1. İşemik İnsultların  müalicəsində yeni  istiqamətlər. 

(Həkimlər ücün metodik tövsiyələr)

Tərtib edənlər: Ə. Əliyev adına Azərbaycan Dövlət həkimləri Təkmilləşdirmə Institutunun  nevrologiya kafedrası. Kafedra müdiri, t.e.d., professor Şirəliyeva R.K., dosent, t.e.d., Həsənov R.L., nevroloq Ələkbərzadə V.

Ümumdünya Səhiyyə Təşkilatı, 2004-cü ildən etibarən insultu dünya əhalisinin səhhətinə və həyatına təhlükə törədən qlobal epidemiya kimi qiymətləndirmişdir. Dünya üzrə ölüm hadisələrinin 45.6% - ni  ürək-damar xəstəlikləri təşkil edir ki, bunların 40%-i insultların payına düşür. İnsult xəstənin ailə üzvləri üçün də ağır problemə çevrilir, onların əmək potensiallarını azaldır və  ciddi maddi çətinliklər yaradır.  Eyni problem Azərbaycan Respublikası üçün də aktualdır.

Insult - 24 saatdan artıq davam edən, qəfil inkişaf edən damar mənşəli nevroloji çatışmazlıqdan ibarət olan sindromdur. İşemik və hemoragik olmaqla 2 qrupa bölünür. Rastgəlmə tezliyinə görə işemik insultlar üstünlük təşkil edirlər, belə ki, bu nisbət  4.2:1 kimidir, yəni hadisələrin təxminən 80%-i işemik insultlardır. İnsultların 50%-nin səbəbi serebral trombozlardır. Aparılan elmi tədqiqatlar nəticəsində müəyyən olunmuşdur ki, hər hansı bir səbəbdən damar mənfəzi tıxanarsa, bir neçə dəqiqədən bir neçə saata qədər müddət ərzində beyində işemiya zonası formalaşır. «Nüvəni» əhatə edən perifokal dairədə isə penumbra meydana çıxır ki, bütün müalicə səyləri yalnız  bu nahiyyədə yerləşən sinir hüceyrələrini yenidən «həyata qaytarmaq» uğrunda aparılır.

Buna görə,  insultun müalicəsində patogenezin əksər həlqələrinə təsir edən, yəni neyroprotektiv, neyroreparativ, neyrostimulyator, antioksidant xassələrə malik preparatların istifadəsi perspektivli hesab olunur. Belə xassələrə malik olan maddələrdən biri sitikolindir. Preparat  aktiv substansiya kimi xolin və sitidindən təşkil olunmuşdur. Bu iki maddə hüceyrə membranını təşkil edən fosfolipidlərin sintezinin aralıq məhsullarıdır. Xolin, həmçinin, aktivləşdirici neyromediator olan asetilxolinin sintezində başlıca maddədir. Qeyd olunan kimyəvi xassələrə malik olduğuna görə, sitikolin membran fosfolipidlərinin sintezini sürətləndirir, beyində metabolik prossesləri artırır, asetilxolin, dofamin, noradrenalin mediasiyasını artırır, qlutamatı isə modulyasiya edir. Sitikolin mitoxondri ATF-azasının,  membran Na/K ATF-azasının fəaliyyətini bərpa edir,  bəzi fosfolipazaların aktivliyini tormozlayır,  beyin ödeminin reabsorbsiyasını tezləşdirir.

Preparatın kəskin insultlar zamanı kliniki effektliyi keçən əsrin 90-cı illərindən öyrənilməyə başlanılmışdır. Müxtəlif sutkalıq dozaların (500, 1000, 2000 mq) istifadəsi bu preparatın  plasebo ilə müqayisədə müalicəvi effektliliyini sübut etmişdir.

«Orta və ağır dərəcəli insultlarda prosesin ilk 24 saatı ərzində sutkada 2 qram sitikolin istifadəsi xəstələrin yaxşı bərpa olma ehtimalını artırır» (Davalos et al. Stroke 2002).

«Kəskin və yarımkəskin insultların müalicəsində sitikolin istifadəsinin  formal meta-analizi sitikolinin əhəmiyyətli dərəcədə effektini, 10-12%  ölüm səviyyəsini və uzunmüddətli əlilliyin azalmasını müəyyən etmişdir.» (Saver and Vilterdink, Stroke 33: 353, 2002).

«Neyrovizualizasiya tədqiqatlarının nəticələri təsdiq edir ki, infarkt zonasının kiçilməsi sitikolinin dozası ilə əlaqəlidir» (Harnett Varach, Stroke 33: 354, 2002)

«Aşkar edilmişdir ki, sitikolin  koqnitiv və davranış  pozğunluqlarında, xüsusilə serebrovaskulyar mənşəli koqnitiv çatışmazlıqlar zamanı effektlidir» (Fioravanti not Yanagi, The Cochrane Library İssue 1, 2005).

Qeyd olunanları nəzərə alaraq bəzi ölkələr və təşkilatlar sitikolinin kəskin insultların ilk günlərindən istifadəsini məqsədəuyğun hesab etmişlər.

«Kəskin serebrovaskulyar xəstəlik zamanı sitikolin istifadəsini məsləhət görürük» (Scottish National Health Systems, the Ministry of Health Guidelines Spain).

Azərbaycanda sitikolin artıq bir neçə ildir ki, istifadə olunur,  lakin indiyədək bu preparatın effektliyini qiymətləndirmək məqsədilə tədqiqatlar aparılmamışdı. Buna görə, bizim tədqiqatın məqsədi SOMAZİNA (sitikolin) preparatının kəskin işemik insult zamanı istifadəsinin kliniki effektlyini və  təhlükəsizliyini qiymətləndirilməkdən ibarət olmuşdur.  Əsas müayinə qrupunu 30 nəfər işemik insult keçirmiş xəstə təşkil etmişdir.  Somazina preparatının effektliyi və təhlükəsizliyini qiymətləndirmək məqsədilə aparılan tədqiqatlar əsas və müqayisə qruplarında müayinənin nəticələrinin müxtəlif dinamikasını müəyyən etməyə imkan vermişdir. Xəstələrin Amerika Milli Sağlamlıq Institutunun Insult Şkalası (NİHSS)  ilə ilk gün, 3 həftə sonra və 3 ay sonra qiymətləndirilməsi göstərmişdir ki, əsas qrupda müsbət dinamika müalicənin ilk günlərindən başlayaraq qeydə alınmışdır. Nevroloji funksiyaların bərpa intensivliyini qiymətləndirmək məqsədilə Bartel şkalasından  istifadə  olunmuşdur.

Alınan nəticələr, göstərmişdir ki, Somazina preparatıının insult baş verdikdən sonra ilk 72 saat ərzində  Somazinanın  istifadəsi  bərpa proseslərinin effektliyini atırır. 6 həftə müdətində istifadəsi nevroloji defisitin,  koqnitiv çatışmazlığın və əlillik dərəcəsinin müqayisə qrupuna nisbətən statistik etibarlı azalmasına səbəb olur.

Rev Neurol. 2012 Feb 1;54(3):173-179.

Probably role of citicoline in stroke rehabilitation: review of the literature.

[Article in Spanish, English]

Secades JJ.

Source

Grupo Ferrer, S.A., 08028 Barcelona, Espana.

Abstract

Stroke is a leading cause of mortality and the main cause of severe and long-term disability in adults. Following treatment during the acute phase, there is a need to continue the treatment of the patients in the rehabilitation phase, in order to improve the outcome and daily life activities. This is the role of rehabilitation programs. Rehabilitation is focused on increasing brain plasticity to recover some of the lost functions, based on different methodologies, including pharmaco-therapy. In this context, the role of citicoline in the rehabilitation of patients with stroke is reviewed.

http://www.ncbi.nlm.nih.gov/pubmed/22278894

Clin Evid (Online). 2011 Jun 9;2011. pii: 0201.

Stroke management.

Warburton E, Alawneh JA, Clatworthy PL, Morris RS.

Source

Neuroscience's Addenbrookes Hospital, Cambridge, UK.

Abstract

INTRODUCTION:

Stroke is the third most common cause of death in most developed countries. It is a worldwide problem; about 4.5 million people die from stroke each year. Stroke can occur at any age, but half of all strokes occur in people aged over 70 years. About 80% of all acute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion of a cerebral artery. The remainder are caused either by intracerebral or subarachnoid haemorrhage. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of specialised care in people with acute stroke? What are the effects of medical treatment in people with acute ischaemicstroke? What are the effects of decompressive hemicraniectomy in acute ischaemic stroke? What are the effects of surgical evacuation for intracerebral haematomas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

RESULTS:

We found 41 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

CONCLUSIONS:

In this systematic review we present information relating to the effectiveness and safety of the following interventions: acute reduction in blood pressure, aspirin, evacuation (early surgical evacuation, or conservative treatment), decompressive hemicraniectomy, neuroprotective agents (calcium channel blockers, citicoline, gamma-aminobutyric acid agonists, glycine antagonists, lubeluzole, magnesium, N-methyl-D-aspartate antagonists), specialised stroke care, systemic anticoagulation (heparinoids, specific thrombin inhibitors, low molecular weight heparin, oral anticoagulants, unfractionated heparin), and thrombolysis.

http://www.ncbi.nlm.nih.gov/pubmed/21658301

Rev Neurol. 2011 Mar 14;52 Suppl 2:S1-S62.

Citicoline: pharmacological and clinical review, 2010 update.

[Article in English, Spanish]

Secades JJ.

Source

Medical Department, Grupo Ferrer, SA, Barcelona, Spain. [email protected]

Abstract

This review is based on the previous one published in 2006 -Secades JJ, Lorenzo JL. Citicoline: pharmacological and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 2006; 28 (Suppl B): S1-56-, incorporating the new references until now, having all the information available to facilitate the access to the informacion in one document. This review is focused on the main indications of the drug, as acute stroke and its sequelae, including the cognitive impairment, and traumatic brain injury and its sequelae. There are retrieved the most important experimental and clinical data in both indications

http://www.ncbi.nlm.nih.gov/pubmed/21432836

Expert Opin Pharmacother. 2009 Apr;10(5):839-46.

Efficacy of citicoline as an acute stroke treatment.

Clark WM.

Source

Department of Neurology CR131, Oregon Health Sciences University, Oregon Stroke Center, Portland, OR97201, USA. [email protected]

Abstract

Citicoline (cytidine-5'-diphosphocholine or CDP-choline) is a precursor essential for the synthesis of phosphatidylcholine, one of the cell membrane components that is degraded during cerebral ischemia to free fatty acids and free radicals. Animal studies suggest that citicoline may protect cell membranes by accelerating resynthesis of phospholipids and suppressing the release of free fatty acids, stabilizing cell membranes, and reducing free radical generation. Numerous experimental stroke studies with citicoline have shown improved outcome and reduced infarct size in both ischemic and hemorrhagic stroke models. Citicoline has been studied worldwide in both ischemic and hemorrhagic clinical stroke with excellent safety and possibly efficacy found in several trials. A meta-analysis of four randomized US clinical citicoline trials concluded that treatment with oral citicolinewithin the first 24 h after a moderate to severe stroke is safe and increases the probability of complete recovery at 3 months. Citicoline clinical efficacy trials are now continuing outside of the US in both ischemic and hemorrhagic stroke. A citicoline supplement is now available from several sources on the internet.

http://www.ncbi.nlm.nih.gov/pubmed/19351232

Stroke. 2002 Dec;33(12):2850-7.

Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials.

Dávalos A, Castillo J, Alvarez-Sabín J, Secades JJ, Mercadal J, López S, Cobo E, Warach S, Sherman D, Clark WM, Lozano R.

Source

Department of Neurology, Hospital Universitari Doctor Josep Trueta, Girona, Spain. [email protected]

Abstract

BACKGROUND AND PURPOSE:

No single neuroprotective agent has been shown to influence outcome after acute stroke. Citicoline has been studied worldwide in many clinical trials with positive findings, but only 1 trial has obtained significant results in the primary efficacy variables. Our objective was to evaluate the effects of oral citicoline in patients with acute ischemic stroke by a data pooling analysis of clinical trials. The primary efficacy end point chosen was the common evaluation of recovery, combining National Institutes of Health Stroke Scale /=95 at 3 months using the generalized estimating equations analysis.

METHODS:

A systematic search of all prospective, randomized, placebo-controlled, double-blind clinical trials with oral citicoline (MEDLINE, Cochrane, and Ferrer Group bibliographic databases) was undertaken. Individual patient data were extracted from each study and pooled in a single data file. The main inclusion criteria included compatible neuroimaging with ischemic stroke, National Institutes of Health Stroke Scale >/=8, and prior modified Rankin Scale score

RESULTS:

Of 1652 randomized patients, 1372 fulfilled the inclusion criteria (583 received placebo, 789 received citicoline). Recovery at 3 months was 25.2% in citicoline-treated patients and 20.2% in placebo-treated patients (odds ratio [OR], 1.33; 95% CI, 1.10 to 1.62; P=0.0034). The dose showing the largest difference with placebo was 2000 mg, with 27.9% of patients achieving recovery (OR, 1.38; 95% CI, 1.10 to 1.72; P=0.0043). The overall safety of citicoline was similar to placebo.

CONCLUSIONS:

Treatment with oral citicoline within the first 24 hours after onset in patients with moderate to severe stroke increases the probability of complete recovery at 3 months.

http://www.ncbi.nlm.nih.gov/pubmed/12468781

Curr Opin Investig Drugs. 2001 Dec;2(12):1757-62.

Citicoline. Ferrer Internacional.

Alexandrov AV.

Source

Department of Neurology, University of Texas, Houston 77030, USA. [email protected]

Citicoline was originally developed and launched by Ferrer for the treatment of stroke, and is now also being investigated for the potential treatment of Alzheimer's disease (AD). In the US, the compound is being developed by Interneuron for the treatment of stroke. A US launch had been rescheduled for 2002 although a decision on future US development of citicoline was intended to be made in conjunction with Takeda, Interneuron's US licensee. Takeda had decided not to pursue development by December 2000 and was in negotiations with Interneuron for another product candidate. Interneuron stated at this time that it would explore other partnership opportunities for citicoline. In 1993, Interneuron licensed exclusive marketing and manufacturing rights to citicoline in the US and Canada from Ferrer. By September 1997, a patent application had been filed worldwide by Interneuron for the use of citicoline in the reduction of cerebral infarct volume, and in September 1998, US-05801160 was issued for citicoline relating to the protection of brain tissue from cerebral infarction following ischemic stroke. In December 1999, US rights to the commercialization of citicoline were licensed to Takeda.

PMID: 11892942 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/11892942?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVcSum 

Cochrane Database Syst Rev. 2005 Apr 18;(2):CD000269.

Update of:

Cochrane Database Syst Rev. 2004;(2):CD000269.

Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly.

Fioravanti M, Yanagi M.

Department of Psychiatric Science and Psychological Medicine, University of Rome "La Sapienza", P.le A. Moro, 5, Rome, Italy, 00185. [email protected]

BACKGROUND: CDP-choline (cytidine 5'-diphosphocholine) is a precursor essential for the synthesis of phosphatidylcholine, one of the cell membrane components that is degraded during cerebral ischaemia to free fatty acids and free radicals. Animal studies suggest that CDP-choline may protect cell membranes by accelerating resynthesis of phospholipids. CDP-choline may also attenuate the progression of ischaemic cell damage by suppressing the release of free fatty acids. CDP-choline is the endogenous compound normally produced by the organism. When the same substance is introduced as a drug it can be called citicoline.CDP-choline is mainly used in the treatment of disorders of a cerebrovascular nature. The many years of its presence in the clinical field have caused an evolution in dosage, method of administration, and selection criteria of patients to whom the treatments were given. Modalities of the clinical studies, including length of observation, severity of disturbance, and methodology of evaluation of the results were also heterogeneous. In spite of uncertainties about its efficacy due to these complexities, CDP-choline is a frequently prescribed drug for cognitive impairment in several European countries, especially when the clinical picture is predominantly one of cerebrovascular disease, hence the need for this review.Due to its effects on the adrenergic and dopaminergic activity of the CNS, CDP-choline has also been used as an adjuvant in the treatment of Parkinson's disease. OBJECTIVES: To assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders in the elderly. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 22 April 2004 using the terms CDP-choline, CDP, citicoline, cytidine diphosphate choline or diphosphocholine. The Register contains records from all major health-care databases and many ongoing trials databases and is updated regularly. SELECTION CRITERIA: All relevant unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for cognitive impairment due to chronic cerebral disorders were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the included studies, extracted the data, and pooled it when appropriate and possible. The pooled odd ratios (95% Confidence Interval (CI)) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. MAIN RESULTS: Fourteen studies were included in this review. Some of the included studies did not present numerical data suitable for analysis. Description of participants varied over the years and by type of disorders and severity, and ranged from aged individuals with subjective memory disorders to patients with Vascular Cognitive Impairment (mild to moderate), Vascular Dementia or Senile Dementia (mild to moderate). Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, four studies used periods extending over 2 and 3 months, one study observed continuous administration over 3 months and one study was prolonged, with 12 months of observation. The studies were heterogeneous in dose, modalities of administration, inclusion criteria for subjects, and outcome measures. Results were reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There was no evidence of a beneficial effect of CDP-choline on attention. There was evidence of benefit of CDP-choline on memory function and behaviour. The drug was well tolerated. AUTHORS' CONCLUSIONS: There was some evidence that CDP-choline has a positive effect on memory and behaviour in at least the short to medium term. The evidence of benefit from global impression was stronger, but is still limited by the duration of the studies. Further research with CDP-choline should focus on longer term studies in subjects who have been diagnosed with currently accepted standardised criteria, especially Vascular Mild Cognitive Impairment (VaMCI) or vascular dementia.

PMID: 15846601 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/15846601?ordinalpos=1&itool=EntrezSystem2.
PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

 Curir Med Res Opin. 2002;18 Suppl 2:s14-7.

Membrane stabilizer: citicoline.

Zweifler RM.

Stroke Center, University of South Alabama, Mobile 36617, USA. [email protected]

Brain ischaemia leads to a cascade of biochemical events, many of which ultimately cause cell membrane injury. Therefore, measures aimed at protecting neuronal membranes could be useful treatment strategies following stroke. Citicoline (cytidine-5-diphosphocholine; CDP-choline) is a naturally occurring nucleotide derivative that may reduce central nervous system (CNS) ischaemic injury by stabilizing cell membranes and reducing free radical generation. Several animal models of ischaemic stroke or hypoxia have shown beneficial effects of citicoline treatment. Randomized clinical stroke treatment trials performed outside of the United States (US) have shown promising results but several recent US trials have failed to support the use of citicoline following middle cerebral artery (MCA) stroke. It remains possible that more specific subgroups of patients may benefit from this well tolerated therapy, but these subgroups have yet to be determined. In addition, there remains the possibility that efficacy may be seen when citicoline is administered in combination with other neuroprotectants with complementary mechanisms of action.

PMID: 12365823 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/12271462?ordinalpos=1&itool=EntrezSystem2.
PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlusDrugs1