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Drug resistance is an important concern in practical medicine, with special relevance in cancer (chemotherapy resistance). Although the molecular mechanisms of drug resistance are still obscure, there is evidence that genetic variation in pathogenic, metabolic, and transporter genes, under the influence of epigenetic events (DNA methylation, chromatin/histone remodeling, miRNA dysregulation), may contribute to drug resistance. Three types of drug efflux pumps, the multidrug resistance gene 1 (MDR1/ABCB1)-encoded P glycoprotein, the multidrug resistance-associated protein (MRP/ABCC1) and breast cancer resistance protein (BCRP/ABCG2) may play an important part in the intrinsic or acquired defense of cells against drugs. Multidrug resistance is often associated with an ATP-dependent decrease in cellular drug accumulation which is attributed to the overexpression of ABC transporter proteins [1,2].

Different polymorphisms of the ADRB2 gene encoding the β2-adrenergic receptor (ADRB2) are associated with changes in a variety of responses of the sympathetic nervous system (SNS). In this study, we have investigated the distribution of frequencies of ADRB2-relaled allelic variants (Arg 16 Gly, Gln 27 Glu, Thr 164 Ile) in the Colombian population, as well as the influence of the Gln 27 Glu polymorphism as a risk factor for the development of dyslipidemia following propranolol administration. Genotyping was performed in unrelated Colombian volunteers, using PCR-RFLP methods. To examine the association between the Gln 27 Glu polymorphism of the ADRB2 gene and dyslipidemia induced by propranolol, we recruited 19 healthy individuals who were homozygous for either the Gln 27 (wild-type, N = 11) or the Glu 27 (homozygous mutant, N = 8) genotype. Electrocardiography (ECG), heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), serum lipid levels (T-CHO, HDL-CHO, TG), and fibrinogen were determined before and after propranolol administration. The distribution of genotypes was as follows: Arg 16 Arg 46%, Arg 16 Gly 47.4%, Cly 16 Gly 6.6%, Gln 27 Gln 44.7%, Gln 27 Glu 48.2%, and Glu 27 Glu 7.1%, with allelic frequencies of 69.7% for Arg 16 , 30.3% for Gly 16 , 68.8% for Gln 27 , and 31.2% for Glu 27 . The Thr 164 Ile polymorphism was found only in one subject, who was heterozygous for the isoleucine variant. Significant changes in physiological parameters (HR, SBP, DBP) have been found in association with ADRB2 variants in both native and mutant subgroups after propranolol intake. HDL-CHO levels diminished (p = 0.005) in native homozygous individuals (Gln 27 Gln). whereas TG levels were found increased (p = 0.012) in the mutant homozygous individuals (Glu 27 Glu). T-CHO levels and serum fibrinogen levels remained unaltered in both subgroups. The evidence that subjects homozygous for Gln 27 in the ADRB2 gene show a significant reduction of HDL-CHO levels, as well as the increased TG levels in subjects homozygous for Glu 27 after propranolol administration, suggest that the Gln 27 Glu polymorphism represents a risk factor for dyslipidemia induced by propranolol. These results may contribute to a better understanding of the mechanisms underlying dyslipidemia induced by ADRB2 antagonists.

Thiopurine methyltransferase (TPMT) catalyzes the inactivation of thiopurine drugs (merecaptopurine, thioguanine and azathioprine) used to treat acute lymphoblastic leukemia, autoimmune diseases and recipients of transplanted organs. No endogenous substrates for this enzyme are known. The TPMT polymorphism is a major determinant of individual differences in the toxicity or therapeutic efficacy of these drugs. The molecular basis of this polymorphism has been established in Caucasians. Africans, African-Americans and Asians, but not yet in the heterogeneous Latin American groups, including the Colombian population. The frequency of the four allelic variants of the TPMT gene, TPMT*2 (G 238 C), TPMT*3A (G 460 A and A 719 G), TPMT*3B (G 460 A) and TPMT*3C (A719G) were determined in 140 Colombian volunteers of Mestizo origin, using allele-specific PCR and PCR-RFLP assays. The *3A allele was found in 10 samples and the *2 allete in one, all heterozygotes; neither homozygous mutant genotypes nor the *3B and *3C alleles were detected. In agreement with these results, 92.1% and 7.9% of the Colombian population correspond to the phenotypes high and intermediate methylators, respectively. These results show that the frequency of mulations and the allelic distribution of the TPMT gene in the Colombian population are similar to the genetic profile found among US and Europcan Cancasian populations, where the *3A allele is prevalent and the *2 allele is currently present.

The enzyme Cu-Zn-SOD is a metalloenzyme that catalyzes the dismutation of the superoxide radical into hydrogen peroxide and molecular oxygen, being a defense system against free radical formation. Free radical reactions are implicated in a variety of physiological and pathological processes as aging, apoptosis and neurodegenerative diseases, and abnormalities associated with SOD have been recently documented in several neurodegenerative processes. In this study, we have evaluated the effect of anapsos on Cu-Zn-SOD activity in rats with injections of beta-amyloid protein or water bilaterally into the hippocampus. These injections caused severe cell depletion in the gyrus dentatus. Anapsos is a biological extract obtained from the fern Polypodium leucotomos with immunomodulatory and anti-neoplastic effects tested in animals and humans. Cu-Zn-SOD activity was measured in the hypothalamus, hippocampus, cerebral cortex, liver and spleen of rats treated i.p. with three doses of anapsos for 7 days (4, 20 and 100 mg/kg/day). Control animals were treated with saline solution under the same conditions. Anapsos significantly modified enzyme activity in all the areas tested. Lower doses of anapsos produced decreased SOD activity in the hypothalamus, hippocampus, liver and spleen, while in the cerebral cortex, a significant dose-dependent increase in SOD activity was observed. These results indicate that anapos was able to modify Cu-Zn-SOD activity in this animal model of neuronal degeneration, which may indicate the participation of anapsos in mechanisms of tissue repair after brain damage.

A general methodology for the analysis of human diseases at the nucleic acid level has been described. This method consists of a semiautomated, nontoxic analytic procedure, staining DNA bands with silver nitrate instead of ethidium bromide after DNA amplification by PCR. This technique provides a sensitive assay with enhanced accuracy and offers the possibility of carrying out the molecular analysis of several polymorphisms in a single day simplifying molecular genetics with diagnostic purposes.

Behavioral dysfunction is a problem in patients with Alzheimer disease (AD), and is apparent in up to 67% of individuals. Such changes are a primary cause of individual institutionalization and often lead to their functional disability. As AD progresses, the worsening of behavioral dysfunction becomes increasingly evident and is linked with decreased patient survival. Unfortunately, some of the more common drug therapies used in AD patients to stabilize other facets of their disease worsen behavioral dysfunction. Behavioral changes are associated with endogenous and exogenous factors such as disease stage, environmental factors, other medical conditions, drug regimen, and AD genotype. The most commonly examined and important genotype in AD is the apolipoprotein E (APO E) series, and APO E genotyping is also a useful diagnostic tool. The most frequent APO E genotypes encountered in AD are APO E-4/4, APO E-3/4, and APO E-3/3. In the current study, AD behavioral dysfunction, anxiety, and psychoses were commonly associated with the APO E-3/3 genotype, whereas disorientation, agitation, depression and motor disorders were common among patients with the APO E-4/4 and APO E-3/4 genotypes. These differences were not statistically significant but they suggest that different APO E genotypes influence the phenotypic expression of specific noncognitive symptoms, including behavioral function, in AD.

Although memory disorders and the aphaso-apraxo-agnosic syndrome are the most relevant clinical symptoms in dementia, behavioral changes, mood-related disturbances and sleep disorders are the major cause of institutionalization and caregiver concern. In the present study we have investigated the frequency and progression of cognitive and noncognitive symptoms in Alzheimer's disease (AD) as well as the APOE-related frequency of clinical symptoms in dementia. Memory decline (100%), aphasia (94%), apraxia (99%), agnosia (94%) and motor dysfunction (90%) appeared in practically all cases with mild (GDS-3), moderate (GDS 3-4) and severe (GDS 6-7) dementia. The most frequent noncognitive symptoms include anxiety (76%), depression (68%), behavioral changes (67%), psychotic symptoms (43%), sleep disorders (43%), incontinence (23%) and cerebrovascular symptoms (75%). Anxiety, depression, behavioral changes, psychotic symptoms, motor dysfunction and cognitive deterioration paralleled the severity of dementia, increasing their frequency from mild to severe dementia. The most important sleep disorders were irregular sleep-wake pattern (67%) and insomnia (47%). Disorientation (90%) and drug administration (88%) appeared to be the most important factors in causing sleep disorders in dementia. Disorientation, agitation and motor disorders were slightly more frequent in patients with APOE-4/4, while anxiety and sleep disorders appeared more frequently in APOE-3/4. Behavioral changes and psychotic symptoms did not show any clear association with specific APOE subtypes. In conclusion, our results suggest that noncognitive symptoms are very important clinical events in the disease progression and in decision making for therapeutic intervention and institutionalization. Furthermore, it is likely that some brain dysfunctions leading to particular clinical symptoms might be associated with specific AD genotypes.