Influence of water-soluble polymers on the in vitro performance of floating mucoadhesive tablets containing metformin.

CONTEXT: The in vitro performance of floating mucoadhesive metformin tablets was optimized using different polymer ratios of polyvinylpyrrolidone (PVP) tamarind seed gum (TSG) and hydroxypropylmethylcellulose (HPMC). OBJECTIVE: The objectives of this investigation were to investigate the combinatorial effects of PVP, TSG and HPMC; to study the work of adhesion measured on stainless steel (Wss) and on rabbit gastric mucosa (Wgm); and a comparison of hydrophilic and more hydrophobic tablets. MATERIAL AND METHODS: In vitro performance was measured as tablet hardness (H), tablet floating lag time (FLT), time needed to release 60% of drug content (t60%), swelling thickness (S), Wss and Wgm. To compare the effects, a simplex lattice mixture design was used. RESULTS AND DISCUSSION: H, FLT, Wss and Wgm were found dependent on polymer ratio. H was increased when PVP ratio was increased. FLT, Wss and Wgm were increased when HPMC ratio was increased. The p value for the lack of fit for all models were greater than 0.05. An approximate linear correlation between Wgm and Wss was established (R(2) = 0.71). The tablets containing PVP resulted in larger H, shorter FLT and t60%, whereas Wss and Wgm were enhanced. CONCLUSION: The different in vitro performance of tablets containing different water-soluble polymers could be explained partially by the differences in the hydrophilic properties of the polymers and the ability of PVP to interact with HPMC or TSG. An equation established is used to conclude mucoadhesion based on adhesion measurements on stainless steel.

Concentrations of homocysteine, related metabolites and asymmetric dimethylarginine in preeclamptic women with poor nutritional status.

BACKGROUND: Hyperhomocysteinemia, a proxy measure for the nutritional status of the B vitamins, may be involved in the etiology of preeclampsia via inducing endothelial dysfunction. Asymmetric dimethylarginine (ADMA) is an inhibitor of NO-synthase that may adversely affect the endothelium. MATERIALS AND METHODS: We investigated serum concentrations of folate, vitamin B12, B6, homocysteine (Hcy) and related metabolites in 139 Syrian preeclamptic women and 93 asymptomatic pregnant women of comparable age, gestational age and socioeconomic status. Plasma concentrations of ADMA were determined in a subset of age- and gestation-age-matched pairs of patients and controls (n=63). RESULTS: Higher concentrations of Hcy, cystathionine and methylmalonic acid (MMA) were closely linked to a lower status of the B vitamins. Higher concentrations of Hcy and cystathionine were observed in the preeclamptic group than in the matched controls (median Hcy 9.3 vs. 6.0 micromol/L; median cystathionine 284 vs. 232 nmol/L). Serum folate was significantly lower in patients than in controls (16.4 vs. 36.0 nmol/L). Folate supplementation was less likely to be used in preeclamptic women. Concentrations of MMA were elevated in patients and controls and did not differ significantly between the two groups. Median plasma concentrations of ADMA were significantly lower in asymptomatic women than in those who developed preeclampsia before the 37th week of gestation (0.61 vs. 0.68 micromol/L). CONCLUSIONS: Elevated serum concentrations of Hcy, cystathionine and MMA indicate poor status of the B vitamins during pregnancy. The adverse effect of Hcy on endothelial function might be related to ADMA in early-onset preeclampsia. More emphasis should be placed on increasing the intake of B vitamins in pregnant women from developing countries.

Prevalence of herpes simplex virus (types 1 and 2), varicella-zoster virus, cytomegalovirus, and human herpesvirus 6 and 7 DNA in cerebrospinal fluid of Middle Eastern patients with encephalitis.

HSV-1 DNA was detected in 32 (30%) of 106 cerebrospinal fluid samples from patients with encephalitis. Cytomegalovirus, varicella-zoster virus, and human herpesvirus 6 (HHV-6) DNAs were each detected in three patients (3%); herpes simplex virus type 2 (HSV-2) and HHV-7 PCRs were negative. HSV detection was associated with seizure (P = 0.02), especially focal seizure (P = 0.0002), and pathological computed tomography (P = 0.02) with focal lesions (P = 0.0004).

Detection of herpes simplex virus, cytomegalovirus and Epstein-Barr virus DNA in atherosclerotic plaques and in unaffected bypass grafts.

BACKGROUND: Herpes virus infections are suspected to be involved in the pathogenesis of atherosclerosis. OBJECTIVE AND METHOD: Viral DNA of herpes simplex virus (HSV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) was analyzed by real-time PCR on 48 biopsies from atherosclerotic plaques extracted by end-arterectomy (46 coronary arteries, 2 carotid arteries), and in tissue from non-atherosclerosis vessels from the same patient as controls (23 internal mammary arteries, 43 saphenous veins). RESULTS: HSV-1 DNA was detected significantly more frequently in plaques (35%) than in control veins (9%, P = 0.006). However, the frequency of HSV-1 DNA detection in the internal mammary artery grafts was as high as in plaques (22%, P = 0.28). CMV and EBV DNA were exclusively found in plaques but not in controls, with 10% for CMV (P = 0.06 versus veins, P = 0.17 versus graft arteries) and 2% for EBV (P = 1.0), respectively. HSV-2 was neither detected in plaques nor in controls. Herpes viral DNA was significantly associated only with arterial hypertension but not with other classical risk factors (P = 0.02), in accordance with the hypothesis that herpes viral infection may alter the vessel wall. CONCLUSION: We conclude that herpes viral infections may have a role in atherosclerosis and that the presence of herpes viral DNA in the grafts used for bypass surgery might constitute a potential risk for atherosclerosis or restenosis.

The risk of venous thromboembolism associated with the factor V Leiden mutation and low B-vitamin status.

Venous thromboembolism (VTE) is a multi-factorial disease involving numerous genetic and environmental risk factors. In this study we investigated the occurrence and the risk associated with factor V Leiden, hyperhomocysteinemia and low folate and vitamin B12 levels in young patients with thrombosis. We studied 78 patients (33 females/45 males, mean age 33 years) with a history of thrombosis in a lower limb. Additionally, 98 healthy subjects (45 females/54 males, mean age 44 years) were included. Serum levels of homocysteine (Hcy), folate and vitamin B12 were assayed. Factor V Leiden and methylenetetrahydrofolate reductase (MTHFR) C677T mutations were investigated in all subjects. Factor V Leiden was highly prevalent in the patients (39% heterozygous, 10% homozygous vs. 6.3% heterozygous in controls). An increase in the risk of idiopathic VTE was associated with Hcy levels > 15.2 micromol/l (odds ratio, OR = 2.83), folate < 15.1 nmol/l (OR = 7.49) and vitamin B12 < 182 pmol/l (OR = 11.97). Low levels of folate or vitamin B12 were independently and strongly associated with the risk of VTE in a multivariate model (OR for idiopathic thrombosis = 16.44 and 10.76, respectively). Twenty patients (53%), carriers of factor V Leiden, had low levels of vitamin B12, compared to 28% of patients who were non-carriers of the mutation (p = 0.03). In contrast, none of the control carriers of the mutation had a low level of vitamin B12. The risk of VTE associated with lower levels of vitamin B12 and folate was stronger than that introduced by elevated Hcy levels. The increased risk of VTE, accompanied by factor V Leiden, may be related to confounding environmental factors.

Hyperhomocysteinemia and vitamin B-12 deficiency are more striking in Syrians than in Germans--causes and implications.

Hyperhomocysteinemia is an accepted risk factor for coronary artery disease, but the determining factors are not fully understood. We investigated hyperhomocysteinemia and vitamin deficiency in Syrian coronary patients and apparently healthy Syrian and German controls. We enrolled 273 Syrian patients with angiographically confirmed stenosis, along with 159 Syrian and 75 German controls. Plasma total homocysteine (HCY), cystathionine, methylmalonic acid (MMA), vitamin B-6, B-12, folate, lipids, apolipoproteins and methylenetetrahydrofolate reductase (C677T-MTHFR) mutation were analysed. There was a very high prevalence of hyperhomocysteinemia (>12 micromol/l) in Syrians (patients 61%, controls 44%, Germans 16%) together with functional vitamin B-12 deficiency diagnosed by elevated MMA (patients 49%, controls 47%, Germans 3%), which was in contrast to the low frequency of decreased serum vitamin B-12 (12% in patients, 7% in Syrian controls). The HCY concentration in German controls was lower than in Syrians, median 8.8 vs. 11.3 micromol/l. The vitamin B-12 deficiency induces folate trapping; higher levels of folate are needed to prevent hyperhomocysteinemia. Germans achieved the HCY level of < or =12 micromol/l at significantly lower folate concentrations > or =4.4 ng/ml, than Syrians with normal MMA (> or =16.7 nmol/l folate) or Syrians with high MMA (> or =23.3 nmol/l folate). Smoking and homozygous state for C677T-MTHFR mutation contributed to hyperhomocysteinemia. We could confirm that the reasons for hyperhomocysteinemia in Syrians were in fact mostly related to a relative folate deficiency, which is due to a vitamin B-12 shortage. Vitamin B-12 deficiency induces folate trapping. Besides lifestyle, other presently unknown factors may contribute to hyperhomocysteinemia and vitamin B-12 deficiency in Syrians.

Mutation in the ARH gene and a chromosome 13q locus influence cholesterol levels in a new form of digenic-recessive familial hypercholesterolemia.

We studied a Syrian family with 3 children who had low-density lipoprotein cholesterol (LDL) concentrations of 13.3, 12.2, and 8.6 mmol/L, respectively. Three other siblings and the parents all had LDL values <4.52 mmol/L, suggesting an autosomal-recessive mode of inheritance. The extended pedigree had 66 additional persons with normal LDL values. A genome-wide scan in the core family with 427 markers showed support for linkage on both chromosomes 1 and 13. Markers on chromosome 1 revealed a 3.07 multipoint LOD score between 1p36.1-p35, an 18-cM interval. Surprisingly, we also found linkage to 13q22-q32, a 14-cM interval, with a 3.08 LOD score. We had identified this locus earlier as containing a gene strongly influencing LDL in another Arab family with autosomal-dominant familial hypercholesterolemia and in normal dizygotic twins. We found evidence for an interaction between these loci. We next genotyped our twin panel and confirmed linkage of the 1p36.1-p35 locus to LDL (P<0.002) in this normal population. Elucidation of ARH, the LDL receptor adaptor protein at chromosome 1p35, caused us to sequence that gene. We first identified the genomic structure of ARH gene and then sequenced the gene in our family. We found an intron 1 acceptor splice-site mutation. This mutation was not found in any other family members, in 31 nonrelated Syrian persons, or in 30 Germans. Our results underscore the importance of ARH on chromosome 1 and the chromosome 13q locus to LDL, not only in families with unusual illnesses, but also to the general population.

Evaluation of an immunoluminometric based assay as a novel method for the quantitative analysis of p53 protein in tumor tissues.

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