[Lys(B28), Pro(B29)]-human insulin. A rapidly absorbed analogue of human insulin.

[Lys(B28, Pro(B29)]-human insulin (LYSPRO) is an insulin analogue in which the natural amino acid sequence of the B-chain at positions 28 and 29 is inverted. These changes result in an insulin molecule with a greatly reduced capacity for self-association in solution. These clinical studies were designed to compare LYSPRO with human Regular insulin after subcutaneous injection in humans. We wanted to evaluate the effect of adding zinc to LYSPRO on its pharmacokinetics and pharmacodynamics. In addition, we compared the pharmacokinetics and pharmacodynamics of LYSPRO and human Regular insulin after subcutaneous injection to those of human Regular insulin given intravenously. Thus, we compared four treatments: solutions of zinc-free LYSPRO given subcutaneously (A), zinc-containing LYSPRO given subcutaneously (B), human Regular insulin given subcutaneously (C), and human Regular insulin given intravenously (D). We gave a 10-U dose of each treatment to 10 healthy (nondiabetic) men during glucose clamps. Serum insulin concentrations peaked more than two times higher (maximum serum insulin level [Cmax], 698 vs. 308 pM, A vs. C) and in less than half the time (time to Cmax [Tmax], 42 vs. 101 min, A vs. C) after subcutaneous injection of zinc-free LYSPRO. At the same time, the glucose infusion rate peaked in about half the time (time to maximum glucose infusion rate [TRmax], 99 vs. 179 min, A vs. C) and was slightly but not significantly higher (maximum glucose infusion rate [Rmax], 3.1 vs. 2.2 mmol/min, A vs. C) than that of human Regular insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Multicenter Insulin Lispro Study Group.

Insulin lispro, an insulin analog recently developed particularly for mealtime therapy, has a fast absorption rate and a short duration of action. We compared insulin lispro and regular human insulin in the mealtime treatment of 1,008 patients with IDDM. The study was a 6-month randomized multinational (17 countries) and multicenter (102 investigators) clinical trial performed with an open-label crossover design. Insulin lispro was injected immediately before the meal, and regular human insulin was injected 30-45 min before the meal. Throughout the study, the postprandial rise in serum glucose was significantly lower during insulin lispro therapy. At the endpoint, the postprandial rise in serum glucose was reduced at 1 h by 1.3 mmol/l and at 2 h by 2.0 mmol/l in patients treated with insulin lispro (P < 0.001). The rate of hypoglycemia was 12% less with insulin lispro (6.4 +/- 0.2 vs. 7.2 +/- 0.3 episodes/30 days, P < 0.001), independent of basal insulin regimen or HbA1c level. The reduction was observed equally in episodes with and without symptoms. When the total number of episodes for each patient was analyzed according to the time of occurrence, the number of hypoglycemic episodes was less with insulin lispro than with regular human insulin therapy during three of four quarters of the day (P < 0.001). The largest relative improvement was observed at night. In conclusion, insulin lispro improves postprandial control, reduces hypoglycemic episodes, and improves patient convenience, compared with regular human insulin, in IDDM patients.

Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Multicenter Insulin Lispro Study Group.

BACKGROUND: Insulin lispro is an insulin analog that was recently developed particularly for a mealtime therapy. It has a fast absorption rate and short duration of action. The efficacy of insulin lispro in the clinical therapy of patients with non-insulin-dependent diabetes mellitus (NIDDM) has not been tested. OBJECTIVES: To compare insulin lispro and human regular insulin in the mealtime treatment of patients with NIDDM. METHODS: A 6-month, randomized, multinational (16 countries), multicenter (80 sites) clinical trial with an open-label, crossover design was performed in 722 patients with NIDDM. Insulin lispro was injected immediately before and human regular insulin 30 to 45 minutes before the meal. RESULTS: Throughout the study, the postprandial rise in serum glucose levels was significantly lower during insulin lispro than human regular insulin treatment. At end point the rise (mean +/- SEM) in serum glucose levels was 30% lower at 1 hour (2.6 +/- 0.1 mmol/L [46.8 +/- 1.8 mg/ dL] for lispro vs 3.7 +/- 0.1 mmol/L [66.6 +/- 1.8 mg/dL] for human regular insulin) and 53% lower 2 hours after the test meal (1.4 +/- 0.1 mmol/L [25.2 +/- 1.8 mg/dL] for lispro vs 3.0 +/- 0.1 mmol/L [54.0 +/- 1.8 mg/dL] for human regular insulin) with insulin lispro compared with human regular insulin therapy (P < .001 for both intervals). During insulin lispro therapy the rate of hypoglycemia overall (P = .01) and overnight (P < .001) was lower and the number of asymptomatic hypoglycemic episodes was smaller (P = .03) than during human regular insulin therapy. Associated with a similar 13% increase (P < .001) in the total daily insulin dose, the glycosylated hemoglobin level decreased (P < .001) equally in both treatment groups. Serum lipid and lipoprotein levels remained unchanged. There were no differences in the adverse events between the 2 treatment groups. CONCLUSIONS: Compared with human regular insulin therapy, mealtime therapy with insulin lispro reduced postprandial hyperglycemia and may decrease the rate of mild hypoglycemic episodes in patients with NIDDM.

Comparative pharmacokinetics and glucodynamics of two human insulin mixtures. 70/30 and 50/50 insulin mixtures.

OBJECTIVE: To compare and contrast the pharmacokinetics and glucodynamics of two insulin mixtures, one of 50% NPH human insulin and 50% Regular human insulin (50/50) and one of 70% NPH human insulin and 30% Regular human insulin (70/30), in healthy male volunteers after subcutaneous administrations of 0.3 U/kg. RESEARCH DESIGN AND METHODS: We administered single doses of 50/50 and 70/30 insulins to 18 volunteers in a randomized crossover fashion. All subjects received 0.3 U/kg of each mixture separated by at least 7 days. Each dose was given after an overnight fast and during a glucose clamp to maintain a euglycemic state. We measured serum insulin and C-peptide concentrations through frequent blood sampling after each treatment. Pharmacokinetic measurements were calculated from insulin data corrected for C-peptide, including maximum insulin concentration (Cmax), time to maximum insulin concentration (tmax), terminal rate constant (beta), area under the curve from 0 to infinity (AUCinfinity0), and mean residence time (MRT). Pharmacodynamic measurements were summarized from C-peptide concentrations (minimum C-peptide concentration [Cmin], time to minimum C-peptide concentration [tmin], area between the C-peptide baseline and the C-peptide suppression curve [AOCc], absolute maximal difference from baseline [Sdiff] and glucose clamp measurements. The glucose clamp measurements included maximum infusion rates (Rmax) and time to Rmax (TRmax) from glucose infusion rate (GIR) documentation, as well as cumulative glucose infused during the first 4 h ((0)4Gtot) and total glucose infused (Gtot) during the study. RESULTS: For the pharmacokinetic assessment, statistically greater values of insulin Cmax and beta were found for the 50/50 mixture, whereas the 70/30 mixture had a greater MRT. Statistical differences were also detected in glucodynamics, with greater values of Rmax and (0)4Gtot found with the 50/50 mixture. Notably, differences were not detected for insulin AUCinfinity0 and Gtot values. CONCLUSIONS: Higher insulin concentrations and a greater initial response were present with the 50/50 mixture, but the two mixtures had equivalent bioavailability and cumulative effects. These results support use of the 50/50 mixture in situations where greater initial glucose control is required.

Analgesic effect of picenadol, codeine, and placebo in patients with postoperative pain.

A double-blind, parallel study was conducted to evaluate the analgesic effect and safety of a single 25 mg oral dose of picenadol, a centrally acting analgesic, and to compare it with a 60 mg dose of codeine and a placebo in patients with postoperative pain. Two sites using similar protocols enrolled a total of 178 inpatients with postoperative pain. Pain intensity, relief, and adverse experiences were then measured for up to 6 hours after administration of the test medications. Both picenadol and codeine were significantly more effective than placebo in reducing pain intensity (mean sum of pain intensity difference scores: picenadol 5.21, codeine 5.19, and placebo 2.82) and increasing total relief (mean total pain relief: picenadol 10.21, codeine 11.07, and placebo 6.96). Adverse experience profiles were similar among the three treatment groups.

[Lys(B28), Pro(B29)]-human insulin: effect of injection time on postprandial glycemia.

BACKGROUND: [Lys(B28), Pro(B29)]-human insulin (lispro) is an insulin analogue with a reduced capacity for self-association and faster absorption from subcutaneous injection sites. We hypothesized that administration of lispro closer to a meal would result in better glucose control than that achieved with regular insulin. METHODS: This trial used a randomized crossover design that consisted of a period of metabolic stabilization lasting 9 days followed by an evaluation period lasting 5 days. The patients received weight-maintenance diets, and insulin doses were adjusted as needed. Calorie intake, insulin dose, and activities were kept constant once the evaluation period began. During the evaluation period, we varied the time between insulin injection and mealtime and assessed glucose control. RESULTS: During the evaluation period, the lowest mean glucose concentrations were 117.9 mg/dl for lispro and 119.8 mg/dl (p = 0.817) for regular insulin. To obtain these, we gave lispro, on average, 22.5 minutes before meals and regular insulin 63.8 minutes before meals (p = 0.006). A similar pattern was evident throughout the glucose control parameters. The exception was mean amplitude of glucose excursion, which was lower after lispro (59 versus 75 mg/dl; p = 0.007) compared with regular insulin. CONCLUSIONS: We achieved equal or slightly better glucose control, as reflected by mean amplitude of glucose excursion, with insulin lispro given much closer to meal time than that achieved with regular insulin. As a result of these findings, we propose that a rapidly absorbed analogue of insulin is capable of achieving better control of postprandial glucose at a more convenient injection time.

The laboratory response to glucagon dosages used in gastrointestinal examinations.

Laboratory studies occasionally are necessary for patients who have undergone hypotonic gastrointestinal examinations. To ascertain the effects of glucagon on these patients, we determined the biochemical and hematologic responses to doses of 0.25-2 mg of glucagon in a double-blind crossover study. When glucagon was given intravenously or intramuscularly in increasing doses, serum values for glucose and insulin increased linearly up to 1 mg with a slight decrease at 2 mg. After intravenous and intramuscular administration of glucagon, the white blood cell count and the percentage of neutrophiles and bands increased, and the percentage of lymphocytes decreased. Reports of side effects included one each of nausea and mouth dryness after intravenous glucagon and four reports of nausea and one of mouth dryness after intramuscular glucagon. No changes in the pulse and blood pressure could be attributed to glucagon administration.

In vivo evaluation of an electroenzymatic glucose sensor implanted in subcutaneous tissue.

Cleanroom processing techniques have been used to mass-produce flexible, electroenzymatic glucose sensors designed for implantation in subcutaneous tissue. In vitro characterization studies have shown the sensor's performance to be acceptable. Initial in vivo studies were conducted with the sensor implanted in the subcutaneous tissue of rabbits. Sensors implanted in the subcutaneous tissue of normal human subjects showed an excellent correlation between glucose concentrations measured by the sensor and capillary finger sticks measured with a commercial analyzer.

Improved mealtime treatment of diabetes mellitus using an insulin analogue. Multicenter Insulin Lispro Study Group.

The absorption of regular human insulin from subcutaneous injection sites is delayed due to the self-association of insulin to multimeric forms. The insulin analogue insulin lispro has a weak self-association and a fast absorption rate. We examined the safety and efficacy of insulin lispro in the premeal treatment of patients with diabetes mellitus. A 12-month study was performed in 336 patients with insulin-dependent diabetes mellitus (IDDM) and 295 patients with non-insulin-dependent diabetes mellitus (NIDDM). The patients were randomized to inject either regular human insulin 30 to 45 minutes before eating, or insulin lispro immediately before each meal, in addition to basal insulin. The postprandial rise in serum glucose was lower in patients receiving insulin lispro than in those receiving regular human insulin therapy. At end point the increment was significantly lower at 1 hour (35%) and at 2 hours (64%) after the meal in IDDM patients; in NIDDM patients, the increment was nonsignificantly lower at 1 hour (19%) and significantly lower at 2 hours (48%). IDDM patients receiving insulin lispro achieved significantly lower glycated hemoglobin (HbA1c) levels in patients receiving regular human insulin (8.1% vs 8.3%). In NIDDM patients, HbA1c levels decreased equally in both treatment groups. Due to its fast absorption rate, insulin lispro improves postprandial control in diabetes. Insulin lispro can be considered one step toward optimal insulin therapy and improved patient convenience.

Picenadol in a large multicenter dental pain study.

STUDY OBJECTIVE: To estimate the analgesic dose of picenadol hydrochloride equal to codeine 60 mg in a dental pain model. DESIGN: Randomized, double-blind, parallel, dose-response study. SETTING: Four university-based dental clinics. PATIENTS: Four hundred eight adult patients with moderate or severe pain after extraction of one or more impacted molar teeth plus bone removal. INTERVENTIONS: Patients received orally administered single doses of picenadol 15 and 30 mg, codeine phosphate 30 and 90 mg, or placebo. METHODS: Single oral doses of picenadol 15 and 30 mg, an opioid agonist-antagonist, were compared with codeine 30 and 90 mg and placebo in 408 patients with moderate or severe pain from third molar extraction in a randomized, double-blind, parallel study. Assessments were performed for pain intensity, pain relief, and adverse events for up to 6 hours after drug administration. MAIN RESULTS: Picenadol 30 mg and codeine 90 mg were more effective than placebo based on sum of pain intensity differences, total pain relief, peak pain relief, and duration of analgesia (p < 0.05). Compared with placebo, the frequency of adverse events was highest for patients receiving codeine 90 mg (p < 0.05). No patients discontinued due to adverse events, and all such events resolved spontaneously. CONCLUSIONS: Picenadol 22 mg was estimated to be equianalgesic to codeine 60 mg, and picenadol 30 mg was safe in this dental pain model.

Gastrointestinal radiography with glucagon.

This report summarizes the results of nine diagnostic radiographic studies done double blind crossover comparing glucagon to placebo and to anticholinergic drugs in volunteers. In seven studies the subjects were administered drug intramuscularly and in two studies intravenously. There were five diagnostic studies of the upper gastrointestinal tract, one for esophageal varices and three of the colon. The results indicate that glucagon can be given intramuscularly and intravenously. When given intravenously it has a rapid onset and predictable length of action depending on the dose given. Reports of side effects were few consisting primarily of nausea and or vomiting. These results indicate that glucagon is the drug of choice for hypotonic diagnostic examinations.

A comparative double-blind study of esophageal barium pastes.

To demonstrate esophageal varices barium sulfate suspensions must coat the lower esophagus for as long as 5 to 10 minutes. This study compared the ability of five barium sulfate preparations to resist disappearance by inadvertent swallowing. Three of the special preparations for esophageal examination, Esophatrast, Barosperse Esophageal Paste, and HD-5000 performed satisfactorily. Examiner skill, persistence, and careful technique are the most important factors in examining the lower esophagus. The authors' procedure for examination of the esophagus for varices is described. It takes into account position, time, phase of respiration, occasional use of drugs, and procedures to insure good coating and relaxation of the lower esophagus.

Comparative efficacy of colon-cleansing methods: standard preparation vs. Colimmac lavage.

A randomized trial was conducted to compare the efficacy of the following preparations for colon cleansing: (1) 24 hr of clear liquids plus two major laxatives plus tap-water enemas (standard preparation), (2) Colimmac lavage, and (3) Colimmac lavage plus one major laxative. Standard preparation was found to be significantly superior to the other methods. Overall it was thought that Colimmac as evaluated by this study is not satisfactory for clinical use.

Effect of D-Val1, D-Trp8-somatostatin on the motility of the stomach, duodenum and jejunum.

D-Val1, D-Trp8-somatostatin was given to seven volunteers to relax the gastrointestinal tract. Doses of drug ranging from 1-250 mcg. were given intravenously, single blind, as one bolus. The seven subjects had a total of 23 studies. The stomach never became hypotonic in any subject. The onset of drug effect on the duodenum and jejunum of moderate hypotonicity after 10-100 mcg. was 4.8 minutes and at 150-250 mcg., was 10.1 minutes. Onset of atonicity after 10-100 mcg. wa 5.7 minutes and at 150-2509 mcg., was 13.0 minutes. Duration of moderate hypotonicity after 10-100 mcg. was 20.9 minutes and at 150-250 mcg., was 22.4 minutes. Duration of atonicity at 10-100 mcg. was 11.5 minutes and at 50-250 mcg., was 14.1 minutes. Preliminary results suggest that the onset and duration of effect, relative to dose, were so variable that the drug appeared to be an unsatisfactory hypotonic agent for upper gastrointestinal radiography.

Dose response to intramuscular glucagon during hypotonic radiography.

In a study to determine a dose response to glucagon during hypotonic duodenography, 15 male and female volunteers received placebo and 0.25 mg 1 mg and 2 mg glucagon intramuscularly, double-blind and cross-over. When 0.25 mg glucagon was given, the onset of drug effect was approximately 13--18 min: the mean duration of moderate hypotonicity was approximately 4--7 min. The larger the dose, the greater the duration of drug action. When 2 mg glucagon was given, the onset of drug effect occurred in approximately 4--7 min; the mean duration of moderate hypotonicity was 22--32 min. There were no changes in pulse or blood pressure attributable to the drug with these doses, and reports of nausea and diarrhea did not increase significantly until a dose above 1 mg was given. One mg glucagon given IM is useful in hypotonic upper Gl radiographic examinations. The onset of hypotonicity was 8--10 min with a duration of 12--27 min when this dose was given. Few reports of side effects were attributable to this dose.

Double-blind radiographic study of dose response to intravenous glucagon for hypotonic duodenography.

This study was undertaken to determine a dose response to glucagon during hypotonic duodenography. Fifteen male and female volunteers received placebo and 0.25 mg, 0.5 mg, 1 mg, and 2 mg of glucagon intravenously, double-blind, and crossover. Onset of drug effect occurred in approximately 45 seconds, regardless of the dose of glucagon given. There was a significant (p less than 0.01) decrease in gastrointestinal tonicity with all doses. The larger the dose, the greater the duration of drug action. Satisfactory stomach, duodenal, and small bowel hypotonicity for radiography were obtained with 0.25 to 0.5 mg of glucagon given intravenously with few side effects.

Quantification of the skin's topography by skin profilometry.

Synopsis A method of skin profilometry is presented. The data generated using this method are used to (a) uncover sources of variation in skin profilometry, (b) provide information regarding the choice of roughness parameters best suited for characterizing the skin's topography, and (c) determine if skin profilometry is a valuable tool for quantitatively assessing changes in the skin's surface pattern. The data show the roughness parameter values to be dependent on the orientation of the tracings with regard to the major grooves and ridges present in the surface patterns. Large variabilities of roughness parameter values obtained for multiple scans within small areas of replicas are indicative of the nonhomogeneity of the skin's surface. The number of peaks, mean peak size, mean depth of roughness, depth of smoothness, and residual profile length appear to be the most utile roughness parameters for quantifying changes in the skin's topography. The ability of skin profilometry to detect subtle changes in the skin's surface pattern due to hydration indicates the method is a sensitive means of quantifying the skin's topography.

Acquired jejunoileal diverticular disease: subject review.

Of 519 consecutive patients examined by enteroclysis, 12 (2.3%) were found to have acquired diverticula of the jejunum and ileum. All except one patient had multiple diverticula, most occurring in the jejunum. In only one patient could symptoms be ascribed to the abnormality. The combination of intraluminal distention and extrinsic abdominal compression provided by the enteroclysis technique appears to be the most reliable method for the demonstration of small-bowel diverticula. A discussion of the complications that may result from acquired jejunoileal diverticulosis and a review of the literature are presented.

Intramuscular picenadol in patients with postoperative pain.

1. The analgesic efficacy and safety of a single 50 mg intramuscular dose of rac-picenadol, a centrally acting agonist-antagonist opioid analgesic, were compared with pethidine (meperidine) 100 mg and placebo in 60 patients with moderate to severe postoperative pain using hourly pain intensity and relief measurements for up to 6 h following injection of the study medications. 2. Both picenadol and pethidine were statistically significantly (P < 0.05) more effective than placebo in reducing pain intensity and in increasing total relief. Patients receiving picenadol and pethidine had higher frequency of somnolence than patients receiving placebo. In addition, patients receiving picenadol 50 mg experienced a higher incidence of confusion (30%), speech disorders (30%), and tremors (25%) than the patients receiving either pethidine or placebo. 3. These results were compared with those of a similar study which investigated the effects of a 25 mg intramuscular dose of picenadol vs pethidine and placebo. This comparison suggests that 25 mg of picenadol is a more acceptable dosage since both 25 and 50 mg were effective dosages.