As it has been shown in the previous section about the experimental data showing that citicoline can induce significant positive effects in different experimental models of TBI, citicoline seems to be a suitable drug for the management of patients suffering TBI. Thus, it is possible to say that citicoline has a pleiotropic effect on several steps of the ischemic cascade involved in the development of the TBI [ 84 ].
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Many years ago, the effect of citicoline stimulating the ascending reticular activating system at the brain stem level was postulated to explain the effects of the drug on the consciousness level [ 84 ]. As citicoline could be considered as a valid pharmacological treatment for TBI, many clinical studies have been performed over time to assess if the drug would have beneficial effects in the treatment of patients with TBI.
The first double-blind randomized and placebo-controlled clinical trial was presented in by Misbach at al. [ 87 ]. In this study, the authors concluded that the use of citicoline was associated with better recovery in patients with severe TBI.
In another double-blind study, performed by Ayuso et al. in , it was demonstrated the effectiveness of citicoline to treat patients with memory disorders of an organic base, in that case induced by bilateral electroshock [ 88 ].
De la Herrán et al. [ 89 ], in an open study with the 32 patients with severe TBI among other types of brain injuries, concluded that the administration of citicoline accelerated normalization of the consciousness state. Similar results and conclusions were obtained in other double-blind studies performed by Espagno et al. [ 90 ] and by Carcasonne and LeTourneau [ 91 ], the last one performed in children population.
Richer and Cohadon [ 92 ] performed a randomized, double-blind and placebo-controlled trial in a sample of 60 patients with severe TBI. Citicoline was administered at a dose of 750 mg/d intravenously for 6 days, and then intramuscularly for 20 days more. At 60 days, the number of patients who had recovered consciousness was significantly greater in the group receiving citicoline. At 90 days, it was also found that the highest rate of recovery of motor deficits was associated with the treatment with citicoline.
Lecuire and Duplay [ 93 ], in a double-blind study, compared the effects of citicoline (750 mg/d/10 d IV) to those of meclofenoxate (3 g/d/10 d IV) in a sample of 25 patients (14 patients treated with citicoline and 11 patients treated with meclofenoxate). Statistical analysis of the results demonstrated significant effects in the citicoline treated group regarding the resolution of consciousness disorders, EEG pattern, and functional recovery. Shortly after, the same authors confirmed these positive results in an open label study performed in a group of 154 patients with TBI injury [ 94 ]. Lecuire [ 95 ] conducted another double-blind study comparing piracetam (6 g/d) versus citicoline (750 mg/d) in a group of 40 patients with head injury. The results of the study showed a better result on consciousness status, vegetative and electric, and on the global final improvements in the group of patients treated with citicoline.
Cohadon et al. [ 96 ] demonstrated the clinical efficacy of citicoline in a double-blind placebo-controlled trial in a sample of 60 patients with severe TBI. A group of 30 patients was treated with citicoline (750 mg/intravenously for 6 days and continued up to 20 days more with intramuscular administration). In the treated group a shortening of the comatose period and an acceleration of the recovery of neurological deficits, especially in the motor area, were observed, these differences being statistically significant compared to placebo. The authors attributed these positive results to the effect of the drug on brain edema. Deleuze et al. [ 97 ] correlated the effectiveness of citicoline with its effect on the cerebral metabolism, reflected in a significant reduction of lactate levels in cerebrospinal fluid after the treatment.
Ogashiwa et al. [ 48 ] performed a study in a sample of patients with disturbances of consciousness associated with stroke, TBI or brain tumours. Fifty-one patients were treated with citicoline ( mg/d/7 d IV) and 50 patients with the same characteristics were used as controls. The effects were evaluated using the principal component analysis score and the global improvement rate. The results of the principal component analysis scoring correlated closely with those of the global improvement rate, the effects in the citicoline-treated group being significantly greater than those obtained in the control group. Citicoline was more effective on the items related to the performance than on the verbal factor. These authors considered the drug to be safe, and they even administered the drug by the intrathecal route in some cases [ 98 99 ].
In another controlled study, De Blas et al. [ 100 ] evaluated the effects of citicoline on the short- and long-term evolution in a group of 100 patients with head injuries, compared with a group of 100 patients treated conventionally. The results obtained suggested that the addition of citicoline to the conventional treatment regimen was associated with a decrease in the length of post-traumatic coma and the incidence of neurological and psychological sequelae, accelerating the recovery of these kind of deficits.
Raggueneau and Jarrige [ 101 ] published the results of a national inquiry conducted in 24 neurosurgical intensive care units in France. The authors obtained information on 921 cases of severe TBI. Among the total sample, 219 patients were treated with citicoline. This, then, allowed the comparison of the results obtained between patients treated and not treated with citicoline. The improvement of the outcome for all patients was significantly linked to citicoline treatment. Nevertheless, no effects on the mortality rate were seen associated with the use of the drug.
Calatayud Maldonado et al. [ 102 ] conducted a single-blind randomized clinical trial in a sample of 216 patients with moderate to severe TBI with the objective of assessing the influence of the addition of citicoline to the standard treatment for head injury. One hundred and fifteen patients received treatment with citicoline (up to 4 g/d parenterally). The total duration of the treatment varied according to the evolution of the patient. The analysis of the results showed that citicoline significantly decreased hospital stay. Similarly, the treatment with citicoline was associated with a significant better global outcome, as evaluated with the Glasgow Outcome Scale, that was more relevant in the subgroup of patients with severe TBI. The duration of outpatient follow-up was also reduced in the group of patients treated with citicoline.
p
< 0.001). Regarding the final outcome, evaluated with the Glasgow Outcome Scale, it was a trend to have a better outcome in the group receiving the active treatment, but these differences did not reach statistical significance, probably due to the small sample size.Lozano [ 103 ] reported the results of a randomized study to assess the impact of the use of citicoline therapy on the evolution of patients with severe TBI. Citicoline was administered to 39 patients at a dose ranging from 3 to 6 g/d by intravenous infusion for 2 weeks. The results were compared with another group of patients with the same characteristics and not treated with citicoline. After 14 days of treatment, cerebral edema was significantly reduced or normalized in a higher number of patients treated with citicoline. Mean hospital stay was also significantly reduced in the active treatment group (28.718 ± 21.6 days) in comparison with control group (37.323 ± 35.22 days;< 0.001). Regarding the final outcome, evaluated with the Glasgow Outcome Scale, it was a trend to have a better outcome in the group receiving the active treatment, but these differences did not reach statistical significance, probably due to the small sample size.
Lazowski et al. [ 104 ] performed a randomized and placebo-controlled study on a sample of 28 patients with traumatic brain injury caused by isolated head trauma. Citicoline was administered at a dose of 1 g IV for 14 days in addition to typical treatment. The GCS and the Glasgow Outcome Scale (GOS) were used to control patients up to 30 days. In the citicoline-treated group the analysis found no correlation between the GCS scores in day 7 and day 14, and this lack of correlation could be interpreted as a result of treatment with citicoline, and the significant correlation found on the GCS at 14 and 21 days could be interpreted as an expanded effect of treatment up to 21 days. In the citicoline-treated group, the GCS score at 21 days was significantly correlated with GOS scores at 30 days, showing the protective effect of the used drug.
Hinev al. [ 105 ] in their study observed that 80% of patients with severe head trauma recovered from neurological symptoms and unconsciousness, concluding that the use of citicoline was associated with reduced coma duration and accelerated recovery of neurological disturbances in patients with severe head trauma, highlighting the safety of the drug.
Krishna et al. [ 106 ] conducted a randomized, single-blind, placebo-controlled, single-center, prospective trial in a sample of 100 patients. Patients were randomized to receive citicoline (2 g/d/60 d PO) or placebo and the evaluations of outcomes were made at discharge and after 30 and 90 days. The authors concluded that the rate of recovery was earlier in the citicoline group in terms of a shorter duration of stay, early gaining of full consciousness and relief from cognitive symptoms.
The Citicoline Brain Injury Treatment Trial (COBRIT) was a double-blind randomized and placebo-controlled trial with a special design [ 107 108 ]. The objective of the trial was to determine the ability of citicoline to positively affect the functional and cognitive status in patients with complicated mild, moderate, and severe TBI. The primary outcome of the study was the functional and cognitive status at 90 days. The outcome was measured by the nine components of the TBI Clinical Trials Network Battery, that includes the Trail Making Test (parts A and B), the extended Glasgow Outcome Scale (GOS-E), the California Verbal Learning Test II, the Controlled Oral Word Association Test, some of the tests included in the Wechsler Adult Intelligence Scale III (Processing Speed Index and Digit Span), and the Stroop Test (Parts 1 and 2). The sample size was calculated assuming an odds ratio (OR) of 1.4 or higher, and the final sample size was fixed as patients, after adding 15% for presumed losses. The patients were randomized to receive either citicoline (2 g/d/90 d) or placebo by enteral route within 24 h after injury. The clinical trial was stopped early for futility with patients included. Rates of favorable improvement for the GOS-E were 35.4% in the citicoline group and 35.6% in the placebo group. For the other scales, the rate of improvement ranged from 37.3% to 86.5% in the citicoline group and from 42.7% to 84.0% in the placebo group. There were no significant differences between groups at the 90-day evaluation: global OR: 0.98 (95% CI: 0.83'1.15), nor at the 180-day evaluation: global OR 0.87 (95% CI: 0.72'1.04). On the basis of the results obtained, the authors concluded that citicoline, compared with placebo, was not effective in the improvement of the functional and cognitive status of patients with TBI.
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Despite the COBRIT trial being the largest study performed with citicoline in the management of TBI, there are some methodological issues that could question the validity and applicability of the results obtained. This study was an independent and academic study, financed by the US National Institute of Health, with a somewhat limited budget. A first point to consider was the sample size calculation that was based on an assumption of an OR of 1.4 as the effect of the treatment; however, this assumption was arbitrary and not based on previous data. Then, it looked as though the sample size was calculated based on the budget rather than on previous data. With a more realistic OR of 1.2 or less the sample size would have been much higher and unaffordable for the authors. Another key point to consider was the inclusion of mixed populations, including mild, moderate, and severe TBI. The pathophysiology and the evolution can be largely different among these groups. To consider these differences, it is mandatory to use a randomized and matched sample design, which was not used in the COBRIT trial. Thus, this is an evident source of heterogeneity, but it has not been considered as an important confounding factor in the analysis and interpretation of the data. Another point to take into the account was the atypical oro-enteral administration of the drug that is not approved in any country and has not previously been tested in any way. The use of this route of administration is not recommended in patients with moderate or severe TBI, at least in the first days. However, the most controversial point was the poor compliance of the treatment. A compliance of only 44.4% of patients having taken more than 75% of the medication expected is exceptionally low and needs to be explained, explanation that was not included in the publication of the trial. We must consider that not receiving the active treatment is not the same as not receiving the placebo, in terms of the standard of care being received. A placebo is a substance or treatment which is designed to have no therapeutic value. In other words, less than half of the patients in the active drug group received something close to a therapeutic dose of citicoline. Thus, this makes it exceedingly difficult to assume a lack of effect of the drug when the patients did not receive the proper treatment regimen.
El Reweny et al. [ 109 ] communicated the results of their study on patients with severe head injury. In their study 40 patients were allocated to 2 groups, where patients in Group I were treated with citicoline (1 g/d/14 d IV) in front of patients in Group II that received conventional therapy. They found that those patients in Group I with brain edema had the best outcome. Indeed, patients in Group II with intracerebral hematoma had the worst outcome. The authors concluded that the addition of citicoline to the conventional therapy of patients with severe TBI offered a trend to improve the outcome. Interesting are the results obtained by Varadaraju and Ananthakishan [ 110 ], demonstrating a certain synergistic effect when citicoline was administered together with cerebrolysin, as the patients treated with this association had a better outcome than patients treated with citicoline alone. Titov et al. [ 111 ] also demonstrated a positive effect of the combination of citicoline and cerebrolysin in the management of TBI in the acute phase.
p
< 0.01), during the hospital stay (9% vs. 24%,p
= 0.035), and after 6 months of follow up (13% vs. 28%,p
= 0.031). A significant reduction in the rates of unfavorable outcome (34% vs. 57%,p
= 0.015) was also detected and in the observed vs. expected ratio for mortality (0.42 vs. 0.84) in the citicoline group (Trimmel et al. [ 112 ] investigated the potential role of citicoline administration in TBI patients treated at the Wiener Neustadt Hospital. In a retrospective subgroup analysis, they compared 67 patients at the study site treated with citicoline (3 g/d/3 weeks IV) and 67 matched patients from other Austrian centers not treated with citicoline. Patients with moderate to severe TBI were included. The analysis found a significant effect of citicoline, expressed by the reduction of the rates of mortality at the intensive care unit mortality (5% vs. 24%,< 0.01), during the hospital stay (9% vs. 24%,= 0.035), and after 6 months of follow up (13% vs. 28%,= 0.031). A significant reduction in the rates of unfavorable outcome (34% vs. 57%,= 0.015) was also detected and in the observed vs. expected ratio for mortality (0.42 vs. 0.84) in the citicoline group ( Figure 2 ). Ahmadi et al. [ 113 ] published a double-blind, randomized clinical trial on 30 patients with severe TBI. According to the protocol (IRCTN7) and the abstract, patients were randomly divided into three groups: A (control), B (citicoline 0.5 g/12 h/24 d IV), and C (citicoline 1.5 g/12 h/14 d IV), but once the authors explained the methods in the article, these groups changed to: A (citicoline 0.5 g/12 h/24 d IV), B (citicoline 1.5 g/12 h/14 d IV), and C (placebo). This incongruence makes it difficult to interpret the results, because if the group assignment was the original, then a significant dose-dependent effect of citicoline can be found, but with the assignment stated in the paper, the results are difficult to interpret, but the authors concluded that citicoline had no positive effect on the outcome of such patients.
11,12,13,14,15,In recent years, the roles of inflammation and oxidative stress have been highlighted as targets to neuroprotection in the management of TBI [ 10 16 ]. Thus, the measurement of the effects of these neuroprotective therapies on the levels of established biomarkers of inflammation and oxidative stress could be of interest to evaluate the efficacy of such treatments.
Salehpour et al. [ 114 115 ] assessed the effects of citicoline in a sample of patients with diffuse axonal injury in a double-blind and randomized clinical trial. The efficacy of citicoline was assessed by the measurement of malondialdehyde (MDA) levels in plasma as a marker of oxidative stress. The MDA levels at the different times of blood sampling improved significantly, whereas the control group showed no difference. The authors concluded that citicoline is an effective neuroprotective agent and can reduce MDA levels in patients with severe TBI and diffuse axonal injuries.
Shokouhi et al. [ 116 ] conducted a double-blind and randomized clinical trial on 58 patients with the diagnosis of diffuse axonal injury and severe TBI to investigate the effects of citicoline on serum levels of fetuin-A and matrix Gla-protein (MGP), that are related with the inflammation and the vascular calcification secondary to head trauma. The findings suggested that citicoline may have protective effects against inflammatory damage and vascular calcification in TBI patients through increasing plasma levels of fetuin-A and MGP.
Table 3. Summary of clinical studies evaluating the effects of citicoline in the management of patients with mild to severe traumatic brain injury.
Table 3. Summary of clinical studies evaluating the effects of citicoline in the management of patients with mild to severe traumatic brain injury.
AuthorsYearn
SeverityType of StudyControlTime WindowSchedule of TreatmentFollow-upMain ResultsMisbach et al. [87]Moderate to severeDouble blind RCT aPlaceboNA b300 mg/d/14 d IV14 dBetter recovery rate (GCS c)Espagno et al. [90]SevereDouble blind RCT aPlaceboNA b250 mg/d/5 d IV + 250 mg/d/15 d IM30 dBetter recovery of consciousnessCarcasonne & LeTourneau [91]Moderate to severe (children)Double blind RCT aPlaceboNA bNAb20 dFaster recovery from comaRicher & Cohadon [92]SevereDouble blind RCT aPlacebo24 h750 mg/d IV (6 d) + IM (14 d)90 dMore independent patients (clinical evaluation)Lecuire & Duplay [93]Moderate to severeDouble blind RCT aMeclophenoxate24 h750 mg/d/10 d IV10 dMore patients with a favorable outcomeLecuire & Duplay [94]Moderate to severeOpen studyBibliographic data24 h750 mg/d/10 d IV + 250 mg/d/10 d IM20 dSignificant improvement of survival and resolution of neurological deficits and consciousness troublesCohadon et al. [96]SevereDouble blind RCT aPlacebo24 h750 mg/d IV (6 d) + IM (20 d)120 dMore independent patients (~GOS d)Lecuire [95]Moderate to severeDouble blind RCT aPiracetam24 h750 mg/d/10 d IV10 dGlobal result favorable to citicoline (p
< 0.01)Deleuze et al. [97]SevereOpen studyNone24 h500 md IV single dose4 dSignificant decrease of lactate and lactate/pyruvate ratio in CSF eDe Blas et al. [100]Moderate to severeOpen RCT aControl24 h200'400 mg/8 h IV or IM in the acute phase, followed by 100'200 mg/8 h PO during follow-up180 dReduction of coma and neurological and psychological sequelaeRagguenneau & Jarrige [101]SevereCohort studyControl24 h500'750 mg/d/20 d IV180 dMore independent patients (~GOS d)Calatayud Maldonado et al. [102]Moderate to severeSingle blind RCT aControl24 h3'4 g/d/4 d IV + 2 g/d/26 d PO90 dMore independent patients (GOS d)p
< 0.01) showing the protective effect of citicolineHinev et al. [105]SevereOpenNone36 h1 g/d/5'7 d IVNA b80% of patients recovered from neurological symptoms and un-consciousnessKrishna et al. [106]Moderate to severeSingle blind RCT aPlacebo24 h2 g/d/60 d PO90 dEarlier rate of recovery, less duration of stay, early gaining of full consciousness and relief from cognitive symptomsZafonte et al. [108]Mild, complicated, moderate and severeDouble blind RCT aPlacebo24 h2 g/d/90 d PO or enteral180 dNo differences on the TBI-Clinical Trials Network Core BatteryEl Reweny et al. [109]SevereOpen RCT aControlNA b1 g/d/14 d IVNA bTrend to improve the outcomeSalehpour et al. [114]Severe with diffuse axonal injurySingle blind RCT aControl24 h2 g/d/12 d IV12 dReduction of MDA plasma levelsShokouhi et al. [116]Severe with diffuse axonal injuryDouble blind RCT aControl24 h2 g/d/15 d IV15 dIncreased plasma levels of fetuin-A and matrix Gla-proteinSalehpour et al. [115]Severe with diffuse axonal injurySingle blind RCT aControl24 h2 g/d/15 d IV15 dReduction of MDA plasma levelsHi, I am wondering how come the pill bottle was already opened with the seal/tamper proof protection already torn away and the remainder on the edges of the opening slightly discolored? I'm hesitant to try these pills because of these safe guards not being present. I'd like to see how I can get a replacement pill bottle or a return of my money, because this comes off as a bit negligent for not ensuring the consumer's safety when it comes to a product one ingests. If it were an electronic item, for example, and the packaging was opened a bit, I would not mind it so much, but this is a food item and can be harmful if the pills were exposed to something potentially toxic, etc. Thank you.
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