative diseases, including AD, Parkinson’s disease (PD), and cerebral stroke, are mitigated by melatonin treatment [19]. However, reports involving melatonin intervention in these diseases in human trials are very limited. Restoration of deranged sleep patterns may account for the majority of benefits seen in clinical testing of melatonin [20].
Melatonin has shown promise for managing some troublesome side effects of drugs used to treat mood disorders. In a study of schizophrenic patients, treatment with 3 mg/day of melatonin for 8 weeks reduced the metabolic side effects of weight gain, abdominal obesity, and hypertriglyceridemia induced by olanzapine [21]. However, 20 mg/day of controlled-release melatonin for 1 month was no more effective than placebo for reducing dependence on benzodiazepines in a group of 92 elderly outpatients [22].

1.2.3. Slowing Of Common Age-Related Processes
Aging is associated with an increasingly elevated level of inflammatory events [23]. Inappropriate and excessive immune responses characterize many diseases associated with aging, including a range of cardiovascular and neurodegenerative disorders. This heightened level of inflammation appears to be unprovoked by exogenous agents andmay reflect the inappropriate continuation of earlier and more relevant immune responses [24]. In the nervous system, many of the genes whose expression is elevated with age relate to immune function, and melatonin treatment has been shown in aged experimental animals to reverse this trend and restore a more youthful pattern of mRNA production [25]. This is also reflected by reversal of age-associated morphological and biochemical changes in brain [26]. Another important feature of brain aging where melatonin may be of value concerns adult neurogenesis, which has significance that is increasingly being acknowledged. Diminished neurogenesis precedes old age [27], and this decline can be delayed by supplementation with melatonin [28]. In addition, the maintenance of dendritic complexity is enhanced by melatonin [29]. Studies on melatonin in aging humans are relatively scarce, but several promising reports exist. Daily use of 3 mg melatonin protected the retina by delaying macular degeneration—a leading cause of severe visual loss in older people [30]. Even low doses of melatonin used during the evening increased daytime activity of healthy elderly people [31].
1.2.4. Melatonin and Disease Related To Immune Function
Melatonin has also been found to be of utility in the treatment of other diseases and adverse health states in which excess inflammation may not constitute a major element of pathogenesis but where immune function is likely a factor, including cancer [32]. Supplementation of the diet of aged mice with melatonin leads to a major reduction of tumor incidence [33]. Although melatonin is generally reported as supporting cell survival, it appears to promote apoptosis in malignant cells [34]. Several meta-analyses have shown that adjuvant treatment of cancer—particularly solid tumor cancers—with melatonin significantly improves outcomes [35]. Similarly, two recent case studies have reported encouraging results in patients with breast cancer [36] and hepatocellular carcinoma [37]. Encouraging but modest benefits were reported very recently in a clinical trial involving 151 advanced nonsmall cell lung cancer patients also receiving chemotherapy. In this study, 10 or 20 mg/day of melatonin taken at night for 6 months following initiation of chemotherapy decreased DNA damage and tended to improve quality of life; however, even though the longest-living survivors were among those patients receiving melatonin, supplementation did not lengthen survival time significantly overall [38]. Melatonin therapy can also speed the rate of healing of diverse types of wound [39]. In an experimental model of multiple sclerosis—which certainly reflects inappropriate immune responses—melatonin was able to reverse demyelination [40].
1.2.5. Melatonin and Oxidative Stress
There are several states that are predominantly characterized by excessive generation of reactive oxidant species. These include strenuous exercise and chronic pulmonary obstructive disease. Melatonin has been shown to be able to reduce indices of free radical damage in each of these in humans [41].
The relatively low tissue content of active unconjugated melatonin is approximately 1 pM [42]
, which makes a direct antioxidant effect unlikely because several other potent antioxidants such as water-soluble glutathione and lipophilic α-tocopherol are present at much higher intracellular concentrations. Nonetheless, melatonin has been shown to reduce indices of oxidative stress in several clinical situations, including metabolic syndrome [43], Duchenne muscular dystrophy [44], and in severely ill children [45].
1.2.6. Melatonin and Nociception
Melatonin may be effective for reducing chronic pain associated with some diseases. Being antinociceptive, it can act to support conventional anesthetics [46]. In a randomized, placebo-controlled clinical trial involving 32 patients with myofascial TMD pain, pain levels evaluated by two different measurements were reduced in those using 5 mg/day at bedtime over a course of 4 weeks; moreover, these patients also reported requiring smaller and smaller amounts of other analgesics to cope with their pain as the trial progressed [47]..

1.2.7. Reduced toxicity of venoms and pharmacological agents after Melatonin administration
Melatonin has been found to ameliorate the venominduced hemorrhage and myonecrosis incurred after a snake bite [48].
. It is also protective against the nephrotoxicity of tenofovir, a reversetranscriptase inhibitor used in the treatment of HIV infection [49]. The toxicity of several antineoplastics, such as neocarbazine and cyclophosphamide, is reduced in the presence of melatonin [50].
1.2.8. Beneficial Effects of Melatonin Use During Surgical Procedures
Melatonin improves survival of animals after heart transplantation both in the presence and absence of cyclosporine [51]. Prior administration of melatonin also improved survival rates after kidney transplantation [52].
. The persistence of ovaries following transplantation was also increased [53]. Clinical studies in these areas are very limited, but melatonin had only marginally beneficial effects in major liver resection surgery [54]. However, it has been shown to be nearly as effective as clonidine as an agent for sleep induction preceding surgical anesthesia in children aged 1–5 years [55]. Moreover, melatonin administration has been reported to lead to improved outcome following organ transplant procedures [56] and neonatal surgery [57]. The more successful reports used much higher doses of melatonin. Melatonin appears to have clinical utility in reducing the damage incurred by ischemia-reperfusion injury in the liver, which is very susceptible to such fluxes in vascular supply [58]. However, several trials on the potential of melatonin to mitigate the effects of reperfusion injury on the heart have not been proven to be successful [59].
1.2.9. Migraine Amelioration by Melatonin
Melatonin shows promise for reducing severity of migraine headaches in adults and children. In a recent study of 60 children (mean age, 10.3 years), monthly frequency of migraines was reduced by 55%, duration was reduced by 51%, and severity was reduced by 43%; the most frequent side effect was daytime sleepiness that occurred in seven subjects [60].
1.2.10. Melatonin Supplementation and Fertility
The quality of oocytes used for in vitro fertilization has been reported to be improved by treatment of the donors with melatonin [61]. The efficacy of oral melatonin supplementation on oocyte and embryo quality in patients in an assisted reproductive technologies program has been studied [62]. Patients were treated with 3 mg/day melatonin for at least 2 weeks. To evaluate the cumulative effect of melatonin supplementation, cycle outcomes between the first (no supplementation) and second cycles (melatonin supplementation) of patients who completed two treatment cycles were compared.
There were no significant differences in maturation rates, blastocyst rates, and the rate of good-quality blastocysts between the first and second cycles. However, melatonin increased the fertilization rate from 35.1% to 68.2% and the proportion of good-quality embryos from 48.0% to 65.6%; these effects were ascribed to a reduction in oxidative damage.
1.3. Safety of Melatonin
The term nutraceutical implies that a substance has little or no toxicity even when consumed for long periods of time. Although melatonin is considered to have little toxicity, much of the evidence for this comes from short-term studies [63]. In attempting to assess its safety as a nutraceutical, in addition to considering short-term toxicity data, a careful evaluation of any information pertaining to melatonin’s long-term consumption should be performed. The only adverse report of potential harmfulness of melatonin is a report indicating that, in an isolated system, its metabolite 6-hydroxymelatonin promoted metalion induced lesions to guanine and thymidine residues in DNA [64]. Most redox-capable antioxidants such as ascorbic acid and lipoic acid can also facilitate this cycling. Neither short-term treatment nor extended treatment of humans with melatonin has led to symptoms of dependence, tolerance, rebound insomnia, or withdrawal [65]. With respect to evaluating the safety of melatonin, it is important to distinguish two possible applications: its low-dose nutraceutical consumption by relatively healthy individuals and the acute administration of high dosages to patients with serious medical conditions. The former involves the oral, possibly chronic, intake of relatively low dosages (0.3–10 mg/day), anticipated to be taken at bedtime or when the induction of nocturnal physiological conditions is desired. Frequently, the goal is the restoration or modulation of normal homeostatic function to compensate for age-related changes or circadian cycle disruption, rather than as treatment of serious disease. Here, safety considerations need to focus on the presence or lack of association of low-dose, possibly chronic, consumption of melatonin with increased incidence of disease or pathology in humans. Although high-quality, long-term clinical studies would provide the best evidence for or against such an association, the lack of such studies means that one has to rely on shorterterm, less powerful ones. Nevertheless, the safety and toxicity of melatonin have been the focus of a number of studies, and this hormone is frequently characterized as being both safe and nontoxic [66]. The safety of melatonin used as a nutraceutical ingredient in food has been challenged on at least one occasion in a Food and Drug Administration (FDA) warning letter [67]. Rather than restate evidence for melatonin’s safety, insight from a different perspective may be gained by scrutinizing—at least as an illustrative case—the opposing evidence provided in this document in which it may be presumed that the strongest available references would be selected for characterizing melatonin as being toxic and/or unsafe. The warning letter cited 23 reports that “have raised safety concerns” about melatonin. Of these, the entire text of 21 could be accessed. Surprisingly, terms such as “safe,” “safety,” “toxic,” “toxicity,” or “adverse” did not occur at all in these 21 or they occurred in statements actually supporting the safety and/or nontoxicity of melatonin. Most of these references provide poor or no support for safety concerns either in humans or in the experimental models studied in rodents or in vitro. Among the references cited as raising concerns over melatonin’s effects on blood glucose homeostasis, two of the studies [68] performed no glucose measurements and mentioned no concerns; a third study in rats [69] found that melatonin induced no change in blood glucose. A fourth study [70] reported decreased glucose tolerance and insulin sensitivity in older women treated with 1 mg of melatonin in the morning. Typically, longterm supplementation of melatonin is recommended to be used only at bedtime, and not in the morning. As noted by the study’s authors, the effects measured may merely represent the induction during the daytime of the reduced nocturnal glucose sensitivity observed in normal, healthy humans. In contrast to the results of this study, beneficial improvements in HbA1c and no such possibly deleterious effects on glucose metabolism were found in a more recent study of diabetic patients [71]. There were two adverse reports among studies cited to support reproductive concerns [72] observed strain-specific mortality in rat pups when dams received a 250-times higher dose (on a weight basis, for a 75-kg human) than the 3 mg/day frequently recommended for humans. The strain-specificity and high dosage suggest these results may not be relevant to typical human nutraceutical usage. A second study reporting reduced semen quality in men receiving 3 mg/day of melatonin for 3 months [73] is of more concern. However, this reduction occurred in only two of eight subjects, suggesting that only a minority of males may be affected; in any case, a much larger study is required for confirmation. With regard to females, an in vitro study merely exposed cultured human granulosa cells to melatonin without expressing any safety implications [74]. Additional human studies in which no safety concerns were mentioned included those of [75] and [76], but only the abstracts could be checked. Rodents were used in seven of the reports cited in the FDA warning letter. In rodents, adverse effects were observed only at melatonin concentrations much higher than the 0.5–10 mg typically suggested for long-term nutraceutical consumption in humans. Moreover, all but one of the rodent experiments were performed on animals that modeled human disease, and thus they may have questionable applicability to healthy humans. For example, [77] studied castrated rats without adverse effects, whereas [78] reported that under normal conditions, increased retinal cell death and thinned outer nuclear layer in retinas of non-pigmented rats were associated with administration of 100 times the melatonin dosage typical of human intake. Because melatonin may have greatly different effects in humans compared to rodents in certain circumstances [79] , caution needs to be used in applying the results of animal studies when evaluating the safety of melatonin consumption by humans [80] showed that large amounts of melatonin fed to mice in an atherogenic diet exacerbate plaque formation, but they state that “melatonin had no toxicity on animal health even at this high dose” and express caution by noting that one cannot infer “that high melatonin doses (in mice) would have any deleterious effect on atherosclerosis development in humans.” In humans, other vascular studies—those of [81],—expressed no safety concerns. Similarly, authors of a vision-related study in humans [82] expressed no concerns about melatonin’s safety. Safety concerns of melatonin may apply when treating patients with specific medical conditions, but not in healthy humans using melatonin at bedtime. [83] .reported that a single 15 mg dose of melatonin administered during the daytime lowered input to subjects’ retinal cones; no safety concerns were raised other than cautioning that melatonin should not be taken during the daytime, and the authors concluded that this effect “may serve to promote (normal) night vision.” Further suggesting that undesirable effects may not be a concern in healthy individuals, serious adverse events were reported only in studies of small numbers of human subjects with medical conditions. In this regard, [84] reported that exogenous melatonin, in conjunction with late-night bright light, exacerbated symptoms in eight patients with restless legs syndrome, and [85] observed an increased incidence of seizures among six children with neurological disabilities who had undergone multiple medical procedures. In summary, this examination of references supporting the “safety concerns” raised against melatonin supports the notion that there is little evidence engendering significant generalized concerns about melatonin’s safety, particularly with regard to typically recommended dosages of melatonin consumption in healthy humans. There is no doubt that the toxicity of melatonin is extremely low. Thus, even 800 mg/kg body weight has not been proven lethal in experimental animals [86]. Few nutraceutical vitamins or cofactors have such a large margin of safety.

2. l-Theanine
Tea is often used as a relaxing beverage. l-Theanine is an amino acid extracted from green or black tea. In the brain, l-theanine increases dopamine, serotonin, and the inhibitory neurotransmitter glycine [87], [88] have reported inhibitory effects of higher doses of theanine on caffeine stimulation evaluated by electroencephalogram (EEG) in the rat. However, when given by itself, lower doses of theanine resulted in excitatory effects, suggesting a dual activity of theanine depending on the dose [89] have reported that even lower doses of l-theanine can induce alpha-wave production as observed in EEG tracings from 54 healthy participants at baseline and at 45, 60, 75, 90, and 105 min after 50 mg l-theanine or placebo. Statistical analysis of data showed a significantly greater increase in alpha-wave production in the theanine group than in the placebo group [90] have reported that the acute stress response elicited by a math test was attenuated by 200 mg theanine, as assessed by heart rate and salivary IgA.

3. Gamma Aminobutyric Acid
GABA is an inhibitory neurotransmitter widely distributed throughout the CNS. Too much excitation can lead to irritability, restlessness, insomnia, seizures, and movement disorders, so it must be balanced with inhibition that is provided by GABA acting like a “brake” during times of stress. Medications for anxiety, such as benzodiazepines, stimulate GABA receptors and induce relaxation. Either low GABA levels or decreased GABA function in the brain is associated with several psychiatric and neurological disorders, including anxiety, depression, insomnia, and epilepsy. Studies indicate GABA can improve relaxation and enhance sleep. Because of the association between low GABA levels and these conditions, many antianxiety and sleepenhancing drugs have been developed that interact primarily with GABA receptors. These include the benzodiazepine drugs—alprazolam, diazepam, flurazepam, quazepam, temazepam, and triazolam—and zolpidem tartrate and baclofen. GABA mediates presynaptic inhibition of primary afferent fibers in the motor system. It regulates brain excitability via GABAA receptors, which are classified into three major groups (alpha, beta, and gamma) with subunits that determine its pharmacological activity. GABAA receptors are highly expressed in the thalamus, a region of the brain involved with sleep processes [91] have reported that gabapentin (structurally similar to GABA; increases brain GABA levels) has been found to be effective for panic disorder and improves sleep disturbances associated with alcohol consumption [92] showed GABA-agonist drugs are sedatives used to treat insomnia. Natural therapies that produce relaxation also act, at least in part, by enhancing GABA levels [93] have reported that valerenic acid potentiates and inhibits GABAA receptors [94] have reported reduced GABAA receptor binding in veterans with posttraumatic stress disorder as demonstrated by positron emission tomography scan. On EEG, alpha waves are generated in a relaxed state, whereas beta waves are seen in stressful situations that make mental concentration difficult. Therefore, the ratio of alpha to beta waves is used as an indication of relaxation and better concentration. In general, the greater the alphato- beta ratio, the more relaxed and alert the person is. [95] have reported relaxation and immunity enhancement effects of GABA administration in humans, and it was seen that GABA produced significant effects on increasing alpha waves and on decreasing beta waves, resulting in a significant increase in the alpha-to-beta wave ratio. Due to its relaxation effects, GABA may be considered to be a sleep aid.

4. l-Tryptophan/5-Hydroxytryptophan (5-HTP)
l-Tryptophan, a large neutral amino acid essential to human metabolism, is the metabolic precursor of serotonin (a neurotransmitter), melatonin (a neurohormone), and niacin (vitamin B3). Tryptophan hydroxylase is the rate-limiting enzyme for serotonin production and involves the conversion of tryptophan to 5-HTP. This enzyme can be inhibited by stress, insulin resistance, magnesium or vitamin B6 deficiency, or increasing age [96] have demonstrated the inhibitory effect of 5-HTP on cholecystokinin-4-induced panic attacks in healthy volunteers. Another study conducted by [97] examined that acute l-5-HTP administration inhibits panic attacks induced by carbon dioxide in panic disorder patients, as displayed by reduced panic symptom scores and number of panic attacks in comparison to placebo [98] have reported that l-5-HT treatment helps in reduction of sleep terrors in children because of its enhancement of serotonin and melatonin as compared to the untreated group.

5. Pyridoxal 5′-Phosphate (Active Vitamin B6)
Pyridoxal 5-phosphate (the active form of vitamin B6) is a necessary cofactor for the formation of several important neurotransmitters associated with stress. Within the brain, glutamic acid is converted to GABA via the enzyme glutamate decarboxylase and its cofactor pyridoxal 5′-phosphate. GABA is metabolized by gamma aminobutyrate transaminase, also a P5Pdependent enzyme, forming an intermediate metabolite succinate semialdehyde. P5P is a cofactor in the conversion of 5-HTP to serotonin. Furthermore, conversion of l-tryptophan to 5-HTP, the rate-limiting step in serotonin synthesis, can be inhibited by stress, insulin resistance, magnesium or vitamin B6 deficiency, or increasing age. The decarboxylation of 5-HTP to serotonin is dependent on the presence of pyridoxal 5′-phosphate. P5P is also a cofactor in the synthesis of dopa to dopamine in the pathway converting tyrosine to epinephrine and norepinephrine [99].
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37. Tomov, B., Popov, D., Tomova, R., et al., 2013. Therapeutic response of untreatable hepatocellular carcinoma after application of the immune modulators IL-2, BCG and melatonin. Anticancer Res. 33, 4531–4535
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39. Celinski, K., Konturek, P.C., Konturek, S.J., et al., 2011. Effects of melatonin and tryptophan on healing of gastric and duodenal ulcers with Helicobacter pylori infection in humans. J. Physiol. Pharmacol. 62, 521–526
40. Kashani, I.R., Rajabi, Z., Akbari, M., et al., 2014. Protective effects of melatonin against mitochondrial injury in a mouse model of multiple sclerosis. Exp. Brain Res. 232, 2835–2846
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42. Lahiri, D.K., Ge, Y.-W., Sharman, E.H., et al., 2004. Age-related changes in serum melatonin in mice, higher levels of combined melatonin and melatonin sulfate in the brain cortex than serum, heart,. liver and kidney tissues. J. Pineal Res. 36, 217–223
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44. Chahbouni, M., Escames, G., López, L.C., et al., 2011. Melatonin treatment counteracts the hyperoxidative status in erythrocytes of patients suffering from Duchenne muscular dystrophy. Clin. Biochem. 44, 853–858
45. Marseglia, L., Aversa, S., Barberi, I., et al., 2013. High endogenous melatonin levels in critically ill children: a pilot study. J. Pediatr. 162, 357–360
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47. Vidor, L., Torres, I., Custódio de Souza, I., et al., 2013. Analgesic and sedative effects of melatonin in temporomandibular disorders: a double-blind, randomized, parallel-group, placebo-controlled study. J. Pain Symptom Manage. 46, 422–432
48. Katkar, G.D., Sundaram, M.S., Hemshekhar, M., et al., 2014. Melatonin alleviates Echis carinatus venom-induced toxicities by modulating inflammatory mediators and oxidative stress. J. Pineal Res. 56, 295–312
49. Ramamoorthy, H., Abraham, P., Isaac, B., 2014. Preclinical efficacy of melatonin in the amelioration of tenofovir nephrotoxicity by the attenuation of oxidative stress, nitrosative stress, and inflammation in rats. J. Basic Clin. Physiol. Pharmacol. 27, 1–13
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51. Liu, C., Hong, T., Shao, M., et al., 2014. Melatonin synergized with cyclosporine A improves cardiac allograft survival by suppressing inflammation and apoptosis. Mol. Med. Rep. 10, 1323–1328
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53. Hemadi, M., Shokri, S., Pourmatroud, E., et al., 2012. Follicular dynamic and immunoreactions of the vitrified ovarian graft after host treatment with variable regimens of melatonin. Am. J. Reprod. Immunol. 67, 401–412
54. Nickkholgh, A., Schneider, H., Sobirey, M., et al., 2011. The use of highdose melatonin in liver resection is safe: first clinical experience. J. Pineal Res. 50, 381–388
55. Almenrader, N., Haiberger, R., Passariello, M., 2013. Steal induction in preschool children: is melatonin as good as clonidine? A prospective, randomized study. Paediatr. Anaesth. 23, 328–333
56. Liu, C., Hong, T., Shao, M., et al., 2014. Melatonin synergized with cyclosporine A improves cardiac allograft survival by suppressing inflammation and apoptosis. Mol. Med. Rep. 10, 1323–1328
57. Gitto, E., Romeo, C., Reiter, R.J., et al., 2004. Melatonin reduces oxidative stress in surgical neonates. J. Pediatr. Surg. 39, 184–189.
58. Li, Y., Yang, Y., Feng, Y., et al., 2014. A review of melatonin in hepatic ischemia/reperfusion injury and clinical liver disease. Ann. Med. 46, 503–511
59. Ekeløf, S.V., Halladin, N.L., Jensen, S.E., et al., 2014. Effects of intracoronary melatonin on ischemia-reperfusion injury in ST-elevation myocardial infarction. Heart Vessels [Epub ahead of print] PMID: 25319673
60. Fallah, R., Shoroki, F., Ferdosian, F., 2015. Safety and efficacy of melatonin in pediatric migraine prophylaxis. Curr. Drug Saf. 10 (2), 132–135
61. Rizzo, P., Raffone, E., Benedetto, V., 2010. Effect of the treatment with myo-inositol plus folic acid plus melatonin in comparison with a treatment with myo-inositol plus folic acid on oocyte quality and pregnancy outcome in IVF cycles. A prospective, clinical trial. Eur. Rev. Med. Pharmacol. Sci. 14, 555–561
62. Nishihara, T., Hashimoto, S., Ito, K., et al., 2014. Oral melatonin supplementation improves oocyte and embryo quality in women undergoing in vitro fertilization-embryo transfer. Gynecol. Endocrinol. 30, 359–362
63. Bruni, O., Alonso-Alconada, D., Besag, F., et al., 2015. Current role of melatonin in pediatric neurology: clinical recommendations. Eur. J. Paediatr. Neurol. 19, 122–133
64. Bruni, O., Alonso-Alconada, D., Besag, F., et al., 2015. Current role of melatonin in pediatric neurology: clinical recommendations. Eur. J. Paediatr. Neurol. 19, 122–133
65. Lyseng-Williamson, K.A., 2012. Melatonin prolonged release: in the treatment of insomnia in patients aged ≥55 years. Drugs Aging 29, 911–923
66. Garfinkel, D., Zorin, M., Wainstein, J., et al., 2011. Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study. Diabetes Metab. Syndr. Obes. 4, 307–313
67. FDA, 2011. Warning Letters: HBB, LLC dba Baked World 7/28/11. Available from: http://www.fda.gov/ICECI/EnforcementActions/ WarningLetters/ucm266129.htm (February 17, 2015)
68. Puchalski, S.S., Green, J.N., Rasmussen, D.D., 2003. Melatonin effect on rat body weight regulation in response to high-fat diet at middle age. Endocrine 21, 163–167
69. Peschke, E., Schucht, H., Mühlbauer, E., 2010. Long-term enteral administration of melatonin reduces plasma insulin and increases expression of pineal insulin receptors in both Wistar and type 2-diabetic Goto-Kakizaki rats. J. Pineal Res. 49, 373–381
70. Cagnacci, A., Arangino, S., Renzi, A., et al., 2001. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin. Endocrinol. 54, 339–346
71. Garfinkel, D., Zorin, M., Wainstein, J., et al., 2011. Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study. Diabetes Metab. Syndr. Obes. 4, 307–313
72. Singh, H.J., Keah, L.S., Kumar, A., et al., 2011. Adverse effects of melatonin on rat pups of Wistar-Kyoto dams receiving melatonin supplementation during pregnancy. Exp. Toxicol. Pathol. 64, 751–752
73. Luboshitzky, R., Shen-Orr, Z., Nave, R., et al., 2002. Melatonin administration alters semen quality in healthy men. J. Androl. 23, 572–578
74. Woo, M.M., Tai, C.J., Kang, S.K., et al., 2001. Direct action of melatonin in human granulosa-luteal cells. J. Clin. Endocrinol. Metab. 86, 4789–4797
75. Okatani, Y., Okamoto, K., Hayashi, K., et al., 1998. Maternal-fetal transfer of melatonin in pregnant women near term. J. Pineal Res. 25, 129–134
76. Cagnacci, A., Paoletti, A.M., Soldani, R., et al., 1995a. Melatonin enhances the luteinizing hormone and follicle-stimulating hormone responses to gonadotropin-releasing hormone in the follicular, but not in the luteal, menstrual phase. J. Clin. Endocrinol. Metab. 80, 1095–1099. Cagnacci, A., Soldani, R., Yen, S.S., 1995b. Exogenous melatonin enhances luteinizing hormone levels of women in the follicular but not in the luteal menstrual phase. Fertil. Steril. 63, 996–999
77. Puchalski, S.S., Green, J.N., Rasmussen, D.D., 2003. Melatonin effect on rat body weight regulation in response to high-fat diet at middle age. Endocrine 21, 163–167
78. Wiechmann, A.F., Chignell, C.F., Roberts, J.E., 2007. Influence of dietary melatonin on photoreceptor survival in the rat retina: an ocular toxicity study. Exp. Eye Res. 86, 241–250
79. Peschke, E., Schucht, H., Mühlbauer, E., 2010. Long-term enteral administration of melatonin reduces plasma insulin and increases expression of pineal insulin receptors in both Wistar and type 2-diabetic Goto-Kakizaki rats. J. Pineal Res. 49, 373–381
80. Tailleux, A., Torpier, G., Bonnefont-Rousselot, D., et al., 2002. Daily melatonin supplementation in mice increases atherosclerosis in proximal aorta. Biochem. Biophys. Res. Commun. 293, 1114–1123
81. Cook, J.S., Sauder, C.L., Ray, C.A., 2011. Melatonin differentially affects vascular blood flow in humans. Am. J. Physiol. Heart Circ. Physiol. 300, H670–H674
82. Rufiange, M., Dumont, M., Lachapelle, P., 2002. Correlating retinal function with melatonin secretion in subjects with an early or late circadian phase. Invest. Ophthalmol. Vis. Sci. 43, 2491–2499
83. Gagné, A.M., Danilenko, K.V., Rosolen, S.G., et al., 2009. Impact of oral melatonin on the electroretinogram cone response. J. Circadian Rhythms 7, 14
84. Whittom, S., Dumont, M., Petit, D., et al., 2010. Effects of melatonin and bright light administration on motor and sensory symptoms of RLS. Sleep Med. 11, 351–355
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88. Kakuda, T., Nozawa, A., Unno, T., et al., 2000. Inhibiting effects of Theanine on caffeine stimulation evaluated by EEG in the rat. Biosci. Biotechnol. Biochem. 64, 287–293
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Tab LMC

Tab     LMC (L-methyl folate + Methylcobalamin +N-Acetylcycteine) Brand: LMC Generic: L-methyl folate + Methylcobalamin +N-Acetylcycteine Class: Medical Food Supplement Route of administration: Oral Dosage form: Tablet Dose: 1 tablet twice a day Pregnancy: Safe Pack Size: 30 tabs. 1. L-METHYLFOLATE Folic acid and Methyl folate both are from Vitamin B9, but folic acid is man-made (synthetic) where methylfolate is obtained from natural source. L-methylfolate, the active form of folate is essential for biological processes throughout the human system involving methylation or one-carbon transfer. Without it there can be a significant breakdown of the human body’s ability to produce healthy DNA, have healthy neurotransmitter production, and optimal cardiovascular, hormonal, cellular, liver and reproductive functions. Folate deficiency is tied to a host of conditions. Because L-methylfolate is required for the synthesis of the neurotransmitters serotonin, dopamine, and norepinehrine, low levels make it less likely that people will respond well to products that support a healthy mood. L-Methylfolate is also the only form of folate able to cross the blood-brain barrier. A decline of folate levels in the cerebral spinal fluid has been associated with reduced cognitive function. L-Methylfolate is essential for the conversion of homocysteine to methionine, supporting cardio and vascular health by lowering homocysteine levels. Since L-methylfolate participates in DNA synthesis and cell division, requirements are increased during pregnancy and periods of rapid growth. Although folate occurs in naturally in some foods, and folic acid is used to fortify others, approximately 60 percent of the population in the United States have genetic variations that make them unable to utilize these nutrients. These variations do not allow the MTHFR enzyme to function properly so methylation of folate does not occur. Without this activation step, folate cannot be used by the body, resulting in negative health side effects and the possible inability to maintain a healthy mood. This deficiency usually occurs because folic acid, the most common form of folate in supplements and fortified foods, must be converted to its active forms to be used by the body. The enzyme needed to convert folate to its active form, methylfolate, is called methylenetetrahydrofolate reductase (MTHFR). The problem lies in the fact that almost half of all people have genetic variations that reduce the ability of the MTHFR enzyme to make this conversion. Folate deficiencies are tied to a host of conditions. For people with MTHFR gene variations, supplementing with the already activated form of folate is far more effective in providing this form of folate than introducing the pre-converted form to the body through typical folate supplements. L-Methylfolate supplements provide theactive form of folate naturally present in the bodyand available for biological action. This image illustrates the folic acid activation cycle. The other forms of vitamin B9 are folic acid and folate. Folate is often called the natural form of vitamin B9, but it actually refers to a family of different compounds that occur naturally in some vegetables. Folic acid is the supplemental or “synthetic” form of vitamin B9 and is typically the first line of treatment for folate deficiency and related health conditions, such as high homocysteine and neural tube defects. Any folic acid we ingest must be metabolized (converted) into Dihydrofolate (DHF), Tetrahydrofolate (THF), and then finally into L-methylfolate to be used in the body. Once in this form it can be transported into cells, tissues and even across the blood-brain barrier. But issues can arise during metabolism for those with an enzyme issue, such as an MTHFR mutation. 1.1. SIGNS AND SYMPTOMS OF AN MTHF DEFICIENCY 1.1.1.Low Brain Chemistry Production L-Methylfolate is essential for maintaining healthy brain chemistry and is responsible for the normal production of the neurotransmitters serotonin, melatonin, dopamine, epinephrine, and norepinephrine. These neurotransmitters are involved in a number of functions including short-term memory, concentration, sleep, motor control, hormone control, mood stability, motivation, and appetite control. Low folate levels have been associated with mood disorders and supplemental folate might be recommended as first line therapy. 1.1.2. Homocysteine Genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) have been proven to be the common hereditary factors of high-level homocysteine. Supporting normal homocysteine levels already in a normal range is important to good health. L-Methylfolate supplements address elevated homocysteine levels in the blood and improve peripheral blood flow in the arteries by increasing nitric oxide production in the vascular endothelium. This mode of action supports heart health. 1.1.3. Peripheral Neuropathy L-Methylfolate supplements can help promote healthy peripheral nerve function by supporting normal homocysteine levels and increasing nitric oxide production. 1.1.4. Uric Acid Gout is a condition characterized by the deposition of monosodium urate crystals in the joints or soft tissue. Acute gout most commonly affects the first metatarsal joint of the foot, but other joints are also commonly involved. Supplementing with L-methylfolate can aide in the normal metabolism of uric acid. 1.1.5.Neural Tube Defects Women who consume healthful diets with adequate folate throughout their childbearing years may reduce their risk of having a child with a birth defect of the brain or spinal cord. Sources of folate include fruits, vegetables, whole grain products, fortified cereals, and dietary supplements. Supplementing with folate significantly reduces the occurrence of neural tube defects. However, a study involving a group of women of childbearing age showed that supplementing with L-methylfolate results in a higher red blood cell folate level than supplementing with folic acid. 2. N-ACETYL CYSTEINE Acetylcysteine is the N-acetyl derivative of the amino acid L-cysteine, and is a precursor in the formation of the antioxidant glutathione in the body. The thiol (sulfhydryl) group confers antioxidant effects and is able to reduce free radicals. 2.1. BENEFITS OF N-ACETLY CYSTEINE 2.1.1. Glutaminergic Neurotransmission The cystine–glutamate antiporter(also called exchanger or counter-transporter) on astrocytes is known to mediate synaptic levels of glutmate, and takes up cystine (the dimer of cysteine) in exchange for glutamate release, which includes inhibitory metabotropic glutamate receptors (known as group II) on glutaminergic nerve terminals and reduced further synaptic release of glutamate. It is thought that provision of additional cysteine, via N-acetylcysteine supplementation, can provide more substrate for this reaction to reduce glutaminergic stimulation. This antiporter may also be downregulated and its function disturbed with usage of drugs, which is involved in the pathology of addiction;N-acetylcysteine may attenuate the reduction seen with drug administrationand disrupt the transporters autoregulation. It is thought that additional cysteine in the brain can reduce glutaminergic transmission by reducing the amount of neuronal glutamate release into the synapse (secondary to aiding its release from astrocytes). In brain injury or disease, they often work in reverse, and excess glutamate can accumulate outside cells. This process causes calcium ions to enter cells via NMDA receptor channels, leading to neuronal damage and eventual cell death, and is called excitotoxicity. The mechanisms of cell death include • Damage to mitochondria from excessively high intracellular Ca2+ • Increased intracellular nitric oxide concentrations[7] • Glu/Ca2+-mediated promotion of transcription factors for pro-apoptotic genes, or downregulation of transcription factors for anti-apoptotic genes Excitotoxicity due to excessive glutamate release and impaired uptake occurs as part of the ischemic cascade and is associated with stroke, autism, some forms of intellectual disability, and diseases such as amyotrophic lateral sclerosis, lathyrism, and Alzheimer's disease. In contrast, decreased glutamate release is observed under conditions of classical phenylketonuria leading to developmental disruption of glutamate receptor expression. Glutamic acid has been implicated in epileptic seizures. Microinjection of glutamic acid into neurons produces spontaneous depolarisations around one second apart, and this firing pattern is similar to what is known as paroxysmal depolarizing shift in epileptic attacks. This change in the resting membrane potential at seizure foci could cause spontaneous opening of voltage-activated calcium channels, leading to glutamic acid release and further depolarization. 2.2. N-acetyl cysteine in Pregnancy N-acetyl cysteine is usually safe for pregnant women to take, but ask your doctor if you are pregnant or trying to get pregnant before taking this supplement. Taking this supplement may help you get pregnant and prevent a miscarriage under certain circumstances. 2.2.1. Increasing Ovulation People who have polycystic ovary disease may experience an improvement in fertility when taking N-acetyl cysteine along with fertility drugs. Polycystic ovary disease is the most common hormonal disorder among women of reproductive age that the cause is unknown, according to the Mayo Clinic. It causes a lack of ovulation and therefore a difficulty getting pregnant. A 2007 study published in the "ActaObstetricia et GynecologicaScandinavica" journal found that N-acetyl cysteine induced or augmented ovulation in polycystic ovary patients. Participants took 50 mg of the fertility drug clomiphene citrate twice a day alone or combined with 1,200 mg daily of N-acetyl cysteine for five days. Medication began on the third day of their menstrual cycle. The study was entitled, "N-Acetyl Cysteine and Clomiphene Citrate for Induction of Ovulation in Polycystic Ovary Syndrome: A Cross-over Trial." 2.2.2. Decreasing Miscarriages Taking N-acetyl cysteine reduces the possibility of pregnant women miscarrying. N-acetyl cysteine may suppress oxidative stress, according to a 2008 study published in the "Reproductive BioMedicine Online" journal. Oxidative stress happens when free radicals attack and destroy healthy brain cells. This may begin a cascade of changes in the body that causes a miscarriage. Humans convert N-acetyl cysteine into the antioxidant, glutathione. Antioxidants fight free radicals. The study found that N-acetyl cysteine and folic acid supplements significantly increased the take-home baby rate of participants compared to taking folic acid alone. The name of the study is "N-acetyl Cysteine for Treatment of Recurrent Unexplained Pregnancy Loss. 3. METHYLCOBALAMIN Methylcobalamin circulates through the bloodstream and is one of two naturally occurring coenzyme forms of vitamin B12 that the body utilizes. It differs from typical B12 in that it has an additional methyl group, and contains metal-alkyl bonds. Adenosylcobalamin is the other form sometimes used in the dietary supplement industry. The body needs B12 to convert homocysteine to methionine, protect DNA and RNA, support energy, protect nerve and brain cells, stimulate serotonin production, contribute to red blood cell formation, support immune function, and maintain a positive mood. Hydroxocobalamin is the main B12 form found in meat, fish, and dairy products. Cyanocobalamin is a common but synthetic B12 that is often added to foods, and the body must use precious energy to convert this form into methylcobalamin. This B12 form has a higher stability and bioavailability and doesn’t require conversion. These next 4 facts will explain the benefits of methylcobalamin. 3.1. BENEFITS OF METHYLCOBALAMIN 3.1.1. Support Brain and Nerve Health Methylcobalamin creates two major effects in the brain which are responsible for many of its neuro-protective and longevity (long life) enhancing benefits. First, the compound eliminates excessive levels of homocysteine in the brain. A high level of homocysteine in the blood (hyperhomocysteinemia) makes a person more prone to endothelial cell injury, which leads to inflammation in the blood vessels, which in turn may lead to atherogenesis, which can result in ischemic injury. This substance is often cited as the leading cause of vascular degeneration in the brain. Next, Methylcobalamin improves the health and function of nerves in the brain. It can rebuild damaged nerves and contributes to the maintenance of function that is normally decayed during the aging process. For people with autoimmune disorders, blood cell conditions like anemia can lead to immunity issues and cognitive impairment. Methyl B12 aids this problem by allowing intrinsic factor to bind appropriately in the intestines.It also raises the available amount of SAMe (S adenosylmethionine), the important compound which lifts mood and works as a tricyclic antidepressant.Higher amounts of methylcobalamin are necessary to correct neurological defects and protect against aging. Published studies show that high doses of methylcobalamin are needed to regenerate neurons as well as the myelin sheath that protects nerve axons and peripheral nerves. Few substances have been shown to regenerate nerves in humans with peripheral neuropathies. However, a study in the Journal of Neurological Science postulated that methylcobalamin could increase protein synthesis and help regenerate nerves. The scientists showed that very high doses of methylcobalamin produce nerve regeneration in laboratory rats. 3.1.2. Increases Available Physical Energy Every chemical reaction in the body expends energy. When the body needs to convert a vitamin into a form the body can use, this reaction also requires energy. For example, supplementing with the cyanocobalamin form of B12 requires the body to expend energy that removes the cyanide molecule and replaces it with a methyl group. Taking methylcobalamin as a B12 supplement eliminates the need for this extra chemical reaction. 3.1.3. Encourages Detox Methyl groups activate hundreds of chemical reactions throughout the body. One such process includes triggering detox reactions. This includes the removal of heavy metals, environmental toxins, and waste products. 3.1.4. Neutralizes Homocysteine High homocysteine levels is undesirable and known to be an indicator of heart disease and stroke risk. Free homocysteine in the blood causes sclerosis of the arteries, putting strain on the vascular system and the heart. One of the primary reactions of methylcobalamin is to convert homocysteine to methionine, reducing the potential for damage. Outcomes from this reaction include the formation of cysteine, a precursor to the super-antioxidant glutathione. Methionine also contributes to the formation of adenosylcobalamin, the other form of B12 used by the body in mitochondrial energy creation, the foundation for all human energy.

BioMar

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Antize

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Marlin

Marlin (Cholin Bitartrate) Brand: Marlin Generic: Cholin Bitartrate Class: Medical Food Supplement Route of administration: Oral Dosage form: Syrup & Tablet Dose: Tablet: 1 tablet daily Syrup: Children: 1 to 2 teaspoon full Adults: 1 to 2 tablespoon full Contraindications: Pregnancy: Cat. C Pack Size: 10 tabs. / 120ml syp. Price: Rs. 750/- Supplement facts: Supplement Amount per serving Citicoline 500mg AnMar specs. 300mg 1. Citicoline Citicoline is the name for cytidine 5′-diphosphocholine (CDP-choline) when this is used as an exogenous sodium salt. In fact, CDP-choline is an endogenous nucleotide naturally found in the body where it is an essential intermediate in the synthesis of the major phospholipid of the cell membranes, phosphatidylcholine (PtdCho). This type of synthesis is called the Kennedy pathway [1]. As a drug, citicoline has been proposed for use in traumatic brain injuries, stroke, vascular dementia, Parkinson’s disease, and brain aging [2] where it has the function of stabilizer of cell membranes and reduces the presence of free radicals [3]. In particular, there is some evidence of a stimulating role of citicoline for the release of dopamine neurotransmitters in the brain [4]. Citicoline, by activating the central cholinergic system, also increases plasma adrenocorticotropic hormone (ACTH) levels and potentiates serum thyrotrophin (TSH) levels. The stimulation of central nicotinic and muscarinic receptors also increases growth hormone (GH) and luteinizing hormone (LH) serum levels [5]. This activity on the cholinergic system is of high therapeutic usefulness in those clinical conditions where alterations of acetylcholine metabolism are considered one of the primary causes of disease [6], eg, Alzheimers Disease (AD). The biological activity attributed to citicoline has suggested a possible role of citicoline on improving memory [7]. Some clinical studies have given evidence to this hypothesis [8] and there is a proposal for studying citicoline in mild cognitive impairment (MCI) with the aim of confirming both its efficacy in these patients and a possible role as a retardant agent for the cognitive deterioration of the eventual subsequent dementia [9]. 1.1. Therapeutic applications of citicoline 1.1.1. Stroke More than 11 000 people, including patients and volunteers have been studied for evaluating citicoline therapeutic effects. 1372 of these patients were included in studies concerning citicoline efficacy in acute ischemic stroke and pooled together in a meta-analysis of these studies [10]. This analysis showed that citicoline increases the probability of a complete recovery after three months from moderate to severe stroke when it is administered within 24 hours from the event, although the odds ratio of improving with citicoline is only 1.33. Citicoline’s therapeutic action has been attributed to its restoring activity of the PtdCho levels which decrease after a stroke [11]. In stroke patients there seems to be a particular problem in efficiently delivering citicoline at high enough blood levels required to be effective, and to avoid those differences in results evidenced between studies done by intravenous (IV) administration of the drug and oral administration, a more effective preparation for the oral administration is suggested [12]. 1.1.2. Vascular dementia The clinical picture of cognitive and behavioural disorders associated with chronic cerebrovascular disorders (CVD) is much less clear-cut and defined than the picture associated with Alzheimer’s dementia. The definition itself of vascular dementia (VD) has been under discussion for a long time and the heterogeneity of the conditions of patients included in this group is probably higher than the similarities between patients [13]. 1.1.3. Correlative studies When attempts are made to identify relevant relationships between neuroimaging and cognitive patterns, most of the studies have not been able to point out consistent and reliable concordance between these two domains [14] primarily because of the low power of these studies due to the small number of cases [15]. There is evidence of different patterns of cognitive deficits in patients with chronic cerebrovascular disorders when it has been possible to differentiate between those with prevalent signs of altered hippocampal volume from those with diffuse alterations in the grey and white matter [16]. Memory deficits are more relevant in the former group and executive function impairment in the latter group. These findings do not overlap with those that emerge when subcortical dementia is studied as an independent clinical entity characterized by defined quantities of leuakariosis. These neuroimaging findings are commonly associated with deficits in executive function, while memory disorders are considered to be a direct function of cortical impairment [17]. In some instances, this apparent contrast among study results was explained by the different origin of the patients included; eg, when patients from stroke clinics are compared with patients from memory clinics, the specificity of relationship between neuroimaging and functional data is much weaker in the latter group [18]. A proposal has been presented that considers subcortical dementia as a specific form of vascular dementia related to a predominantly small vessel pathogenesis. Mixed dementia is then considered as a nonspecific form of vascular dementia and related to prevalent large infarcts pathogenesis associated with cortical primary atrophy [19]. This model points out the need of considering possible different pathogeneses for different forms of vascular encephalopathy, but does not yet help in identifying specific cognitive patterns of decline associated with them. These issues have largely confounded the studies of citicoline. 1.1.4. Population studies In studies aimed to identify the relationship between presence of cerebrovascular disorders and prevalence of cognitive disorders in the general population, signs of vascular pathogenesis such as arterial stiffness or generalized atherosclerosis are consistently related to cognitive deterioration which ranges from mild severity to dementia [20]. 1.1.5. Specificity of cognitive deficits The most common way of defining the specificity of cognitive deficits in vascular dementia is based on comparison with AD patients. Cognitive deficits in these two forms of dementia are consistently found to be more severe in AD patients, while the specificity of deficits in vascular dementia is less clear and more difficult to be replicated in diverse studies. Executive function deficits seem to be more prevalent in vascular dementia, while memory deficits are more typical for AD [21]. Another line of research focuses on the identification of specific predictors of developing vascular dementia in groups of patients characterized by those pathologies which are commonly considered as risk factors for cardiovasculopathies such as diabetes and hypertension. The evidence of slight and not evenly distributed signs of cognitive impairment in hypertensive patients [22] and its relationship with the daily temporal distribution of elevated picks of systolic blood pressure (more than with the level of high blood pressure of picks) [23] can be considered as the evidence of a progressive development of a cerebrovascular pathology even before gross anatomical signs of abnormality can be identified in the brain tissues. These findings provide support for the proposal to introduce early therapeutic intervention in patients with mild signs of cerebrovasculopathy or even with risk factors for it [24]. 1.1.6. Treatment of cognitive deficits Attempts to treat symptoms of decline in cerebrovasculopaties have been made since the first years of the last century [25] starting with niacin and continue today. At the beginning of the 1980s, citicoline was used in these clinical areas after having been already in use in treatment for stroke. In most of the clinical studies with citicoline in VD, memory has been the principal end point in the efficacy evaluation. There is a large experimental database of experimental studies on memory and learning performed on aged animals treated with citicoline. Most of these studies have shown that treatment with citicoline ameliorates cognitive deficits but does not necessarily improve normal cognitive functions [26]. The few studies done on memory in aged human subjects with memory disorders, but no dementia, have underlined the extreme variability of positive outcomes depending on the type of patients and the kind of measures used in the studies. Memory is a very complex and multidimensional variable to quantify in humans and, consequently, results from different studies which have in common the assessment of memory are not necessarily homogeneous and comparable if the specific modality of memory evaluation is not taken into account. We have seen that those studies which are trying to identify specific patterns of memory disorders in vascular dementia are not yet able to define a definite and reliable cognitive model of functioning of these patients. As a consequence, it is almost impossible to try to systematically apply a specific memory parameter for the evaluation of treatment efficacy in this clinical area, as it has been possible for AD. There is a possibility that memory disorders might be contaminated by other disorders attributable to executive function including attention. This problem has been examined by looking for methods of evaluating primary memory deficits as distinct from those secondary to other cognitive impairments external to memory per se [27]. Another relevant problem that emerges from a critical analysis of the current and past literature is the relatively poor reliability of single studies performed on small samples of patients with various forms of vascular dementia (a further level of complexity is derived by the different criteria given to these patients in different periods of time). A metanalysis is the best solution available for circumventing these limitations. In the case of citicoline, a meta-analysis for examining the reliability and validity of effects on memory which have been studied in different ways and types of patients in various studies, could fail to confirm the positive results of the single studies once these data are pooled together. A metanalysis has been performed on the available published and unpublished data obtained from controlled clinical trials done with citicoline. This metanalysis carried out according to the Cochrane Collaboration guidelines is periodically updated in order to include all the studies available [28]. Results of the metanalysis are divided by domains. This allows for a comparative analysis between different areas of assessment; for example, attention and memory. It is possible to verify the homogeneity of results within each domain. Memory is one of the domains in this analysis and includes results from 884 patients. While studies in this domain include other types of patients as well as cerebrovascular patients, there was no heterogeneity among their results. This indicated that the effect of citicoline on memory was significantly different from the placebo effect, and did not specifically depend on the pathogenesis of the cerebral disorder (effect size 0.19; confidence interval [CI] 95% 0.06, 0.32; p<0.005). In fact, when only cerebrovascular disorders studies were pooled together (for a total of 675 patients), the homogeneity and entity of results was about the same (effect size 0.22; CI 95% 0.07, 0.37; p<0.004). Within the domain that deals with behavior control and competence (a total of 814 patients), there was a citicoline effect significantly different from placebo and independent from type of measure and pathology examined (effect size −0.26; CI 95% −0.49, −0.04; p<0.004). These results coupled with those of the domain clinical evaluation of improvement concerning a total of 217 patients (effect size determined as the odds ratio of improving under active treatment 8.89; CI 95% 5.19, 15.22; p<0.001) showed that the cognitive effects of citicoline are clearly evident at the behavioral level and can be easily appreciated with a clinical observation of patients irrespective of the functional paradigm used to measure them. The attention domain, even though based on a substantial number of 790 patients, revealed a large amount of variance because of the large individual differences. These data did not permit an interpretation of how much of the results evidenced by memory measures can be considered as specific of the “true” memory processes or as secondary to an effect on other cognitive components of the cognitive decline. Finally, the tolerability of citicoline has never constituted a problem whatever the modality of administration or the dosage. 1.2. Conclusions Treatment in patients with disorders attributed to a cerebrovascular pathogenesis has a long history. Unfortunately, many problems are still unresolved, including the taxonomy of these disorders and a definition of cognitive pattern of decline to be associated to this taxonomy. These intrinsic problems have not helped to develop accepted methods of research and treatment for these patients. 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