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Technologically useful methods of preparing defined polymorphic forms of indomethacin (especially gemma-form) have been described. The influence of various crystallization parameters on the formation of individual form of indomethacin have been discussed.
A procedure is described, which make it possible to determine the content of individual polymorphic forms of indomethacin in their mixture by IR spectrometry. IR spectra recorded in the range of 1600--1800 cm-1 have been used in the determinations. The method is especially useful for analytical control of the technological process of preparing the most pharmacologically active-gemma-form of indomethacin.
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In the present study, HLA-A, B, C, DR, DQ, and DP loci were analyzed in a group of Mataco Amerindians of Argentina. Using reagents from the 11th International Histocompatibility Workshop (11th IHW), class I specifities such as Bw70, Bw75, and Bw48 were found in this population, other than the HLA determinants commonly described in South American Indians. The class II antigens found were DR4, DRw14, and DRw8 at the DR locus, and DQw4 and DQw7 at the DQ locus. The analysis of DRB1-DR4 related alleles, performed by PCR amplification and oligonucleotide probe hybridization, showed the presence of DRB1*0403, *0404, *0405, and *0411 in individuals from this ethnic group. By the analysis of DRB1-DRw14 related alleles, two variants were found: DRB1*1402 and DRB1*1406, the latter provisionally called DRB1 14.6 in 11th IHW. The DRw8-related allele present was DRB1*0802. The analysis of DRB3 gene revealed only the presence of DRB3*0101 allele in DRw14 individuals. DPB1 locus was also analyzed in unrelated individuals of the same population. Only five DPB1 alleles were found: DPB1*0201, *0301, *0402, *0501, and *1301 over the 19 previously described in the literature. These findings emphasize the restricted HLA class I and II variation observed in this ethnic group as it has been previously shown in other American groups. Some particular haplotypes in this Mataco tribe are described in this work.
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Despite the well-documented efficacy of lovastatin, a wide inter-individual variation in treatment responses has been observed. The aim of the present study was to investigate the possible roles of apolipoprotein E (apo E) phenotype and apolipoprotein B (apo B) XbaI genotype on this variation. The apo E phenotype was determined in 232 subjects (78 cases of familial hypercholesterolaemia [FH] and 154 cases of non-familial hypercholesterolaemia [non-FH]) and the apo B XbaI genotype was determined in 211 subjects (67 cases of FH, 144 cases of non-FH). Depending on their baseline total serum cholesterol levels, these patients used a starting dose of lovastatin of either 20 or 40 mg nightly. After 6 weeks of therapy, slightly but significantly smaller reductions in LDL-cholesterol were observed in patients with the E4/3 phenotype compared with those with the E3/3 phenotype in non-FH with lovastatin 20 mg (-20 vs. -28%; P = 0.043) and in total cholesterol in FH with lovastatin 40 mg (-23 vs. -27%; P = 0.023). No significant differences were found in non-FH patients starting with lovastatin, 40 mg. After doubling of the lovastatin doses, all treatment responses became similar among apo E phenotypes. Moreover, when all patients using lovastatin 40 mg either at 6 or 12 weeks were pooled (n = 224), no differences in treatment responses were observed between the E3/2, E3/3, E4/3 and E4/4 phenotypes. The apo B XbaI genotype did not affect the hypocholesterolaemic efficacy of lovastatin in any of the patient groups. Thus our results indicate that inter-individual variation in the treatment response to lovastatin in both familial and non-familial hypercholesterolaemia is mainly due to factors other than the apo E phenotype or apo B XbaI genotype.
A study was made of heat resistance (36+/-0.2 degrees C) of m. interphalangealis of the third finger of a hind extremity in animals of one population of Rana temporaria L. living on the boundary between Leningrad region and Pskov region. Within this population, the existence of three groups of individuals differing in heat resistance levels of their m. interphalangealis is postulated. This conclusion is based on the distribution curve of heat resistance values and on the application of the probit-method. The distribution of the frequency of occurrence of individuals in these three groups follows Hardy-Weinberg's equation.
We recently developed an enzyme-linked immunosorbent assay (ELISA) for total protein S (PS) antigen using the monoclonal antibody S-12. During the screening of thrombophilic patients we identified a patient, who was using marcoumar, with 0% PS by monoclonal ELISA and 23% PS by polyclonal ELISA. Further analysis of this patient and his family showed that the patient was a compound heterozygote for type 1 PS deficiency and for an abnormal PS molecule (PS-Heerlen) that was not recognized by the S-12 antibody. Similar observations were made in two sisters from an unrelated Dutch family. Subsequent studies showed that PS Heerlen has a slightly lower molecular weight (71,000) than normal PS (73,000), binds normally to C4b-binding protein, and retains full activated protein C cofactor activity. The alteration in the PS Heerlen molecule was identified as a substitution of Ser460 by Pro, which is due to a unique T---C transition in exon 13 of the active PS-alpha gene. The substitution occurs in the consensus sequence for the potential N-linked glycosylation of Asn458. Digestion with N-glycanase showed that normal PS probably contains three N-linked oligosaccharide side chains, while PS Heerlen contains only two (Asn458 not glycosylated?). Segregation analysis in the two original families showed that the presence of the genetic abnormality was always associated with the PS-Heerlen phenotype. The frequency of the PS-Heerlen allele was found to be 0.52% in the general population and 0.67% in a population of patients with unexplained thrombophilia. There is no evidence that the PS Heerlen allele is associated with an increased risk for thrombosis.
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BACKGROUND AND PURPOSE: The presence of known restriction fragment length polymorphisms in the apoprotein A-I-C-III gene cluster, which encodes their respective apoproteins, was investigated using the restriction enzymes Sac I and Pst I to determine the potential role of genetic variations for stroke risk in an American population. METHODS: Ninety-eight subjects (70 white, 28 black subjects), both normal controls with no carotid stenosis and those with carotid stenosis believed at risk for stroke, defined as showing stenosis focally or diffusely at that site, composed the study population. RESULTS: Sac I polymorphic S2 allele frequency was higher in stroke-risk groups, whereas Pst I polymorphic P2 allele frequency was similar in control and stroke-risk groups. Significantly higher levels of serum cholesterol, triglycerides, and low density lipoprotein (p less than 0.05) and significantly lower levels of high density lipoprotein (p less than 0.05) were observed in stroke-risk groups with diffuse stenosis. Results of our study with the two racial groups show the following: the frequency of Sac I polymorphism was significantly higher in American black compared with American white subjects (chi 2 = 3.92, p less than 0.05). Among serum lipids, triglycerides were significantly higher in white compared with black subjects (p less than 0.05). In white subjects, carotid artery stenosis was associated with significantly elevated total cholesterol and low density lipoprotein (p less than 0.01) but not with Sac I polymorphism. In black subjects the converse was observed, namely, the Sac I polymorphic S2 allele seemed to be associated with carotid bifurcation stenosis but did not reach statistical significance because of the small number of subjects. In addition, Sac I polymorphism did not correlate with any lipid profile. Pst I polymorphism was not associated with any lipid profile or carotid artery stenosis abnormalities. CONCLUSIONS: Our results indicate that carotid artery stenosis identifies white subjects with increased plasma total cholesterol and low density lipoprotein, an atherogenic profile, but not with Sac I polymorphism. These findings suggest that carotid bifurcation stenosis in white subjects is associated with an atherogenic lipid profile but not with apoprotein A-I-C-III restriction fragment length polymorphisms. In black subjects, Sac I polymorphism seems to identify those individuals with significant carotid stenosis, a necessary precursor to atherothrombotic brain infarction, but not those with elevated total cholesterol, elevated low density lipoprotein, and/or reduced high density lipoprotein. These results suggest that Sac I polymorphism may identify black subjects at increased risk for atherothrombotic brain infarctions.
Association studies were carried out in a sample of 87 patients from Sweden who had survived a myocardial infarction (MI) before the age of 45, and 91 age-matched healthy individuals, to compare the impact of polymorphisms at the apolipoprotein (apo) E and B gene loci on among-individual differences in plasma lipid traits and progression of atherosclerosis. In the group of healthy individuals, polymorphisms creating the common apo E isoforms were, as expected, associated with significant differences in total and low density lipoprotein (LDL) cholesterol (11.7% and 11.6% of sample variance). For apo B, the polymorphism with the largest effect on apo B levels (16% of sample variance) was the C to T transition 265 bp 5' of the cap site, in the promoter (detectable by MspI). Both this polymorphism and the threonine2488 neutral substitution (detectable by XbaI) were associated with significant effects on LDL-cholesterol (8.3% and 9.3% of sample variance, respectively). The asparagine/serine4311 polymorphism was associated with a significant effect on high density lipoprotein (HDL) cholesterol alone, and there was no significant association with the glutamate/lysine4154 polymorphism (detectable by EcoRI) or the leucine-alanine-leucine (LAL) insertion/deletion polymorphism in the signal peptide. In the patients, polymorphisms creating the three common apo E isoforms were associated with large effects on cholesterol, apo B and triglyceride levels (19.9%, 20.3% and 23.9% of sample variance) of similar magnitude as in the healthy individuals. Apo B polymorphisms were found to be associated with much smaller effects on lipid traits than in the healthy individuals. The only significant association was between the asparagine/serine4311 polymorphism and HDL-triglyceride levels. However, global severity of coronary atherosclerosis at the first angiography was found to be significantly associated with the LAL insertion/deletion polymorphism (P = 0.008). Thus variation at the apo B gene locus is associated with the development of atherosclerosis, but the data suggests that this may act through mechanisms not directly related to effects on measured lipid traits.
Many characters are genetically regulated as polymorphisms. This means that discrete groups are seen within the distribution of a certain character. Drug metabolism is no exception and the polymorphism of acetylation is recognised since the 50's. Polymorphic drug oxidation was discovered in the 70's and has been extensively studied. There are two fully established polymorphisms in drug oxidation named as the debrisoquine/sparteine and the s-mephenytoin hydroxylation polymorphisms. The metabolism of a number of important drugs cosegregates with that of debrisoquine. Among these drugs are beta-blockers, antiarrhythmics, tricyclic antidepressants and neuroleptics. Apart from accumulation of parent drug and active metabolite, also reduced formation of active metabolite occur for some drugs in slow metabolisers. There are, however, few cases where the presence of polymorphic drug metabolism is of significant disadvantage. The polymorphisms will add to variability in drug clearance but the potential clinical importance should be evaluated for each drug. The cytochrome P-450 isozyme responsible for debrisoquine hydroxylation is of high affinity-low capacity character, which means that it can be saturated under certain circumstances. This will decrease the difference in drug metabolic rate between rapid and low metabolisers as will inhibitors of the debrisoquine isozyme like cimetidine, quinidine and propafenone. The debrisoquine isozyme is not readily inducible. In cases where a major metabolic route or the formation of an active metabolite are polymorphically controlled, knowledge about a patient's oxidator status might be of practical value for dose adjustments especially if there is a narrow therapeutic ratio or an established concentration-effect relationship. For some drugs it is difficult to differentiate between insufficient therapeutic effect and symptoms of overdosage. Tricyclic antidepressants and neuroleptics meet some of these criteria and patients who get recurrent treatment may benefit if the physician has knowledge about debrisoquine metabolic phenotype. Otherwise, the clinical consequences of polymorphisms in drug oxidation seem so far to be limited, considering that a number of disease conditions have not shown any clear association with oxidation status. The polymorphisms in drug metabolism should be considered as a part of natural variability which could in fact be larger with other drugs that do not show polymorphic elimination.
The current predominant method of analyzing base substitution polymorphisms, RFLP analysis, is likely to be gradually supplanted by methods based on PCR because of the improved sensitivity and genotyping rate. The most promising PCR methods for analysis appear to be allele-specific PCR and single-stranded conformational analysis. The single-stranded conformation approach has already been applied to the scanning of cystic fibrosis exons for new mutations. Linkage mapping projects that cover large segments of the human genome will probably rely, in the coming years, primarily on tandem repeat polymorphisms, particularly microsatellite polymorphisms. Microsatellite polymorphisms have at least a fourfold advantage over base substitution RFLPs because they are twice as informative and can be typed at at least twice the rate. The facioscapulohumeral muscular dystrophy gene was recently mapped in just 6 weeks using microsatellite polymorphisms. Because of the informativeness handicap, it will be difficult for base substitution polymorphisms to overtake tandem repeat markers for large-scale linkage mapping. Methods that allow base substitution polymorphisms to be typed at two or three times the rate of microsatellite markers would have to be developed. Most of the other applications of DNA polymorphisms described in the introduction are also increasingly likely to rely on highly informative tandem repeat markers in the future. Methods for analysis will probably be based on PCR. It is easy to envisage, for example, an automated method for large-scale DNA fingerprinting of individuals based upon a standard set of highly informative, dependable microsatellite polymorphisms. Methods for analyzing base substitution polymorphisms will continue to be important for the diagnostic detection of disease-gene alleles.(ABSTRACT TRUNCATED AT 250 WORDS)