Assessment of 28-day oral toxicity and antipyretic activity of the saline extract from Pilosocereus gounellei (Cactaceae) stem in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Pilosocereus gounellei is a plant found in the Brazilian Caatinga and is popular due to its traditional uses in the treatment of inflammation. The present study was conducted to investigate the sub-acute toxicity of the saline extract from the stem of P. gounellei. AIM OF THE STUDY: To evaluate the 28-day oral toxicity (through behavioral, biochemical, hematological, and morphological analysis) and the antipyretic activity of the extract in mice. MATERIALS AND METHODS: A single oral dose (250, 500, and 1000 mg/kg) was administered daily over 28 consecutive days to male and female mice. Body weight, food and water intake, blood biochemical and hematological parameters, and urine composition were recorded. Histopathological examinations of the liver, kidney, spleen, lungs, and heart were performed and oxidative stress in the organs was evaluated by lipid peroxidation, superoxide dismutase (SOD), catalase (CAT), and nitrite analysis. The antipyretic effect of the 500 mg/kg dose was assessed using a yeast-induced pyrexia model. RESULTS: Oral administration of the extract over 28 days did not affect body weight gain, food and water consumption, body temperature, and hematological parameters in male and female mice. Blood glucose, total cholesterol, and triglyceride levels in male and female mice were reduced. Protein in the urine and histological alterations in both the liver and lungs were detected in male and female mice treated with the highest dose of the extract. SOD levels in the liver and the spleen increased significantly in both sexes, whereas lipid peroxidation decreased in the spleen of male mice. The extract also exerted an antipyretic effect after the first 60 min of the evaluation until the end of the observation duration (180 min). CONCLUSION: The saline extract from the stem of P. gounellei did not present significant toxic effects over 28 consecutive days and demonstrated antipyretic activity when administered orally. Moreover, the results suggest that the extract has potential hypoglycemic and hypolipidemic effects. Future studies are needed to investigate its pharmacological potential.

Different temperature thresholds for antipyretic intervention in critically ill children with fever due to infection: the FEVER feasibility RCT.

BACKGROUND: Fever accelerates host immune system control of pathogens but at a high metabolic cost. The optimal approach to fever management and the optimal temperature thresholds used for treatment in critically ill children are unknown. OBJECTIVES: To determine the feasibility of conducting a definitive randomised controlled trial (RCT) to evaluate the clinical effectiveness and cost-effectiveness of different temperature thresholds for antipyretic management. DESIGN: A mixed-methods feasibility study comprising three linked studies - (1) a qualitative study exploring parent and clinician views, (2) an observational study of the epidemiology of fever in children with infection in paediatric intensive care units (PICUs) and (3) a pilot RCT with an integrated-perspectives study. SETTING: Participants were recruited from (1) four hospitals in England via social media (for the FEVER qualitative study), (2) 22 PICUs in the UK (for the FEVER observational study) and (3) four PICUs in England (for the FEVER pilot RCT). PARTICIPANTS: (1) Parents of children with relevant experience were recruited to the FEVER qualitative study, (2) patients who were unplanned admissions to PICUs were recruited to the FEVER observational study and (3) children admitted with infection requiring mechanical ventilation were recruited to the FEVER pilot RCT. Parents of children and clinicians involved in the pilot RCT. INTERVENTIONS: The FEVER qualitative study and the FEVER observational study had no interventions. In the FEVER pilot RCT, children were randomly allocated (1 : 1) using research without prior consent (RWPC) to permissive (39.5 °C) or restrictive (37.5 °C) temperature thresholds for antipyretics during their PICU stay while mechanically ventilated. MAIN OUTCOME MEASURES: (1) The acceptability of FEVER, RWPC and potential outcomes (in the FEVER qualitative study), (2) the size of the potentially eligible population and the temperature thresholds used (in the FEVER observational study) and (3) recruitment and retention rates, protocol adherence and separation between groups and distribution of potential outcomes (in the FEVER pilot RCT). RESULTS: In the FEVER qualitative study, 25 parents were interviewed and 56 clinicians took part in focus groups. Both the parents and the clinicians found the study acceptable. Clinicians raised concerns regarding temperature thresholds and not using paracetamol for pain/discomfort. In the FEVER observational study, 1853 children with unplanned admissions and infection were admitted to 22 PICUs between March and August 2017. The recruitment rate was 10.9 per site per month. The majority of critically ill children with a maximum temperature of > 37.5 °C received antipyretics. In the FEVER pilot RCT, 100 eligible patients were randomised between September and December 2017 at a recruitment rate of 11.1 per site per month. Consent was provided for 49 out of 51 participants in the restrictive temperature group, but only for 38 out of 49 participants in the permissive temperature group. A separation of 0.5 °C (95% confidence interval 0.2 °C to 0.8 °C) between groups was achieved. A high completeness of outcome measures was achieved. Sixty parents of 57 children took part in interviews and/or completed questionnaires and 98 clinicians took part in focus groups or completed a survey. Parents and clinicians found the pilot RCT and RWPC acceptable. Concerns about children being in pain/discomfort were cited as reasons for withdrawal and non-consent by parents and non-adherence to the protocol by clinicians. LIMITATIONS: Different recruitment periods for observational and pilot studies may not fully reflect the population that is eligible for a definitive RCT. CONCLUSIONS: The results identified barriers to delivering the definitive FEVER RCT, including acceptability of the permissive temperature threshold. The findings also provided insight into how these barriers may be overcome, such as by limiting the patient inclusion criteria to invasive ventilation only and by improved site training. A definitive FEVER RCT using a modified protocol should be conducted, but further work is required to agree important outcome measures for clinical trials among critically ill children. TRIAL REGISTRATION: The FEVER observational study is registered as NCT03028818 and the FEVER pilot RCT is registered as Current Controlled Trials ISRCTN16022198. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 5. See the NIHR Journals Library website for further project information.

Intravenous acetaminophen use in pediatrics.

Acetaminophen is a commonly used pediatric medication that has recently been approved for intravenous use in the United States. The purpose of this article was to review the pharmacodynamics, indications, contraindications, and precautions for the use of intravenous acetaminophen in pediatrics.

Temperature management in patients with acute neurological lesions: an Australian and New Zealand point prevalence study.

BACKGROUND: Given the scientific uncertainty of the efficacy and safety of normothermia (36.0°C to 37.5°C) on disability and death after acute neurological lesions, we sought to understand how temperature is managed in usual clinical care for this patient population in Australia and New Zealand. OBJECTIVE: To describe temperature management in patients with acute neurological lesions. DESIGN: Prospective, observational, multicentre, single-day point-prevalence study. PARTICIPANTS, SETTING AND METHODS: Observational data of usual practice were recorded for all patients with an intensive care admission diagnosis of acute neurological lesions and who were present in 33 intensive care units at 10:00 on the study day. Data were collected prospectively for the ensuing 24-hour period. MAIN OUTCOME MEASURES: Achieved temperature, interventions used to modify temperature and target temperature. RESULTS: There were 106 patients with acute neurological lesions (61% with either stroke or traumatic brain injury) with a mean APACHE (Acute Physiology and Chronic Health Evaluation) II score of 19.3 ± 7.4, age of 53.5 ± 19.0 years and median time from intensive care admission to data capture of 3 days (interquartile range, 1-9). A target temperature was specified in 24% of patients. Although paracetamol was commonly used (56%), it was infrequently used at the maximum licensed dose and there was no use recorded of non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors. Physical cooling was used in 25% of patients and core temperature was measured in 32%. Measured temperature often exceeded 37.0°C (62% of readings), 37.5°C (43%) and 38.0°C (22%). CONCLUSIONS: Temperature readings above 37.5°C are common. Further cohort studies are required to validate these preliminary, exploratory findings.

Assessment of the safety and feasibility of administering antipyretic therapy in critically ill adults: a pilot randomized clinical trial.

PURPOSE: To assess the safety and feasibility of treating critically ill adults with different fever control strategies. METHODS: This was a pilot, open-label clinical trial (ClinicalTrials.gov, number NCT01173367) that randomized febrile patients to an aggressive or permissive fever control strategy. For the aggressive and permissive groups, antipyretic therapy (acetaminophen, physical cooling) was administered when the temperature was ≥ 38.3°C and ≥ 40.0°C respectively. The primary outcome was 28-day mortality. RESULTS: Two hundred patients experienced a fever (31% of the originally projected estimate), among which 26 were randomized to the aggressive (n = 14) or permissive (n = 12) arm. The aggressive group received a greater dose of acetaminophen (2275 mg vs 0 mg, P = .0001), and more frequently received physical cooling than patients in the permissive group (57% vs 8%, P = .01). The mean daily temperature was lower in the aggressive group (37.8°C vs 38.0°C, P = .02). There was no difference in the primary outcome (21% vs 17%, P = 1.0) or in any safety outcome between the treatment groups. CONCLUSIONS: This study demonstrated the safety and feasibility of administering antipyretic therapy in critically ill adults. The key finding was a lower than expected incidence of fever.

Assessment of the safety and feasibility of administering anti-pyretic therapy in critically ill adults: study protocol of a randomized trial.

BACKGROUND: Fever is one of the most commonly observed abnormal signs in patients with critical illness. However, there is a paucity of evidence to guide the management of febrile patients without acute brain injury and little is known about the biologic response to treatment of fever. As such, observational studies suggest that the treatment of fever is inconsistent. This pilot clinical trial will assess the safety and feasibility of treating febrile critically ill adult patients with an aggressive versus a permissive temperature control strategy. The biologic response to these two different temperature control strategies will also be assessed through analysis of a panel of inflammatory mediators. FINDINGS: The study population will include febrile adult patients admitted to one of two general medical-surgical intensive care units (ICUs) in Calgary, Alberta, Canada. Patients will be randomized to either an aggressive or permissive fever treatment strategy. The aggressive group will receive acetaminophen 650 mg enterally every 6 hours upon reaching a temperature ≥ 38.3 °C and external cooling will be initiated for temperatures ≥ 39.5 °C, whereas the permissive group will receive acetaminophen 650 mg every 6 hours upon reaching a temperature ≥ 40.0 °C and external cooling for temperatures ≥ 40.5 °C. The study will take place over 12 months with the goal of enrolling 120 patients. The primary outcome will be 28-day mortality after study enrolment, with secondary outcomes that will include markers of feasibility (e.g. the enrolment rate, and the number of protocol violations), and levels of select inflammatory and anti-inflammatory mediators. DISCUSSION: Results from this study will lead to a better understanding of the inflammatory effects of anti-pyretic therapy and will evaluate the feasibility of a future clinical trial to establish the best treatment of fever observed in nearly one half of patients admitted to adult ICUs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01173367.

Recent patents on oral combination drug delivery and formulations.

Oral combination drug delivery systems have been proven to be highly beneficial and vital in the treatment of several dreadful diseases such as cancer, HIV (AIDS) and tuberculosis. Further, pharmaceutical companies have often explored the strategy of combination drug therapy for treating diseases such as diabetes (Type 2), cardiovascular diseases, central nervous system (CNS) disorders, and for treating several other microbial infections. Patenting combination drug delivery systems and formulations has been proven to be very beneficial for the sustainment and growth of pharmaceutical industry. Several pharmaceutical companies have explored this opportunity in extending the life cycle of their blockbuster molecules, and providing additional sources of revenues when the new chemical entity (NCE) discovery is scarce. The article reviews some recent combination formulation patents and patent publications, particularly the US patents and patent applications, relevant to oral delivery of pharmaceuticals. Examples of some oral combination products on the US and worldwide market are presented. Patents and patent applications on combination oral formulations relevant to analgesics (including anti-inflammatory and antipyretics), cardiovascular system (CVS) products, antibacterial and antiviral, and central nervous system (CNS) products are briefly discussed.