Tab       DiOne (Diacerein, Glucosamine, Chondroitin and MSM) Brand: DiOne Generic: Diacerein, Glucosamine, MSM and Chondroitin Class: Medical Food Supplement Route of administration: Oral Dosage form: Tablet Dose: 1 tablet twice a day Contraindications: Pregnancy: Cat. C Pack Size: 30 tabs. Price: Rs. 960/- Supplement facts: Supplement Amount per serving Diacerein 50mg Glucosamine 600mg Chondroitin 400mg MSM 168mg 1. Diacerein The use of diacerein for the treatment of osteoarthritis is still under sometimes controversial discussion. Its postulated modes of action, all indicating IL-1 antagonism, make the drug an interesting option for the treatment of osteoarthritis not only for symptom relief but also for structure modification. Studies in different animal models [1-8] showed that diacerein consistently moderated cartilage loss in osteoarthritis. In humans, the ECHODIAH trial [9] showed a reduction in the progression of hip osteoarthritis in the diacerein-treated patients compared with the placebo group. Overall, this meta-analysis provides evidence for statistically significant and clinically relevant efficacy of diacerein on improvement of pain and function in patients with hip and/or knee osteoarthritis. The large number of patients included in this meta-analysis gives the basis for well-founded conclusions to be drawn. Considering the pain relief results, one has to consider that complete withdrawal of analgesic co-medication was not possible during the studies analyzed. In most of the trials, acetaminophen, which is also considered an appropriate treatment modality for moderate osteoarthritis, [10,11] was allowed as an escape medication in both the diacerein and control groups, and the amount taken was recorded by the patient in a diary. However, although mean intake of acetaminophen was similar during the active treatment period, its consumption increased significantly in the NSAID-treated patients, but not in the diacerein group, during the treatment-free follow-up period. After the end of treatment, SYSADOAs are supposed to have a carryover effect [12] In this meta-analysis, we found evidence for this carryover effect with respect to pain and consumption of escape medication in all sub analyses performed, not only in the individual trials but also in the pooled population, and not only compared with placebo [13,14] but also with active treatment modalities comprising diclofenac sodium, [15,16] tenoxicam, [17] piroxicam,[18,19] and naproxen [20]. Given the fact that all selected studies had a randomized, controlled, parallel-group de-sign, these findings indicate a positive impact of diacerein on the clinical status of patients with osteoarthritis. The patient’s global tolerability ratings at the end of active treatment showed no statistically significant differences between other active treatments and diacerein. However, as expected, a significant inferiority of diacerein vs placebo was observed, also indicating reproducibility of the results obtained here. The risk-benefit ratio associated with long-term use of NSAIDs and analgesics is well documented in the literature, [20,21-23] but clinical studies on the use of NSAIDs for more than 6 weeks in patients with osteoarthritis are rare [20,24]. Nonsteroidal anti-inflammatory drugs, particularly the selective cyclooxygenase-2 inhibitors, are known to exert a higher risk for thromboembolic disorders such as myocardial infarction or stroke [25]. In this context, it is important to consider that most patients affected by osteoarthritis also experience disorders, or at least risk factors, of the cardiovascular system and that according to the European Agency for the Evaluation of Medicinal Products [26] and the Food and Drug Administration, [27] NSAIDs should be administered at the lowest possible dose for the shortest period. In contrast, cardiovascular adverse events in patients treated with diacerein can be considered very rare. In France, over a period of 11 years (from September 1994 to November 2005) and with more than 14 million prescriptions of diacerein, only 9 cases of cardiovascular adverse events with diacerein were spontaneously reported (information collected by the Drug Safety Department, Negma-Lerads, Toussus-Le-Noble, France). In particular, no acute coronary syndrome or myocardial infarction was reported. Thus, with respect to tolerability, diacerein may have some advantages compared with long-term application of NSAIDs. 2. Glucosamine and Chondroitin Currently, glucosamine (glucosamine sulfate (GS); glucosamine hydrochloride (GH)) and CS are the most commonly used supplements to ease the pain and discomfort of arthritis in humans and animals. Glucosamine and chondroitin are components of the ECM of articular cartilage. Glucosamine (2-amino-2-deoxy-d-glucose) is an amino sugar and a constituent of glycosaminoglycan (GAG), which plays a role in the normal growth and repair of articular cartilage. In fact, glucosamine is considered a building block of cartilage. Glucosamine is extracted from crab, lobster, and shrimp shells. Following oral administration of either GS or GH, these salts are ionized in the stomach, making glucosamine available for absorption in the small bowel. Ninety percent of GS is absorbed, but due to an extensive first-pass metabolism, bioavailability approaches only 25% [28] Its excretion is mainly through the kidneys, with only a small unmodified amount eliminated through the stool. CS is a sulfated GAG composed of a chain of alternating sugars, N-acetyl-d-galactosamine and d-glucuronic acid. CS is a normal constituent of aggrecan, the major proteoglycan of articular cartilage. It is extracted from animal cartilage, such as trachea and shark cartilage. Due to its larger size as compared to glucosamine, approximately 30% of CS is absorbed, with 12–13% bioavailability [29]. Studies suggest that glucosamine helps relieve pain by enhancing proteoglycan synthesis, which is impaired in osteoarthritic cartilage [30] . [31] investigated the effects of glucosamine on MMP production, MAPK phosphorylation, and activator protein (AP)-1 transcription factor activation in human chondrocytes. Findings revealed that glucosamine reduced the expression of MMPs (MMP-1, MMP-3, andMMP-13) and inhibited c-jun amino terminal kinase, p38 phosphorylation, and, consequently, c-jun binding activity. In essence, glucosamine inhibits IL-1β-stimulated MMP production in human chondrocytes by affecting MAPK phosphorylation. The glucosamine and CS combination suppresses IL-1-induced gene expression of iNOS, COX-2, mPGEs, and NF-κB in cartilage explants. This leads to reduced production of NO and PGE2, two mediators responsible for the cell death of chondrocytes and inflammatory reactions [32]. CS provides hydration, assists in cushioning impact stress, helps create osmotic pressure within the ECM to maintain the compressive resistance of cartilage, improves function/mobility of the joint, reduces the progression of OA, and reduces joint pain [33] CS has been shown to increase hyaluronan production by human synovial cells, which has a beneficial effect on maintaining viscosity in the SF. CS stimulates chondrocyte metabolism, leading to the synthesis of collagen and proteoglycan, the basic components of new cartilage [34]. CS also provides elasticity and assists in cushioning impact stress. It is suggested that CS may help the body to repair damaged cartilage and help restore joint integrity. It may also protect existing cartilage from premature breakdown. Because CS production by the body decreases with age, its supplementation may be especially helpful for older humans. Furthermore, CS inhibits the enzymes leukocyte elastase and hyaluronidase, which are found in high concentrations in SF of patients with rheumatic diseases. It has also been hypothesized to reduce inflammation, inhibit synthesis of degradative enzymes including MMPs, increase synthesis of ECM constituents, and reduce apoptosis of articular chondrocytes [35]. [36] reviewed details of the biochemical basis of the effect of CS on OA articular tissue. At molecular levels, CS inhibits NF-κB nuclear translocation and phosphorylation of p38 MAPK, ERK1/2, and JNK [37]. When given in combination, these two supplements: stimulate the synoviocyte and chondrocyte metabolism; inhibit the enzymatic degradation and reduce the fibrin thrombi in the periarticular microcirculation; and can regulate the genetic expression and the synthesis of NO and PGE2, thereby exerting anti-inflammatory properties. In addition to anti-inflammatory action, GS and CS exhibit an antioxidant expression that leads to a significant reduction in iNOS expression and activity [38], thereby reducing the otherwise NO-induced cell death of chondrocytes. In several studies, GS and CS have been evaluated as single agents and in combination for the treatment of OA. In fact, it is a common practice for glucosamine and chondroitin to be used together because they offer a greater beneficial effect than when given alone, although they work through different mechanisms of action. In a clinical trial, GS was found to be as effective or slightly more effective than analgesics [39,40,41,] or NSAIDs [42] for decreasing pain. A trial by [43] did not show a difference between GS and placebo. In another clinical trial,GS was found to be ineffective for reducing pain in patients with severe knee OA, but it was more effective when it was used in combination with CS due to a synergistic effect in patients with moderate to severe pain [44] found that the chondroprotective agents (GS and CS) were effective in improving the function of patients with OA, but the radiological modifications in the knee were statistically insignificant after 12 months of monitoring. However, the findings of Narvy and Vangsness (2010) supported a role of these nutraceuticals in reducing radiographic progression of knee OA. Recently, Kozakcioğlu (2012) revealed that GS and CS both have a suppressor effect on the structural deformities of OA. In a recent study, Erhan et al. (2012) showed that topical glucosamine treatment combined with physical therapy in patients with knee OA had no superiority over placebo, based on radiological findings (Kellgren– Lawrence score) and joint stiffness index (Western Ontario and McMaster Osteoarthritis, WOMAC score). In all clinical trials, GS, GH, and CS were found to be as safe as placebo [45]. The acute oral LD50 of glucosamine is >8 g/kg in rats and 15 g/kg in mice, which can be considered nontoxic. Oral administration of glucosamine at 2,700 mg/kg for 12 months in animals produced no adverse effects. Oral administration of large doses of glucosamine in animals has no documented effects on glucose metabolism. However, Lafontaine-Lacasse et al. (2011) reported that, at beyond recommended dosages, glucosamine may damage pancreatic cells, thereby possibly increasing the risk of developing diabetes. In a few patients, hepatotoxicity (hepatitis and/or cholestasis) developed following exposure to glucosamine [46] These authors established a temporal relationship between onset of liver injury and glucosamine ingestion. Clinical studies have not identified any significant side effects of CS, which suggests its long-term safety [47]. Recently, the Task Force of the European League against Rheumatism (EULAR) committee also granted CS a level of toxicity of 6 on a 0–100 scale, confirming that CS is one of the safest remedies for OA. Currently, glucosamine and chondroitin are not recommended by Osteoarthritis Research Society International (OARSI) and the American College of Rheumatology (ACR) [48]. In dogs with moderate OA, daily administration of GH (2,000 mg) and CS (1,600 mg) for a period of 120–150 days significantly reduced pain associated with OA [49]. Gupta et al. (2009) also reported significant reduction of pain in horses with moderate OA receiving GH (5.4 g) and CS (1.8 g) daily for a period of 150 days. In both dogs and horses, GH and CS produced no side effects and were well-tolerated. Previously, in a number of in vivo and in vitro studies, GS and CS have been found to be very effective against OA in animal models [50]. These studies suggested that the combination of GS and CS appears to be more effective in preventing or treating OA in animals than either product alone. A Golden Retriever developed polyuria and polydipsia when treated with 1,000 mg of glucosamine/day [51]. The polyuria and polydipsia resolved after the glucosamine dose was lowered to 500 mg/day. In an experimental study, glucosamine was reported to cause hyperglycemia, insulin resistance, and a diabetic-like state in rats [52]. Beriault et al. did not confirm hyperglycemia and insulin resistance with glucosamine, but it promoted endoplasmic reticulum stress, hepatic steatosis, and accelerated atherogenesis in mice. 3. Methylsylfonylmethane (MSM) Methylsylfonylmethane (MSM), also known as methyl sulfonate or dimethyl sulfone, is a naturally occurring organosulfur compound and a putative methyl donor. MSM is the first oxidized metabolite of dimethyl sulfoxide (DMSO). It occurs naturally in some plants and it is added in small amounts to many foods and beverages as a dietary supplement. Currently, MSM is sold via 52 different products as a single agent in capsule, caplet, lotion, and cream forms, and in more than 30 different products in combination with other dietary supplements. MSM is sold as a dietary supplement and marketed with a variety of claims often in combination with glucosamine and/or chondroitin for helping to treat or prevent OA. However, there is a paucity of scientific evidence to support the use of MSM. It has been suggested that the benefits claimed for MSM far exceed the number of scientific studies. In October 2000, the US Food and Drug Administration (FDA) warned one MSM promoter, Karl Loren, to cease and desist from making therapeutic claims for MSM. Due to its sulfur content, MSM is used by the body to maintain normal connective tissue. MSM may have anti-inflammatory activity, chemopreventive property, prostacyclin (PGI2) synthesis inhibition, antiatherosclerotic action, salutary effect on eicosanoid metabolism, and free radical scavenging activity [53,54]. MSM is an analgesic, anti-inflammatory, and blood vessel dilator. In OA, MSM works by reducing inflammation and blocking the pain response in nerve fibers. However, like any other nutraceutical, MSM does not cure OA. MSM serves the same purpose as the NSAIDs, but MSM has none of the negative outcomes associated with NSAIDs. In a randomized, double-blind, placebo-controlled trial,[54] reported that compared to placebo, 3 g of MSM twice per day (6 g/day total) for 12 weeks produced significant decreases in WOMAC pain and physical function impairment (P < 0.041 and P < 0.045, respectively). No notable changes were found in WOMAC stiffness and aggregated total symptoms scores. MSM ameliorated symptoms of pain and improved physical function during the intervention without major adverse events. In another clinical trial, patients with OA of the knee taking MSM daily (1.125 g three times) for 12 weeks showed a decrease in pain and improvement in physical function [55]. In a 12-week trial,[56] treated patients with knee OA with 1.5 g MSM (500 mg three times per day), 1.5 g glucosamine sulfate (GS), MSM plus GS, or placebo for 12 weeks. Significant decreases in the Lequesne Index were reported with MSM, GS, and their combination (P < 0.05). The authors reported a 33% decrease in pain in the MSM group; joint mobility, swelling, global evaluation, and walking time were also improved. The MSM dosage used by [56] was lower than the recommended dosage of MSM for clinical practice. In all of these studies, the improvements were small; therefore, further studies are warranted to establish their clinical significance. For further details on the effects of MSM and DMSO in OA, readers are referred to [57]. Acute and subchronic toxicity studies in rats using a single dose of 2 g/kg and a daily dose of 1.5 g/kg MSM for 90 days showed no adverse events, organ pathology, or mortality [58]. These doses of MSM are considered five times to seven times the maximum dose used in humans [54]. There are no clinical studies on adverse effects, changes in blood chemistry, safety monitoring data, or possible subclinical neurotoxicity symptoms. Side effects of MSM following its oral use are mild and may include digestive upset, headaches, increased blood pressure, increased hepatic enzymes, allergic reactions, and skin rashes. References: 1. Pavelka K, Trc T, Karpas K, et al. The efficacy and safety of diacerein in the treatment of painful knee osteoarthritis: a randomised, double-blind, placebo controlled multicentre study. Poster presented at: The Annual European Congress of Rheumatology, EULAR; June 8-11, 2005; Vienna, Austria. 2. Brandt KD, Smith G, Kang SY, et al. Effects of diacerhein in an accelerated canine model of osteoarthritis.Osteoarthritis Cartilage 1997;5:438-449 3. Smith GN Jr, Myers SL, Brandt KD, Mickler EA, Albrecht ME. Diacerhein treatment reduces the severity of osteoarthritis in the canine cruciate-deficiency model of osteoarthritis. Arthritis Rheum 1999;42:545-554. 4. Ghosh P, Xu A, Hwa SY, Burkhardt D, Little C. Evaluation of the effects of diacerhein in the sheep model of arthritis [in French]. Rev Prat. 1998;48(17) (suppl):S24-S30. 5. Bendele AM, Bendele RA, Hulman JF, Swann BP. The beneficial effects of diacerein treatment in a guinea pig model of osteoarthritis [in French]. Rev Prat.1996;46:S35-S39. 6. Bendele A, Bendele R, Hulman J, Swann B. A chronic study of the efficacy and toxicity of diacerhein treatment of guinea pigs with osteoarthritis. Abstract presented at: The 2nd OARS International Congress Symposium: Research and Therapeutics in Osteoarthritis: IL-1 Inhibitors; February 4-5, 1995; Nice, France. 7. Mazieres B, Berda L. Effect of diacerhein (art 50) on an experimental postcontusive model of OA [abstract]. Osteoarthr Cartil. 1993;1:47. 8. Douni E, Sfikakis PP, Haralambous S, Fernandes P, Kollias G. Attenuation of inflammatory polyarthritis in TNF transgenic mice by diacerein: comparative analysis with dexamethasone, methotrexate and anti-TNF protocols. Arthritis Res Ther. 2004;6:R65-R72. 9. Dougados M, Nguyen M, Berdah L, et al. Evaluation of the structure-modifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo controlled trial: Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip. Arthritis Rheum. 2001;44:2539-2547. 10. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis, II: osteoarthritis of the knee.Arthritis Rheum. 1995;38:1541-1546. 11. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis, I: osteoarthritis of the hip.Arthritis Rheum. 1995;38:1535-1540. 12. Lequesne M, Brandt K, Bellamy N, et al. Guidelines for testing of slow acting drugs in osteoarthritis. J Rheumatol Suppl. 1994;41:65-73. 13. Pelletier JP, Yaron M, Haraoui B, et al; the Diacerein Study Group. Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo controlled trial. Arthritis Rheum. 2000;43:2339-2348. 14. Lequesne M, Berdah L, Gerentes I. Efficacy and tolerance of diacerhein in the treatment of gonarthrosis and coxarthrosis [in French]. Rev Prat. 1998;48(17) (suppl):S31-S35. 15. Tang FL, Wu DH, Lu ZG, Huang F, Zhou YX. The efficacy and safety of diacerein in the treatment of painful osteoarthritis of the knee. Poster presented at: The 11th Asia Pacific League of Associations for Rheumatology (APLAR) Congress, International Convention Center (ICC); September 11-15, 2004; Jeju, Korea 16. Mantia C. A controlled study of the efficacy and tolerability of diacetylrhein in the functional manifestations of osteoarthritis of the hip and the knee: a double blind study versus diclofenac. Unpublished clinical study report; Palermo Hospital, Palmero, Italy; 1987 17. Nguyen M, Dougados M, Berdah L, Amor B. Diacerhein in the treatment of osteoarthritis of the hip. Arthritis Rheum. 1994;37:529-536 18. Louthrenoo W, Nilganuwong S, Aksaranugraha S, et al. The efficacy and safety of diacerein in the treatment of painful osteoarthritis of the knee: a randomised, multicentre, double-blind, piroxicam-controlled, parallel-group, phase III study. Poster Presented at: The 11th Asia Pacific League of Associations for Rheumatology (APLAR) Congress, International Convention Center (ICC); September 11-15, 2004; Jeju, Korea 19. Pietrogrande V, Leonardi M, Pacchioni C. Results of a clinical trial with a new drug, diacerhein in arthrosic patients. Report presented at: The LXXXVI Congress of the Italian National Society of Internal Medicine; September 24, 1985; Sorrento, Italy. 20. Portioli IA. Naproxen-controlled study on the efficacy and tolerability of diacetylrhein in the functional manifestations of osteoarthritis of the knee and hip: a double- blind study versus naproxen. Unpublished clinical study report; Santa Maria Nuova Hospital, Reggio Emilia, Italy; 1987 21. Leeb BF, Bucsi L, Keszthelyi B, et al. Treatment of osteoarthritis of the knee joint. efficacy and tolerance to acemetacin slow release in comparison to celecoxib [in German].Orthopade. 2004;33:1032-1041. 22. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual nonsteroidal anti-inflammatory drugs. Lancet.1994;343:769-772. 23. Brandt KD. Should osteoarthritis be treated with nonsteroidal anti-inflammatory drugs? Rheum Dis Clin North Am. 1993;19:697-712 24. Dieppe P, Cushnaghan J, Jasani MK, McCrae F, Watt IA. Two-year, placebo controlled trial of non-steroidal anti-inflammatory therapy in osteoarthritis of the knee joint. Br J Rheumatol. 1993;32:595-600 25. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004;364:2021-2029 26. The European Agency for the Evaluation of Medicinal Products. Questions and answers on non-selective NSAIDs: CHMP review of safety of non-selective NSAIDs. London, England: European Agency for the Evaluation of Medicinal Products; 2005. Publication EMEA/250423/2005 27. Food and Drug Administration. Public health advisory non-steroidal anti-inflammatory drug products (NSAIDs). 2006. http://www.fda.gov/cder/drug/advisory/nsaids.htm. Accessed February 1, 2006 28. Setnikar, J., Rovati, L.C., 2001. Absorption, distribution, metabolism and excretion of glucosamine sulfate. A review. Arzneimittelforschung 51, 699–725. 29. Deal, C.L., Moskowitz, R.W., 1999. Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen hydrolysate. Rheum. Dis. Clin. North Am. Huskisson, E.C., 2008. Glucosamine and chondroitin for osteoarthritis. J. Int. Med. Res. 36, 1161–1179 25, 379–395. 30. Hooper, M., 2001. Is glucosamine an effective treatment for osteoarthritic pain? Cleve. Clin. J. Med. 68, 494–495. 31. D’Abusco, A.S., Calamia, V., Cicione, C., et al., 2007. 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Rheumatol. 2011, 1–17. 35. Vangness, C.T., Spiker, W., Erickson, J., 2009. A review of evidencebased medicine for glucosamine and chondroitin sulfate use in knee osteoarthritis. Arthroscopy 25, 86–94. 36. Monfort, J., Pelletier, J.P., Garcia-Giralt, N., Martel-Pelletier, J., 2008. Biochemical basis of the effect of chondroitin sulfate on osteoarthritis articular tissues. Ann. Rheum. Dis. 67, 735–740. 37. Jomphe, C.R., Gabriac, M., Hale, T.M., et al., 2008. Chondroitin sulfate inhibits the nuclear translocation of nuclear factor-kappa B ininterleukin-1beta-stimulated chondrocytes. Basic Clin. Pharmacol. Toxicol. 102, 59–65. 38. Valvason, C., Musacchio, E., Pozzuoli, A., et al., 2008. Influence ofglucosamine sulfate on oxidative stress in human osteoarthritic chondrocytes: effects of HO-I, p22(Phox) and iNOS expression. Rheumatology 47, 31–35. 39. Lopez, V.A., 1982. 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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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