Comparison of intravenous/oral ciprofloxacin plus metronidazole versus piperacillin/tazobactam in the treatment of complicated intraabdominal infections.

OBJECTIVE: To compare the safety and efficacy of intravenous (IV) ciprofloxacin plus IV metronidazole (CIP+MET) with that of IV piperacillin/tazobactam (PIP/TAZO) in adults with complicated intraabdominal infections, and to compare the efficacy of sequential IV-to-oral CIP+MET therapy with that of the IV CIP-only regimen. SUMMARY BACKGROUND DATA: Treatment of intraabdominal infections remains a challenge, mainly because of their polymicrobial etiology and attendant death and complications. Antimicrobial regimens using sequential IV-to-oral therapy may reduce the length of hospital stay. METHODS: In this multicenter, randomized, double-blind trial involving 459 patients, clinically improved IV-treated patients were switched to oral therapy after 48 hours. Overall clinical response was the primary efficacy measurement. RESULTS: A total of 282 patients (151 CIP+MET, 131 PIP/TAZO) were valid for efficacy. Of these patients, 64% CIP+MET and 57% PIP/TAZO patients were considered candidates for oral therapy. Patients had a mean APACHE II score of 9.6. The most common diagnoses were appendicitis (33%), other intraabdominal infection (29%), and abscess (25%). Overall clinical resolution rates were statistically superior for CIP+MET (74%) compared with PIP/TAZO (63%). Corresponding rates in the subgroup suitable for oral therapy were 85% for CIP+MET and 70% for PIP/TAZO. Postsurgical wound infection rates were significantly lower in CIP+MET (11%) versus PIP/TAZO patients (19%). Mean length of stay was 14 days for CIP+MET and 17 days for PIP/TAZO patients. CONCLUSION: CIP+MET, initially administered IV and followed by CIP+MET oral therapy, was clinically more effective than IV PIP/TAZO for the treatment of patients with complicated intraabdominal infections.

Efficacy and Safety of Nifedipine Coat-Core versus Amlodipine in Patients With Mild to Moderate Essential Hypertension: Comparison of 24-Hour Mean Ambulatory Diastolic Blood Pressure.

BACKGROUND: Calcium channel blockers have been successfully used for the treatment of hypertension. In this study, the antihypertensive efficacy and safety of the dihydropyridine calcium channel blockers nifedipine coat-core 30 mg and amlodipine 5 mg were evaluated. METHODS: This multicenter, double-blind, prospective, randomized, parallel-arm study compared once daily administration of nifedipine coat-core 30 mg with once daily amlodipine 5 mg in subjects with mild-to-moderate essential hypertension. A 4-week placebo run-in period was followed by an 8-week active treatment period. Blood pressure reduction was measured by ambulatory blood pressure monitoring and casual office blood pressure measured by mercury sphygmomanometer. RESULTS: Nifedipine coat-core and amlodipine produced equivalent reductions in mean diastolic blood pressure, as determined by 24-hour ambulatory blood pressure monitoring. Mean reduction in diastolic blood pressure was 5.4 mmHg and 5.8 mmHg for nifedipine coat-core and amlodipine, respectively. Both drugs were well tolerated and neither treatment resulted in a significant change in heart rate. CONCLUSIONS: Nifedipine coat-core 30 mg once-daily is comparable to amlodipine 5 mg once-daily for blood pressure reduction.

Effect of a novel 5-lipoxygenase activating protein inhibitor, BAYx 1005, on asthma induced by cold dry air.

BACKGROUND: Leukotrienes have been implicated in the mediation of airway obstruction induced by hyperventilation of cold dry air in asthmatic subjects. The effect of a novel inhibitor of 5-lipoxygenase activating protein, BAYx 1005, on the bronchospastic response to cold dry air hyperventilation was investigated in asthmatic patients. METHODS: After a screening cold dry air hyperventilation challenge to document cold air responsiveness, 16 asthmatic subjects (baseline forced expiratory volume in one second (FEV1) > 60% of predicted) underwent cold air challenge three hours after receiving 750 mg of BAYx 1005 or placebo using a randomised, double blind, crossover design. Leukotriene synthesis inhibition was estimated by measuring the concentration of leukotriene B4 in whole blood stimulated with calcium ionophore A21387. RESULTS: Treatment with BAYx 1005 produced a 34% (95% CI 11 to 63) increase in the amount of cold air minute ventilation required for a 10% decrease in FEV1 (PD10VE) compared with placebo (mean (SE) 37.6 (1.12) 1/min compared with 28.0 (1.13) 1/min, p < 0.006). The PD20VE increased 19% (95% CI 8 to 31) after treatment with BAYx 1005 compared with placebo (57.3(1.10)1/min versus 48.1 (1.10) 1/min, p < 0.002). Treatment with BAYx 1005 produced a 15.4% decrease in ionophore-stimulated LTB4 production, while treatment with placebo produced a 7.1% increase in ex vivo LTB4 (p < 0.02). CONCLUSIONS: Treatment with BAYx 1005, a novel inhibitor of leukotriene synthesis, produced a significant blunting of cold dry air responsiveness consistent with the hypothesis that leukotrienes mediate part of the bronchoconstriction induced by hyperventilation of cold dry air.

The efficacy and safety of once-daily nifedipine administered without food: the coat-core formulation compared with the gastrointestinal therapeutic system formulation in patients with mild-to-moderate hypertension. Nifedipine Study Group.

A parallel-group, randomized, double-blind, forced-titration, multicenter study was done to compare the efficacy and safety of once-daily nifedipine coat-core (NIF CC) and once-daily nifedipine gastrointestinal therapeutic system (NIF GITS) dosed in the fasting state in patients with mild-to-moderate essential hypertension. Both formulations have been shown to effectively and safely lower blood pressure in placebo-controlled trials. After a 4-week placebo run-in period, 228 patients were randomized to 4 weeks of treatment with either NIF CC 30 mg daily or NIF GITS 30 mg daily. This period was followed by a forced-titration period to nifedipine 60 mg daily for an additional 4 weeks of double-blind therapy. After the 30-mg treatment period (the primary time point), there were no statistically significant differences between treatment groups in mean change from baseline in trough supine diastolic blood pressure, the primary efficacy variable (NIF CC patients, -7.0 mm Hg; NIF GITS patients, -8.4 mm Hg; P = 0.139). Also, because the upper bound of the treatment difference confidence interval was < 3.0 mm Hg, equivalence--as defined in the protocol--was established. After the 60-mg treatment period, the change from baseline in trough supine diastolic blood pressure was significantly greater for patients treated with NIF GITS than for patients treated with NIF CC (NIF GITS patients, -12.0 mm Hg; NIF CC patients, -8.4 mm Hg; P < 0.001). Because the upper bound of the confidence interval was > 3 mm Hg, equivalence cannot be claimed. No statistically significant differences were noted for the comparison of mean 24-hour ambulatory blood pressure monitoring changes. Both formulations were well tolerated.

Biosynthesis, maturation, and acid activation of the Semliki Forest virus fusion protein.

The Semliki Forest virus spike protein has a potent membrane fusion activity which is activated in vivo by the low pH of endocytic vacuoles. The spike protein is composed of two transmembrane subunits, E1 and E2, plus E3, a peripheral polypeptide. Acid-induced conformational changes in the E1 or E2 subunits were analyzed by using monoclonal antibodies specific for the acid-treated spike protein. E1 and E2 reacted with the antibodies after treatment of wild-type or mutant virus at the pH of fusion. The E1 conformational change resembled fusion in its requirement for both low pH and cholesterol. Pulse-chase analysis and intracellular pH treatment were then used to determine the ability of the newly synthesized spike to undergo acid-induced conformational changes. p62, the precursor to E2 and E3, was shown to undergo a pH-dependent conformational change similar to that of E2 and was sensitive to acid very soon after biosynthesis. In contrast, a posttranslational maturation event was required for the conversion of E1 to the pH-sensitive form. E1 maturation occurred fairly late in the exocytic pathway, after the virus spike had passed the medial Golgi but before incorporation of the spike into a new virus particle.

Mechanisms of enveloped virus entry into cells.

Enveloped animal viruses enter their host cells by a process of membrane fusion. This fusion can occur at the cell plasma membrane or within the endocytic vacuolar system, depending on the characteristics of the virus fusion protein. Examples of both pathways of viral entry are detailed in this review. Semliki Forest virus (SFV) is presented as a well-studied prototype of those viruses which use endocytic uptake in order to infect cells. Fusion of endocytosed SFV is specifically triggered by the acidic pH present within the endocytic pathway, which causes specific conformational changes in the SFV spike protein. While the overall features of endocytic uptake are similar for all viruses which use this pathway, the mechanism by which the viruses then cause fusion appears to differ significantly between them. The best understood fusion mechanism is that of influenza virus, for which sequences involved in pH-dependent fusion can be correlated with the crystallographic structure of the spike protein. In contrast to these pH-dependent virus systems, the entry of human immunodeficiency virus (HIV) into cells occurs by a pH-independent fusion mechanism probably involving fusion at the plasma membrane. The data to date on HIV fusion, endocytosis and entry are summarized as an example of this pathway.