Genetic susceptibility to adverse drug effects - Epidemiology ...

More documents

Recommendations

Info

3.3 ABCB1 (MDR1) gene polymorphisms are associated with neuropsychiatric adverse effects of mefloquine Abstract Background. Mefloquine, a drug used for treatment and prophylaxis of malaria, is known for its neuropsychiatric adverse effects. We hypothesized that neuropsychiatric adverse effects of mefloquine are associated with polymorphisms in the MDR1/ABCB1 gene that encodes for the efflux pump P-glycoprotein. Methods. The association between MDR1 C1236T, G2677T and C3435T single nucleotide polymorphisms (SNPs) and the occurrence of neuropsychiatric adverse effects were examined in a prospective cohort study of 89 healthy white travellers taking mefloquine. Results. Of the subjects, 27 (28%) reported neuropsychiatric adverse effects, women significantly more frequently than men. Allele frequencies of the C1236T, G2677T and C3435T polymorphisms were similar to those found in other white populations and there was no significant association between any of the individual polymorphisms and neuropsychiatric adverse effects. However, 1236TT, 2677TT and 3435TT women had a higher risk of neuropsychiatric adverse effects than the reference groups of women with heterozygous and homozygous CC or GG genotypes with odds ratios of 6.3 (95% CI 1.1;36.9), 10.5 (95% CI 1.1;100.6) and 5.4 (95% CI 1.1;30.0), respectively. The association for women homozygous for the 1236-2677- 3435 TTT haplotype was even stronger (p= 0.004) than the effect of any of the individual polymorphisms. No associations with mefloquine blood levels were observed. Conclusion. In this study, the MDR1 1236TT, 2677TT and 3435TT genotypes along with the 1236-2677-3435 TTT haplotype were associated with neuropsychiatric adverse effects of mefloquine in women. MDR1 polymorphisms may play an important role in predicting the occurrence of neuropsychiatric adverse effects of mefloquine, particularly in female travellers. 59
Chapter 3.3 Introduction The quinolone derivative mefloquine is widely used in the treatment and prophylaxis of malaria in travellers to areas with chloroquine-resistant falciparum malaria. It has gained popularity because of its weekly dosing regimen. In the past decade, however, a number of case reports and studies on severe neuropsychiatric adverse effects of mefloquine have been reported. 1-3 Two main classes of neuropsychiatric adverse effects have been attributed to mefloquine: type I effects, consisting of mild neuropsychiatric events such as dizziness, dysphoria, lightheadedness and concentration problems occurring within 6 hours after intake and usually resolving quickly in the following days; and type II effects, including severe neuropsychiatric disorders such as acute psychosis with agitation or depression. 1, 3 Risk factors identified so far include history of seizures or psychiatric disorders, female gender and low body mass index (BMI). 4, 5 It has been suggested that the distribution volume or blood concentration of mefloquine plays a role, although no clear association between mefloquine blood level and neuropsychiatric adverse effects could be demonstrated. 5, 6 P-glycoprotein (P-gp) is a product of the Multi Drug Resistance 1 gene/ATP-binding cassette B1 (MDR1/ABCB1), located on chromosome 7p21, and plays a role in the uptake and distribution of mefloquine. P-gp is an efflux pump for various toxins and drugs and is expressed in the intestine (regulating uptake into the systemic circulation) and the blood-brain barrier (affecting exposure to the brain). 7, 8 Mefloquine is a substrate for P-gp, but it is also an inhibitor of P-gp function. 9 A number of single nucleotide polymorphisms (SNPs) have been found to be associated with decreased P-gp expression and function, 7, 8, 10, 11 the most intensively studied SNPs being C1236T, G2677T/A and C3435T. We examined the association between the MDR1 SNPs C1236T, G2677T and C3435T and neuropsychiatric adverse effects in a subgroup of a cohort of mefloquine users previously studied to assess neuropsychiatric effects of mefloquine to determine whether MDR1 genotype is associated with adverse effects. Patients and methods Study population. We performed a genetic re-analysis in a subgroup from a prospective cohort of mefloquine users previously studied to assess the neuropsychiatric effects of mefloquine. 2, 4 In brief, during a 1-year study period, we recruited subjects who received a prescription for mefloquine (baseline) for malaria prophylaxis at the Travel Clinic at the Institute for Tropical Diseases in the Harbour hospital, in the Rotterdam area in the Netherlands. Subjects with one or more contraindications for mefloquine or subjects who used mefloquine in the preceding two months or who had risk factors for concentration impairment (e.g. use of opioids, hypnotics or tranquilizers during the two weeks before testing or use of alcohol 4 hours before testing) were not included in the study. For the genetic analyses we further excluded subjects who refused to undergo blood sampling or who did not take 3 tablets of mefloquine 60
Page 1 and 2:
Genetic susceptibility to adverse d
Page 3 and 4:
The work presented in this thesis w
Page 5:
Promotiecommissie Promotoren: Prof.
Page 10: 1 General Introduction
Page 13 and 14: Chapter 1 genome. Every SNP represe
Page 15 and 16: Chapter 1 References 1. 2. 3. 4. 5.
Page 18: 2 Quantifying the risk of adverse d
Page 21 and 22: Chapter 2 Introduction The cardiac
Page 23 and 24: Chapter 2 Table 1 Characteristics o
Page 25 and 26: Chapter 2 digoxin treatment appears
Page 27 and 28: Chapter 2 References 1. 2. 3. 4. 5.
Page 30: 3 Common variants in the ABCB1 gene
Page 33 and 34: Chapter 3.1 Introduction The ATP-Bi
Page 35 and 36: Chapter 3.1 Co-variables. Covariate
Page 37 and 38: Chapter 3.1 Table 3 Frequencies of
Page 39 and 40: Chapter 3.1 Table 5 Risk of serum d
Page 41 and 42: Chapter 3.1 Table 6 Other studies o
Page 43 and 44: Chapter 3.1 References 1. 2. 3. 4.
Page 46 and 47: 3.2 Common ABCB1 variants increase
Page 48 and 49: Common ABCB1 variants increase QTc
Page 58: Common ABCB1 variants increase QTc
Page 63 and 64: Chapter 3.3 In addition to the diar
Page 65 and 66: Chapter 3.3 Table 1 General charact
Page 67 and 68: Chapter 3.3 confounding by contrain
Page 69 and 70: Chapter 3.3 adverse effects of mefl
Page 74: 4 Common variants in the NOS1AP gen
Page 77 and 78: Chapter 4.1 Introduction Sudden car
Page 79 and 80: Chapter 4.1 Assessment of QTc inter
Page 81 and 82: Chapter 4.1 Table 1 Baseline charac
Page 83 and 84: Chapter 4.1 Table 3 Number of indiv
Page 85 and 86: Chapter 4.1 ditional GG haplotype c
Page 90 and 91: 4.2 Common NOS1AP variants potentia
Page 92 and 93: Common NOS1AP variants potentiate d
Page 102: Common NOS1AP variants potentiate d
Page 105 and 106: Chapter 4.3 Introduction In the pas
Page 107 and 108: Chapter 4.3 Figure 1 Flowdiagram of
Page 109 and 110:
Chapter 4.3 Table 1 Characteristics
Page 111 and 112:
Chapter 4.3 Table 2 Cardiovascular
Page 113 and 114:
Chapter 4.3 Table 3 Drugs, NOS1AP a
Page 115 and 116:
Chapter 4.3 found indication that t
Page 117 and 118:
Chapter 4.3 References 1. 2. 3. 4.
Page 120 and 121:
4.4 Common variation in the NOS1AP
Page 122 and 123:
Common variants in the NOS1AP gene
Page 124 and 125:
Page 126 and 127:
Page 128 and 129:
Page 130 and 131:
Page 132:
Page 136 and 137:
5 Effect of ABCB1 and NOS1AP genoty
Page 138 and 139:
Effect of ABCB1 and NOS1AP genotype
Page 140 and 141:
Page 142 and 143:
Page 144 and 145:
Page 146 and 147:
Page 148 and 149:
Page 150:
Page 154 and 155:
6 General discussion Despite all re
Page 156 and 157:
General discussion ening properties
Page 158 and 159:
General discussion or the excess [C
Page 160 and 161:
General discussion continuously mon
Page 162 and 163:
General discussion cardiovascular d
Page 164 and 165:
General discussion for non-cardiova
Page 166 and 167:
General discussion 25. 26. 27. 28.
Page 168 and 169:
General discussion QTc interval in
Page 170:
General discussion 169
Page 174 and 175:
7.1 Summary Despite all research ef
Page 176:
Summary reduced mortality in patien
Page 179 and 180:
Chapter 7.2 steeds aanzienlijk is e
Page 182 and 183:
8 Dankwoord Een proefschrift schrij
Page 184:
Dankwoord Bijzondere dank aan alle
Page 188 and 189:
10 Bibliography Manuscripts based o
Page 190:
Bibliography Van der Hooft CS, Diel
show all

Genetic susceptibility to adverse drug effects - Epidemiology ...

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?