U-100, pH-Neutral formulation of VIAject(®) : faster onset of action than insulin lispro in patients with type 1 diabetes.

AIMS: VIAject® is a formulation of human insulin with a very fast onset of action. Previous studies used VIAject in a concentration of 25 U/ml and a pH of 4 [VIAject 25 (VJ25)]. Objective of this double blind, three-way crossover study was to compare the pharmacodynamic/pharmacokinetic properties of a novel formulation of VIAject with a concentration of 100 U/ml and a neutral pH [VIAject 7 (VJ7)] with VJ25 and insulin lispro (LIS). METHODS: Forty-three patients with type 1 diabetes [aged 43 (21-65) years, BMI 24.1 (20-28) kg/m(2) and HbA1c 7.5 (5.7-9.5) %] participated in this study. They received subcutaneous injections of 12 U of each insulin formulation under euglycaemic glucose clamp conditions. RESULTS: VJ7 was bioequivalent to VJ25 [90% confidence interval (CI) of the ratios for total insulin AUCs and maximum insulin concentration (C(INS max) ) was within 0.80-1.25]. VJ7 showed a faster absorption compared to LIS [time to C(INS max) 23 vs. 60 min; difference (CI) -30 (-35 to -23)] and faster onset of action [time to early half-maximal glucose infusion rate (GIR) 25 vs. 44 min; -18 (-26 to -10)], and a higher AUC of glucose infusion rate (AUC(GIR) ) in the first 60 min after injection [176 vs. 107 mg/kg; ratio 1.65 (1.27 to 2.14)], contributing to a slightly higher value for AUC(GIR 0-480) [1263 vs. 1095 mg/kg; 1.15 (1.06 to 1.26)]. Maximum GIR was similar between VJ7 and LIS [6.1 vs.6.6 mg/kg/min; ratio 0.93 (0.86 to 1.01)], whereas the duration of action (t(GIR50%-late) ) was longer with VJ7 [274 vs. 228 min; 50 (25 to 73)]. CONCLUSIONS: This formulation of VIAject is bioequivalent to the previously used formulation and has a faster absorption/onset of action than LIS.

Recovery from sevoflurane anesthesia: a comparison to isoflurane and propofol anesthesia.

BACKGROUND: Sevoflurane has a lower blood:gas partition coefficient than isoflurane, which may cause a more rapid recovery from anesthesia; it also might cause faster emergence times than for propofol-based anesthesia. We evaluated a database that included recovery endpoints from controlled, randomized, prospective studies sponsored by Abbott Laboratories that compared sevoflurane to isoflurane or propofol when extubation was planned immediately after completion of elective surgery in adult patients. METHODS: Sevoflurane was compared to isoflurane in eight studies (N=2,008) and to propofol in three studies (N=436). Analysis of variance was applied using least squares method mean values to calculate the pooled mean difference in recovery endpoints between primary anesthetics. The effects of patient age and case duration also were determined. RESULTS: Sevoflurane resulted in statistically significant shorter times to emergence (-3.3 min), response to command (-3.1 min), orientation (-4.0 min) and first analgesic (-8.9 min) but not time to eligibility for discharge (-1.7 min) compared to isoflurane (mean difference). Times to recovery endpoints increased with increasing case duration with isoflurane but not with sevoflurane (patients receiving isoflurane took 4-5 min more to emerge and respond to commands and 8.6 min more to achieve orientation during cases longer than 3 hr in duration than those receiving sevoflurane). Patients older than 65 yr had longer times to orientation, but within any age group, orientation was always faster after sevoflurane. There were no differences in recovery times between sevoflurane and propofol. CONCLUSIONS: Recovery from sevoflurane was 3-4 min faster than with isoflurane in all age groups, and the difference was magnified in longer-duration surgical cases (> 3 hr).

Effect of moderate or severe hepatic impairment on clarithromycin pharmacokinetics.

The pharmacokinetic and safety profiles of clarithromycin (C) and its 14-hydroxy-clarithromycin (HC) metabolite were determined after a multiple-dose oral clarithromycin regimen (250 mg twice daily for five doses) in six healthy subjects and seven patients with moderate or severe hepatic impairment (Pugh grades B and C). Plasma and urine C and HC concentrations were determined using high-performance liquid chromatography. Hepatic impairment resulted in increased harmonic mean C terminal disposition half-life and mean +/- SD C renal clearance (CLR) compared with normal volunteers (5.0 vs. 3.3 hr and 170 +/- 69 vs. 111 +/- 17 mL/min, respectively). Hepatic impairment also resulted in decreased metabolite peak plasma concentration and area under the plasma concentration-versus-time curve and decreased metabolite/parent concentration ratios compared with normal volunteers. These data suggest that 14-hydroxylation of C was reduced by moderate to severe hepatic impairment. No adverse events were noted in either study group and there were no study-related clinically significant changes in laboratory parameters. The decrease in C metabolic clearance appears to be partially offset by an increase in C CLR, resulting in comparable steady-state concentrations of parent drug. In those indications in which the metabolite may be a necessary element of the antimicrobial activity of C, it would seem prudent to be cautious in using C in patients with moderate to severe hepatic impairment due to reduced production of HC. Otherwise, no dosage adjustment for C appears necessary for subjects with moderate or severe hepatic impairment provided that renal function is not impaired.

Treatment of community-acquired pneumonia. A multicenter, double-blind, randomized study comparing clarithromycin with erythromycin. Canada-Sweden Clarithromycin-Pneumonia Study Group.

The efficacy and safety of orally administered clarithromycin and erythromycin in the treatment of community-acquired pneumonia were assessed in a multicenter, double-blind, randomized study. Two hundred sixty-eight patients were randomized to receive either clarithromycin, 250 mg twice a day, or erythromycin stearate, 500 mg 4 times a day, for 7 to 14 days. Efficacy was evaluable in 173 patients (92 for clarithromycin, 81 for erythromycin). No statistically significant difference in clinical success rate (cure or improvement) was observed between the two groups (clarithromycin, 97 percent; erythromycin, 96 percent). Both groups had identical radiologic response (97 percent with resolution or improvement). Similarly, no statistically significant difference in bacteriologic response toward the target pathogens was observed among evaluable patients (clarithromycin, 23/26; erythromycin, 17/17; p value = 0.287). Clinical response toward Mycoplasma and Chlamydia pneumonia was comparable between the two groups (clarithromycin, 15/16; erythromycin, 10/11). However, patients receiving erythromycin had a twofold higher incidence of adverse events, mostly related to the gastrointestinal system, and were five times more likely to withdraw from therapy because of drug-related adverse events. These results show that clarithromycin is as effective as erythromycin in the outpatient treatment of community-acquired pneumonia. Furthermore, the lower incidence of adverse events associated with clarithromycin indicates that it is more acceptable to patients and, therefore, can enhance compliance.

Erythromycin versus cefadroxil in the treatment of skin infections.

Erythromycin is often overlooked for the treatment of skin and skin structure infections. We evaluated the efficacy and safety of erythromycin particles in tablets and of cefadroxil in 164 patients with skin infections; both treatments were given as 500 mg twice daily. One hundred percent of erythromycin and 96% of cefadroxil patients were clinically cured or improved, and 98% of susceptible pathogens were eradicated in both groups. Only three erythromycin patients and one cefadroxil patient left the study early because of GI-related adverse events. Erythromycin, therefore, was as effective and safe as cefadroxil in the treatment of mild-to-moderate skin infections.