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Aims The aim of the LAICA study was to evaluate the long‐term effectiveness and safety of intermittent levosimendan infusion in patients with advanced heart failure (AdHF). Methods and results This was a multicentre, randomized, double‐blind, placebo‐controlled clinical trial of intermittent levosimendan 0.1 μg/kg/min as a continuous 24‐h intravenous infusion administered once monthly for 1 year in patients with AdHF. The primary endpoint [incidence of rehospitalization (admission to the emergency department or hospital ward for >12 h) for acute decompensated HF or clinical deterioration of the underlying HF] occurred in 23/70 (33%) of the levosimendan group (Group I) and 12/27 (44%) of the placebo group (Group II) (P = 0.286). The incidence of hospital readmissions for acute decompensated HF (Group I vs. Group II) at 1, 3, 6, and 12 months was 4.2% vs. 18.2% (P = 0.036); 12.8% vs. 33.3% (P = 0.02); 25.7% vs. 40.7% (P = 0.147); 32.8% vs. 44.4% (P = 0.28), respectively. In a secondary pre‐specified time‐to‐event analysis no differences were observed in admission for acute decompensated HF between patients treated with levosimendan compared with placebo (hazard ratio 0.66; 95% CI, 0.32–1.32; P = 0.24). Cumulative incidence for the aggregated endpoint of acute decompensation of HF and/or death at 1 and 3 months were significatively lower in the levosimendan group than in placebo group [5.7% vs. 25.9% (P = 0.004) and 17.1% vs. 48.1% (P = 0.001), respectively], but not at 6 and 12 months [34.2% vs. 59.2% (P = 0.025); 41.4% vs. 66.6% (P = 0.022), respectively]. Survival probability was significantly higher in patients who received levosimendan compared with those who received placebo (log rank: 4.06; P = 0.044). There were no clinically relevant differences in tolerability between levosimendan and placebo and no new safety signals were observed. Conclusions In our study, intermittent levosimendan in patients with AdHF produced a statistically non‐significant reduction in the incidence of hospital readmissions for acute decompensated HF, a significantly lower cumulative incidence of acute decompensation of HF and/or death at 1 and 3 month of treatment and a significant improvement in survival during 12 months of treatment.

Therapies with the continuous administration of anti-hormonal agents in sex-hormone-dependent malignancies such as prostate and breast carcinomas often lead to the development of resistant tumor cells. A systematic evaluation of the use and effects of the intermittent application of endocrine therapy could provide information on the state of knowledge in this research area. PubMed, Cochrane Library, Embase, and Web of Science will be systematically searched using pretested search strategies. Randomized and non-randomized controlled trials, pragmatic trials, case–control, and comparative cohort studies will be eligible. Primary outcomes will be progression-free survival, disease-free survival, and overall survival. The literature retrieved will be selected based on predefined inclusion and exclusion criteria. Relevant data will be extracted from included references into a pre-designed table. The risk of bias will be assessed, and the report of the results will follow PRISMA recommendations and include any deviations from this protocol. The increasing prevalence of breast and prostate cancer and limitations of current therapeutic approaches require a closer look at alternatives. Additionally, to explore new therapeutic agents, modalities of administration should be rigorously reviewed to determine the best regimens for patients. This proposed systematic review aims to summarize and evaluate the current knowledge regarding intermittent endocrine cancer therapy to provide a basis for further research.

Aims Standard inotropic treatment is often necessary in end-stage heart failure but may be harmful. We performed a meta-analysis of randomized controlled trials to investigate the effect of repeated administration of levosimendan on survival in patients with chronic heart failure. Methods and results Four investigators independently searched in CENTRAL, Google Scholar MEDLINE/PubMed, Scopus and the Cochrane Central Register of clinical trials to identify any randomized study ever performed with intermittent levosimendan intravenous administration in adult patients with chronic heart failure with no restrictions on dose or time of administration. Data from a total of 326 patients from six randomized controlled studies using intermittent levosimendan in a cardiological setting were included in the analysis. Levosimendan was associated with a significant reduction in mortality at the longest follow-up available [32 of 168 (19 %) in the levosimendan group 46 of 133 (35 %) in the control arm, RR = 0.55 (95 % CI 0.37–0.84), p for effect = 0 0.005, p for heterogeneity = 0.3, I 2  = 23.4 %, NNT = 6 with 5 studies included]. Brain natriuretic peptide values, ejection fraction and number of patients with New York Heart Association ≥III status were similar in survivors of both groups. Conclusions A large randomized trial is necessary to confirm the promising beneficial effects of intermittent levosimendan administration on the mid-term survival of patients with chronic heart failure.

Background There is lack of information on the efficacy and safety of piperacillin–tazobactam administered by continuous infusion. Objective The aim of this study was to investigate whether continuous infusion of piperacillin–tazobactam is superior in terms of efficacy to a 30 % higher dose administered by intermittent infusion to treat suspected or confirmed infection due to Pseudomonas aeruginosa . Setting Multicenter clinical trial with 11 third level Spanish hospitals. Method Randomized, double-blind parallel-group clinical trial, controlled by conventional administration of the drug. Patients randomly assigned in a 1:1 ratio to receive piperacillin–tazobactam as continuous infusion (CI) or intermittent (II). Main outcome measure Primary efficacy endpoint was percentage of patients having a satisfactory clinical response at completion of treatment, defined as clinical cure or clinical improvement. Adverse events were reported. Results 78 patients were included, 40 in the CI group and 38 in the II group. Mean (standard deviation) duration of treatment was 7 (±4.44) days. 58 patients (74.4 %) experienced cure or improvement at the end of the treatment. There were no statistical differences in cure rates between the two treatment arms and no adverse events were reported. Conclusion Continuous infusion of piperacillin–tazobactam is an alternative administration drug method at least similar in efficacy and safety to conventional intermittent infusion. Multivariate analysis is needed to determine whether continuous administration might be more beneficial than intermittent in certain patient subgroups.

Studies using either continuous or intermittent access cocaine self-administration procedures showed that cocaine seeking increases during abstinence (incubation of cocaine craving), and that this effect is higher after intermittent cocaine access. Other studies showed that cocaine abstinence is characterized by the emergence of stress- and anxiety-related states which were hypothesized to increase relapse vulnerability. We examined whether incubation of cocaine craving and anxiety-related behaviors are correlated and whether intermittent cocaine self-administration would potentiate these behaviors during abstinence. Male rats self-administered cocaine either continuously (6 h/day) or intermittently (5 min ON, 25 min OFF x 12) for 14 days, followed by relapse tests after 1 or 21 abstinence days. A group of rats that self-administered saline served as a control. Anxiety-related behaviors were measured on the same abstinence days, using the novelty induced-hypophagia test. Finally, motivation for cocaine was measured using a progressive ratio reinforcement schedule. Lever-presses after 21 abstinence days were higher than after 1 day and this incubation effect was higher in the intermittent access group. Progressive ratio responding was also higher after intermittent cocaine access. Intermittent and continuous cocaine access did not induce anxiety-like responses in the novelty-induced hypophagia test after 1 or 21 abstinence days. Independent of the schedule, incubation of cocaine seeking was not correlated with the novelty-induced hypophagia measures. Results suggest that cocaine-induced anxiety-related states during protracted abstinence do not contribute to incubation of cocaine craving. However, this conclusion is tentative because we used a single anxiety-related measure and did not test female rats.

Background and Objectives: Management of infectious diseases is a huge burden to every healthcare system worldwide. Antimicrobial resistance, including antibacterial resistance, is an increasing problem worldwide; therefore, more new antibiotics are necessary to be discovered. Meanwhile, “old” antibacterial agents are still administered to fight infectious diseases caused by resistant bacteria. One of these antibacterial agents is vancomycin, which is effective in treating serious systemic infections caused by gram-positive bacteria. Thus, it is necessary to perform vancomycin concentration measurements in plasma due to its narrow therapeutic index. Various approaches are implemented for more precise therapy, including therapeutic drug monitoring (TDM) of vancomycin and with a supervision of a clinical pharmacist. The purpose of the study was to investigate if the TDM practice is improved with a local vancomycin TDM protocol applied in a hospital. The results of TDM in two multidisciplinary hospitals, one with a local TDM protocol implemented and applied and the other with no local TDM protocol implemented and applied, were compared. Materials and Methods: A retrospective study was performed in two multidisciplinary hospitals in Latvia. The data were collected for a time period of 4 years (2016–2020) in a hospital without a local TDM protocol and for a time period of 2 years (2018–2020) in a hospital with a local TDM protocol, starting with a period of time when the vancomycin TDM protocol was developed. The data about the patients included in the study were analyzed based on gender, age, body weight, and renal function. Vancomycin therapy was analyzed based on dosing schemes (vancomycin dose and dosing interval), data about loading and maintenance doses, vancomycin concentration, and details about vancomycin concentration (sampling time and concentration level). Results: Differences between the hospitals were found in terms of the initiation of vancomycin administration and concentration sampling. In the hospital with a TDM protocol compared with the hospital without a TDM protocol, more accurate initiation was found, alongside adaption of therapy (97.22% vs. 18.95%, p < 0.001), better performance of administration of a loading dose (22.73% vs. 1.29%, p < 0.01), and reaching of target concentration (55.56% vs. 35.29%, p < 0.01). Concentration sampling in the correct timeframe before the vancomycin dose and vancomycin administration did not show statistically better results in either of the hospitals (4.60% vs. 6.29%, p = 0.786). Conclusions: Better results of adequate adjustments of vancomycin therapy were achieved in the hospital with a TDM protocol. In the long term, sustainable results and regular medical professionals’ training is necessary.

Background: Thoracic epidural anesthesia (TEA) is frequently used to maintain intraoperative analgesia. After injecting the initial bolus dose of epidural local anesthetics (LA), intermittent injection of LA through an epidural catheter is required to maintain the intraoperative analgesia. For intermittent epidural administration, usually 2 – 5 mL of LA has been used. However, no studies have suggested an optimal volume of LA of TEA for intermittent epidural administration of TEA. Objective: We focused on identifying an optimal volume of LA of TEA using epidurography of the thoracic level with 2 different volumes of contrast dye. Study Design: Prospective, randomized study. Setting: An interventional pain management practice in South Korea. Methods: After Institutional Review Board approval, 70 patients undergoing thoracic epidural catheterization for upper abdominal and thoracic surgery were randomly assigned to one of the 2 contrast dye volume groups of 35 patients each (A, 2.5 mL and B, 5.0 mL). Epidurography was evaluated to confirm how many spinal segments were covered by contrast dye. The spreads in the cephalad and caudad directions were also evaluated. Results: The total number of vertebral segments evaluated by contrast dye were 7.5 ± 2.0, and 8.4 ± 2.6, respectively in groups A and B. The number of patients who showed contrast dye spread of more than 5 vertebral segments was 34/35 (97%) in both groups. Group B resulted in higher contrast dye distribution in the cephalad direction compared to group A (T2.6 vs. T3.6 ). Limitations: We used a test dose of contrast dye to confirm the contrast was in epidural space, not intrathecal or vascular, before injection of the main dose of contrast dye. The present study did not include the volume of test dose. Conclusion: The volume of 2.5 mL for intermittent epidural administration would be enough for the analgesic effect of upper abdominal and thoracic surgery while avoiding excessive upper thoracic and cervical spread. Key words: Thoracic epidural anesthesia, intermittent epidural administration, optimal volume, epidurography, cephalad, caudad, analgesic effect

Intermittent administration of low doses of human parathyroid hormone (h-PTH) has been reported to exhibit an anabolic effect on bone, increasing its mass. We investigated the effects of intermittent administration of h-PTH on bone changes in streptozotocin- (STZ-) induced diabetes mellitus (DM) rats by measuring bone mineral density and bone mineral contents and by bone histomorphometry. Wistar rats, 7-8 months old, were used. Osteoporosis was induced by diabetes mellitus, which was established by an intraperitoneal injection of STZ. Rats were separated into five groups: sham-injected, baseline control, vehicle-only-administered, and low-dose (6.0μg/kg) or high-dose (60.0μg/kg) h-PTH-administered groups. h-PTH or vehicle was injected subcutaneously six times a week for 4 weeks beginning 9 weeks after STZ administration. Bone mineral density and mineral contents were significantly lower in the baseline control and vehicle groups than in the control group. The PTH-administered groups showed higher values compared with both vehicle and baseline control groups. In bone histomorphometry, both bone volume and bone formation in the STZ group were markedly reduced. The h-PTH-administered rats showed increase in both bone volume and bone formation, which are related parameters, but administration of h-PTH did not alter the extent of eroded surface. Our results suggest that intermittent administration of h-PTH is effective in activating bone formation and in preventing further bone loss in osteoporosis developed by STZ-induced DM.[PUBLICATION ABSTRACT]

The monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D(2)/D(3) dopamine agonist quinpirole and sensitizes self-directed mouthing behavior in rats by a mechanism independent of MAO inhibition. Clorgyline has a high affinity for imidazoline I(2) and sigma receptors, which could account for its effects on quinpirole sensitization. To examine whether the effect of clorgyline on quinpirole sensitization is attributed to stimulation of either I(2) or sigma receptors. In one experiment, rats received injections of the I(2) receptor agonist 2-BFI (0.2 mg/kg, IP) or vehicle, 90 min prior to each injection of quinpirole (0.5 mg/kg, SC, x 8, twice weekly) or saline. A similar protocol was used to examine the effects of the MAOI Ro 41-1049 (10 mg/kg, SC) on quinpirole sensitization. Unlike clorgyline, Ro 41-1049 has no affinity for sigma or I(2) sites. An initial experiment demonstrated that intermittent injections of clorgyline (1 mg/kg, SC) are as effective as a continuous clorgyline administration (1 mg/kg per day via osmotic mini-pump) on quinpirole sensitization. Like clorgyline, Ro 41-1049, but not 2-BFI, blocked the development of quinpirole-induced locomotor sensitization and induced instead sensitization of self-directed mouthing. Because Ro 41-1049 produced the same effects as clorgyline, and 2-BFI had no effects on quinpirole sensitization, it is unlikely that clorgyline exerts its effects via an action at sigma or I(2) receptors. Our results are consistent with the suggestion that clorgyline and Ro 41-1049 affect the behavioral response to quinpirole via the MAOI-displaceable quinpirole binding (MQB) site, and the hypothesis that the MQB site selects what motor output becomes sensitized to repeated injections of quinpirole.