Concomitant use of policosanol and

Revista CENIC Ciencias Biológicas, Vol. 38, No. 2, 2007.
Concomitant use of policosanol and benzodiazepines
in older patients
Gladys Castaño, Rosa Más,* Rafael Gámez,* Lilia Fernández,* José Illnait,* Julio Fernández,*
Sarahí Mendoza* and Melbis Mesa.
Surgical Medical Research Center, *Centre of Natural Products, National Centre for Scientific Research, 198 steet, between
19 and 21 avenue, Atabey, Playa, Havana City. Telephone: (37) 271 4225, Email: [email protected]
Recibido: 17 de julio de 2006.
Aceptado: 30 de octubre de 2006.
Palabras clave: policosanol, benzodiazepinas, interacciones medicamentosas, ancianos.
Key words: policosanol, benzodiazepines, DDI, drug interactions, elderly.
RESUMEN. El policosanol es un medicamento hipocolesterolemizante bien tolerado
en diferentes poblaciones, incluyendo aquellas con elevado consumo de medicamentos
concomitantes, y la frecuencia de eventos adversos (EA) ha sido muy baja, sugiriendo
un bajo riesgo de interaciones adversas de medicamentos. Las benzodiazepinas (BZPs)
se consumen ampliamente para el manejo de la ansiedad y los trastornos del sueño en
la vejez. Las interaciones medicamentosas (IM) con BZP son frecuentes debido a que
esta se metaboliza principalmente a través del sitema hepático citocromo P450 (CYP
450), subsistema CYP 3A4, el cual oxida muchas drogas, representando un riesgo potencial para serios EA. A pesar de que el policosanol no se elimina a través del sistema
CYP 450, existen reportes de IM con BZP. Por esta razón se ha investigado si la BZP
administrada conjuntamente con el policosanol induce EA distinto que cuando se administra con placebo sobre la base de los registros de todos los pacientes que tomaron
BDP (118 que recibieron placebo + BZPs y 121 policosanol + BZPs) incluidos en un
estudio de prevención a largo plazo. El análisis fue realizado según el criterio de intención de tratar. Ambos grupos fueron homogéneos al inicio del tratamiento. Después
de un año de tratamiento el policosanol redujo (p < 000 1) el colesterol de lipoproteína
de baja densidad (LDL-C) (21,3 %), el colesterol total TC (15,8 %), y los triglicéridos TG
(p < 0,01) mientras que por otra parte incremento el colesterol de lipoproteína de alta
densidad (HDL-C) (10,2 %), manteniéndose estos efectos durante el ensayo. Al finalizar
el estudio, el policosanol redujo (p < 0,0001 LDL-C (31,0 %), TG (23,0 %) e incrementó
HDL-C (17,8 %). Hubo 43 (18,0 %) bajas (27 placebo y 16 policosanol), 17 (10 placebo y
7 policosanol) debido a EA. El tratamiento no afectó los indicadores de seguridad, el policosanol redujo la presión sanguínea diastólica y sistólica, siendo sus valores normales.
La proporción de EA fue similar en ambos grupos. El policosanol mostró una eficacia
persistente y fue bien tolerado en pacientes ancianos bajo tratamiento con BZP, ya que
no se incrementaron los EA ni se afectaron los indicadores de seguridad. El policosanol
puede por tanto ser indicado conjuntamente con BZP en pacientes ancianos.
ABSTRACT. Policosanol is a cholesterol-lowering drug well tolerated in different
populations, including those with high consumption of concomitant drugs, and the
frequency of adverse events (AE) has been very low, suggesting a low risk of adverse
drug interactions. Benzodiazepines (BZPs) are widely consumed to manage anxiety
and sleep disorders in the elderly. Drug to drug interactions (DDI) with BZP are
frequent since they are metabolised mainly through the cytochrome P450 (CYP 450)
hepatic system, subsystem CYP3A4, which oxidises many drugs, representing a risk
for potentially serious AE. Despite policosanol is not metabolized through CYP 450
system, it can be frequently consumed with BZP, and there are increasing reports
of DDI with BZPs. Then, we researched whether policosanol administered together
with BZP induced AE different from placebo based on the records of all older patients
taking BZP (118 receiving placebo + BZPs, 121 policosanol + BZPs) included in a
long-term prevention study. Analysis was by intention-to-treat. Both groups were
well matched at baseline. After 1 year, policosanol reduced (p < 0.0001) low-density
lipoprotein-cholesterol (LDL-C) (21.3 %), total cholesterol (TC) (15.8 %) and triglycer-
ides (TG) (p < 0.01) (21.2 %), and raised
high-density lipoprotein-cholesterol
(HDL-C) (10.2 %), effects persisted during
the trial. At study completion, policosanol
lowered (p < 0.000 1) LDL-C (31.0 %), TC
(21.6 %), TG (23.0 %) and raised HDL-C
(17.8 %). There were 43 (18.0 %) withdrawals
(27 placebo, 16 policosanol), 17 (10 placebo,
7 policosanol) due to AE. Treatment did
not impair safety indicators, policosanol
reduced diastolic and systolic pressure,
individual values being normal. The rate
of AE was similar in both groups. Then,
policosanol showed a persistent efficacy
and was well tolerated in older patients
taking BZP, not increasing AE or impairing safety indicators. Then, policosanol
can be indicated in older hypercholesterolemic patients taking BZP.
INTRODUCTION
Atherosclerotic diseases are major causes of morbidity and mortality
in older people.1 Clinical studies have
demonstrated the direct relationship
between coronary heart disease
(CHD) and raised serum levels of
low-density lipoprotein cholesterol
(LDL-C),2 and the benefits of lowering LDL-C on clinical events.3-9
Hypercholesterolemia management in the elderly was controversial
because the contribution of raised
levels of LDL-C as predictor of the
relative coronary risk decays with
age,10 but actually remains as strong
predictor of the absolute coronary
risk in the elderly.11 Also, a prevention trial has shown that the clinical
benefits of lowering LDL-C were
also evident in older patients.9
107
Revista CENIC Ciencias Biológicas, Vol. 38, No. 2, 2007.
108
The elderly has impaired hepatic
and renal drug clearance, a high
frequency of co-morbidity and concomitant drugs, and consequently,
the greatest frequency of drug-related adverse events (AE).10,11
Policosanol is a mixture of high
molecular weight alcohols from
sugarcane wax,12 with cholesterollowering effects proven in type II
hypercholesterolemia13-24 and in type
2 diabetes mellitus.25-27 Policosanol
lowers LDL-C and total cholesterol
(TC), raises high-density lipoprotein cholesterol (HDL-C) in most
trials,13-27 except in a recent study
with negative results.28 Its effects
on triglycerides (TG), however, are
modest and not reproducible.12-27 In
particular, policosanol has shown to
be effective, safe and well tolerated
in older individuals.
Policosanol lowers cholesterol
by inhibiting cholesterol synthesis
before mevalonate production,29-31
through the regulation of HMG–CoA
reductase, 31 that a recent study
demonstrated is produced via AMP
kinase activation.32 Policosanol also
raises the LDL receptor-dependent
processing29 and the catabolic rate
of LDL.30 Policosanol also inhibits
platelet aggregation,12,17,33 and LDL
lipid peroxidation.34,35
Clinical data, including postm a r ke t i n g s u r v e i l l a n c e , h a v e
shown that policosanol is safe and
well tolerated,12–25,36,37 the report of
adverse events (AE) being relatively low, even in populations with
high consumption of concomitant
therapy, suggesting that its potential risk for drug to drug interactions (DDI) is low.
Benzodiazepines (BZPs) are
widely consumed in the elderly to
manage anxiety and sleep disorders,
and DDI with BZP are frequent
and represent a risk for potentially
serious AE (SAE). 38,39 BZPs are
mainly metabolised through the
cytochrome P450 (CYP 450) hepatic
system, subsystem CYP3A4, which
oxidises a broad spectrum of drugs,
most DDI resulting from this fact.40
Thus, excessive sedation can result
from concomitant use of BZD and
CYP3A4 inhibitors, like selective serotonin reuptake inhibitors, cimetidine, lansoprazole, antiepileptics,
macrolide antibiotics, grapefruit
juice,38-40 and some herbal drugs, as
SAE emerging from concomitant
use of kava-kava and BZP.41
Considering the populations
amenable to policosanol treatment
and the high frequency of BZP
consumption, the possibility of con-
suming simultaneously policosanol
and BZP is high. Many drugs, not
policosanol, 42,43 are metabolized
through the cytochrome P450 hepatic system, which minimizes the
possibility of pharmacokinetic DDI
between policosanol and such drugs.
Nevertheless, pharmacodynamic
DDI between policosanol and other
drugs cannot be discarded, and some
clinical studies, including a high
frequency of hypertensive patients,
mainly long-term studies, have
shown that policosanol decreased
arterial pressure compared with placebo. Since BZPs induces sedation,
the possibility of pharmacological
DDI between policosanol and BZP
cannot be ruled-out.
In light of these issues, the interest to search DDI between longterm treatment with policosanol
and BZPs is supported, mainly in
older subjects. Thus, this study
analysed the data of all patients
taking BZD included in a prevention study with policosanol in the
elderly44 for determining whether
concomitant therapy with policosanol and BZPs impairs safety
indicators or increase AE. It was
also investigated if BZD impaired
the cholesterol-lowering efficacy of
policosanol in such population.
PATIENTS AND METHODS
Ethic considerations
An independent Ethics Committee approved study protocol. The patients were enrolled after providing
informed written consent (Visit 1).
Study design
The present analysis was based
on a prospective, randomized, double-blinded, placebo -controlled
study including 1 470 older patients
receiving placebo or policosanol for
tree years. In brief, patients were
recruited at four Policlinical Centers,
“Ramón González Coro”; “Elpidio
Berovides,” “Educational” and “26
de Julio”, followed by medical staff
of the Surgical Medical Research
Center. Patients aged 60 to 80 attended to assess their risk factors (Visit
1) and instructed to follow a step one
cholesterol-lowering diet during a
baseline period of five weeks, after
which lipid profile and safety laboratory indicators were determined.
The following week they assisted to
Visit 2, when eligible patients were
randomized to policosanol 5 mg or
placebo tablets, and were followed
at tree months intervals during the
first year (Visits 3 to 6) and every
six months thereafter (Visits 7 – 10).
Study patients
Patients of both sexes, 60 to 80
with documented coronary or cerebrovascular disease, hypertension,
dyslipidemia, smoking habits and
(or) diabetes were enrolled. The
rationale for the lowest age was to
include older individuals with a
considerable life expectancy.
Patients with the following values
(mmol/L) after the baseline period:
TC ≥ 5.2, LDL-C ≥ 3.4 and TG < 4.52
were included in the trial.
Exclusion criteria were patients
with renal or diagnosed neoplastic
diseases, severe hypertension (diastolic pressure ≥ 120 mm Hg), uncontrolled diabetes or poor cognitive
function, those who had experienced
unstable angina, myocardial infarction, stroke or any SAE within the
tree months prior to enrollment
were also excluded.
Study protocol established as
causes of premature withdrawals the
following: AE justifying such decision, unwillingness to follow-up, TC
≥ 9 mmol/L and (or) major study violations, like > 6 weeks without taking study drugs and/or consumption
of forbidden concomitant drugs.
Treatment
Study drugs were indistinguishable and coded, and assigned as per
progressive inclusion. Treatment
was randomised through a computer generated random allocation,
consisting of balanced blocks, and
randomization ratio 1 : 1. Tablets
were taken once a day (oid) with
evening meal, and titrated to 2 or 4 oid
if serum TC was ≥ 7 mmol/L after 6 or
12 months on therapy.
Compliance assessment
Compliance with study drugs
was assessed by tablet counts and
patient request. Compliance was
defined as good if ≥ 85 % of the
scheduled tablets having been taken
since the prior visit.
Concomitant medications
Consumption of lipid-lowering
drugs was prohibited from the enrolment. Cases at secondary prevention
were advised to consume aspirin.
Concomitant drugs were controlled
through patient interview.
Assessments
At each visit patients underwent
a physical examination. TC was determined at baseline and every 6
months, lipid profile and lab safety
indicators at baseline and after 1,
2 and 3 years of randomization.
Revista CENIC Ciencias Biológicas, Vol. 38, No. 2, 2007.
Laboratory tests included lipid
profile, glucose, creatinine, aspartate aminotransferase (AST) and
alanine aminotransferase (ALT).
Compliance and AE were assessed
from visits 3 to 10.
Effects on lipid profile
For efficacy analysis, LDL -C
reduction was the primary variable,
treatment being considered effective
if LDL-C was significantly reduced
by ≥ 15 %,45 while other lipid parameters were secondary variables.
Safety and tolerability analyses
For this report, patient records
were reviewed and processed. All patients taking BZPs were included in
the analysis. Physical and laboratory
safety indicators were analysed.
Safety and tolerability analysis
included the analysis of AE. An AE
was defined as any new undesirable
experience or change in physical or
laboratory data or the worsening of
any pre-existing condition occurred
through the study, independently if
was or not drug-related.
AE were classified according to
their intensity in mild, moderate
and serious. Mild AE were those not
requiring treatment or withdrawal of
study drugs, moderate AE required
withdrawal of study drugs and/or
treatment of the AE.
A SAE was considered any AE
leading to patient hospitalisation
or death, being evaluated through
the official records of the hospitals,
death Registry and Family Doctors.
At each visit, the occurrence of SAE
was documented from patients’
recall, and the information verified
with hospitals and Family Doctors.
Thus, they were diagnosed by personnel not involved in the study. For
each category, events with definite
+ suspect causes were included.
Death certificates were requested
for all deaths and the causes of death
ascertained from hospital records
and official certificates, helped by
interviews to Family Doctors and
relatives. Whether the patients were
alive was corroborated by contact
with patients, and in cases travelling abroad, household and Family
Doctors were contacted.
Laboratory analysis
Blood samples were drawn after
a 12 h overnight fasting. Serum TC
and TG were determined by enzymatic methods using reagent kits.
HDL-C was assessed as the cholesterol content of the supernatant
obtained after β-lipoproteins pre-
cipitation.46 LDL-C was calculated
using the Friedewald equation. 47
Laboratory analyses were performed
in the Hitachi 719 autoanalyzer (Tokyo, Japan) located at the Medical
Surgical Research Center. A quality
control was performed, so that precision (within and between-day variations) and accuracy versus reference
standards were controlled.
Statistical analysis
All data here presented were
analysed according to intention
to-treat principle, including data
of all randomized patients. ANOVA
test was used to compare continuous variables throughout the study.
Comparisons between groups of
categorical data were made using
the chi square test. All statistical
tests were two-tailed, with significance at α = 0.05. Statistical analyses
were performed using Statistics for
Windows (Release 4.2; Copyright
StatSoft, Inc. USA) and SAS/STAT
(Stat Soft, Version 8, USA).
RESULTS
Baseline characteristics
Both groups were well matched
at baseline (Table 1). Most patients
were women (213/239, 89.1%), and
hypertensive (178/239, 74.5 %). Also,
there was a high frequency of CHD,
smoking and diabetes among study
patients. The frequency of other
concomitant drugs was relatively
high, the drugs most consumed being diuretics, antiplatelets, calcium
channel blockers and β-blockers,
well matched also in both groups.
There were 43 premature withdrawals (18.0 %) (27 in placebo, 16 in
policosanol) (p = 0.052), 17 (10 placebo, 7
policosanol) due to some AE (Table 2).
Effects in serum lipid profile
Compliance with study drugs
was good as defined by compliance
criterion, which is relevant for efficacy analysis.
After 1 year, policosanol reduced
significantly (p < 0.000 1) LDL-C
(21.3 %), total cholesterol (TC) (15.8 %)
and TG (p < 0.01) (21.2 %), whereas
increased HDL-C (10.2 %) (Table 3).
Policosanol effects persisted during
the study, after 3 years achieving
the following changes (p < 0.000 1)
LDL-C (31.0 %), TC (21.6 %), TG (23.0 %)
and raised HDL-C (17.8 %).
Safety and tolerability
No impairment of safety indicators was observed (Table 4). Nevertheless, a reduction of systolic
and diastolic blood pressure was
observed in policosanol patients
compared with placebo, not accompanied by decrease on pulse rates.
Individual values did not show any
evidence of hypotension.
The frequency of policosanol
patients referring some AE (27/121,
22.3 %) was similar than in respective placebo (33/118, 28.0 %) (Table 5).
From them, 16 patients (10 placebo,
8.5 %, and 6 policosanol, 5.0 %) experienced some SAE, 8 vascular (5
placebo, 4.2 %, 3 policosanol, 2.5 %)
and 8 non-vascular SAE (5 placebo,
4.2 %, 3 policosanol, 2.5 %). The
other AE reported were moderate
or mild, without differences policosanol and placebo.
DISCUSSION
The present report demonstrates
that in elderly patients receiving
BZPs, policosanol showed persistent efficacy and did not impair any
safety indicator or increased the
frequency of AE.
Both groups were comparable at
baseline, which supports their homogeneity. The mean age of study patients (around 65 years at randomisation) shows that they were still young
for preventive measures addressed to
improve life quality and expectancy.
The larger proportion of women
with regards to men is typical of the
patients attending these visits and
supported by the high motivation of
these women to participate in clinical
studies with regards to men.
The frequency of concomitant
medications was relatively high, as
expected for older patients. Then,
the analysis here reported was not
obtained from a population only
treated with BZPs and placebo or
BZPs and policosanol, but receiving
other concomitant therapy, as commonly occurs in clinical practice.
The other concomitant drugs were
mostly consistent with the risk condition of study population.
The present results support that
BZPs do not prevent policosanol
efficacy, since it reduced LDL-C,
CT and TG, and increased HDL-C.
The responses persisted, even improved, throughout the study. The
changes here reported for LDL-C;
TC and HDL-C are consistent with
those expected.13–27 Reductions on
TG, however, were superior that in
previous studies, a finding without
conclusive explanation.The withdrawal frequency in policosanol
group (16/121, 13.2 %) tended to be
(p = 0.052) significantly lower than
in placebo (27/118, 22.9 %), while
109
Revista CENIC Ciencias Biológicas, Vol. 38, No. 2, 2007.
Table 1. Main baseline characteristics of patients taking BZPs.
Placebo
(n = 118)
Characteristics
Policosanol
(n = 121)
(X ± SD)
Age (years)
Body mass index (kg/m2)
66 ± 5
65 ± 5
25.15 ± 6.00
25.69 ± 4.59
Gender
n
(%)
n
(%)
Female
106
89.8
107
88.4
Male
12
10.2
14
11.6
87
73.7
91
75.2
22
18.6
25
20.7
Coronary heart disease (CHD)
32
27.1
22
18.2
Diabetes mellitus
16
13.6
19
15.7
Risk factors
Arterial hypertension
Smoking
1
Obesity (kg/m2 > 30)
9
7.6
9
7.4
Cerebrovascular disease2
5
4.2
6
5.0
Diuretics
31
26.3
37
30.6
Antiplatelet
33
28.0
25
20.7
Calcium antagonists
24
20.3
31
25.6
β-blockers
16
13.6
21
17.4
Vitamins
12
10.2
17
14.0
Antidepressants
14
11.9
11
9.1
Myorelaxants
11
9.3
13
10.7
Vasodilators
11
9.3
12
9.9
Oral hypoglycemic drugs
11
9.3
9
7.4
Neuroleptics
9
7.6
12
9.9
Other concomitant medications (CM)3
BZPs benzodiazepines, n Number of patients; X mean, SD standard deviation,1 myocardial infarction, unstable angina, coronary
surgery,2 stroke, ischemic transient attacks;3 CM consumed by > 6 % of study patients. All comparisons were not significant.
Table 2. Withdrawal analysis of study patients taking BZD.
Placebo
(n = 118)
Policosanol
(n = 121)
P value1
Total
Withdrawals due to vascular SAE 5
3
ns
8
Withdrawals due to SAE from other causes
5
3
ns
8
Subtotal due to SAE
10
6
ns
16
Withdrawals due to mild and moderate AE
0
1
ns
1
Subtotal due to all AE
10
7
ns
17
Unsatisfactory efficacy
7
1
P < 0.05
8
Travels abroad + changes of living areas
4
4
ns
8
Unwillingness to follow-up
4
3
ns
7
Protocol violations
2
1
ns
3
Subtotal due to other reasons
17
9
ns
26
Total of withdrawals
27
16
P = 0.052
43
Withdrawals due to AE
Withdrawals due to other reasons
1
110
Comparison with placebo (χ2 test).
Revista CENIC Ciencias Biológicas, Vol. 38, No. 2, 2007.
Table 3. Long-term effects of policosanol on lipid profile of study patients taking BZPs.
Study groups
Baseline
1 year
2 years
3 years
TC
(mmol/L)
Policosanol
6.82 ± 0.90
5.74 ± 0.73+++
5.38 ± 0.58+++
5.35 ± 0.76+++
Placebo
6.67 ± 0.87
6.64 ± 0.85
6.63 ± 0.88
6.64 ± 0.71
LDL-C
(mmol/L)
Policosanol
4.80 ± 0.83
3.78 ± 0.73+++
3.40 ± 0.60+++
3.31 ± 0.72+++
Placebo
4.66 ± 0.84
4.64 ± 0.81
4.74 ± 0.90
4.71 ± 0.71
HDL-C
(mmol/L)
Policosanol
1.18 ± 0.35
1.30 ± 0.28
1.31 ± 0.25+++
1.39 ± 0.24+++
Placebo
1.24 ± 0.34
1.23 ± 0.32
1.11 ± 0.18
1.11 ± 0.12
Triglycerides
(mmol/L)
Policosanol
2.26 ± 0.93
1.78 ± 0.60++
1.76 ± 0.46+++
1.74 ± 0.22+++
Placebo
2.14 ± 0.79
2.05 ± 0.66
2.13 ± 0.70
2.11 ± 0.59
++
p < 0.01;
+++
p < 0.000 1 ANOVA test. The results were espressed as (X ± SD).
withdrawals due to AE (10 in placebo, 7 in policosanol) were similar.
The premature discontinuations due
to unsatisfactory efficacy, however,
were more frequent (P < 0.05) in
placebo (7/118, 5.9 %) than in policosanol (1/121, 0.9 %).
Policosanol was safe and well tolerated. No drug-related impairment
of safety indicators was observed.
Policosanol significantly reduced
blood pressure compared with placebo, an effect relatively beneficial
in the elderly, since lowering systolic pressure significantly reduces
coronary events and total mortality
in older individuals.48 Hypotension
was not reported in policosanol patients and pulse rate did not decrease,
which reduces the probability of a
potential risk resulting from DDI
between policosanol and BZPs.
Overall frequency of patients
reporting AE was similar in both
groups. This result, together with
withdrawal analysis, discards any
increase in particular AE due to policosanol administered with BZPs.
CONCLUSIONS
Policosanol was well tolerated
in elderly patients at high coronary
risk taking BZPs. Cholesterol-lowering efficacy of policosanol persisted
throughout the study. Treatment was
safe and policosanol administered to
patients taking BZPs did not impair
safety indicators nor induce specific
AE with respect to placebo patients
also taking BZPs. Then, policosanol
can be indicated for lowering LDLC to hypercholesterolemic older
patients taking BZPs, a population
highly medicated and sensitive to
drug-related AE.
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111
Revista CENIC Ciencias Biológicas, Vol. 38, No. 2, 2007.
Table 4. Long-term effects of policosanol on safety indicators of study patients taking BZPs.
Study groups
Baseline
1 year
2 years
3 years
Weight
(kg)
Policosanol
64.11 ± 11.27
63.83 ± 10.80
64.07 ± 10.60
63.58 ± 10.45
Placebo
64.19 ± 12.03
64.38 ± 12.19
64.08 ± 11.59
63.84 ± 11.28
Pulse
(beats/min)
Policosanol
72.25 ± 6.88
72.39 ± 6.29
72.20 ± 5.86
71.28 ± 4.68
Placebo
72.45 ± 6.88
71.91 ± 6.44
72.64 ± 6.43
72.29 ± 6.39
Diastolic pressure
(mm Hg)
Policosanol
82.99 ± 11.85
81.07 ± 8.01
79.66 ± 5.93
79.71 ± 6.80++
Placebo
82.74 ± 9.39
80.90 ± 7.43
80.98 ± 6.32
82.80 ± 4.67
Systolic pressure
(mm Hg)
Policosanol
139.2 ± 19.98
132.1 ± 13.89
130.0 ± 11.19++
127.7 ± 11.94++
Placebo
137.4 ± 17.41
134.3 ± 14.66
135.3 ± 12.76
133.9 ± 11.14
ALT
(U/L)
Policosanol
20.88 ± 9.16
19.39 ± 7.98+
19.35 ± 6.58+
20.42 ± 7.17+
Placebo
20.18 ± 9.08
22.21 ± 8.51
21.48 ± 6.75
23.39 ± 5.10
AST
(U/L)
Policosanol
23.41 ± 7.49
19.23 ± 6.47+
19.40 ± 6.35++
20.37 ± 18.60
Placebo
23.25 ± 8.58
21.71 ± 6.98
22.34 ± 6.66
21.64 ± 4.91
Creatinine
(µmol/L)
Policosanol
90.37 ± 17.49
86.49 ± 11.54
89.28 ± 11.65
89.00 ± 11.79
Placebo
90.60 ± 15.53
86.41 ± 12.32
90.81 ± 11.47
90.58 ± 10.33
Glucose
(mmol/L)
Policosanol
5.23 ± 1.15
5.30 ± 0.99
5.18 ± 0.77
5.27 ± 0.92
Placebo
5.45 ± 1.97
5.47 ± 1.51
5.24 ± 0.68
5.36 ± 0.58
X mean, SD standard deviation,
ANOVA.
112
ALT alanin amino transferase, AST aspartate amino transferase.
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+
p < 0.05;
++
p < 0.01;
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Table 5. Adverse events (SAE) in older patients taking BZPs.
Placebo
(n = 118)
Policosanol
(n = 121)
SAE
n
(%)
n
(%)
All cardiovascular SAE
4
3.4
1
0.8
All vascular SAE
5
4.2
3
2.5
SAE (fatal + non fatal)
10
8.5
6
5.0
Muscle-skeletal system
15
(12.7)
13
(10.7)
Nervous system disorders
13
(11.0)
6
(5.0)
Body as a whole
9
(7.6)
5
(4.1)
Skin and appendages
7
(5.9)
3
(2.5)
Gastrointestinal system
3
(2.5)
7
(5.8)
Cardiovascular system
4
(3.4)
6
(5.0)
Urinary system disorders
4
(3.4)
3
(2.5)
Endocrine system
1
(0.8)
1
(0.8)
Respiratory system
1
(0.8)
1
(0.8)
33
(28.0)
27
(22.3)
Moderate and mild AE
Patients with moderate or mild AE
1
1
One patient can report more than 1 AE, Comparison with placebo (χ2 test).
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113