Multicentric clinical trials regarding effect of vinpocetine on cerebral vascular disorders

clinical study


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Introduction Objetives Methods and material Results Discussion and Conclusions

An indepth,multicentric clinical trial was carried out to evaluate the safety and efficacy of Vinpocetine, a new medicinal drug that treats vascular and metabolic disorders at the CNS level, with a daily dosage of 20 mg, in disorders such as Degenerative Cerebral Vascular Disorders (D.C.V.).

839 doctors participated in the study throughout the country; 8940 subjects were studied, from both sexes, with the average age being 63, and for an average duration of 51 days of therapeutic treatment.

A clinical evaluation was conducted using the SCAG Scale for the evaluation of clinical symptomatology, obtaining positive results with the exception of 127 subjects: 91 reflected no change, and 36 had a negative response.

The individualized analysis of each of the 17 items of the scale indicated an improvement in all of them, being more accentuated in some such as vertigo, headaches and tinnitus.

The overall clinical evaluation was favorable in 76% of the cases and unfavorable to Vinpocetine in less than 1%.

A reduced number of side effects was noted – 500 patients (5.59%) had adverse reactions, with the most frequent being hypotension (192) and tachychardia (160) – with justified dropouts – only 63 of these.

In conclusion: it was confirmed that there was a good tolerance to this medicinal drug, with a good indication of its efficacy.

Introduction

VINPOCETINE is a new synthetic product, derived from eburnamenine (3,16-eburnamenine-14-carboxylic acid ethyl ester) with high lipid solubility and relatively rapid renal degradation.

Vinpocetine positively influences both cerebral vascular resistance and the extraction of oxygen, as well as the “turnover” of glucose and the cerebral neuromediators.

Part of its main action was related with its indirect “adenosine-like” effect. Imamoto described the effect of reducing the cerebral vascular resistance both in animals and in humans, accompanied by an increase in the content of GMPs in the smooth vascular musculature obtained by the selective inhibition of the Ca2+-calmodulin->dependent phosphodiesterases and without producing vasodilation; therefore, it increases cerebral blood flow without significantly affecting the systemic arterial pressure.

The increase of the arteriovenous oxygen difference demonstrates an increase in the utilization of oxygen in the cerebral blood flow; the uptake of glucose, a percentage of cyclic nucleotides, as well as the content and “turnover” of cerebral biogenic amines (serotine, dopamine, noradrenaline) are also increased by the Vinpocetine.

The improvement or optimization of the cerebral metabolism leads to an increase in the tolerance of the neurons to hypoxemia, with these anti-hypoxic and tropic effects on the brain being clinically and experimentally demonstrated.

Enlightening results have been obtained through techniques such as computerized axial tomography and Doppler Ultrasonography.

Its efficacy in clinical situations was demonstrated by controlled trials in subjects with intellectual, cognitive, behavioral or other deficiencies as a consequence of chronic vascular or degenerative cerebral disorders.

A recent study carried out in a large number of trial subjects – in a double-blind, placebo-controlled, multicentric clinical trial, – showed a more accentuated therapeutic action with higher daily dosages (10 and 20 mg per day) in subjects with psycho-organic syndrome evaluated clinically and psychometrically.

With the progressive increase in the average life span, the current society places more importance on more advanced ages, and with them, accentuated geriatric illnesses. There is likewise an increased need to tackle specific disorders such as cerebral aging.

Objetives

This multicentric clinical trial intends to target the following objectives:

Evaluate the dosage of 10 mg (2 tablets) every 12 hours, determining:

  1. The tolerance in a large number of patients, in conditions similar to the clinical trial.
  2. The clinical efficacy, where possible with the reference of medicines previously administered to the patients.

Methods and material

The open, multicentric trial was carried out in 839 geriatric clinics all over the country, including patients from both sexes and any age with Degenerative Cerebral Vascular Disorders (D.C.V.) whether coexisting or not with other disorders and therapeutic treatment, observed in institutional or day clinics: using criteria relating to intolerance to Vinpocetine.

All the clinics were asked to specify the symptomatology and complementary means of diagnosis of D.C.V.

Treatment with Vinpocetine should be carried out for a period of six weeks and the evaluation was effected twice – with data at the beginning and at the end of the trial – with a set dosage of 20 mg daily, split into 10 mg (2 tablets) taken twice.

The evaluation was exclusively carried out on a clinical basis using the S.C.A.G. scale with 17 items, at the beginning and at the end of the clinical trial (Fig. 1), with a global appreciation of improvement, worsening or no alterations.

FIG. 1 - SCAG Scale

1. Inner vitality: Confusion

  1. Monitoring. Sensitivity and normal attitude.
  2. Some hesitation in the formative process of concentration in responses and in speech. Without confusion.
  3. Moderate reduction in the training capacity of concentration and responses. Temporary period of slight confusion.
  4. Clear reduction of the formative processes of concentration and responses. More frequent periods of accentuated confusion.

2.Memory of recent events

  1. Memory intact.
  2. Intermittent lapses of memory regarding unimportant, recent events.Memory intact for important recent events.
  3. Lapses of memory for recent unimportant events, and forgetfulness regarding important, intermittent recent events.
  4. Significant loss of memory regarding minor, important, or recent events.

3. Orientation

  1. Normal. Aware of surroundings (place and time).
  2. Orientation concerning the premises. Intermittent disorientation in terms of time. Identifies people.
  3. Has problems identifying people, the surroundings and time, but can find the way.
  4. Can not find the way without help. Disoriented in time.

4. Anxiety

  1. Relaxed. Calm
  2. Slight anxiety. Maintains self control.
  3. Moderate anxiety. Shows somatic symptoms but without disrupting daily activities.
  4. Important level of anxiety (pronunced). Somatic symptoms that disrupt daily activities.

5. Depression

  1. Sense of wellbeing.
  2. Sense of guilt. Indifferent. Sad.
  3. Sad and dejected with somatic and hypochondriacal concerns.
  4. Marked mental retardation or pronounced restlessness. Withdrawn, but answers the questions.

6. Emotional stability

  1. Normal.
  2. Very good. Sometimes, inappropriate emotional response.
  3. Moderate modification of the emotional response, little related with the situation.
  4. Quite inappropriate emotional responses.

7. Motivation. Initiative

  1. Normally motivated. Spontaneously undertakes his/her activities.
  2. Existence of a lack of motivation. Sometimes, but not always takes charge of his/her activities.
  3. A clear lack of motivation, sometimes taking charge of his/her activities. Frequently needs to be motivated.
  4. Pronounced lack of motivation. Rarely undertakes his/her activities.

8. Cooperation

  1. Spontaneous cooperation.
  2. Passive cooperation. Needs some guidance and motivation.
  3. Frequently needs motivation and persuasion.
  4. Passively refuses any help. Lack of cooperation in many areas.

9. Sensitivity

  1. Normal. Spends quite a lot of time with friends or other people.
  2. Has relatively few friends. Spends little time with them.
  3. Normally tries to meet other people normally, but remains socially passive.
  4. Isolated (distant), rarely speaks to others.

10. Personal care

  1. He/she dresses and feeds him/herself correctly. Good personal hygiene.
  2. He/she dresses and feeds him/herself in a manner that is imperfect but acceptable.Personal hygiene without assistance within acceptable limits.
  3. He/she dresses and feeds him/herself conveniently with minimal supervision. The personal hygiene also requires some supervision.
  4. Does not dress or feed him/herself correctly without constant supervision.

11. Locomotion

  1. Normal.
  2. Walks slowly and unsteadily.
  3. Walks with some difficulty. Supervision is essential, sometimes.
  4. Walks with great difficulty. Supervision is essential.

12. Appetite

  1. Normal
  2. Slight loss of appetite. No weight loss.
  3. Moderate anorexia. Undernourishment. No weight loss.
  4. Pronounced anorexia. Undernourishment if there is no supervision. Weight loss.

13. Vertigo

  1. Some
  2. Mild intermittent episodes of dizziness.
  3. Very frequent dizziness of moderate importance.
  4. Severe attacks of vertigo with short intervals between them.

14. Fatigue

  1. Not under normal conditions.
  2. Slight. Without interfering in the physical behavior.
  3. Moderate interference with physical behavior.
  4. Pronunciation (very strong) with certain interference in the physical behavior.

15. Headaches

  1. No.
  2. Slight.
  3. Moderate.
  4. Intense.

16. Sleep

  1. Normal
  2. No need for sleeping pills.
  3. Irregular use of sleeping pills.
  4. Constant use of sleeping pills.

17. Ringing in the ears

  1. No ringing.
  2. Slight ringing that does not cause discomfort.
  3. Intense ringing, disrupting to normal life.
  4. Very violent ringing, disrupting normal life and sleep.

Special attention was paid to the detection of adverse reactions and the possible existence of interactions with other medicinal drugs; registering the adverse reactions, with the affects being noted in clinical interviews by means of an active survey regarding hypotension or tachycardia; details of any other medical treatments and respective dosages were requested and noted.

The results of the S.C.A.G. scale were analyzed in three ways: a) comparing the score in each of the two parameters, b) the evolution of the total scores (17 items) at the beginning and at the end, c) calculating the percentage of “normal approximation” using the following formula:

(DO-D1/DO-17)x100

DO = score at the beginning of the treatment
D1 = score at the end of the treatment

A special digital computer program was used to ensure that exhaustive checks were carried out to verify the correct introduction of data, a tool which proved indispensable taking into account the enormous quantity of information processed.

Statistical software (Statgraphics) was used to calculate the average intervals (student’s t-test, bilateral) as well as the normal distribution (Kolmogorov-Smirnov).

Results

<20
2
 
20-29
7
22
30-39
22
75
40-49
123
283
50-59
570
824
60-69
1031
1298
70-79
573
799
80-89
108
184
90-99
3
13
  63.6 cases
men
women
63 cases
FIG.2 - Age and sex distribution

8940 records were collected between April 1986 and November 1989.

Some of these records had only slight omissions or errors in certain items, as a result of which they were not discarded.

Figure 2 reflects the distribution according to sex (n=5947).

The analysis immediately highlights a predominance related with the female sex, with 59% of cases, and in most cases the decades 50 to 70 in both sexes, the average ages of which were similar – 63 years of age in the women and 63.6 years of age for the men.

The distribution would be virtually symmetrical for both sexes and consistent with a normal combined distribution for a global average of 63.2 years of age; the minimum and maximum ages were 18 to 99 respectively.

The majority was observed in day clinics (7740 – 86.6%) and the residential areas of the patients (not indicated in 398) were distributed as follows:

Urban: 3664 (41%) Suburban: 1939 (22%) Rural: 2939 (33%).

Regarding risk factors actively researched, the following responses were obtained – regular drinkers in 715 cases (8%), smokers in 701 (7.8%) and both simultaneously in 828 (9,3%), amounting to a total of 2244 (25%).

The related pathologies and principal corresponding medicinal treatments are indicated in Tables I and II:

Associated Diseases (table I)
Arterial Hypertension -- 4703 (53%)
Dyslipidemia -- 1614 (18%)
Heart Isquemia -- 1569 (18%)
Diabetes -- 1417 (16%)
Cerebrovascular Accident -- 1152 (13%)
Hyperuricemia -- 890 (10%)
Not Marked -- 2005 (22%)
Major Therapeutic Drugs (table II)
Antihypertensive -- 4447 (50%)
Lipid-lowering -- 1316 (15%)
Antidiabetic -- 1301 (15%)
Antiplatelet -- 1301 (15%)
Coronary Vasodilators -- 1148 (13%)
Calcium Antagonists -- 956 (11%)
Antihyperuricamiantes -- 818 (9%)
Not Marked -- 2272 (25%)

A high frequency of arterial hypertension was registered, and as could be expected, of therapeutic anti-hypertensors.

According to the protocol, the trial should cover a period of at least 6 weeks, and this was fulfilled in the majority of the cases – 6405 (71%) – being a global average calculated for 50.8 days (in 555 files this information was omitted).

The D.C.V. symptomatology with most frequency was psychic (61%) and neurological (50%), assimilating O.R.L. symptomatology in 33% of cases with less representation for ophthalmology (18%).

The complementary resources or means of diagnosis were relatively scarce: the T.A.C. and the arteriograph in 203 and in 43 cases respectively. Furthermore, in 87% of the patients the diagnosis was based on exclusively clinical criteria (907 records omitted any information to this respect).

Overall Assessment of Patients
After Vinpocetine Overall Assessment of Patients
After Vinpocetine Precede by Other(s) Therapeutic(s) for DCV

Figure 3 indicates the overall clinical evaluation was assimilated in 5586 cases: in 76% of the patients (n=5586) the doctor considered the administration of Vinpocetine had had favorable effects.

From these, 4120 patients were selected who had previously undergone other treatments; for this group, the results were very similar and are reflected in Figure 4.

In the 8394 cases evaluated by the S.C.A.G. scale (it was not possible in 546 cases as they had not been filled in completely) an initial average score of 51.76 and an average final score of 34.23 were obtained, which represents a reduction of 17.53 points, meaning a normal evolution for 50.4% for the formula indicated (see material and method).

There was a negative evolution in only 36 cases, no change in 91 cases, and a positive outcome in the remaining 8267 cases; there was an evolution of more than 50% situating 5041 (60% of the total evaluated), with 517 of these having a total remission of the symptomatology.

On analyzing reduced points per item the values indicated in Figure 5 were obtained. That reduction gave an average per item of -1.04 points; the parameters with most significant improvement were those related with vertigo, headaches, ringing in the ears, anxiety, fatigue, depression and memory.

Those cases in which the patients had previously been medicated for D.C.V. were grouped in accordance with the respective therapeutic treatment, which allowed an indication of the comparative efficacy of Vinpocetine with such drugs to be obtained.

The S.C.A.G. scores of the groups are recorded in Charts III and IV.

Previously Administered Drug Used Alone (Chart III)
Drug Nº of cases
where it
was used
Average Scorig
S.C.A.G.
Symptom
Reduction
with
Vinpocetine
(D0-D1) Confidence
Intervals
(99%)
D0 D1
Piracetam 1017 55 37,6 48,90 % 17,5 16,5-18,4
Cirannizine 565 55,1 34,7 50,70 % 17,2 16-18,4
Co-Dergocrine 419 53 35,8 48,20 % 17,2 15,7-18,7
Ginko Biloba 177 57 38 50,50 % 19 16,8-21,2
Flunarizine 174 49,9 33,1 53,30 % 16,8 14,6-19,1
Vincamine 164 52,9 33,8 55,30 % 19 16,2-21,9
Nicergoline 133 53 36,7 47,80 % 16,4 14-18,6
Buflomedil 112 54,2 37,6 44,90 % 16,6 13,8-19,4
Pentoxifylline 46 55,7 39,4 44,30 % 16,4 11,8-20,9

Drugs Administered Previously in Association (Chart IV)
Drug Nº of cases
where it
was used
Average Scorig
S.C.A.G.
Symptom
Reduction
with
Vinpocetine
(D0-D1) Confidence
Intervals
(99%)
D0 D1
Piracetam + Vincamine 286 59,4 40 47,90 % 19,4 17,5-21,2
Piracetam + Cirannizine 280 61,1 42 46 % 19,1 17,3-20,9
Piracetam + Co-Dergocrine 220 62,3 44,2 42,80 % 18,1 16-20,1
Piracetam + Ginko Biloba 136 60,8 41,1 47,10 % 19,7 16,6-22,7
Piracetam + Flunarizine 78 59,6 41,1 48,10 % 18,5 14,7-22,2
Piracetam + Buflomedil 69 62,7 43,5 44,70 % 19,3 15,7-22,9
Piracetam + Nicergoline 55 58,6 43 40,50 % 15,6 11,8-19,4

There were secondary effects in only 500 cases (5.59% in total), in some cases more than one in the same patient – see Chart V.

Side Effects (Chart V)
Hypotension 192 Tachycardia 160
Epigastric 35 Gastric Intolerance 31
Headache 30 Nausesa/Vomiting 22
Dizzines/Vertigo 17 Rash 9
Malaise/Flashes 8 Drowsiness 8
Diarrhea 5 Excitability 4
Edema 3 Palpitations 3
Several 44    

Personal C
Orientation
Locomotion
Sociability
Cooperation
Appetite
Sleep
Motivation
Emotional State
Confusion
Memory
Depression
Fatigue
Anxiety
Tinnitus
Headache
Vertigo

Fig 5. Improvement of the items after treatment with vinpocetine

The most frequent were hypotension in 192 and tachychardia in 160 cases.

In a total of 63 cases (0.7%) the side effects led to the interruption of the therapeutic treatment undergone with Vinpocetine and the subjects in question dropping out of the trial, with the most frequent causes being epigastralgia (9), dyspeptic symptoms (8), hypotension (8), headaches (7), nausea/vomiting (4), unwellness (4), tachychardia (3) and vertigo (3).

There were 18 deaths during the period of the clinical trial. A standard pharmacovigilance card was sent to each clinic, and it was determined that none of the deaths were related with the medicinal drug object of the study. The causes of death were: A.V.C. (8), myocardial infarction (2), pneumonia (1), respiratory failure (1), pulmonary tuberculosis (1), intestinal occlusion (1) and sudden death (1), with 3 cases not being noted due to lack of detailed information.

Discussion and Conclusions

The large number of cases and the diversity allowed us to demonstrate the results obtained as a trial representative of the population under study – individuals of any age or sex with Cerebral Vascular Disorder; this presumption was supported by the fact that the distribution was consistent with the normal global distribution of 63.2 years of age.

We verified that the patients with associated disorders had a more advanced average age (64.5 years of age) than those without any other illness than the D.C.V. (59.3 years of age); 78% of the cases had related illnesses, and of these the highest incidences were of arterial hypertension in almost half of the total, with more than one pathology in 3348 patients, which is to say, 37% of the total: 449 patients with at least one illness were not medicated.

With respect to the duration of the trials, it was in general satisfactory, and in 71.6% of it was the same or superior to the time period recommended (6 weeks); in 496 cases the clinical trial concluded before completing 1 month, and in 810 cases it was prolonged to 10 weeks, with a vast majority (6837) lasting between 29 and 69 days.

The D.C.V. diagnostic was almost always clinical and based on psychic and/or neurological symptomatology; the need to resort to additional diagnostic examinations was very low, as would generally be expected in day clinics.

The global clinical evaluation of the efficacy of Vinpocetine gave favorable results as it was considered positive in 76% of patients; this value was significantly very similar to that obtained (73%) in cases in which the patient had already previously been medicated (with a pharmaceutical drug other than Vinpocetine) for D.C.V.

The evaluation using the S.C.A.G. scale using the 3 methods indicated was likewise positive: a reduction of 17.5 points (51.8 to 34.2) implies, with the formula indicated, a normal approximation (minimum score – 17 points) of 50.4%, which is to say, the symptomatological “charge” was reduced to half, which was considered satisfactory.

A high number of cases (5041 which are 60% of the total evaluated) were also observed as having more than 50% evolution.

In an individualized analysis of each parameter there is a noteworthy group of symptoms with improved evolution – vertigos, tinnitus and headaches – all with somatic involvement and which are believed to correspond to an important vascular action of the pharmaceutical drug; it is also suggested that there is a good scoring in items relating to affective incidents – anxiety, depression – as well as cognitive – memorization and confusion – all with above average progress.

This positive influence in the performance of memorization named short term is described in several works published, and very particularly a placebo controlled study in healthy adults, although the subjacent mechanisms remain uncertain.

On comparing the sub-group S.C.A.G. values with the aforementioned therapeutic ones the intention is to obtain values indicative of the efficacy of Vinpocetine, as the trial was not designed to be comparative.

The progression seems to be very similar in all of them, with confidence intervals of 99%, suggesting that the efficacy of Vinpocetine does not vary significantly with the existence or nature of patients’ previous medication.

Regarding the tolerance evaluation, all reactions during the trial period were noted.

571 occurrences were registered – in some, there was more than one in the same patient – with only 63 patients dropping out of the trial for this motive, and only 8 due to hypotension and 3 due to tachychardia, which were the most frequent side effects.

The average age (62.6) and the distribution of the sexes of these patients with side effects which coincide with the overall details seem to confirm the conclusion of the controlled study, which did not reveal increased risks in the use of Vinpocetine in comparison with younger aged patients. It can be concluded that there was a good tolerance to Vinpocetine.


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