The Ralstonia pseudosolanacearum effector RipE1 is recognized at the plasma membrane by NbPtr1, the Nicotiana benthamiana homologue of Pseudomonas tomato race 1.

The bacterial wilt disease caused by soilborne bacteria of the Ralstonia solanacearum species complex (RSSC) threatens important crops worldwide. Only a few immune receptors conferring resistance to this devastating disease are known so far. Individual RSSC strains deliver around 70 different type III secretion system effectors into host cells to manipulate the plant physiology. RipE1 is an effector conserved across the RSSC and triggers immune responses in the model solanaceous plant Nicotiana benthamiana. Here, we used multiplexed virus-induced gene silencing of the nucleotide-binding and leucine-rich repeat receptor family to identify the genetic basis of RipE1 recognition. Specific silencing of the N. benthamiana homologue of Solanum lycopersicoides Ptr1 (confers resistance to Pseudomonas syringae pv. tomato race 1) gene (NbPtr1) completely abolished RipE1-induced hypersensitive response and immunity to Ralstonia pseudosolanacearum. The expression of the native NbPtr1 coding sequence was sufficient to restore RipE1 recognition in Nb-ptr1 knockout plants. Interestingly, RipE1 association with the host cell plasma membrane was necessary for NbPtr1-dependent recognition. Furthermore, NbPtr1-dependent recognition of RipE1 natural variants is polymorphic, providing additional evidence for the indirect mode of activation of NbPtr1. Altogether, this work supports NbPtr1 relevance for resistance to bacterial wilt disease in Solanaceae.

Population pharmacokinetics of palonosetron and model-based assessment of dosing strategies.

PURPOSE: Palonosetron is the most recent 5-hydroxytryptamine-3 receptor antagonist, and its fixed dose of 0.075 mg is indicated for the prevention of postoperative nausea and vomiting. This study aimed to examine whether fixed dosing is more appropriate than body size-based dosing through the development of a population pharmacokinetic model and model-based simulations. METHODS: Fifty-one adult patients undergoing general anesthesia received single intravenous palonosetron administrations 30 min before the end of surgery. Palonosetron concentrations were measured in blood samples collected at various timepoints within 48 h. A population pharmacokinetic analysis was performed by non-linear mixed-effects modeling, and the area under the curves (AUCs) for fixed dosing and body size-based dosing were simulated. RESULTS: The pharmacokinetics of palonosetron were best described by the three-compartment model, and lean body weight (LBW) was the most significant covariate for all pharmacokinetic parameters. In a patient with LBW of 40 kg, typical clearance and central volume of distribution were 0.102 L/min and 6.98 L, respectively. In simulations, the overall interindividual variability in AUC (0, 48 h) of fixed dosing was not much higher than that of body size-based dosing. In subgroup analysis, the AUCs (0, 48 h) of fixed dosing were considerably lower in the high-weight subgroup and higher in the low-weight subgroup than the median-weight subgroup. In contrast, LBW-based dosing showed similar AUC distributions among the three subgroups. CONCLUSION: LBW-based dosing might be suitable for high-weight patients to avoid possible underdosing. Nevertheless, the current fixed dosing of palonosetron is acceptable for adult patients with normal weight.

The effect of triazolam premedication on anxiety, sedation, and amnesia in general anesthesia.

BACKGROUND: Benzodiazepines have been used preoperatively as part of an anesthesia regimen to attenuate the anxiety of patients. In this study, we aimed to examine the effect of oral triazolam, a short-acting benzodiazepine, on anxiety, sedation, and amnesia. METHODS: Ninety patients, aged 20-55 years, were randomly assigned to receive no premedication, or to receive triazolam 0.25 mg or 0.375 mg 1 h before anesthesia. Anxiety score, sedation score, blood pressure, heart rate and psychomotor performance were measured on the evening before surgery and on the day of surgery. Additional tests of psychomotor performance were performed in the postanesthesia care unit and on the next day of surgery. The occurrence of amnesia, bispectral index (BIS), recovery profiles and patient satisfaction with overall anesthesia care were also evaluated. RESULTS: Changes in the anxiety and sedation scores on the day of surgery were not significantly different among groups, whereas the increases in systolic blood pressure and heart rate were significantly less in both triazolam groups. The triazolam groups both showed a higher incidence of high satisfaction scores (≥ 2). The two triazolam groups also showed similar outcomes, except for a dose-dependent increase in the number of patients with amnesia and BIS values < 90. Delayed recovery from general anesthesia and psychomotor impairment were not observed in the triazolam groups. CONCLUSIONS: Triazolam 0.25 mg or 0.375 mg reduced the hemodynamic changes associated with anxiety, produced potent amnesia, and improved patient satisfaction. We suggest that triazolam can be used effectively as anesthetic premedication in adults.

Results of a phase III, 8-week, multicenter, prospective, randomized, double-blind, parallel-group clinical trial to assess the effects of amlodipine camsylate versus amlodipine besylate in Korean adults with mild to moderate hypertension.

BACKGROUND: Amlodipine besylate has been used in Korea for the treatment of hypertension for >17 years, with well-established efficacy and tolerability. Amlodipine camsylate is a newer formulation developed for generic use. It has been assessed in terms of physical stability and pharmacokinetic and pharmacodynamic properties and been found to be effective in lowering blood pressure in preclinical and Phase I and II trials. However, to date, no studies have compared the clinical effectiveness of amlodipine camsylate and amlodipine besylate in treating hypertension. OBJECTIVE: This study was designed to determine the effectiveness and tolerability of amlodipine camsylate compared with amlodipine besylate in Korean patients with mild to moderate hypertension. METHODS: This Phase III, 8-week, prospective, randomized, double-blind, parallel-group study was conducted in 13 cardiology centers across the Republic of Korea. Male and female Korean patients aged 18 to 75 years having uncomplicated, mild to moderate, essential hypertension (sitting diastolic blood pressure [SiDBP] 90-<110 mm Hg) and receiving no antihypertensives in the 2 weeks before randomization were eligible. Patients were randomly assigned to receive oral treatment with amlodipine camsylate or amlodipine besylate. For the first 4 weeks, patients received amlodipine 5 mg QD (morning). After 4 weeks, if either blood pressure was > or =140/ > or =90 mm Hg or SiDBP had not decreased by > or =10 mm Hg from baseline, the dose of amlodipine was increased to 10 mg QD for 4 weeks. Trough blood pressure and heart rate were measured in duplicate with the patient in the sitting position at each clinic visit (baseline [week 0] and weeks 4 and 8 of treatment); mean values were calculated and recorded. At weeks 4 and 8, tolerability was assessed using history taking and laboratory analysis, and compliance was assessed using pill counts. The primary end point was change from baseline in SiDBP at week 8. Secondary end points were change from baseline in sitting systolic blood pressure (SiSBP) at week 8 in the total population and in the subgroup of patients who had previously received antihypertensive treatment versus those who had not. RESULTS: A total of 189 patients were enrolled (mean age, 53 years; 105 women, 84 men; mean body weight, 65.8 kg). One patient in the amlodipine camsylate group dropped out of the study at week 0 of treatment (this patient did not use any study medication) and was excluded from the modified intent-to-treat (ITT) analysis. Thus, 188 patients were treated and included in the ITT analysis (94 patients per treatment group; ITT analysis); 161 patients were included in the perprotocol (PP) analysis (n = 80 for amlodipine camsylate, n = 81 for amlodipine besylate) (14 patients in the amlodipine camsylate group and 13 patients in the amlodipine besylate group were excluded from the PP analysis due to consistent withdrawal or protocol violation). Mean (SD) SiSBP and SiDBP were significantly decreased from baseline in both groups (amlodipine camsylate, from 146.7 [12.3]/96.6 [5.4] to 127.9 [14.8]/83.4 [7.7] mm Hg [both, P < 0.001]; amlodipine besylate, from 146.8 [12.8]/96.7 [5.1] to 128.0 [10.1]/83.8 [7.5] mm Hg [both, P < 0.001]). The differences in SiSBP/SiDBP between the 2 groups at week 8 were not significant. The SiDBP response rates in the subgroups that had and had not been previously treated with antihypertensives were statistically similar (56/69 [81.2%] and 83/92 [90.2%], respectively). The prevalences of clinical adverse events (AEs) were not significantly different between the 2 treatment groups (amlodipine camsylate, 27.3 %; amlodipine besylate, 28.7%). The most common AEs were dizziness and dyspnea (both in 3/94 [3.2%] and 1/94 [1.1%] patients who received amlodipine camsylate and amlodipine besylate, respectively). CONCLUSION: The effectiveness and tolerability of amlodipine camsylate were not significantly different from those of amlodipine besylate in these Korean adults with mild to moderate hypertension.