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Biomedical subjects

R Bender

Publications and source records attributed to R Bender.

At least 73 records · Page 4Linked to original sources
PubMed1995

Mortality and morbidity in treated hypertensive type 2 diabetic patients with micro- or macroproteinuria.

In order to describe the natural history of high risk diabetic patients treated for hypertension we have followed a sequential sample of 100 hypertensive Type 2 diabetic patients with elevated urinary protein excretion ( > or = 60 mg 24 h-1) for a period of 1-7 years. Antihypertensive treatment was instituted in all patients and, in addition, the patients were offered the possibility of participation in an intensified antihypertensive therapy programme. After a mean follow-up of 4 years overall mortality was 13%. Nineteen percent of all patients experienced a cardiovascular event and 7% a cerebrovascular event. In conclusion, in this study the overall mortality was lower that previously reported in proteinuric Type 2 diabetic patients. Antihypertensive treatment may account for this outcome.

Age Factors↗
PubMed1995

Preclinical evaluation of HBY 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication.

HBY 097 [(S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydroquinoxaline-2(1H)-thione] was selected from a series of quinoxalines as a nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (NNRTI). HBY 097 was shown to be a highly potent inhibitor of HIV-1 induced cell killing and HIV-1 replication in a variety of human cell lines as well as in fresh human peripheral blood lymphocytes and macrophages. The compound was also active against a variety of clinical isolates of HIV-1 including different HIV-1 subtypes and viruses resistant to 3'-deoxy-3'-azidothymidine. Mutant reverse transcriptases which arise as a consequence of treatment with other nonnucleoside inhibitors of HIV-1 reverse transcriptase were still inhibited by HBY 097 at relatively low concentrations. An HIV-1MN variant resistant to inhibition by HBY 097 displayed in the reverse transcriptase gene a mutation causing a substitution at position 190 of a glutamic acid for a glycine residue (G190 --> E), which is characteristic for quinoxaline derivatives. The drug was demonstrated to possess a favorable toxicity profile and to show good oral bioavailability in both mice and dogs. As a consequence of its outstanding properties, HBY 097 was selected for further development and is at present undergoing clinical trials.

Animals↗
PubMed1995

Impact of new population estimates on health and vital statistics.

Changes in Statistics Canada's annual population estimates, introduced in 1993, have an impact on a wide range of social, economic and demographic indicators. Any indicator that relies on population estimates will be affected by the new figures. This article describes the adjustment and examines its impact on health and vital statistics rates. With rare exceptions, all rates decrease as the denominators are adjusted upward. For example, accident rates, suicide rates, and age-specific fertility rates based on the adjusted population are lower than those previously calculated. The extent of the adjustment, however, depends on the geographic and demographic characteristics of the population at risk. Analysts whose work concentrates on special subgroups for whom the adjustment is particularly great (such as young adult men) may wish to pay closer attention to the new population figures. Although the new rates are lower than before, underlying trends and patterns over time or across subcategories are quite similar. The revised series incorporates estimates of net census undercoverage, and for the first time, includes non-permanent residents. In 1991, net census undercoverage and non-permanent residents together amounted to about one million persons, or 3.6% of the revised Canadian population of 28,120,100.

Adolescent↗
PubMed1995

Pregnancies in women with diabetic nephropathy: long-term outcome for mother and child.

In order to improve the basis upon which to advise women with diabetic nephropathy about pregnancy, we studied the effect of diabetic nephropathy on the course of pregnancy, perinatal outcome, infant development and long-term outcome of the mothers. All pregnancies of women with diabetic nephropathy (defined as proteinuria > 400 mg/day (n = 26), creatinine clearance < 80 ml/min and hypertension in the first trimester (n = 10)) followed at our centre from 1982 to 1992 were identified (34 White class F and 2 White class T) and the women and their children re-examined in the spring 1993. From the first to the third trimester the percentage of women with proteinuria over 3 g/day increased from 14 to 53% and those treated with antihypertensive medication from 53 to 97%. There were no intrauterine or perinatal deaths, but one child died suddenly 4 weeks postpartum. Of 36 newborns (gestational week at birth 36(3), birth weight 2384(834) g)), 11 were born before week 34 and 8 had respiratory distress syndrome. Renal function in the first trimester, diastolic blood pressure in the third trimester and an HbA1c above normal were predictive of gestational age at delivery and low birth weight (stepwise regression analysis). At follow up of the children (n = 35, age 4.5 (0.4-10) years) the majority (n = 27) were normally developed but seven had psychomotor retardation (four of them major). One child had a severe motor retardation due to a congenital anomaly. At follow up, 21 of the 29 mothers had preserved renal function (creatinine 1.3 (0.8-4.3) mg/dl and 8 had developed end stage renal disease and required dialysis (2 of whom were White class T) within 3 (1-9) years postpartum.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Time-action profiles of the intermediate-acting insulin analogue des(64,65)-human proinsulin.

Des(64,65)-proinsulin (DPRO) is one of several endogenous intermediates arising during the conversion of proinsulin to insulin. In pharmaceutic preparations it is a clear solution containing no other proteins. Animal experiments and preliminary human studies indicated that DPRO should have a protracted time-action profile similar to that of NPH-insulin. Accordingly, we compared the time-action profiles of these two preparations, using the euglycaemic glucose clamp-technique in 9 healthy male volunteers. Different doses of DPRO (0.1, 0.15, 0.2 U/kg) or equipotent doses of NPH ( 0.2, 0.3, 0.4 U/kg) were injected subcutaneously into the abdominal wall. The maximal metabolic effect (GIRmax) of DPRO was greater than that of NPH-insulin (p < 0.05). With increasing doses, GIRmax differed significantly for DPRO but not for NPH-insulin. The time to maximal metabolic effect (tmax) was similar for the three doses of either preparation. However, tmax was reached 30 min earlier with DPRO than with NPH-insulin (p < 0.01). the decline to half-maximal after maximal activity was significantly faster with DPRO than with NPH-insulin (p < 0.0001). Subcutaneous injection of DPRO thus produced a time-action profile between that of regular insulin and NPH-insulin.

Adult↗
PubMed1994

Expression of the cholecystokinin gene in rat hippocampal interneurons is independent of extrinsic input.

In the present study we have used slice cultures of hippocampus and in situ hybridization techniques in order to study the ability of hippocampal neurons to synthesize CCK mRNA in the absence of extrinsic afferents. Our results show that very similar types of hippocampal neurons express CCK mRNA in culture as in situ. We conclude that the expression of the CCK gene in hippocampal neurons is not dependent on extrinsic afferent input.

Animals↗
PubMed1994

Mutational analysis of residue 190 of human immunodeficiency virus type 1 reverse transcriptase.

S-2720 and other members of the quinoline/quinoxaline class of HIV-1-specific nonnucleoside reverse transcriptase inhibitors (NNRTIs) select for a glycine to glutamate substitution at residue 190 (Gly 190 Glu) of the reverse transcriptase (RT), when drug-resistant viruses are generated in cell culture. This mutation has not been described to appear upon selection for resistant viral variants using derivatives of any other class of NNRTIs. Notably, the RNA-dependent DNA polymerase activity of the Gly 190 Glu mutant enzyme is drastically diminished with respect to the wild-type RT. We describe here the effects of other amino acid substitutions at position 190 of the RT that were introduced by using site-directed mutagenesis. Polymerase activities and sensitivities to inhibition by a number of NNRTIs were determined for the different RT mutants. In general, an inverse correlation was found between the enzymatic activity and increasing length of the side chain, whereas the size of the residue and the level of resistance to NNRTIs appeared to be positively related. Double mutants, which contain the Gly 190 Glu mutation together with substitutions that confer resistance to other RT inhibitors, were all shown to possess severely diminished polymerase activity.

Antiviral Agents↗
PubMed1994

The nuclear-magnetic-resonance solution structure of the mutant alpha-amylase inhibitor [R19L] Tendamistat and comparison with wild-type Tendamistat.

The recombinant mutant alpha-amylase inhibitor [R19L]Tendamistat, with Arg19 replaced by Leu, was prepared and its NMR solution structure determined. Based on complete sequence-specific 1H-NMR assignments, 845 nuclear Overhauser effect upper-distance constraints and 156 dihedral angle constraints were collected using two-dimensional homonuclear 1H-NMR experiments. The structure was calculated with the program DIANA, using the redundant dihedral angle constraints strategy for improved convergence. For restrained energy minimization, the programs FANTOM and AMBER were used. The wild-type NMR solution structure was similarly recalculated from the previously published input of conformational constraints [Kline, A., Braun, W. & Wüthrich, K. (1988) J. Mol. Biol. 204, 675-724]. For each protein a group of 20 conformers represents a well-defined solution structure, with average root-mean-square-distance values for the backbone atoms of the individual conformers relative to the mean coordinates of 50 pm. The two structures are nearly identical to each other and to the previously published Tendamistat structures in solution and in crystals. The only significant difference is strictly localized near the single amino acid substitution in the presumed active site -Trp18-Arg(Leu)-Tyr-, i.e. Leu19 and Tyr20 are more precisely defined in the solution structure of [R19L]Tendamistat than the corresponding residues Arg19 and Tyr20 in wild-type Tendamistat.

Amino Acid Sequence↗
PubMed1994

Pyrido[2,3-d]pyrimidine angiotensin II antagonists.

A series of pyrido[2,3-d]pyrimidine angiotensin II (A II) antagonists was synthesized and tested for antagonism of A II. Compounds with a biphenylyltetrazole pharmacophore and small alkyl groups at the 2- and 4-positions of the pyridopyrimidine ring were found to be the most potent in an AT1 receptor binding assay and in blocking the A II pressor response in anesthetized, ganglion-blocked A II-infused rats. 5,8-Dihydro-2,4-dimethyl-8-[(2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl)methyl]pyrido[2,3-d]pyrimidin-7(6H)-one (4a) was one of the more potent compounds in the binding assay and was the most efficacious compound in the A II-infused rat model. Further study of 4a in Goldblatt (2K-1C) rats showed the compound to have oral bioavailability and to be an efficacious and potent compound in a high renin form of hypertension.

Animals↗
PubMed1994

Early skeletal muscle development proceeds normally in parthenogenetic mouse embryos.

In mouse chimeras with parthenogenetic cell contribution, the skeletal musculature appears to be largely devoid of parthenogenetically derived cells. To analyze the appearance and early distribution of myotomal cells in parthenotes, we determined the expression of the muscle-specific transcription factors myogenin, MYF-5, and MYF-6 by in situ hybridization in somites of Day 10 and 11 embryos. Here, we report that these myogenic regulatory proteins are expressed in parthenogenetic animals together with desmin, one of the early muscle-specific structural proteins. We also show that parthenogenetic cells contribute equally to dermatome, sclerotome, and myotome in Day 10 and 11 chimeras. These results suggest that early myotomal cells expressing the myogenic control proteins develop and allocate normally in parthenogenetic embryos and in parthenogenetic<==>normal chimeras. The underrepresentation in older chimeras may therefore be due to selective elimination. These data also argue against imprinting of the myogenic factor genes myogenin, Myf-5, and Myf-6.

Animals↗
PubMed1994

Comparative dose-related time-action profiles of glibenclamide and a new non-sulphonylurea drug, AG-EE 623 ZW, during euglycaemic clamp in healthy subjects.

Insulin and glucose responses to glibenclamide were studied in comparison to a novel non-sulphonylurea drug (AG) by means of the euglycaemic clamp technique. Nine fasting male subjects were connected to a Biostator and 1.75, 3.5 or 7.0 mg glibenclamide or 1.0, 2.0 or 4.0 mg AG were given and blood glucose concentrations were clamped at 10% below basal values. Glucose infusion rates were registered over 10 h after administration of the tablet. Maximal glucose infusion rates after glibenclamide were 40% higher compared to AG (1.75 vs 1.0 mg, 3.5 vs 2.0 mg, 7.0 vs 4.0 mg, respectively) and were reached after 3-3.5 h for all doses. After glibenclamide, area under the glucose infusion curves and maximal incremental serum insulin responses were higher by 25-40% and by 30% compared to AG when low, medium and high doses of each drug were tested. However, a linear dose relationship was obtained for both drugs when the glucose infusion rate was plotted against the area under the insulin curve. In fact, both drugs were equipotent on a molecular weight basis. The hypoglycaemic index of both drugs (integrated glucose infusion rate divided by integrated insulin release) expressed per mumol of drug revealed a dose-dependent and parallel inverse curvilinear relation to increasing doses. This methodological approach allowed us to quantify and compare the metabolic effects of oral hypoglycaemic agents under standardised experimental conditions.

Administration, Oral↗
PubMed1994

Predictors of glycaemic control in type 1 diabetic patients after participation in an intensified treatment and teaching programme.

The aim of the study was to identify predictors of long-term glycaemic control in Type 1 diabetic patients after participation in an intensified insulin treatment and teaching programme. The study population consisted of 697 Type 1 diabetic patients (mean age 26 +/- 7 (SD) years, duration of diabetes 8 +/- 7 years) who participated in the same structured intensified insulin treatment and teaching programme in 10 hospitals and who were re-examined after 1, 2, and 3 years. Multiple and logistic regression analyses were performed including a set of demographic, disease-related, social, and psychosocial variables as potential predictors. As dependent variables the average HbA1 values during the 3-year follow-up period and a composite variable (average HbA1 values/frequency of severe hypoglycaemia)--dividing patients into three groups with good, moderate or poor metabolic control--were considered. Regression analysis of average HbA1 values revealed significance (p < 0.05) for seven independent predictors in descending order: smoking, age at onset of diabetes, frequency of home blood glucose monitoring, socioeconomic status, diabetes-related knowledge, perceived coping abilities, and sex (R2 (percentage of variation explained by the model) = 17%). In a second regression model, HbA1 values before the intervention programme were added to the model and achieved the highest standardized regression coefficient (0.38), increasing R2 to 29%. In the logistic regression models considering both HbA1 and severe hypoglycaemia as a composite dependent variable, diabetes-related knowledge, HbA1 values before the intervention, smoking, perceived coping abilities, age at onset of diabetes, and C-peptide levels were the strongest predictors of glycaemic control. In conclusion, the relationship between demographic, disease-related, psychosocial, and social variables and metabolic control is complex. Therefore, simplistic concepts of linear causality should be abandoned. In addition to HbA1 values before the intervention, smoking, diabetes-related knowledge, home blood glucose monitoring, age at onset of diabetes, perceived coping abilities and C-peptide levels were the most significant and consistent predictors of glycaemic control.

Adolescent↗
PubMed1994

Smoking is associated with progression of diabetic nephropathy.

OBJECTIVE: To investigate the association between cigarette smoking and the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS: A prospective, follow-up study over one year was conducted in a sequential sample of 34 smokers, 35 nonsmokers, and 24 ex-smokers with type I diabetes, hypertension, and diabetic nephropathy. Progression of renal disease was defined according to the stage of nephropathy as an increase in proteinuria or serum creatinine or a decrease in the glomerular filtration rate. RESULTS: Progression of nephropathy was less common in nonsmokers (11%) than in smokers (53%) and patients who had quit smoking (33%), P < 0.001. In a stepwise logistic regression analysis, cigarette pack years, 24-h sodium excretion, and GHb were independent predictive factors for the progression of diabetic nephropathy. Because blood pressure (BP) was well controlled in these patients and most values were within a normotensive range, neither standing, sitting, nor supine BP values were associated with progression of nephropathy. CONCLUSIONS: Cigarette smoking represents an important factor associated with progression of nephropathy in treated hypertensive type I diabetic patients.

Adult↗
PubMed1993

Activity of a novel quinoxaline derivative against human immunodeficiency virus type 1 reverse transcriptase and viral replication.

S-2720 [6-chloro-3,3-dimethyl-4-(isopropenyloxycarbonyl)-3,4- dihydroquinoxalin-2(1H)-thione], a quinoxaline derivative, was found to be a very potent inhibitor of both human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) activity and HIV-1 replication in tissue culture. Like other nonnucleoside RT inhibitors, S-2720 does not affect the HIV-2 RT. A S-2720-resistant virus was selected and shown to possess a mutation within the RT-coding region that has not previously been described. Notably, this mutation gives rise to a dramatic decrease in enzyme activity. S-2720, therefore, belongs to a new class of RT inhibitors that bind differently to the RT than other known nonnucleoside RT inhibitors. As no toxic effects were observed with S-2720 in mice, these quinoxaline derivatives deserve further evaluation to prove their potency as possible therapeutic agents for HIV-1 infection.

Acquired Immunodeficiency Syndrome↗