Establishment of a Rapid Detection System for ISG20-Dependent SARS-CoV-2 Subreplicon RNA Degradation Induced by Interferon-α.

Inhaled nebulized interferon (IFN)-α and IFN-ß have been shown to be effective in the management of coronavirus disease 2019 (COVID-19). We aimed to construct a virus-free rapid detection system for high-throughput screening of IFN-like compounds that induce viral RNA degradation and suppress the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We prepared a SARS-CoV-2 subreplicon RNA expression vector which contained the SARS-CoV-2 5'-UTR, the partial sequence of ORF1a, luciferase, nucleocapsid, ORF10, and 3'-UTR under the control of the cytomegalovirus promoter. The expression vector was transfected into Calu-3 cells and treated with IFN-α and the IFNAR2 agonist CDM-3008 (RO8191) for 3 days. SARS-CoV-2 subreplicon RNA degradation was subsequently evaluated based on luciferase levels. IFN-α and CDM-3008 suppressed SARS-CoV-2 subreplicon RNA in a dose-dependent manner, with IC50 values of 193 IU/mL and 2.54 µM, respectively. HeLa cells stably expressing SARS-CoV-2 subreplicon RNA were prepared and treated with the IFN-α and pan-JAK inhibitor Pyridone 6 or siRNA-targeting ISG20. IFN-α activity was canceled with Pyridone 6. The knockdown of ISG20 partially canceled IFN-α activity. Collectively, we constructed a virus-free rapid detection system to measure SARS-CoV-2 RNA suppression. Our data suggest that the SARS-CoV-2 subreplicon RNA was degraded by IFN-α-induced ISG20 exonuclease activity.

A randomized controlled study of finerenone versus placebo in Japanese patients with type 2 diabetes mellitus and diabetic nephropathy.

AIMS: Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of finerenone (1.25-20mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker. METHODS: ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study. RESULTS: Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of finerenone. The UACR at day 90 relative to baseline for each finerenone treatment group was numerically reduced compared with placebo. No serious adverse events (AEs) or deaths were reported and no patients experienced treatment-emergent AEs resulting in discontinuation of study drug. Small mean increases in serum potassium level were observed in the finerenone treatment groups (0.025-0.167mmol/L) compared with the placebo group (-0.075mmol/L); no patients developed hyperkalemia. CONCLUSION: When given in addition to a RAS inhibitor, finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN.

Preclinical evaluation of AMG 925, a FLT3/CDK4 dual kinase inhibitor for treating acute myeloid leukemia.

Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard-of-care treatment, the disease eventually relapses in a major proportion of patients. Activating Fms-like tyrosine kinase 3 (FLT3) mutations are found in approximately 30% of patients with AML. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research. We report here the preclinical evaluation of AMG 925, a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and sorafenib). CDK4 is a cyclin D-dependent kinase that plays an essential central role in regulating cell proliferation in response to external growth signals. A critical role of the CDK4-RB pathway in cancer development has been well established. CDK4-specific inhibitors are being developed for treating RB-positive cancer. AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve and prolong clinical responses.

Efficacy of gemifloxacin for the treatment of experimental Staphylococcus aureus keratitis.

PURPOSE: The objective of the present study was to evaluate the effectiveness of topically applied gemifloxacin for the treatment of experimental Staphylococcus aureus keratitis in a rabbit model. METHODS: Rabbit corneas were intrastromally injected with ~100 colony-forming units (CFU) of S. aureus ATCC25923. Eight hours (early treatment) or 16 h (late treatment) after the injection, 1 topical drop of balanced salt solution (BSS), gemifloxacin ophthalmic solution (0.5%), levofloxacin ophthalmic solution (0.5%), or gatifloxacin eye gel (0.3%) was applied to each eye every 15 min for 5 doses and then, every 30 min for 14 doses. The eyes were examined both before and after treatment. The corneas were harvested from treated and untreated rabbits for the quantitation of bacteria and histological observation. RESULTS: In the early-treatment groups, all 3 fluoroquinolones significantly lowered the clinical severity of infection and the median erosion area of the cornea compared with the BSS control (P=0.000). In the late-treatment groups, gemifloxacin and levofloxacin did not cause a significant reduction in clinical scores compared with the BSS control (P=0.107 and 0.531, respectively), but the gatifloxacin caused a significant reduction in clinical scores compared with the BSS control (P=0.011). The median erosion area significantly decreased with treatment with gemifloxacin, gatifloxacin, and levofloxacin in both early- and late-treatment groups, when compared with the control group (P≤0.022). In the early-treatment groups, the gemifloxacin, gatifloxacin, and levofloxacin groups had significantly lower CFU recovered from the corneas compared with the control group (P<0.01), while in the late-treatment groups, levofloxacin failed to reduce the CFU recovered from the corneas compared with the control group (P=0.695). The minimal inhibitory concentrations for gemifloxacin, gatifloxacin, and levofloxacin against S. aureus ATCC25923 were 0.0625, 0.0625, and 0.125 mg/L, respectively. CONCLUSIONS: Gemifloxacin, similar to gatifloxacin and levofloxacin, can significantly lower the clinical severity and CFU per cornea observed in S. aureus keratitis when early treatment is implemented. Significantly, gemifloxacin showed a significant efficacy improvement in reducing the bacterial load recovered from the corneas in the late-treatment experiment.

Case studies addressing human pharmacokinetic uncertainty using a combination of pharmacokinetic simulation and alternative first in human paradigms.

PF-184298 ((S)-2,3-dichloro-N-isobutyl-N-pyrrolidin-3-ylbenzamide) and PF-4776548 ((3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo[2,3-c][1,7]naphthyridin-6-one)) are novel compounds which were selected to progress to human studies. Discordant human pharmacokinetic predictions arose from pre-clinical in vivo studies in rat and dog, and from human in vitro studies, resulting in a clearance prediction range of 3 to >20 mL min⁻¹ kg⁻¹ for PF-184298, and 5 to >20 mL min⁻¹ kg⁻¹ for PF-4776548. A package of work to investigate the discordance for PF-184298 is described. Although ultimately complementary to the human pharmacokinetic data in characterising the disposition of PF-184298 in humans, these data did not provide any further confidence in pharmacokinetic prediction. A fit for purpose human pharmacokinetic study was conducted for each compound, with an oral pharmacologically active dose for PF-184298, and an intravenous and oral microdose for PF-4776548. This provided a relatively low cost, clear decision making approach, resulting in the termination of PF-4776548 and further progression of PF-184298. A retrospective analysis of the data showed that, if the tools had been available at the time, the pharmacokinetics of PF-184298 in human could have been predicted from a population based simulation tool in combination with physicochemical properties and in vitro human intrinsic clearance.

Phosphodiesterase inhibitors block the acceleration of skin permeability barrier repair by red light.

We previously demonstrated that exposure to red light (550-670 nm) accelerates epidermal permeability barrier recovery after barrier disruption. Furthermore, we showed that photosensitive proteins, originally found in retina, are also expressed in epidermis. In retina, transducin and phosphodiesterase 6 play key roles in signal transmission. In this study, we evaluate the role of phosphodiesterese 6 in the acceleration by red light of epidermal permeability barrier recovery. Immunohistochemical study and reverse transcription-PCR assays confirmed the expression of both transducin and phosphodiesterase 6 in epidermal keratinocytes. Topical application of 3-isobutyl-1-methylxanthine, a non-specific phosphodiesterase inhibitor, blocked the acceleration of the barrier recovery by red light. Topical application of zaprinast, a specific inhibitor of phosphodiesterases 5 and 6, also blocked the acceleration, whereas T0156, a specific inhibitor of phosphodiesterase 5, had no effect. Red light exposure reduced the epidermal hyperplasia induced by barrier disruption under low humidity, and the effect was blocked by pretreatment with zaprinast. Our results indicate phosphodiesterase 6 is involved in the recovery-accelerating effect of red light on the disrupted epidermal permeability barrier.

[Effectiveness of switch therapy for peritonitis].

The usefulness of switch therapy, from injection to oral medicine, for the treatment of peritonitis was evaluated. Thirty-five patients, who agreed to enroll the study, were randomly assigned to four treatment groups; one group treated with carbapenem antibacterial agent alone and three groups treated with switch therapy, in which injectable quinolone was switched to oral quinolone. For the intravenous administration group, if the patient showed the tendency of improvement by the third day, the intravenous injection was continued. However, if the patient did not show any improvement, the medication was changed to other medicine. For the switch therapy group, if the body temperature dropped to 37.5 degrees C or lower for at least 8 hours and if blood findings and clinical findings showed the tendency of improvement by the fourth day, the medication was switched to oral medicine. There was no difference in therapeutic effects among treatment groups. However, both duration of hospitalization and total medical costs were significantly reduced in the switch therapy groups comparing to those in the intravenous administration group. The results of this study showed that the switch therapy, from injection to oral medicine, was one of useful treatments in treating peritonitis.

The alkaloid 4-methylaaptamine isolated from the sponge Aaptos aaptos impairs Herpes simplex virus type 1 penetration and immediate-early protein synthesis.

We describe in this paper that the alkaloid 4-methylaaptamine, isolated from the marine sponge Aaptos aaptos, inhibited HSV-1 infection. We initially observed that 4-methylaaptamine inhibited HSV-1 replication in Vero cells in a dose-dependent manner with an EC50 value of 2.4 microM. Moreover, the concentration required to inhibit HSV-1 replication was not cytotoxic, since the CC50 value of 4-methylaaptamine was equal to 72 microM. Next, we found that 4-methylaaptamine sustained antiherpetic activity even when added to HSV-1-infected Vero cells at 4 h after infection, suggesting that this compound inhibits initial events during HSV-1 replication. We observed that 4-methylaaptamine impaired HSV-1 penetration without affecting viral adsorption. In addition, the tested compound could inhibit, in an MOI-dependent manner, the expression of an HSV-1 immediate-early protein, ICP27, thus preventing the inhibition of macromolecular synthesis induced by this virus. Our results warrant further investigation on the pharmacokinetics of 4-methylaaptamine and propose that this alkaloid could be considered as a potential compound for HSV-1 therapy.

p38 MAP kinase inhibitors. Part 5: discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold.

A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 16 reduced inflammation in animal disease models at EC(50) doses as low as 0.2mpk.

Gemifloxacin once daily for 7 days compared to amoxicillin/clavulanic acid thrice daily for 10 days for the treatment of community-acquired pneumonia of suspected pneumococcal origin.

CONTEXT: Community-acquired pneumonia (CAP) is common among adults and contributes considerably to morbidity and mortality. OBJECTIVE: To compare the safety and efficacy of gemifloxacin to high-dose amoxicillin/clavulanate for the treatment of CAP of suspected pneumococcal origin. DESIGN: Randomized, multicentre, double-blind, double-dummy, parallel group Phase III study. SETTING AND PARTICIPANTS: From September 1998 to July 1999, 324 patients with CAP were randomized at 102 centers in France, Poland and the Republic of South Africa. INTERVENTION: Patients were double-blind randomized to receive either oral gemifloxacin 320 mg once daily for 7 days or oral amoxicillin/clavulanate 1 g/125 mg three times daily for 10 days. MAIN OUTCOME MEASURES: The main outcome measures were clinical, bacteriological, and radiological responses at the end of therapy (day 12-14) and follow-up (day 24-30) visits. RESULTS: In 228 PP patients, clinical resolution at follow-up was 88.7% for 7-day gemifloxacin and 87.6% for 10-day amoxicillin/clavulanate [95% CI, -7.3, 9.5]. In 249 PP patients, clinical resolution at end of therapy was 95.3% for 7-day gemifloxacin vs. 90.1% for 10-day amoxicillin/clavulanate [95% CI, -1.2, 11.7]. Bacteriologic response rates for the PP patients at end of therapy were 96.3% for 7-day gemifloxacin and 91.8% for the amoxicillin/clavulanate group [95% CI, -4.7, 13.6]. Bacteriologic response rates at follow-up were 87.2% for 7-day gemifloxacin and 89.1% for the amoxicillin/clavulanate group [95% CI, -15.0, 11.2]. Specifically gemifloxacin eradicated 95.7% of Streptococcus pneumoniae including penicillin and macrolide resistant strains. Radiological response rates for the PP patients at end of therapy were 89.1% for 7-day gemifloxacin and 87.6% for the amoxicillin/clavulanate group. The most frequently reported drug-related events were in the gemifloxacin group, diarrhea (6.0%) and rash (3.0%) and in the amoxicillin/clavulanate group, diarrhea (11.1%) and fungal infection, vaginitis and vomiting (each 2.0%). Overall there were statistically fewer withdrawals due to lack of therapeutic effect in the gemifloxacin group compared with the amoxicillin/clavulanate cohort, (95% CI, -8.8;0.6; P = 0.03). CONCLUSION: Gemifloxacin 320 mg once daily for 7 days was found to be clinically, bacteriologically, and radiologically as effective as 10 days of amoxicillin/clavulanate 1 g/125 mg three times daily for the treatment of suspected pneumococcal CAP.

Antiremodeling effects of iloprost and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in chronic experimental pulmonary hypertension.

Severe pulmonary hypertension is a disabling disease with high mortality. We investigated acute and chronic effects of iloprost, a long-acting prostacyclin analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days after administration of the alkaloid, right ventricular systolic pressure increased from 25.8+/-2.0 to 62.9+/-3.4 and 70.5+/-7.4 mm Hg, with concomitant decline in cardiac index, central venous oxygen saturation, and arterial oxygenation. Marked right heart hypertrophy was demonstrated by the strongly elevated ratio of right ventricle/left ventricle plus septum weight, and massive thickening of the precapillary artery smooth muscle layer was shown histologically. Western blot analysis demonstrated increased levels of matrix metalloproteinases (MMPs) -2 and -9 and increased gelatinolytic activities in isolated pulmonary arteries. In these animals, both intravenous iloprost and tolafentrine displayed characteristic features of pulmonary vasodilators. When chronically infused from days 14 to 28, both agents significantly attenuated all monocrotaline-induced hemodynamic and gas exchange abnormalities as well as right heart hypertrophy. Full normalization of all variables including right ventricle size was achieved on combined administration of both agents during this period. This was also true for MMP-2 and MMP-9 expression and activity. Moreover, when iloprost plus tolafentrine was used for late therapeutic intervention, with infusion from days 28 to 42 after full establishment of severe pulmonary hypertension and cor pulmonale, hemodynamic, gas exchange, and cardiac and pulmonary vascular remodeling changes were significantly reversed. We conclude that the combined administration of iloprost and a dual-selective phosphodiesterase 3/4 inhibitor prevents and reverses the development of pulmonary hypertension and cor pulmonale in response to monocrotaline in rats. This regimen may therefore offer a possible antiremodeling therapy in severe pulmonary hypertension.

Treatment of experimental bacterial keratitis with topical trovafloxacin.

OBJECTIVE: To investigate the therapeutic role of trovafloxacin mesylate, a newer-generation fluoroquinolone with an expanded spectrum of activity, in the treatment of experimental bacterial keratitis. METHODS: Susceptibility studies were performed on various strains of ocular isolates to determine the minimum inhibitory concentration (MIC) of trovafloxacin compared with ciprofloxacin and ofloxacin, using the E-test method. Pharmacokinetic studies were performed by a single topical administration of trovafloxacin to rabbit eyes with either an intact or denuded corneal epithelium. Aqueous humor, vitreous, and corneal concentrations of trovafloxacin were determined at different time points. Experimental bacterial keratitis studies were performed in rabbit eyes. Three identical studies were conducted using Staphylococcus aureus, Streptococcus pneumoniae, or Pseudomonas aeruginosa. Therapy groups included 0.5% trovafloxacin, 0.3% ciprofloxacin, 0.3% ofloxacin, and isotonic sodium chloride solution. After 12 hours of drops administration, corneas were excised, homogenized, and serially plated. The main outcome measure was quantitative bacteriologic analysis for residual colony-forming units. RESULTS: In vitro susceptibility study findings indicated that the MIC of trovafloxacin was significantly lower than the MIC of ciprofloxacin and ofloxacin for S. aureus, S. pneumoniae, and Haemophilus influenzae, lower than the MIC of ciprofloxacin and ofloxacin for Staphylococcus epidermidis, and intermediate between ciprofloxacin and ofloxacin for P. aeruginosa. Pharmacokinetic studies showed a significant concentration of trovafloxacin in the treated corneas, especially in eyes with a denuded epithelium. All serum samples had undetectable trovafloxacin concentrations. Experimental keratitis studies showed a statistically significant decrease of colony-forming units in trovafloxacin-treated eyes in the S. aureus model and a similar decrease in the S pneumoniae and P aeruginosa models. CONCLUSIONS: Topical 0.5% trovafloxacin proved to be an effective ocular medication for the therapy of gram-positive and gram-negative keratitis. Clinical Relevance Trovafloxacin may provide an excellent therapeutic alternative in bacterial keratitis.

Sequential IV/PO moxifloxacin treatment of patients with severe community-acquired pneumonia.

BACKGROUND: IV/PO moxifloxacin was evaluated in the treatment of hospitalized patients with severe community-acquired pneumonia (CAP). METHODS: Data were pooled from two prospective, randomized studies. In the multinational study, patients received 7-14 days IV/PO moxifloxacin 400 mg QD or IV/ PO amoxicillin clavulanate 1200/625 mg TID +/- IV/PO clarithromycin 500 mg BID. In the North American study, patients received 7-14 days IV/PO moxifloxacin 400 mg QD, IV/ PO alatrofloxacin/trovafloxacin 200 mg QD, or IV/PO levofloxacin 500 mg QD. The primary endpoint was clinical success at the test-to-cure visit. Severe CAP was defined according to the 1993 ATS criteria. RESULTS: In the clinically valid population, clinical success rates were 88% (167/190) for moxifloxacin- and 83% (155/186) for comparator-treated patients (95% CI = -1.9%, 12.2%). Corresponding clinical success rates for the microbiologically valid population were 87% (59/68) and 84% (54/64), respectively (95% CI = 8.6%, 15.0%). A switch from IV to PO therapy was made by day 5 of therapy for 73% of moxifloxacin- vs. 60% of comparator-treated patients (P < 0.01). Clinical success rates were similar in a retrospective analysis using the revised 2001 ATS definition of severe CAP. Mortality rates were 6% (15/241) and 10% (24/238) in the moxifloxacin and comparator treatment groups, respectively. The incidence of drug-related adverse events was similar in both treatment groups. CONCLUSION: Sequential IV/PO moxifloxacin 400 mg QD is as safe and effective as other fluoroquinolones and a beta-lactam/macrolide combination for treating hospitalized patients with severe CAP.

The efficacy of trovafloxacin versus ceftriaxone in the treatment of experimental brain abscess/cerebritis in the rat.

Current estimates of the mortality associated with brain abscesses range from 0-24%, with neurological sequellae in 30-55% of survivors. Although the incidence of brain abscess appears to be increasing, likely due to an increase in the population of immunosuppressed patients, the condition is still sufficiently uncommon to make human clinical trials of therapy problematic. An animal model to study the efficacy of new treatment regimens, specifically, new antimicrobial agents is therefore necessary. This study uses a well-defined experimental paradigm as an inexpensive method of inducing and studying the efficacy of antibiotics in brain abscess. The rat model of brain abscess/cerebritis developed at this institution was used to determine the relative efficacy of trovafloxacin as compared to ceftriaxone in animals infected with Staphylococcus aureus. S. aureus ( approximately 10(5) CFU in 1 microliter) was injected with a Hamilton syringe, very slowly, over the course of 70 minutes after a two mm burr hole was created with a spherical carbide drill just posterior to the coronal suture and four mm lateral to the midline. Eighteen hours later treatment was begun; every 8 hours the rats were dosed with subcutaneous ceftriaxone (n = 10), trovafloxacin (n = 11) or 0.9% sterile pyogen-free saline (n = 10). After four days of treatment the brains were removed and sectioned with a scalpel. The entire injected hemisphere was homogenized and quantitative cultures performed. The mean +/- SEM log(10) colony forming units/ml S. aureus recovered from homogenized brain were as follows: controls 6.10 +/- 0.28; ceftriaxone 3.43 +/- 0.33; trovafloxacin 3.65 +/- 0.3. There was no significant difference in bacterial clearance between ceftriaxone versus trovafloxacin (p = 0.39). Trovafloxacin or other quinolones may provide a viable alternative to intravenous antibiotics in patients with brain abscess/cerebritis.

Antifungal compounds from Zanthoxylum chiloperone var. angustifolium.

An alkaloidal extract of the stem barks of Zanthoxylum chiloperone var. angustifolium exhibited antifungal activity against Candida albicans, Aspergillus fumigatus and Trichophyton mentagrophytes var. interdigitale using a TLC bioautographic method. Bioassay-guided fractionation of this extract resulted in the isolation of two active compounds identi fi ed as canthin-6-one and 5-methoxycanthin-6-one. Canthin-6-one exhibited a broad spectrum of activities against Aspergillus fumigatus, A. niger, A. terreus, Candida albicans, C. tropicalis, C. glabrata, Cryptococcus neoformans, Geotrichum candidum, Saccharomyces cerevisiae, Trichosporon beigelii, Trichosporon cutaneum and Trichophyton mentagrophytes var. interdigitale with MICs values between 5.3 and 46 micro mol/L. 5-methoxy-canthin-6-one was active against only Trichophyton mentagrophytes var. interdigitale with a MIC value of 12.3 micro mol/L.

[Study on treatment of multi-drug resistant falciparum malaria by using a combination of dihydroartemisinin and pyronaridine].

OBJECTIVE: To provide a combined medication scheme for the treatment of multi-drug resistant falciparum malaria. METHODS: Combined administration of dihydroartemisinin and pyronaridine was given to the 32 cases of falciparum malaria cases with multi-drug resistance. The indices for evaluation on day 14, 21, and 28 after treatment included the mean fever subsidence time, mean asexual form clearance time, mean recrudescence time of asexual form and recrudescence rate, proportion of gametocyte carriers, mean density of gametocytes and its mean clearance time, cure rate and rate of side-effects. A double blind clinical test was performed with standard schemes of dihydroartemisinin (20 cases) and pyronaridine (25 cases) as control. RESULTS: The mean fever subsidence time of treated patients by dihydroartemisinin/pyronaridine combination, dihydroartemisinin and pyronaridine was 35.7 +/- 24.7 h, 52.6 +/- 38.9 h and 35.8 +/- 16.5 h respectively, showing a significant difference between the combination group and dihydroartemisinin groups (P < 0.01). The mean asexual form clearance time was 23.8 +/- 10.1 h, 22.9 +/- 6.5 h and 49.4 +/- 20.3 h respectively, showing significantly faster in the combination group than the pyronaridine group (P < 0.01). The recrudescence rate was 0, 4.2% and 0 respectively. The proportion of gametocyte carriers was 20.0%, 16.7% and 60.9% respectively, with a significantly higher rate in the group of pyronaridine than the group of combination (P < 0.01). CONCLUSION: The combination of dihydroartemsinin and pyronaridine is an ideal medication scheme for the treatment of falciparum malaria cases with multi-drug resistance.

Lower lipoteichoic and teichoic acid CSF concentrations during treatment of pneumococcal meningitis with non-bacteriolytic antibiotics than with ceftriaxone.

In the rabbit model of Streptococcus pneumoniae meningitis, treatment with rifabutin, quinupristin-dalfopristin, moxifloxacin and trovafloxacin led to smaller increases of the CSF concentrations of the pro-inflammatory cell wall components lipoteichoic and teichoic acids (LTA and TA) than did treatment with ceftriaxone. Low doses of moxifloxacin were associated with higher LTA and TA concentrations in CSF than were high doses.

Activity of quinolones against viridans group streptococci isolated from blood cultures of patients with haematological malignancy.

Use of fluoroquinolones for antimicrobial prophylaxis during neutropenia is often cited as a significant predisposing factor for viridans group streptococcus (VGS) bacteraemia. Newer compounds in this class are reputed to have enhanced activity against Gram-positive bacteria, and we determined the minimal inhibitory concentrations (MICs) for ciprofloxacin and three of the newer compounds: trovafloxacin, fleroxacin and clinafloxacin, against 44 isolates of VGS. On a gravimetric basis, clinafloxacin was most active (MIC90 0.19 mg/l), whereas ciprofloxacin and fleroxacin were the least active (both MIC90 16 mg/l). Clinafloxacin warrants further study as an agent of prophylaxis against bacterial infection in neutropenic patients.

Trovafloxacin versus high-dose amoxicillin (1 g three times daily) in the treatment of community-acquired bacterial pneumonia.

Once-daily trovafloxacin 200 mg was compared with high-dose amoxicillin, 1 g three times daily, given for 7 to 10 days. At end of treatment (day 10), the response was clinically successful (cure + improvement) in 93% of 152 clinically evaluable trovafloxacin patients and in 89% of 160 amoxicillin patients. At study end (day 35), respective rates were 91% and 81% (95% confidence interval: 1.6, 17.6; P=0.01). In evaluable patients with positive baseline radiographs, 93% of trovafloxacin and 88% of amoxicillin patients demonstrated radiological resolution at end of treatment. Streptococcus pneumoniae and Haemophilus influenzae eradication rates were comparable at end of treatment in both treatment groups, but at study end Streptococcus pneumoniae eradication rates were higher in trovafloxacin patients (100% vs 81%). At study end, all four trovafloxacin patients with baseline penicillin-resistant Streptococcus pneumoniae were clinically cured with pathogen eradication, whereas two of five amoxicillin patients with baseline penicillin-resistant Streptococcus pneumoniae were clinical failures with pathogen persistence. For patients in whom no pathogen was identified, trovafloxacin was significantly more effective at end of treatment (P=0.096) and study end (P=0.013). Treatment-related adverse events were comparable; the most common were headache, vomiting and dizziness in trovafloxacin patients, and diarrhoea. headache and abdominal pain in amoxicillin patients.