Miglitol: assessment of its role in the treatment of patients with diabetes mellitus.

OBJECTIVE: To evaluate miglitol, a new oral alpha-glucosidase inhibitor, and discuss its pharmacology, therapeutics, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy. DATA SOURCES: A MEDLINE English-language only database search using the keywords miglitol, glyset, and Bay m 1099 (1985 to December 1999), was completed to identify relevant articles including reviews, recent studies, and abstracts; American Diabetes Association 1999 Annual Meeting abstracts; Pharmacia & Upjohn data on file and product information. STUDY SELECTION: The clinical trials that were selected to be reviewed in detail were randomized, double-blind studies with at least 100 patients in the intention-to-treat group. DATA EXTRACTION: All articles and abstracts were reviewed along with the product labeling from Pharmacia & Upjohn. DATA SYNTHESIS: Miglitol is an alpha-glucosidase inhibitor that exerts its effect through the delayed absorption of complex carbohydrates in the small intestine, resulting in a decrease in postprandial glucose concentrations that are directly correlated with the dietary carbohydrate content. Both small, short-term trials and large, clinical trials show a decrease in postprandial glucose concentrations and a modest decrease in glycosylated hemoglobin of approximately 0.5-1.0% as a result of miglitol's action. The adverse effects of miglitol are mild and transitory and include flatulence, diarrhea, and abdominal pain. The incidence of gastrointestinal problems may be reduced with a small initial dose, which is slowly titrated as tolerated. CONCLUSIONS: Miglitol is an effective and safe treatment option in patients with type 2 diabetes mellitus who are inadequately controlled with diet or oral sulfonylurea therapy. Miglitol is a good choice of therapy in Hispanic, African-American, and elderly patients, or any patients in whom hypoglycemia, weight gain, or lactic acidosis are risks. No published studies comparing miglitol with acarbose have been published, but there appears to be no major clinical or financial advantages to using one agent over the other.

Troglitazone: review and assessment of its role in the treatment of patients with impaired glucose tolerance and diabetes mellitus.

OBJECTIVE: To introduce troglitazone (CS-045, Rezulin), a new oral antidiabetic agent and discuss its pharmacology, therapeutics, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy. DATA SOURCES: A MEDLINE database search was completed to identify relevant articles including reviews, recent studies and abstracts, and data from Parke-Davis. STUDY SELECTION: Due to the small number of published human studies available, some data are derived from animal studies and abstracts of human studies. Studies and abstracts chosen summarize the clinical action of troglitazone in healthy volunteers, in subjects with impaired glucose tolerance, and in patients with diabetes mellitus. Three of the six published human studies used subjects in a placebo-controlled, multicenter, randomized environment (type 2 diabetic patients or obese subjects with insulin resistance). DATA EXTRACTION: All clinical trials available, including unpublished reports, were reviewed. DATA SYNTHESIS: Troglitazone is the first member of a new class of medications, the thiazolidinediones, to be approved for clinical use. Troglitazone increases insulin sensitivity in skeletal muscle and in hepatic and adipose tissue. It has been shown to decrease hepatic glucose output while having no effect on stimulating insulin secretion from the pancreatic beta-cells. Its metabolic effects decrease fasting and postprandial hyperglycemia, insulin concentrations, and triglyceride concentrations, while increasing high-density lipoprotein concentrations. There is some evidence, based on short-term trials, that troglitazone causes only minimal decreases in glycosylated hemoglobin A1C (HbA1C) concentrations. Data suggest that troglitazone decreases impaired glucose tolerance in nondiabetic obese subjects and leads to a reduction in both systolic and diastolic blood pressure in hypertensive type 2 diabetes mellitus patients. Troglitazone has a mild adverse effect profile, with rare instances of abnormal liver function tests. CONCLUSIONS: Troglitazone appears to be a safe, effective, and useful new agent in the treatment of insulin-requiring type 2 diabetes mellitus patients, although its HbA1C-lowering effects have been minimal in short-term trials, and its insulin dosage-reduction activity remains unclear. The Food and Drug Administration has also approved its use as monotherapy and in combination with sulfonylureas for patients with type 2 diabetes. It may have use in the treatment of patients with impaired glucose tolerance, but more clinical experience is needed before definitive conclusions can be made. The role of troglitazone therapy in diabetes mellitus and impaired glucose intolerance will continue to evolve as the results of studies and our clinical experience with this agent become available.

Cost drivers in diabetes care: the problems they present and potential solutions.

Diabetes mellitus is a chronic disease that affects many aspects of the lives of diagnosed patients and their families, the health care industry, and society. The majority of the economic literature on diabetes addresses the cost of treating diabetes but not the outcomes of clinical interventions. The primary cost of treating diabetes is related to short-term care to achieve euglycemia and long-term care associated with complication of the disease. The short-term costs of achieving euglycemia can be overshadowed by the decreased risk of long-term complications. The difficulty of providing care for a chronic disease such as diabetes arises from the high short-term costs of clinical interventions, the positive benefits of which may not be realized for many years. The results of the Diabetes Control and Complications Trial show a correlation between the intensive treatment of diabetes and a decreased risk of the development of long-term complications. Whether intensive treatment is practical, effective, and cost-effective in a real-world setting is a topic for further study. In the meantime, health care providers with a good knowledge of the clinical and economic elements of available therapeutic options can develop individualized care regimens for their patients with diabetes that are high quality and cost-effective.

Acarbose: its role in the treatment of diabetes mellitus.

OBJECTIVES: To review the clinical pharmacology of acarbose, an alpha-glucosidase inhibitor, and to summarize its role in the pharmacotherapy of diabetes mellitus. DATA SOURCES: A MEDLINE search identified all relevant articles, including reviews; Bayer Pharmaceuticals. STUDY SELECTION: Due to the large number of clinical trials available, specific criteria were used to narrow the focus of this review: (1) randomized, double-blind, placebo-controlled, parallel-group study design; (2) a minimum of 25 patients enrolled per treatment arm; (3) a treatment duration of 90 days or more; and (4) adherence to Food and Drug Administration Good Clinical Practice guidelines. DATA EXTRACTION: All clinical trials that were available up to December 1995 were reviewed. Preliminary trials and unpublished reports were not reviewed. DATA SYNTHESIS: Acarbose is effective in reducing postprandial hyperglycemia. It does not stimulate endogenous insulin secretion and, therefore, will not cause hypoglycemia when used as monotherapy. The enhanced glycemic control achieved with acarbose is additive to that of sulfonylureas. It lowers postprandial serum glucose and insulin concentrations and does not promote weight gain. Acarbose can be used as first-line therapy with diet and exercise, or it can be used in combination with sulfonylureas to lower hemoglobin A1c concentrations an additional 0.5-0.9%. Acarbose is not a cure for diabetes, nor is it a substitute for diet, exercise, oral hypoglycemic agents, or insulin. Adverse effects are gastrointestinal and can be diminished by starting with an initial dosage of 25 mg tid. Depending on patient response, the dosage can be increased up to a maximum of 100 mg tid over time. CONCLUSIONS: Acarbose, through its unique mechanism of action, appears to be a safe and effective adjunctive agent to diet/exercise therapy or sulfonylurea therapy for treatment of non-insulin-dependent diabetes mellitus.

Insulin lispro: its role in the treatment of diabetes mellitus.

OBJECTIVE: To introduce a rapid-acting human insulin analog, insulin lispro; to review its pharmacology, therapeutics, pharmacokinetics, dosing guidelines, adverse effects, and drug interactions; and to summarize the clinical trials of its efficacy and safety alone and in comparison with regular human insulin in the treatment of diabetes mellitus. DATA SOURCES: A MEDLINE database search was completed to identify all relevant articles, including reviews; Eli Lilly and Co.; published articles and abstracts; and review chapters from medical textbooks. STUDY SELECTION: Due to the relatively few citations listed in MEDLINE (12 as of December 1995), most of the studies reported were found from abstracts summarizing the clinical action, adverse effects, or pharmacokinetics of insulin lispro in healthy volunteers or patients with diabetes mellitus. A few of the studies used patients with diabetes mellitus in multicenter, randomized, crossover trials of insulin lispro. DATA EXTRACTION: All clinical trials that were available prior to submission of this manuscript for publication, including unpublished reports, were reviewed. DATA SYNTHESIS: The human insulin analog, insulin lispro, which is biosynthetically made by inverting the amino acid sequence of human insulin at B-28 and B-29, is more effective than regular human insulin in improving postprandial glucose control. Subcutaneous injections of insulin lispro result in decreased blood glucose peaks following meals and a potential decreased risk of hypoglycemic episodes, including nighttime hypoglycemia in patients with type 1 diabetes. Insulin lispro in comparison with regular human insulin provides equal or slightly better blood glucose control. When compared with subcutaneous injections of regular human insulin, the peak serum insulin concentration of insulin lispro is three times higher, time to peak is 4.2 times faster, the absorption rate constant is double, and the duration of action is half as long. Insulin lispro is similar to regular human insulin with reference to dose, toxicity, adverse effects, drug interactions, and immunogenicity. When insulin lispro is mixed with human NPH (isophane) or Lente insulins, insulin lispro should be drawn into the syringe first, mixed with the long-acting insulin, and injected immediately after mixing. Patients using insulin lispro perceive an improvement in their well-being and quality of life due to flexible injection times and less frequent hypoglycemic reactions. Insulin lispro is believed to be suitable for patients using insulin infusion pumps. CONCLUSIONS: Insulin lispro is equipotent to human insulin and has a much more rapid onset and shorter duration of action than human insulin does, which may reduce the risk of hypoglycemia. In addition, insulin lispro improves the dosing convenience for patients with diabetes and provides a more natural control of blood glucose concentrations. Insulin lispro is a useful new agent in the treatment of diabetes mellitus.

Apparent stereochemical complementarity of estrogens and helical cavities between DNA base pairs: implications for the mechanism of action of steroids.

The shape of the space occupied by a model of the estrogenic steroid hormone estradiol-17 beta conforms closely to a helical cavity between neighboring base pairs in partially coiled B-DNA. The orientation of estradiol-17 beta when fitted into DNA allows stereochemically complementary hydrogen bonding of both the 3- and 17 beta-hydroxyl groups to phosphate oxygens of the deoxyribose-phosphate backbone on adjacent strands. Changes in the chirality (handedness) of the steroid skeleton or in the absolute stereochemistry of hydrogen bonding groups prevent formation of complementary fits in the DNA. Synthetic estrogens can also adopt conformations which are stereochemically complementary to the cavities between base pairs. The complementary relationships between active estrogens and nucleic acids may be related to constraints on the evolution of the structure and the biological function of steroids.

Characterization of polysaccharide antigens of Streptococcus mutans B13 grown under various conditions.

Bacteria may respond to changes in their environment by varying the synthesis of surface components. This study examined the effects of various culture conditions on two wall polysaccharides of Streptococcus mutans B13 (serotype d): serotype d antigen, a galactose-glucose polymer, and RGP antigen, a rhamnose-glucose polymer. Cells were grown in a chemostat at various dilution rates (D) and pH values, including D = 0.05, 0.1, and 0.5 h-1 at pH 6.0 and D = 0.1 h-1 at pH 5.5, 6.0, 6.5, and 7.5. The cells were examined for protein and carbohydrate content by colorimetric assays and gas-liquid chromatography. Rantz-Randall extracts (120 degrees C, 30 min) and M-1 N-acetylmuramidase digests were prepared and examined for the presence of specific antigens by agar gel diffusion and quantitative precipitation assays. Cell preparations did not vary significantly with respect to total protein or carbohydrate content; however, cells grown at D = 0.1 h-1 and pH 7.5 had a significantly higher rhamnose content than did the other preparations. Rapidly growing cultures appeared to be more resistant to M-1 N-acetylmuramidase digestion than did slower-growing cultures. Agar gel diffusion studies demonstrated that both serotype d and RGP antigens were present in all samples, although significantly less RGP antigen was noted in the pH 7.5 culture. These observations were confirmed by quantitative precipitation assays. M-1 N-acetylmuramidase digests of the pH 7.5 culture were lacking in RGP precipitation activity although RGP inhibition activity was demonstrated. The data suggest that the cell content of serotype d antigen was relatively constant under the growth conditions tested, whereas the synthesis of RGP antigen was modified under conditions of high pH.

Detection of antigens in enzymic lysates of cell wall from Streptococcus mutans strains.

Lysis of cell wall preparations from strains representing serotypes a - g of Streptococcus mutans has provided a convenient and efficient means of obtaining the typing antigens in a soluble undegraded form, and has demonstrated that, in each case, the antigen is a cell wall component in the strict sense of a component joined covalently to peptidoglycan. This influences the choice of extraction procedures.

Characterization of serological cross-reactivity between polysaccharide antigens of Streptococcus mutans serotypes c and d.

Immunological assays with antisera prepared against purified Streptococcus mutans serotype c polysaccharide demonstrated that a cross-reacting determinant on c polysaccharide reacted with the wall-associated rhamnose-glucose polysaccharide from S. mutans serotype d. Studies with 60 antisera prepared against chemostat cultures of S. mutans Ingbritt (c) demonstrated that the rhamnose-glucose polysaccharide cross-reactive determinant was consistently expressed on c antigen under a variety of growth conditions.

Effect of growth conditions on production of rhamnose-containing cell wall and capsular polysaccharides by strains of Lactobacillus casei subsp. rhamnosus.

Strains of Lactobacillus casei subsp. rhamnosus possessing two cell wall polysaccharides, a hexosamine-containing H-polysaccharide and a rhamnose-containing R-polysaccharide, were examined for the effect of growth conditions on the production of these two components. In strain NCTC 6375, R- and H-polysaccharides accounted for an estimated 44 and 20%, respectively, of the cell wall for organisms grown in batch culture with glucose as the carbohydrate source. Growth on fructose-containing media reduced the amount of R-polysaccharide by approximately 50% without affecting the amount of H-polysaccharide. Subculture of fructose-grown organisms in glucose restored the original proportions of the two polysaccharides. Galactose- and sucrose-grown cells behaved similarly to glucose-grown cells with respect to polysaccharide production, whereas growth in rhamnose or ribose showed values close to those for fructose-grown cells. Continuous culture of strain NCTC 6375 for more than 100 generations showed a gradual and irreversible reduction of the R-polysaccharide to less than 5% of the cell wall and an increase of the H-polysaccharide to 40% of the cell wall. Other type culture strains of L. casei subsp. rhamnosus, NCIB 7473 and ATCC 7469, behaved similarly in batch and continuous culture. In contrast, strains of L. casei subsp. rhamnosus isolated at the Institute of Dental Research showed phenotypic stability with respect to the relative proportions of R- and H-polysaccharides in both batch and continuous culture. Changes in polysaccharide composition of type culture strains were also mirrored in changes in the immunogenicity of the two components and resistance to the rate of enzymic lysis of whole organisms. For L. casei subsp. rhamnosus strain NCTC 10302 the R-polysaccharide is present entirely as capsular material. The amount of R-polysaccharide produced was also markedly dependent on the carbohydrate component of the medium in batch culture and both dilution rate and nature of the limiting carbohydrate in continuous culture, varying over a 10-fold range, whereas the cell wall H-polysaccharide remained constant.

Influence of growth conditions on adherence of Streptococcus mutans ingbritt to saliva-coated hydroxyapatite.

Streptococcus mutans Ingbritt grown under standardized conditions adhered less effectively to saliva-coated hydroxyapatite beads than did Streptococcus sanguis G9B, and there was competition for binding. The results with Ingbritt were influenced by the generation time, the pH of growth, and the carbohydrate source as shown by studies on organisms grown in continuous culture.

Teichoic acids from chemostat-grown cultures of Streptococcus mutans and Lactobacillus plantarum.

We examined the effect of growth conditions in chemostat culture on the quantity and composition of the cell wall teichoic acids of Streptococcus mutans BHT and Lactobacillus plantarum NCIB 7220 and the membrane lipoteichoic acid from S. mutans Ingbritt. With the cell wall teichoic acids, which are covalently linked to peptidoglycan, the amount of teichoic acid is independent of the growth conditions employed. However, the extent of glucosyl substitution of the polymer from L. plantarum was dependent on growth conditions. S. mutans Ingbritt lipoteichoic acid, on the other hand, was little affected by growth conditions in terms of composition or serological activity, but the amount produced was markedly affected by changes in growth conditions.

Chemostat studies of the effect of environmental control on Streptococcus sanguis adherence to hydroxyapatite.

Streptococcus sanguis is a major component of early dental plaque. The ability of S. sanguis to adhere to salivary pellicle appears to involve specific bacterial surface receptors. The nature of these receptors is still not known; however, the component molecules may be subject to environmental control as has been shown for teichoic acids and certain proteins. To study these environmental effects, a chemostat was employed to vary the growth conditions of Streptococcus sanguis strain G9B. This strain has been used extensively to study the adhesion of [(3)H]thymidine-labeled batch-grown cells to saliva-coated hydroxyapatite beads. The effects of dilution rate, pH, and carbon source on adhesion were studied with a competition assay in which the labeled batch cells were used as a reference standard. In this assay, cells from the chemostat were harvested and compared for their ability to inhibit adhesion of labeled cells relative to unlabeled control batch-grown cells. Subsequent studies used chemostat grown cells labeled with [(3)H]thymidine as a reference standard so that results were internally controlled and reflected only the particular alteration in environment which was studied. These results indicated that when glucose was used as a growth-limiting substrate, cells grown at relatively high dilution rates (D = 0.5 h(-1); mean generation time = 1.4 h) behaved similarly to batch-grown cells and appeared to compete for the same binding sites. Cells grown at D = 0.1 h(-1) (mean generation time = 7 h) no longer competed with either batch-grown cells or chemostat cells grown at D = 0.5 h(-1). Moreover, adsorption isotherms of such slow-growing cells (D = 0.1 h(-1)) suggested that binding was no longer specific. When fructose was used as the growth-limiting carbohydrate, cells grown at D = 0.1 h(-1) did not show this loss of specificity and competed nearly as well as control batch-grown glucose cells. However, the effect of pH appeared to be independent of carbohydrate source, because cells grown in either glucose or fructose at pH 5.5 at D = 0.1 h(-1) lost the ability to compete with reference batch or chemostat cells grown at D = 0.5 h(-1). This effect was very sharp, since cells grown in the pH range from 6 to 7.5 at D = 0.5 h(-1) competed nearly as well as control cells. A similar effect of pH was found for batch cultures grown with excess glucose. These studies reinforce the idea that the environment can profoundly affect the bacterial surface and consequently the ability of the organism to adhere, a property which appears to be a primary event in some infectious diseases and in dental plaque formation.

First approximation of a stereochemical rationale for the genetic code based on the topography and physicochemical properties of "cavities" constructed from models of DNA.

To examine the question of whether or not the genetic code has a stereochemical basis, we used artificial constructs of the topography and physicochemical features of unique "cavities" formed by removal of the second codon base in B-DNA. The effects of base changes on the stereochemistry of the cavities are consistent with the pattern of the genetic code. Fits into the cavities of the side chains of the 20 L amino acids involved in protein synthesis can be demonstrated by using conventional physicochemical principles of hydrogen bonding and steric constraints. The specificity of the fits is remarkably consistent with the genetic code.

Effect of fructose and other carbohydrates on the surface properties, lipoteichoic acid production, and extracellular proteins of Streptococcus mutans Ingbritt grown in continuous culture.

Streptococcus mutans Ingbritt was grown in a chemostat at destined dilution rates in either 0.5% fructose or 0.5% sorbitol and at destined pH values in 0.5% fructose. The yield of cells was affected by the carbohydrate source, as well as by the pH, with the lowest yield being at pH 5.5 in 0.5% fructose. Fructose-grown cells showed greater susceptibility to lysis by a muramidase than the corresponding glucose-grown cells, but there were no marked differences in the lytic susceptibilities of the corresponding cell wall preparations or in the serological reactivities of wall lysates with antiserum to S. mutans Ingbritt. The greatest amounts of cellular lipoteichoic acid were obtained at high dilution rates in both fructose and sorbitol, as well as at high pH values in fructose. The greatest amounts of extracellular lipoteichoic acid were found at low dilution rates, as estimated by rocket immunoelectrophoresis and also by hemagglutination. Three major extracellular protein components were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the effects of growth conditions on these components were determined. Results for batch-grown cultures showed that there was genotypic variation in the susceptibility of cells to lysis by a muramidase. The enhancement of lipoteichoic acid production by fructose and sorbitol in batch cultures was not identical in representative strains of S. mutans serotype c, nor was the effect of fructose found uniformly in representative strains of the different S. mutans serotypes.

Identification of the group G antigen of Lactobacilli.

The group G antigen of lactobacilli was identified as a negatively-charged cell wall polysaccharide. The components of the preparation isolated from cell walls of L. salivarius subsp. salivarius by mild acid hydrolysis were glucose, galactose and lesser amounts of rhamnose, N-acetylglucosamine and phosphate. Quantitative serological studies on acid-released polysaccharide and enzymic lysates of cell walls showed that rhammose was the immunodominant component. The antigen was also detected in L. salivarius subsp. salicinus but not in a recent isolate of L. salivarius, strain IV CL-37.

Phenotypic stability of the cell wall of Streptococcus mutans Ingbritt grown under various conditions.

Quantitative analyses of cell walls from Streptococcus mutans Ingbritt grown under carbohydrate limitation in the chemostat showed that growth conditions had no statistically significant effect on the composition of polysaccharide, peptidoglycan, or the proportion of polysaccharide in the cell wall. Lysis of cell wall preparations with a muramidase supported this conclusion and further indicated that there was little difference in their overall structure. In contrast, there was a consistent difference between the rates of lysis by this enzyme of organisms grown in 0.2% glucose and 0.5% glucose. Extremes of pH or dilution rate essentially did not influence the immunogenicity of type c antigen in whole organisms irrespective of whether the carbohydrate source was glucose or sucrose. However, differences were found in the immunogenicity of lipoteichoic acid under similar circumstances. The results indicated there was an inherent phenotypic stability in the cell walls of S. mutans Ingbritt despite changes in pH, generation time, and carbohydrate source, and that any changes that did occur were probably due to associated cell-surface components.

Effect of carbohydrate source and growth conditions on the production of lipoteichoic acid by Streptococcus mutans Ingbritt.

Streptococcus mutans Ingbritt was grown in a chemostat at defined dilution rates and pH values and under carbohydrate limitation. At a constant dilution rate of D = 0.1 h-1 and with either 0.5% glucose or 0.5% sucrose, the amounts of both cellular and extracellular lipoteichoic acid increased as the culture pH increased from 5.0 to 7.5. At a constant pH of 6.0, the amount of cellular lipoteichoic acid formed by cultures growing in 0.2% or 0.5% glucose was relatively constant over a range of dilution rates, although the amount of extracellular lipoteichoic acid formed in 0.2% glucose at intermediate dilution rates was less than that formed in 0.5% glucose. Organisms grown in 0.5% sucrose at pH 6.0 contained increasing amounts of cellular lipoteichoic acid as the dilution rate was increased. A comparison of the amounts of cellular lipoteichoic acid formed by organisms growing at D = 0.5 h-1 and pH 6.0 in glucose, sucrose, fructose, or mixtures of glucose and fructose in limiting amounts suggested that the enhanced production of lipoteichoic acic by sucrose-grown organisms was due to the fructose component. The culture fluids from both glucose- and sucrose-grown organisms contained detectable amounts of serotype c antigen, whereas glucose-grown cultures also contained significant amounts of an extracellular hexose-containing polymer.