Meta-analysis of individual patient data to assess the risk of hypoglycaemia in people with type 2 diabetes using NPH insulin or insulin glargine.

AIM: To estimate absolute and relative incidence rates of hypoglycaemia when using once-daily evening or morning regimens of insulin glargine (glargine) versus once-daily evening NPH insulin (NPH) using individual patient data (IPD). MATERIALS AND METHODS: Randomized controlled trials with accessible IPD and including white European people with type 2 diabetes (T2DM) using glargine or NPH once-daily (with oral glucose-lowering drugs) were identified. Two study pools were analysed: evening glargine versus evening NPH (pool 1); and morning glargine versus evening NPH (pool 2). The number-needed-to-treat to avoid hypoglycaemia was calculated for glargine versus NPH. RESULTS: In study pool 1 (n = 2711), the risk of nocturnal hypoglycaemia was approximately halved with glargine compared with NPH [odds ratios (OR): 0.44-0.52, p < 0.001-0.047]. This led to a significant reduction in anytime risk of symptomatic hypoglycaemia [plasma glucose (PG) <3.9 mmol/l, OR: 0.64, p = 0.018; PG <2.0 mmol/l, OR: 0.51, p < 0.001]. In study pool 2 (n = 470), although a strong numerical reduction in all types of nocturnal hypoglycaemia was observed (OR: 0.16-0.64), statistical significance was reached only for symptomatic hypoglycaemia with PG <3.9 mmol/l (p < 0.001). Eight (pool 1) or five (pool 2) people with T2DM needed to use glargine rather than NPH to avoid one person from experiencing a nocturnal symptomatic hypoglycaemic event within a median of about 25 weeks of starting insulin. CONCLUSIONS: This meta-analysis of open-label studies provides confidence that reductions of around 50% of risk for nocturnal hypoglycaemia can be achieved with using glargine instead of NPH.

Activity of different desoximetasone preparations compared to other topical corticosteroids in the vasoconstriction assay.

INTRODUCTION: We report on a double-blind, vehicle-controlled, single-center confirmatory study with random assignment. The purpose of the study was to investigate the topical bioavailability of different topical corticosteroid formulations in healthy human beings focussing on desoximetasone (DM). MATERIALS AND METHODS: Two DM 0.25% formulations [ointment (DM-o) and fatty ointment (DM-fo, water-free); class III corticosteroids], the corresponding active ingredient-free vehicles and three comparators of different strength [clobetasol propionate 0.05% (CP 0.05%), fatty ointment, class IV; hydrocortisone (HC) 1%, fatty ointment, class I, and betamethasone (BM) 0.05%, fatty ointment, class III] were tested using the vasoconstriction assay. The degree of vasoconstriction (blanching) in the treatment field was compared to the one found in untreated control fields using chromametric measurements and clinical assessment. RESULTS/CONCLUSION: DM-o 0.25%, DM-fo 0.25% and BM 0.05% showed similar vasoconstrictive potential, i.e., clear blanching. In fact, both DM preparations were proven to be noninferior to BM 0.05%, while CP 0.05% was found a little less active. HC 1.0% and the DM vehicles showed no clear-cut vasoconstrictive effect. No adverse events related to the study medications were observed. Good topical bioavailability of both DM formulations was detected by chromametric measurement and clinical assessment.

Prospective, randomized, multicentric, open, comparative study on the efficacy of a prophylactic single dose of 500 mg levofloxacin versus 1920 mg trimethoprim/sulfamethoxazole versus a control group in patients undergoing TUR of the prostate.

OBJECTIVES: Transurethral resection of the prostate (TUR-P) is one of the most frequent urological procedures. The efficacy of a prophylactic single dose of levofloxacin vs. trimethoprim/sulfamethoxazole (TMP/SMZ) vs. a control group, receiving no antibiotic prophylaxis, in patients undergoing TUR-P was investigated in a multicentre study. The aims were to assess the rate of bacteriuria (cfu> or =10(4)/ml) 5 to 7 days, and 3 to 5 weeks after TUR-P, as well as postoperative complications. METHODS: The study was prospective, randomized, multicentric, open and comparative. Patients without bacteriuria (cfu<10(4)/ml) scheduled for TUR-P and not having received antibiotics prior within four days were enclosed. Patients received an oral single dose prophylaxis with either 500 mg levofloxacin, or 320/1600 mg TMP/SMZ, or no prophylaxis according to a 2:2:1 randomization. Clinical examination of the patients and urine culture were performed prior to, 5 to 7 days and 3 to 5 weeks after TUR-P. RESULTS: 14 urological centres throughout Germany recruited 400 patients. 376 patients were evaluable until day 5 to 7, 339 until week 3 to 5. Overall bacteriuria rate at day 5 to 7 was 22% (levofloxacin 21%; TMP/SMZ 20%; control group 30%). Bacteriuria rate at week 3 to 5 was 28% (levofloxacin 26%; TMP/SMZ 26%; control group 36%). Complication rate at week 3 to 5 was 10% (levofloxacin 8%; TMP/SMZ 10%; control group 16%). The rates of postoperative bacteriuria ranged widely between centers (0%-75%). Statistically significant (p<0.05) risk factors for bacteriuria (range) were qualification of surgeon (19%-37%), presence of a suprapubic catheter (22%-34%), disconnection of the closed drainage system (25%-52%), operating time (12%-31%) and operative centre (0%-75%). Total antibiotic consumption (for prophylaxis and treatment) in the control group was higher and more expensive than in groups with antibiotic prophylaxis (6.9 vs. 5.0 doses/patient; 24.9 vs. 19.7 /patient) (p<0.0001). Postoperative complications in patients with bacteriuria (cfu> or =10(4)/ml) were more frequent than in non bacteriuric (cfu<10(4)/ml) patients (17% vs. 8%) (p<0.01). CONCLUSIONS: It is debatable whether postoperative bacteriuria is the key parameter to define efficacy of antimicrobial prophylaxis in patients undergoing TUR-P. The rate of bacteriuria, however, correlated well with the overall rate of postoperative complications. Therefore, it seems reasonable to lower the rate of bacteriuria by prophylaxis. Since patients without antibiotic prophylaxis received at the end even more antibiotic doses than patients with prophylaxis, the overall selection pressure by antibiotic usage can obviously not be lowered by resigning prophylaxis. Therefore we conclude that at least patients at risk should receive antibiotic prophylaxis prior to TUR-P.

Ciclopiroxolamine cream for treating seborrheic dermatitis: a double-blind parallel group comparison.

BACKGROUND: The aim of this study was to compare the efficacy and tolerability of topically applied ciclopiroxolamine cream with that of the corresponding vehicle in patients with seborrheic dermatitis of the face. PATIENTS AND METHODS: The study was conducted as a multicenter prospective, randomized, double-blind parallel group comparison at 14 centers in Australia and New Zealand. 189 patients with clinically diagnosed seborrheic dermatitis participated in the study. Each patient applied ciclopiroxolamine 1% cream or the corresponding vehicle twice daily as a thin film to the affected skin areas and to clinically unaffected skin areas surrounding the lesions for 29 days. RESULTS: The rate of treatment success was significantly higher with ciclopiroxolamine than with vehicle (73.9 vs 53.6%; p = 0.003). Treatment with ciclopiroxolamine reduced the sum score of the clinical signs of seborrheic dermatitis to a greater extent than the vehicle (p

Magnetic resonance imaging following fat obliteration of the frontal sinus.

The paper describes the evaluation of magnetic resonance imaging (MRI) following osteoplastic flap procedure with fat obliteration. MRI scans performed in patients after surgery between 1st January 1986 and 31st December 1997 were evaluated. Outcome parameters were time-dependent changes in the distribution of adipose or connective tissue, development of necroses or oil cysts, recurrences, inflammatory complications, or mucocoeles. Eighty-six postoperative MRI scans from 51 operations were evaluated. In 19 cases between two and five MRI scans were available. Time between surgery and the last MRI scan was 24.1 months on average. We found five mucocoeles. The amount of adipose tissue depictable on the last scan was less than 20% in the majority of cases (53%) and more than 60% in only 18% of cases. Statistical tests and modelling showed a significant decrease of adipose tissue with time, with a median half-life of 15.4 months in a subgroup with at least two MRIs. MRI is at times the most valuable diagnostic tool after frontal sinus obliteration using adipose tissue. The method has some limitations with regard to detection of small (recurrences of) mucocoeles and differentiation between vital adipose tissue and fat necroses in the form of oil cysts. In difficult cases long-term MRI follow-up is necessary for definitive evaluation.

The topology of lysine-containing amphipathic peptides in bilayers by circular dichroism, solid-state NMR, and molecular modeling.

In order to better understand the driving forces that determine the alignment of amphipathic helical polypeptides with respect to the surface of phospholipid bilayers, lysine-containing peptide sequences were designed, prepared by solid-phase chemical synthesis, and reconstituted into membranes. CD spectroscopy indicates that all peptides exhibit a high degree of helicity in the presence of SDS micelles or POPC small unilamellar vesicles. Proton-decoupled (31)P-NMR solid-state NMR spectroscopy demonstrates that in the presence of peptides liquid crystalline phosphatidylcholine membranes orient well along glass surfaces. The orientational distribution and dynamics of peptides labeled with (15)N at selected sites were investigated by proton-decoupled (15)N solid-state NMR spectroscopy. Polypeptides with a single lysine residue adopt a transmembrane orientation, thereby locating this polar amino acid within the core region of the bilayer. In contrast, peptides with > or = 3 lysines reside along the surface of the membrane. With 2 lysines in the center of an otherwise hydrophobic amino acid sequence the peptides assume a broad orientational distribution. The energy of lysine discharge, hydrophobic, polar, and all other interactions are estimated to quantitatively describe the polypeptide topologies observed. Furthermore, a molecular modeling algorithm based on the hydrophobicities of atoms in a continuous hydrophilic-hydrophobic-hydrophilic potential describes the experimentally observed peptide topologies well.

Osteoplastic frontal sinus surgery with fat obliteration: technique and long-term results using magnetic resonance imaging in 82 operations.

OBJECTIVE: To evaluate the intraoperative and late complications of osteoplastic sinus surgery with fat obliteration with long-term magnetic resonance imaging (MRI) follow-up. METHODS: The operative records of all patients who underwent osteoplastic frontal sinus surgery with fat obliteration between January 1, 1986 and December 31, 1997 were reviewed and the postoperative clinical course and magnetic resonance imaging (MRI) scans were analyzed if available. MRI analyses revealed that changes in the distribution of fatty and fibrous tissue, the development of necrosis or oil cysts, recurrences, inflammatory complications, and mucoceles were time-dependent occurrences. RESULTS: Eighty-two operative records were evaluated and 59 patients were followed 1 to 12 years after surgery. Eighty-six MRI scans in 51 patients were available for analysis. The most frequent intraoperative complications were exposure of orbital fat (19.5%), unintentional fracture of the anterior wall (19.5%), incorrect placement of the anterior wall (17%), and dural injury (9.8%). Persistent changes of the frontal contour (embossment, depression) occurred in 10.2% and the esthetic result was unfavorable in 5.1% of the cases. Mucoceles could be detected in 5 of 51 cases (9.8%). The amount of adipose tissue detectable in the last scan was less than 20% in the majority of cases (53%), and more than 60% in only 18% of the cases. The amount of adipose tissue decreased significantly with time (the median half-life was 15.4 mo). CONCLUSIONS: Osteoplastic frontal sinus surgery with fat obliteration is very useful and successful in patients in whom the frontal sinus is not accessible via an endonasal approach or the natural drainage cannot be reestablished. MRI is currently the most valuable diagnostic tool to evaluate the frontal sinus after obliteration with adipose tissue. The method has some limitations with regard to detection of small recurrent mucoceles and differentiating vital adipose tissue from fat necroses in the form of oil cysts. In these difficult cases, long-term MRI follow-up is necessary.

Peptide structural analysis by solid-state NMR spectroscopy.

Solid-state nmr spectroscopy provides a robust method for investigating polypeptides that have been prepared by chemical synthesis and that are immobilized by strong interactions with solid surfaces or large macroscopic complexes. Solid-state nmr spectroscopy has been widely used to investigate membrane polypeptides or peptide aggregates such as amyloid fibrils. Whereas magic angle spinning solid-state nmr spectroscopy allows one to measure distances and dihedral angles with high accuracy, static membrane samples that are aligned with respect to the magnetic field direction allow one to determine the secondary structure of bound polypeptides and their orientation with respect to the bilayer normal. Peptide dynamics and the effect of polypeptides on the macroscopic phase preference of phospholipid membranes have been investigated in nonoriented samples. Investigations of the structure and topology of membrane channels, peptide antibiotics, signal sequences as well as model systems that allow one to dissect the interaction contributions in phospholipid membranes will be presented in greater detail.

Effect of cimetidine on the pharmacokinetics of the metabolites of metamizol.

Metamizol (dipyrone) is hydrolyzed in the gastrointestinal tract to the pharmacologically active metabolite 4-methyl-amino-antipyrine (4-MAA), which is transformed by both, oxidation to 4-formyl-amino-antipyrine (4-FAA) and demethylation to 4-amino-antipyrine (4-AA). 4-AA is acetylated to 4-acetyl-amino-antipyrine (4-AcAA). The aim of the present study was to investigate whether cimetidine will alter the pharmacokinetics of the metabolites of metamizol due to cimetidine-induced inhibition of the metabolic transformation of 4-MAA. The study was carried out in 12 patients with duodenal ulcer treated with cimetidine 1,000 mg daily over 20 days. A single oral dose of metamizol 1,500 mg was administered 2 days prior to commencement of cimetidine therapy to all patients. Two further doses of 750 and 1,500 mg of metamizol were given in a randomized order on days 8 and 13 during cimetidine treatment. Blood samples for determination of metamizol metabolites were drown over 48 hours post dose. Drug assays for metamizol metabolites and cimetidine were performed using HPLC methods. The patients were phenotyped for CYP2D6 and acetylation polymorphism. The results revealed that cimetidine interacted with 4-MAA by increasing the systemic availability, prolonging the elimination half-life and decreasing the systemic clearance of 4-MAA, whereas the renal clearances of 4-MAA remained unchanged. Consistent with cimetidine-induced changes in the oxidation of 4-MAA to 4-FAA, as well as in the demethylation of 4-MAA to 4-AA, were the decreased rates of production and the lower maximum concentrations of 4-FAA and 4-AA when metamizol was administered during cimetidine treatment (p < 0.05). No correlation was found between the decrease in the production rates of 4-FAA induced by cimetidine and the hydroxylation abilities of the patients, this suggesting that CYP2D6 is not involved in the metabolism of 4-MAA to 4-FAA. The acetylation of 4-AA to 4-AcAA was not affected by cimetidine. Cimetidine produced an increase not proportional to the dose in the systemic availability only of 4-MAA, whereas the kinetics of the other metabolites changed proportionally to the increasing dose of metamizol.

[Endonasal frontal sinus surgery with permanent implantation of a place holder]. / Endonasale Stirnhöhlenchirurgie mit Langzeiteinlage eines Platzhalters.

BACKGROUND: Endonasal frontal sinus surgery is well established. It is not yet clear what degree of enlargement of the frontal sinus neoostium is required to achieve permanent drainage or whether stenting improves the results. PATIENTS AND METHODS: Prospective survey with two groups: Group 1. included 10 patients (15 operations) who underwent endonasal sinus surgery because of chronic polypoid sinusitis with stenting of the frontal sinus neoostium for 6 months. Group 2. included 11 patients (21 operations) without stenting. INTERVENTION: Endonasal frontal sinus surgery with extended drainage Draf Type II (NFA II according to May) with (group 1) and without (group 2) long-term stenting of the neoostium for 5 months using a silicone stent. MAIN OUTCOME MEASURE: 12-16 months postoperatively: flexible endoscopy of nose and frontal sinus; computed tomography; magnetic resonance tomography; Wilcoxon-Mann Withney-Test. RESULTS: With stenting: neoostium endoscopically patent in 80% (including 20% with edematous swelling only at the opening to the frontal sinus), occluded by scar tissue in 6.7%, occluded by polyps in 13.3%. Endoscopy and CT/MRT together: normal mucosa and aeration in 93.3%, complete opacification in 6.7%. Without stenting: neoostium endoscopically patent in 33%, occluded by scar tissue in 48%, occluded by polyps in 19%. Endoscopy and CT together: normal mucosa and aeration in 71.4%, aeration and mucosal swelling in 14.3%, complete opacification in 14.3%. With stenting of the frontal sinus neoostium for six months endoscopic evaluation of the frontal sinus was possible in a significantly higher proportion of cases (p = 0.0416). CONCLUSION: Long-term stenting of the frontal sinus significantly reduces the rate of recurrent stenosis of the frontal neoostium and is recommended in all cases where an extended frontal sinus drainage is necessary. The optimal design for such a stent has not yet been clearly defined.

Influence of spasmolytic analgesics on motility of sphincter of Oddi.

The effects on the sphincter of Oddi of intravenous administration of dipyrone, 2.5 g; tramadol, 50 mg; indomethacin, 75 mg; N-butylscopolamine, 20 mg; and nitroglycerin, 1 mg, in comparison to physiological saline were assessed in a single-blind study in 36 patients hospitalized with upper abdominal pain. Basal sphincter pressure and sphincter motility were measured for a 5-min period after treatment by endoscopic manometry. Nitroglycerin and dipyrone both caused a significant fall in basal sphincter pressure, while N-butylscopolamine and nitroglycerin produced a significant decrease in contraction frequency. Therefore, dipyrone, in contrast to tramadol and indomethacin, exhibits spasmolytic activity in addition to analgesia in biliary pain.

Parenteral dipyrone versus diclofenac and placebo in patients with acute lumbago or sciatic pain: randomized observer-blind multicenter study.

Two hundred and sixty patients with lumbago or sciatic pain participated in a multicenter observer-blind randomized trial to compare the efficacy and tolerability of dipyrone 2.5 g, diclofenac 75 mg, and placebo administered as an intramuscular injection once daily for the duration of one to two days. The effectiveness of the test treatments in relieving sciatic pain was measured by a visual analog scale (VAS) before and 30 minutes, 1, 2, 3, 6 and 24 hours after each injection. In addition, the patient's general well-being was measured on a 5-point rating scale on day 0, 1 and 2. At the end of the trial, the patients evaluated the overall efficacy of the study drugs on a 5-point rating scale. Minimal finger-toe distance was measured every day of the trial. Pain intensity on VAS (primary endpoint) showed a significantly greater reduction with dipyrone than with diclofenac or placebo between 1 and 6 hours after application (p < 0.01) and at the end of the trial (after 48 hours). Improvement in general well-being and minimal finger-toe distance was greatest in the dipyrone group. 59% of the patients with dipyrone assessed the overall efficacy as "excellent" or "very good", compared with 30% with diclofenac, and 18% with placebo. Adverse reactions were reported in only 7 patients (3%), 4 (5%) in the dipyrone, 1 (1%) in the diclofenac, and 2 (2%) in the placebo group.

Double-blind study with dipyrone versus tramadol and butylscopolamine in acute renal colic pain.

To investigate the combined analgesic and spasmolytic effect of dipyrone, 104 patients suffering from "severe" or "excruciating" colic pain due to a confirmed calculus in the upper urinary tract were randomized to receive i.v. either 2.5 g dipyrone (36 patients), 100 mg tramadol (35 patients), or 20 mg butylscopolamine (33 patients) in a multicentre, observer-blind, parallel-group study conducted in 8 German centres. The three treatment groups were homogeneous when analyzed by age, sex, height, and baseline pain intensity. Dipyrone was significantly more effective than tramadol in reducing pain for the primary endpoint, pain intensity differences (PID) at 20, 30, and 50 min after drug administration, and was significantly more effective than butylscopolamine at 30 and 50 min for the secondary efficacy endpoint, pain intensity differences on a categorical scale. Dipyrone had the highest SPID0-2 h of the three drugs (P < 0.05). Only 5 patients receiving dipyrone needed "rescue" medication as compared with 13 patients given tramadol and 11 patients receiving butylscopolamine. Adverse events were observed in 4 patients receiving butylscopolamine and in 1 patient each given dipyrone and tramadol. "Distinct" pain relief as assessed on a visual analogue scale (VAS) is a reliable method of determining the onset of analgesic action in the colic pain model.

Observer-blind study with metamizole versus tramadol and butylscopolamine in acute biliary colic pain.

To investigate the combined analgesic and spasmolytic effect of metamizole (dipyrone, Novalgin, CAS 68-89-3) this drug was compared with an opioid analgesic (tramadol) and a pure spasmolytic drug (butylscopolamine). In a multicentre, observer-blind, parallel-group study conducted in five German centres 74 patients suffering from "severe" or "excruciating" colic pain caused by a calculus in the bile duct were randomized to receive intravenously 2.5 g metamizole (25 patients), 100 mg tramadol (25 patients), or 20 mg butylscopolamine (24 patients). The three treatment groups were homogeneous for age, sex, height, weight and baseline pain intensity. Metamizole was significantly more effective in reducing pain than tramadol and butylscopolamine for the primary endpoint, pain intensity on a visual analogue scale (VAS) when evaluated as the area under the curve (AUC) from baseline to onset of analgesic action (p < 0.05) and the sum of pain intensity differences (SPID) for the observation period of 2 h (p < 0.005). The mean time until the onset of analgesic action occurred was shortest (p < 0.005) for metamizole (10.9 +/- 5.8 min) compared with tramadol (15.8 +/- 11.7 min) and butylscopolamine (25.6 +/- 24.3 min). Metamizole was also more effective for the secondary efficacy endpoint, pain intensity on a 5-point ordinal scale. In the patient's overall assessment of treatment efficacy at the end of the trial, metamizole was rated as the most effective drug (p < 0.005). Fewer patients in the metamizole (3) and the tramadol (1) groups than in the butylscopolamine group (8) needed a second injection of the "rescue" medication (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

A multi-centre comparative study between ramipril and enalapril in patients with mild to moderate essential hypertension.

A multi-centre, randomized, double-blind, parallel group study was undertaken in order to assess efficacy and tolerability of ramipril as compared to enalapril in mild to moderate hypertension. A 4-week placebo run-in period was followed by 4 weeks of treatment with active medication (5 mg ramipril or 10 mg enalapril in a single morning dose). In patients not responding to this dosage regimen at the end of a 4-week treatment period, the dose was doubled. After 8 weeks of active medication, 3 mg daily of the diuretic piretanide was added to the treatment of patients not responding to the doubled dose. A total of 202 patients was admitted in the placebo phase from which 174 patients who had evaluable data at the end of the study were included in the efficacy analysis. Based on the definition of a 'responder' as a patient who achieved a supine diastolic blood pressure of 90 mmHg or less, 40% of those on 5 mg ramipril achieved this level within 4 weeks; in the enalapril group, the corresponding figure was 36.6%. By the end of 12 weeks of active treatment, a total of 55% of the ramipril group had responded to a daily dose of 5 to 10 mg ramipril. An additional 18% responded when 3 mg piretanide was added to the regimen. In the enalapril group, 59% responded to 10 to 20 mg enalapril. A further 17% responded to addition of piretanide to 20 mg enalapril. A total of 19 patients developed 29 adverse drug events while receiving ramipril, alone and in combination with piretanide. In the enalapril group, 24 patients developed 36 adverse events during enalapril monotherapy and combination treatment. It is concluded that ramipril and enalapril in a ratio of 1:2 have comparable antihypertensive efficacy in mild to moderate hypertension but the number of adverse reactions was slightly higher with enalapril in this study.