Effect of blood glucose concentrations on the development of chronic complications of diabetes mellitus.

Diabetes is associated with increased risk of cardiovascular disease, coronary heart disease, stroke, acute myocardial infarction, blindness, and renal failure. Strategies to reduce their occurrence are an essential focus of patient care. More than one pathogenic process is involved, and genetics influence the risk. Hyperglycemia is a factor in the development of microvascular and possibly macrovascular complications. Two possible mechanisms of glucose damage are glycation of proteins and the polyol pathway. Research led to the identification of drugs that block parts of the pathways. In clinical trials, intensive control of blood glucose concentrations decreased the risk of microvascular complications. Adverse effects associated with intensive therapy, however, include hypoglycemia and weight gain.

Evaluation of the potential interaction between felbamate and erythromycin in patients with epilepsy.

Effects of erythromycin on hepatic CYP450 3A4 isozymes can profoundly influence the metabolism of many therapeutic agents. An open-label, randomized, two-period, crossover study was therefore conducted to evaluate the pharmacokinetics of felbamate before and after a concurrent 10-day regimen (333 mg three times daily) of erythromycin. Patients were receiving either 3,000 or 3,600 mg/day felbamate monotherapy for treatment of epilepsy. Mean dose-normalized values for maximum concentration (Cmax) and area under the concentration-time curve (AUC tau) of felbamate were not statistically different in patients taking felbamate as monotherapy than in patients after erythromycin coadministration. Estimates of time to Cmax (tmax), minimum concentration (Cmin), apparent clearance (Cl/kg), average concentration (Cav), and degree of fluctuation (DFss) were likewise unchanged. The incidence of mild and moderate adverse events increased during coadministration of the two drugs. Because patients with epilepsy can not be treated with erythromycin alone, it could not be determined whether the adverse events were attributable to erythromycin or to the combination of the two drugs. Steady-state pharmacokinetic parameters of felbamate were not influenced by erythromycin coadministration.

Acarbose: an alpha-glucosidase inhibitor.

The chemistry, pharmacology, pharmacokinetics, and clinical efficacy of acarbose, a new antidiabetic agent, are reviewed. Acarbose reversibly inhibits intestinal alpha-glucosidases, enzymes responsible for the metabolism of complex carbohydrates into absorbable monosaccharide units. This action results in a diminished and delayed rise in blood glucose following a meal, resulting in a reduction in post-prandial hyperglycemia, area under the glucose concentration-time curve, and glycosylated hemoglobin. Other effects include a reduction in postprandial insulin and variable changes in plasma lipid concentrations. In placebo-controlled trials, acarbose caused significant improvements in glycemic control indicators, including glycosylated hemoglobin. Acarbose has demonstrated additional glycemic control when added to other antidiabetic therapies, including sulfonylureas and insulin. Efficacy of acarbose appears to be comparable to or slightly less than that of sulfonylureas or metformin, although it has not been compared with maximal dose of these agents. The most commonly reported adverse drug reactions with acarbose are abdominal pain, diarrhea, and flatulence, which tend to lessen with time. Acarbose may affect the bioavailability of metformin and may be less effective when used in conjunction with intestinal adsorbents and digestive enzyme preparations. Concurrent use with hypoglycemic agents (sulfonylureas and insulin) may cause an increased frequency of hypoglycemia. Acarbose should not be used in individuals with certain intestinal disorders, including inflammatory bowel disease. The dosage should start at 25 mg one to three times daily given with the first bite of each main meal and should be adjusted to a maximum of 50 mg three times daily for patients weighing up to 60 kg or 100 mg three times daily for heavier patients. Acarbose may be considered for first-line antidiabetic therapy in certain patients and may be useful as combination therapy in selected instances. Acarbose is efficacious in improving metabolic control in non-insulin-dependent diabetes mellitus. Further evaluation of its effects on the long-term complications of diabetes is needed.

Administration of insulin by continuous ambulatory peritoneal dialysis.

Many patients with diabetic nephropathy undergoing continuous ambulatory peritoneal dialysis (CAPD) use their peritoneal access to administer insulin. Compared with the subcutaneous route, intraperitoneal (IP) insulin may display more consistent absorption, produce more physiologic insulin concentrations, and be more convenient to administer. However, there are no well-controlled trials that have demonstrated a clinically significant difference in glycemic control between IP and subcutaneous administration. For patients who choose to begin IP insulin at the time CAPD is initiated, the starting dose is 2-3 times the previous subcutaneous dose. For patients previously stabilized on CAPD, the conversion factor may be less. Doses are divided equally between bags. Some authors recommend adding more insulin to bags with a higher concentration of dextrose. In addition, the dose should be decreased when added to a bag used for an overnight dwell. Exchanges performed during the day may be timed to start 30 minutes before a meal. Unless clinical trials demonstrate a difference in efficacy between subcutaneous and peritoneal insulin administration, the route will remain a matter of patient preference.

A truncated intracellular HER2/neu receptor produced by alternative RNA processing affects growth of human carcinoma cells.

Cloned sequences encoding a truncated form of the HER2 receptor were obtained from cDNA libraries derived from two HER2-overexpressing human breast cancer cell lines, BT-474 and SK-BR-3. The 5' 2.1 kb of the encoded transcript is identical to that of full-length 4.6-kb HER2 transcript and would be expected to produce a secreted form of HER2 receptor containing only the extracellular ligand binding domain (ECD). The 3' end of the truncated transcript diverges 61 nucleotides before the receptor's transmembrane region, reads through a consensus splice donor site containing an in-frame stop codon, and contains a poly(A) addition site, suggesting that the truncated transcript arises by alternative RNA processing. S1 nuclease protection assays show a 40-fold variation in the abundance of the truncated 2.3-kb transcript relative to full-length 4.6-kb transcript in a panel of eight HER2-expressing tumor cell lines of gastric, ovarian, and breast cancer origin. Expression of this truncated transcript in COS-1 cells produces both secreted and intracellular forms of HER2 ECD; however, immunofluorescent labeling of HER2 ECD protein in MKN7 tumor cells that natively overexpress the 2.3-kb transcript suggests that transcriptionally generated HER2 ECD is concentrated within the perinuclear cytoplasm. Metabolic labeling and endoglycosidase studies suggest that this HER2 ECD (100 kDa) undergoes differential trafficking between the endoplasmic reticulum and Golgi compartments compared with full-length (185-kDa) HER2 receptor. Transfection studies indicate that excess production of HER2 ECD in human tumor cells overexpressing full-length HER2 receptor can result in resistance to the growth-inhibiting effects of anti-HER2 monoclonal antibodies such as muMAb4D5. These findings demonstrate alternative processing of the HER2 transcript and implicate a potentially important growth regulatory role for intracellularly sequestered HER2 ECD in HER2-amplified human tumors.

Human breast tumors containing non-DNA-binding immunoreactive (67 kDa) estrogen receptor.

Evidence to date indicates that structurally abnormal estrogen receptor (variant ER) can be detected in some human breast tumors. Based on in vitro ability to bind DNA sequences containing the cognate estrogen response element (ERE), these variant receptors may be categorized into DNA-binding ER (Type-1 variants) and non-DNA-binding ER (Type-2 variants). To look for Type-2 variants of normal size (67 kDa ER) that lack the ability to form immunoreactive ER-ERE complexes, a panel of 40 cryopreserved primary breast tumors were extracted and analyzed by enzyme immunoassay (ER-EIA), gel-shift, and Western blot techniques. For the 33 tumor extracts containing > or = 10 fmol/mg ER (by ER-EIA), the amount of 67 kDa ER detectable by D75 anti-ER monoclonal antibody under fully denatured and reduced assay conditions (Western blotting) did not correlate well with the presence or intensity of D75 immunoreactive ER-ERE bands seen under native conditions by gel-shift assay. Overall, 30% (10 of 33) of these extracts containing 67 kDa ER failed to produce immunoreactive ER-ERE complexes, with this frequency varying from over 40% in tumor samples with lower ER content (10-49 fmol/mg) to 11% in tumor samples with the highest ER content (> 100 fmol/mg). These results indicate that Type-2 variant receptors characterized as non-DNA-binding 67 kDa ER may be present in a significant fraction of ER-positive primary breast tumors; preliminary evidence suggests that further study of abnormalities in ER tertiary or quaternary structure, such as those produced by intracellular oxidation of ER thiol groups, is warranted.

Absorption of flurbiprofen in the fed and fasted states.

The oral absorption of flurbiprofen, an antiinflammatory nonsteroidal compound, was compared in the fasted vs the fed state. When ingested as an aqueous solution of the sodium salt, absorption kinetics followed a monoexponential pattern in half of the subjects and a bimodal pattern with a lag time before the onset of the second phase of absorption in the other half of the subjects. When ingested in the free acid form as a tablet either with water (fasted state) or with water 15 min after 330 ml of apple juice (fed state), flurbiprofen absorption was always bimodal, and the lag time before the onset of the second phase was shown to be dependent on the gastric emptying time (r = 0.623, P less than 0.01). The gastric emptying times were significantly longer when the drug was administered in the fed state (average GET = 57 min in the fasted state and 102 min in the fed state; P less than 0.01). These results suggest that gastric emptying effects are one important way in which absorption of drugs can be affected by meal intake.

Combination use of sulfonylureas and insulin in the treatment of noninsulin-dependent diabetes mellitus.

Combination therapy with insulin and sulfonylureas for treatment of noninsulin-dependent diabetes mellitus has been evaluated frequently. However, many of the trials either lacked proper control or were of inadequate duration, and none compared combination therapy to intensive insulin therapy using several daily injections. Such a combination decreases, but does not return to normal, glycosylated hemoglobin and fasting glucose concentrations in comparison to therapy with one or two daily injections of insulin in some subjects. Alternatively, adding a sulfonylurea to insulin therapy may allow a reduction in the insulin dosage without compromising glycemic control. When considering the use of the two agents, the possible advantage of a simplified insulin regimen must be weighed against the disadvantages of an increased potential for adverse effects and increased cost.

p185HER2 signal transduction in breast cancer cells.

A partially agonistic monoclonal antibody, 4D5, known to bind to the extracellular domain of p185HER2 and shown to inhibit long term growth of p185HER2-overexpressing breast cancer cells, was used to study signal transduction and phosphotyrosyl protein substrates associated with this receptor. Normal breast epithelial cells and breast carcinoma cells expressing low levels of p185HER2 were not affected by 4D5. HER2/neu-overexpressing breast cancer cells (BT-474 and SK-Br-3) exposed to 4D5 exhibited rapid phosphorylation of both p185HER2 and an associated 56-kDa phosphotyrosyl protein (ptyr56). Paralleling the 4D5- stimulated phosphorylation of p185HER2 and ptyr56 was a 5-10-fold induction of c-fos mRNA and phosphatidylinositol 4-kinase activity and a 2-fold induction of inositol 1,4,5-trisphosphate 3'-kinase activity. The increased phosphatidylinositol 4-kinase activity immunoprecipitated with p185HER2 and also co-eluted with ptyr56 from an antiphosphotyrosine immunoaffinity column. These results indicate that short term (less than 6 h) 4D5 activation of p185HER2 in overexpressing breast cancer cells produces agonistic-like signaling typical of homologous tyrosine kinase growth factor receptors such as epidermal growth factor receptor. The data also suggest that ptyr56 represents a novel phosphorylated substrate associated with 4D5-stimulated p185HER2.

Appropriate but not cost effective ceftazidime use in a university hospital.

An evaluation of ceftazidime use at a university hospital was performed. Drug utilization evaluations usually categorize therapies as appropriate or inappropriate, with the inappropriate category including all regimens which are not cost effective. This may be misleading since therapy which is therapeutically appropriate may be labeled as inappropriate. Therefore, ceftazidime use was classified as appropriate, appropriate but not cost effective, or inappropriate. Clinical pharmacists reviewed the charts of 72 patients over a 1 month period. Courses of therapy were first categorized as empiric or definitive and as appropriate or inappropriate. Those that were appropriate were further analyzed to determine cost effectiveness. When a more cost effective regimen was available, the difference in cost was calculated; the cost of inappropriate therapy was compared to that of an appropriate alternative regimen. Ceftazidime use was appropriate and cost effective in 22% of courses, appropriate but not cost effective in 66%, and inappropriate in 11%. Annual savings of up to $72,000 could be realized in our 550 bed hospital by intervention into appropriate but not cost effective therapy and inappropriate therapy.

Gel electrophoretic analysis of proteins in human milk and colostrum.

Protein patterns of skim milk and fat globule phases were relatively unchanging throughout 9 months lactation, the only notable differences being a rise in lysozyme and a decline up to 6 months with increase thereafter in lactoferrin. Profound changes in protein patterns of the breast secretion were observed during the first week postpartum. True colostrum, in which peptides of sIgA dominate the protein patterns, exists for at most the 2 initial days of secretion. Proteins of mature milk are not coordinated to appear in the colostral secretion simultaneously. A band corresponding to alpha-lactalbumin is present from the initial secretion; that for beta-casein emerges approximately 2 days layer.

Clinical experience with flupirtine in the U.S.

Flupirtine, a chemically unique, orally effective, non-narcotic, centrally acting analgesic was evaluated for efficacy and safety in five parallel, double-blind randomized clinical trials which included both placebo and active control comparisons. Flupirtine was given in oral doses of 100 to 300 mg, with a maximum daily dose of 600 mg to patients with pain resulting from episiotomy, surgical or dental procedures. Patients rated pain intensity, pain relief and adverse experiences at regular intervals up to 6 hours following medication. Assessments of efficacy included measures of the sum of pain intensity differences (SPID), total pain relief (TOPAR) and peak analgesia (PPID). More than 1300 patients have been evaluated at 26 study sites in the United States. More than 170 of them received flupirtine 100 mg, 250 received 200 mg and 50 received 300 mg. An additional 415 patients received positive control medications (paracetamol 650 mg, codeine 60 mg, pentazocine 50 mg or oxycodone 10 mg plus paracetamol 650 mg). All doses of flupirtine produced analgesia after a single dose. Pharmacokinetic evaluations have shown linear kinetics for flupirtine and a 100 mg t.i.d. dosage schedule produces average steady-state blood levels equivalent to the peak response for a single 200 mg dose. Adverse experiences occurring in flupirtine clinical studies have been minimal in incidence, nature and degree, with drowsiness being the most frequently reported reaction (approximately 10%).

Adoption planning for handicapped children. A medical-social work partnership.

Major changes are taking place in the field of adoption. Once concerned primarily with the placement of newborn infants, the field has broadened, with a major emphasis on the adoption of older children, often from foster care and many times with major handicaps or problems. These children require special families who are willing to adopt them. They require the services of skilled social workers to effectively place them, and they require understanding of the physician who may be involved either with their placement examination or with their subsequent management as an adoptee. A new objective approach to the problem is necessary.