Intramuscular Placebo Research Articles

Randomized trial comparing the safety and antibody responses to live attenuated versus inactivated influenza vaccine when administered to breastfeeding women

BackgroundLive attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are both licensed for administration to nursing mothers. Little is known about the potential for transmission of LAIV viruses from the mother to the infant and the comparative breast milk antibody responses to LAIV and IIV. MethodsWe performed a randomized, double-blind study comparing the immunogenicity of LAIV to IIV when administered to nursing mothers. The safety of LAIV to IIV in women and their infants was also compared. Women received LAIV + intramuscular placebo, or IIV + intranasal placebo on Day 0. Breast milk and nasal swabs (from women and infants) were collected on Days 0, 2, and 8 for detection of LAIV. Breast milk and serum antibody responses were measured at Days 0 and 28. The primary hypothesis was that LAIV would provide superior induction of breast milk IgA responses to influenza as compared to IIV when administered to nursing mothers. ResultsBreast milk IgG, breast milk IgA (H1N1 only), serum hemagglutination inhibition (HAI), and serum IgG responses were significantly higher following administration of IIV compared to LAIV. Receipt of either LAIV or IIV was safe in women and their infants. One (1%) LAIV recipient transmitted vaccine virus to her infant who remained well. No influenza virus was detected in breast milk. ConclusionsBreast milk and serum antibody responses were higher for IIV compared to LAIV. LAIV and IIV were safe for nursing women but there was one (1%) possible transmission of LAIV to an infant. This study suggests that IIV may be the preferred vaccine for nursing mothers.

Parenteral opioids for maternal pain management in labour.

Parenteral opioids (intramuscular and intravenous drugs including patient-controlled analgesia) are used for pain relief in labour in many countries throughout the world. This review is an update of a review first published in 2010. To assess the effectiveness, safety and acceptability to women of different types, doses and modes of administration of parenteral opioid analgesia in labour. A second objective is to assess the effects of opioids in labour on the baby in terms of safety, condition at birth and early feeding. We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (11 May 2017) and reference lists of retrieved studies. We included randomised controlled trials examining the use of intramuscular or intravenous opioids (including patient-controlled analgesia) for women in labour. Cluster-randomised trials were also eligible for inclusion, although none were identified. We did not include quasi-randomised trials. We looked at studies comparing an opioid with another opioid, placebo, no treatment, other non-pharmacological interventions (transcutaneous electrical nerve stimulation (TENS)) or inhaled analgesia. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of each evidence synthesis using the GRADE approach. We included 70 studies that compared an opioid with placebo or no treatment, another opioid administered intramuscularly or intravenously or compared with TENS applied to the back. Sixty-one studies involving more than 8000 women contributed data to the review and these studies reported on 34 different comparisons; for many comparisons and outcomes only one study contributed data. All of the studies were conducted in hospital settings, on healthy women with uncomplicated pregnancies at 37 to 42 weeks' gestation. We excluded studies focusing on women with pre-eclampsia or pre-existing conditions or with a compromised fetus. Overall, the evidence was graded as low- or very low-quality regarding the analgesic effect of opioids and satisfaction with analgesia; evidence was downgraded because of study design limitations, and many of the studies were underpowered to detect differences between groups and so effect estimates were imprecise. Due to the large number of different comparisons, it was not possible to present GRADE findings for every comparison.For the comparison of intramuscular pethidine (50 mg/100 mg) versus placebo, no clear differences were found in maternal satisfaction with analgesia measured during labour (number of women satisfied or very satisfied after 30 minutes: 50 women; 1 trial; risk ratio (RR) 7.00, 95% confidence interval (CI) 0.38 to 128.87, very low-quality evidence), or number of women requesting an epidural (50 women; 1 trial; RR 0.50, 95% CI 0.14 to 1.78; very low-quality evidence). Pain scores (reduction in visual analogue scale (VAS) score of at least 40 mm: 50 women; 1 trial; RR 25, 95% CI 1.56 to 400, low-quality evidence) and pain measured in labour (women reporting pain relief to be "good" or "fair" within one hour of administration: 116 women; 1 trial; RR 1.75, 95% CI 1.24 to 2.47, low-quality evidence) were both reduced in the pethidine group, and fewer women requested any additional analgesia (50 women; 1 trial; RR 0.71, 95% CI 0.54 to 0.94, low-quality evidence).There was limited information on adverse effects and harm to women and babies. There were few results that clearly showed that one opioid was more effective than another. Overall, findings indicated that parenteral opioids provided some pain relief and moderate satisfaction with analgesia in labour. Opioid drugs were associated with maternal nausea, vomiting and drowsiness, although different opioid drugs were associated with different adverse effects. There was no clear evidence of adverse effects of opioids on the newborn. We did not have sufficient evidence to assess which opioid drug provided the best pain relief with the least adverse effects. Though most evidence is of low- or very-low quality, for healthy women with an uncomplicated pregnancy who are giving birth at 37 to 42 weeks, parenteral opioids appear to provide some relief from pain in labour but are associated with drowsiness, nausea, and vomiting in the woman. Effects on the newborn are unclear. Maternal satisfaction with opioid analgesia was largely unreported. The review needs to be examined alongside related Cochrane reviews. More research is needed to determine which analgesic intervention is most effective, and provides greatest satisfaction to women with acceptable adverse effects for mothers and their newborn.

Effects of a P-class CpG-ODN administered by intramuscular injection on plasma cytokines and on white blood cells of healthy horses

Cytosine-phosphate-guanosine (CpG-ODN) has been described as a potent immunostimulatory agent in different species. No study reported the effect of a P-class CpG when administered systemically in healthy horses. The aim of this study was to evaluate the tolerance and the effect of an intramuscularly administered P-class CpG-ODN on hematology and on plasma cytokines (IFN-α, IL-10, TNF-α, IFN-γ) in 8 healthy horses. Intra-muscular CpG-ODN or placebo (PBS) was administered twice at a 7 days-interval. Groups were inversed after 2 months of washout period. A physical examination, complete blood count (CBC) and plasma cytokine measurements were performed from 2 days before injection up to 21 days after injection. P-class CpG-ODN injection was well tolerated with minor side effects. After the first injection a significant transient drop in circulating total leukocytes, lymphocytes and an increase in monocytes were observed. A transient drop in eosinophils was also noted after each CpG injection. P-class CpG-ODN at a dose of 5 mg did not create major side effects in 7 horses, one horse showed transient pyrexia. A redistribution of white blood cells was observed in horses receiving CpG, but no change in plasma cytokines was observed at the indicated dose, route of administration and sampling times.

Muscular responses to testosterone replacement vary by administration route: a systematic review and meta-analysis.

BackgroundInconsistent fat‐free mass (FFM) and muscle strength responses have been reported in randomized clinical trials (RCTs) administering testosterone replacement therapy (TRT) to middle‐aged and older men. Our objective was to conduct a meta‐analysis to determine whether TRT improves FFM and muscle strength in middle‐aged and older men and whether the muscular responses vary by TRT administration route.MethodsSystematic literature searches of MEDLINE/PubMed and the Cochrane Library were conducted from inception through 31 March 2017 to identify double‐blind RCTs that compared intramuscular or transdermal TRT vs. placebo and that reported assessments of FFM or upper‐extremity or lower‐extremity strength. Studies were identified, and data were extracted and validated by three investigators, with disagreement resolved by consensus. Using a random effects model, individual effect sizes (ESs) were determined from 31 RCTs reporting FFM (sample size: n = 1213 TRT, n = 1168 placebo) and 17 reporting upper‐extremity or lower‐extremity strength (n = 2572 TRT, n = 2523 placebo). Heterogeneity was examined, and sensitivity analyses were performed.ResultsWhen administration routes were collectively assessed, TRT was associated with increases in FFM [ES = 1.20 ± 0.15 (95% CI: 0.91, 1.49)], total body strength [ES = 0.90 ± 0.12 (0.67, 1.14)], lower‐extremity strength [ES = 0.77 ± 0.16 (0.45, 1.08)], and upper‐extremity strength [ES = 1.13 ± 0.18 (0.78, 1.47)] (P < 0.001 for all). When administration routes were evaluated separately, the ES magnitudes were larger and the per cent changes were 3–5 times greater for intramuscular TRT than for transdermal formulations vs. respective placebos, for all outcomes evaluated. Specifically, intramuscular TRT was associated with a 5.7% increase in FFM [ES = 1.49 ± 0.18 (1.13, 1.84)] and 10–13% increases in total body strength [ES = 1.39 ± 0.12 (1.15, 1.63)], lower‐extremity strength [ES = 1.39 ± 0.17 (1.07, 1.72)], and upper‐extremity strength [ES = 1.37 ± 0.17 (1.03, 1.70)] (P < 0.001 for all). In comparison, transdermal TRT was associated with only a 1.7% increase in FFM [ES = 0.98 ± 0.21 (0.58, 1.39)] and only 2–5% increases in total body [ES = 0.55 ± 0.17 (0.22, 0.88)] and upper‐extremity strength [ES = 0.97 ± 0.24 (0.50, 1.45)] (P < 0.001). Interestingly, transdermal TRT produced no change in lower‐extremity strength vs. placebo [ES = 0.26 ± 0.23 (−0.19, 0.70), P = 0.26]. Subanalyses of RCTs limiting enrolment to men ≥60 years of age produced similar results.ConclusionsIntramuscular TRT is more effective than transdermal formulations at increasing LBM and improving muscle strength in middle‐aged and older men, particularly in the lower extremities.

Efficacy of Postoperative Analgesia of Local Ketamine Wound Instillation Following Total Thyroidectomy: A Randomized, Double-blind, Controlled Clinical Trial.

Total thyroidectomy is recommended as a line of management of thyroid cancer in many cases. Our aim was to compare postoperative analgesic effect of local ketamine 1 mg/kg instilled in the wound to that of intramuscular (IM) ketamine and placebo after total thyroidectomy. A total of 90 patients aged 18 to 60 years, American Society of Anesthesiologists (ASA) class I to II, with a body weight of 50 to 90 kg, scheduled for total thyroidectomy were enrolled after ethics committee approval in this prospective, randomized, double-blind, controlled study and divided randomly into 3 groups to receive treatment after hemostasis. Group (I) received 1 mg/kg ketamine in a total volume of 10 mL normal saline instilled in the wound. Group (II) received 1 mg/kg of IM ketamine. Group (III) received 10 mL of normal saline instilled in the wound. Total amount of morphine consumption, first request of analgesia, and side effects were recorded. Visual analog scale at rest and movement and hemodynamics were assessed immediately, 1, 2, 4, 6, 12, and 24 hours postoperatively. Total morphine consumption was reduced and first request of analgesia was delayed in group I compared with that in groups II and III, and in group II compared with that in group III (P=0.000). Visual analog scale at rest and movement were decreased immediately postoperatively in groups I and II in comparison with their values in group III; group II had higher sedation scores. Local wound ketamine instillation provided superior postoperative analgesia with lower incidence of side effects in comparison with IM ketamine and placebo following total thyroidectomy.

Safety, immunogenicity, and preliminary clinical efficacy of a vaccine against extraintestinal pathogenic Escherichia coli in women with a history of recurrent urinary tract infection: a randomised, single-blind, placebo-controlled phase 1b trial

Escherichia coli infections are increasing worldwide in community and hospital settings. The E coli O-antigen is a promising vaccine target. We aimed to assess the safety and immunogenicity of a bioconjugate vaccine containing the O-antigens of four E coli serotypes (ExPEC4V). In this multicentre phase 1b, first-in-human, single-blind, placebo-controlled trial, we randomly assigned (1:1) healthy adult women with a history of recurrent urinary tract infection (UTI) to receive a single injection of either intramuscular ExPEC4V or placebo. The primary outcome was the incidence of adverse events among vaccine and placebo recipients throughout the study. Secondary outcomes included immunogenicity and antibody functionality, and the incidence of UTIs caused by E coli vaccine serotypes in each group. This study is registered with ClinicalTrials.gov, number NCT02289794. Between Jan 20, 2014, and Aug 27, 2014, 93 women received target-dose ExPEC4V and 95 received placebo. The vaccine was well tolerated: no vaccine-related serious adverse events occurred. Overall, 56 (60%) target-dose vaccines and 47 (49%) placebo recipients experienced at least one adverse event that was possibly, probably, or certainly related to injection. Vaccination induced significant IgG responses for all serotypes: at day 30 compared with baseline, O1A titres were 4·6 times higher, O2 titres were 9·4 times higher, O6A titres were 4·9 times higher, and O25B titres were 5·9 times higher (overall p<0·0001). Immune responses persisted at 270 days but were lower than those at 30 days. Opsonophagocytic killing activity showed antibody functionality. No reduction in the incidence of UTIs with 103 or more colony-forming units per mL of vaccine-serotype E coli was noted in the vaccine compared with the placebo group (0·149 mean episodes vs 0·146 mean episodes; p=0·522). In post-hoc exploratory analyses of UTIs with higher bacterial counts (≥105 colony-forming units per mL), the number of vaccine serotype UTIs did not differ significantly between groups (0·046 mean episodes in the vaccine group vs 0·110 mean episodes in the placebo group; p=0·074). However, significantly fewer UTIs caused by E coli of any serotype were noted in the vaccine group compared with the placebo group (0·207 mean episodes vs 0·463 mean episodes; p=0·002). This tetravalent E coli bioconjugate vaccine candidate was well tolerated and elicited functional antibody responses against all vaccine serotypes. Phase 2 studies have been initiated to confirm these findings. GlycoVaxyn, Janssen Vaccines.

Transcriptome Analysis in Human Breast Milk and Blood after Inactivated or Attenuated Influenza Immunization

BackgroundThe goal of this study was to identify transcriptomic signatures (RNA-Seq) in human peripheral blood mononuclear cells (PBMCs) and breast milk lymphocyte cells (BMLCs) in response to trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV).MethodsWe performed a randomized, double-blind study in breastfeeding women who received either LAIV and intramuscular placebo, or TIV and intranasal placebo. A subset of subjects with available samples (LAIV, n = 10 and TIV, n = 6) was used for this study. Human milk was collected on days 0, 2, 8, and 28, and blood samples were collected on days 0 and 28. PBMC and BMLC RNA was extracted for RNA-Seq and differentially expressed (DE) gene analysis.ResultsWe identified a total of 382 DE BMLC genes in the LAIV group, most of which were up-regulated at day 28. DE genes were preferentially involved in innate immune signaling pathways including cytokine-cytokine receptor interaction, TNF signaling, and NF-kappa B signaling. For TIV, 3 DE genes were identified of which 2 (IL1A and IL1B) overlapped with LAIV. Response time trends for co-expressed gene clusters by vaccine group showed that LAIV generally induced an early (day 2) up-regulation of innate immune signaling pathway genes, while TIV induced peak innate immune signaling gene responses ahead of LAIV (day 8 vs. day 28). A group of known interferon-alpha/β-inducible genes (IFIT3, OAS3, IFI44L, MX1, OAS2, IFIT1, IFI6) showed higher responses at day 2 for TIV but stronger peak levels by day 28 for the LAIV group (Fig 1). While no such innate immune signaling responses were observed in PBMCs at day 28, we identified an up-regulation of IgG gene (IGHG1 and IGHG3) expression in the TIV group (Fig 2).ConclusionWe observed increased innate immune signaling responses in BMLC but not in PBMC at day 28 for the LAIV group. We hypothesize that breastfeeding extends the innate response to LAIV via mucosal immunity. Gene cluster time trends indicated an earlier innate immune signaling response for TIV. The day 28 increase in IGHG3 gene expression levels in TIV group PBMCs was correlated with corresponding increases in serum ELISA IgG titers for the influenza B antigen (Fig 3). Additional studies are required to investigate the differences in innate response signaling seen for BMLC and PBMC in this study.Disclosures All authors: No reported disclosures.

Intramuscular corticosteroid injection versus placebo effective in pain reduction in patients with hip osteoarthritis

Intramuscular corticosteroid injection versus placebo effective in pain reduction in patients with hip osteoarthritis

Comparison of the analgesic efficacy of oral ketorolac versus intramuscular tramadol after third molar surgery: A parallel, double-blind, randomized, placebo-controlled clinical trial.

BackgroundPreemptive analgesia is considered an alternative for treating the postsurgical pain of third molar removal. The aim of this study was to evaluate the preemptive analgesic efficacy of oral ketorolac versus intramuscular tramadol after a mandibular third molar surgery.Material and MethodsA parallel, double-blind, randomized, placebo-controlled clinical trial was carried out. Thirty patients were randomized into two treatment groups using a series of random numbers: Group A, oral ketorolac 10 mg plus intramuscular placebo (1 mL saline solution); or Group B, oral placebo (similar tablet to oral ketorolac) plus intramuscular tramadol 50 mg diluted in 1 mL saline solution. These treatments were given 30 min before the surgery. We evaluated the time of first analgesic rescue medication, pain intensity, total analgesic consumption and adverse effects.ResultsPatients taking oral ketorolac had longer time of analgesic covering and less postoperative pain when compared with patients receiving intramuscular tramadol.ConclusionsAccording to the VAS and AUC results, this study suggests that 10 mg of oral ketorolac had superior analgesic effect than 50 mg of tramadol when administered before a mandibular third molar surgery. Key words:Ketorolac, tramadol, third molar surgery, pain, preemptive analgesia.

Inhaled loxapine and intramuscular lorazepam in healthy volunteers: a randomized placebo-controlled drug-drug interaction study.

Pharmacodynamic effects and safety of single‐dose inhaled loxapine administered via the Staccato® system and intramuscular (IM) lorazepam in combination versus each agent alone were compared in a randomized, double‐blind, crossover study in healthy volunteers. Subjects received: inhaled loxapine 10 mg + IM lorazepam 1 mg; inhaled loxapine 10 mg + IM placebo; IM lorazepam 1 mg + Staccato placebo in random order, each separated by a 3‐day washout. Primary endpoints were maximum effect (minimum value) and area under the curve (AUC) from baseline to 2 h post treatment for respirations/min and pulse oximetry. Least‐squares means (90% confidence interval [CI]) for concomitant treatment versus each agent alone were derived and equivalence (no difference) confirmed if the 90% CI was within 0.8–1.25. Blood pressure (BP), heart rate (HR), sedation (100‐mm visual analog scale), and adverse events (AEs) were recorded. All 18 subjects (mean age, 20.4 years; 61% male) completed the study. There was no difference between inhaled loxapine + IM lorazepam and either agent alone on respiration or pulse oximetery during the 12‐h postdose period, confirmed by 90% CIs for AUC and C min ratios. BP and HR were no different for inhaled loxapine + IM lorazepam and each agent alone over a 12‐h postdose period. Although the central nervous system sedative effects were observed for each treatment in healthy volunteers, the effect was greater following concomitant lorazepam 1 mg IM + inhaled loxapine 10 mg administration. There were no deaths, serious AEs, premature discontinuations due to AEs, or treatment‐related AEs.

Insulin Resistance and Inflammation in Hypogonadotropic Hypogonadism and Their Reduction After Testosterone Replacement in Men With Type 2 Diabetes.

One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH. A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks. Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (-3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1β, tumor necrosis factor-α, and leptin (P < 0.05 for all). Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat.

Pilot Study Examining the Effects of Atropine on Performance during Uncompensable Heat Stress

In many operational scenarios, hypohydration can be corrected with oral rehydration following the work interval. Although rare, there are potential situations that require extended intervals of uncompensable heat stress exposure while working in personal protective equipment (PPE). Under these conditions, retention of body water may be valuable to preserve work capacity and reduce cardiovascular strain. We conducted a pilot study comparing intramuscular atropine sulfate versus saline placebo to establish the safety profile of the protocol and to provide pilot data for future investigations. Five, healthy, heat-acclimated subjects completed this crossover design laboratory study. Each subject performed up to one hour of exertion in a hot environment while wearing a chemical resistant coverall. Atropine sulfate (0.02 mg/kg) or an equivalent volume of sterile saline was administered by intramuscular injection. Core temperature, heart rate, perceptual measures, and changes in body mass were measured. All five subjects completed the acclimation period and both protocols. No adverse events occurred, and no pharmacologically induced delirium was identified. Change in body mass was less following exercise influenced by atropine sulfate (p = 0.002). Exertion time tended to be longer in the atropine sulfate arm (p = 0.08). Other measures appeared similar between groups. Intramuscular atropine sulfate reduced sweating and tended to increase the work interval under uncompensable heat stress when compared to saline placebo. Heart rate and temperature changes during exertion were similar in both conditions suggesting that the influence of an anticholinergic agent on thermoregulation may be minimal during uncompensable heat stress. Key words: thermoregulation; cholinolytic; anticholinergic; reaction time

Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing−remitting multiple sclerosis: A retrospective analysis

Background: Changes in gray matter (GM) volume may be a useful measure of tissue loss in multiple sclerosis (MS). Objectives: To investigate the rate, patterns, and disability correlates of GM volume change in an MS treatment clinical trial. Methods: Patients (n=140) with relapsing−remitting MS were randomized to intramuscular (IM) interferon (IFN) beta-1a or placebo. Treatment effects on GM fraction (GMF) and white matter (WM) fraction (WMF) changes, differences in rates of GMF and WMF change in year one and two on treatment, and differences in atrophy rates by disease progression status were assessed retrospectively. Results: Significantly less GM atrophy (during year two), but not WM atrophy (at any point), was observed with IM IFN beta-1a compared with placebo. Pseudoatrophy effects were more apparent in WM than in GM; in year one, greater WM volume loss was observed with IM IFN beta-1a than with placebo, whereas GM volume loss was similar between groups. Risk of sustained disability progression was significantly associated with GM, but not WM, atrophy. Conclusions: These results suggest that GMF change is more meaningful than WMF as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials.

Glucagon regulates orexin A secretion in humans and rodents.

Orexin A (OXA) modulates food intake, energy expenditure, and lipid and glucose metabolism. OXA regulates the secretion of insulin and glucagon, while glucose regulates OXA release. Here, we evaluate the role of glucagon in regulating OXA release both in vivo and in vitro. In a double-blind crossover study, healthy volunteers and type 1 diabetic patients received either intramuscular glucagon or placebo. Patients newly diagnosed with type 2 diabetes underwent hyperinsulinaemic-euglycaemic clamp experiments, and insulin-hypoglycaemia tests were performed on healthy volunteers. The primary endpoint was a change in OXA levels after intramuscular glucagon or placebo administration in healthy participants and patients with type 1 diabetes. Secondary endpoints included changes in OXA in healthy participants during insulin tolerance tests and in patients with type 2 diabetes under hyperinsulinaemic-euglycaemic conditions. Participants and staff conducting examinations and taking measurements were blinded to group assignment. OXA secretion in response to glucagon treatment was assessed in healthy and obese mice, the streptozotocin-induced mouse model of type 1 diabetes, and isolated rat pancreatic islets. Plasma OXA levels declined in lean volunteers and in type 1 diabetic patients injected with glucagon. OXA levels increased during hyperinsulinaemic hypoglycaemia testing in healthy volunteers and during hyperinsulinaemic euglycaemic conditions in type 2 diabetic patients. Plasma OXA concentrations in healthy lean and obese mice and in a mouse model of type 1 diabetes were lower after glucagon treatment, compared with vehicle control. Glucagon decreased OXA secretion from isolated rat pancreatic islets at both low and high glucose levels. OXA secretion declined in pancreatic islets exposed to diazoxide at high and low glucose levels, and after exposure to an anti-insulin antibody. Glucagon further reduced OXA secretion in islets pretreated with diazoxide or an anti-insulin antibody. Glucagon inhibits OXA secretion in humans and animals, irrespective of changes in glucose or insulin levels. Through modifying OXA secretion, glucagon may influence energy expenditure, body weight, food intake and glucose metabolism.

Efficacy and tolerability of benzodiazepines for the treatment of behavioral and psychological symptoms of dementia: a systematic review of randomized controlled trials.

The objective of this review is to summarize the available data on the use of benzodiazepines for the treatment of behavioral and psychological symptoms of dementia (BPSD) from randomized controlled trials (RCTs). A systematic search of 5 major databases, PubMed, MEDLINE, PsychINFO, EMBASE, and Cochrane Collaboration, yielded a total of 5 RCTs. One study compared diazepam to thioridazine, 1 trial compared oxazepam to haloperidol and diphenhydramine, 1 trial compared alprazolam to lorazepam, 1 trial compared lorazepam to haloperidol, and 1 trial compared intramuscular (IM) lorazepam to IM olanzapine and placebo. The data indicates that in 4 of the 5 studies, there was no significant difference in efficacy between the active drugs to treat the symptoms of BPSD. One study indicated that thioridazine may have better efficacy than diazepam for treating symptoms of BPSD. In 1 study, the active drugs had greater efficacy in treating BPSD when compared to placebo. There was no significant difference between the active drugs in terms of tolerability. However, in 2 of the 5 studies, about a third of the patients were noted to have dropped out of the studies. Available data, although limited, do not support the routine use of benzodiazepines for the treatment of BPSD. But these drugs may be used in certain circumstances where other psychotropic medications are unsafe for use in individuals with BPSD or when there are significant medication allergies or tolerability issues with certain classes of psychotropic medications.

Impact of Supplemental Vitamin K1 Administration on Postoperative Blood Component Requirements After Craniosynostosis Repair

Total cranial vault craniosynostosis repairs often require additional blood transfusions in the intensive care unit. Vitamin K1 participates in hepatic production of procoagulant proteins, and body stores of vitamin K1 are limited and dietary dependent. Surgical stress and diet interference may place infants at risk for vitamin K deficiency. Through design of a surgically stratified, randomized, placebo-controlled, blinded pilot study, we evaluated impact of vitamin K1 supplementation on coagulation parameters in infants after craniosynostosis repair. Patients received intramuscular vitamin K1 or placebo coincident with surgical incision. Serum vitamin K1 levels, protein induced in vitamin K absence-prothrombin, and factor VII were obtained at predetermined intervals after surgery. Patients received blood products in the intensive care unit in accordance with transfusion thresholds. Fifteen patients (vitamin K1 = 6, placebo = 9) completed the study procedures. Despite group assignment, patients received an average of 3 postoperative transfusions. Variations were observed with respect to intraoperative resuscitation of patients between comparably trained pediatric anesthesiologists. Thirty-three percent of patients were vitamin K1 deficient on 1 or more laboratory specimens. All breast-fed patients became deficient. Compared with placebo, elevated serum vitamin K1 levels at 6, 12, and 24 hours in the active drug group (P < 0.0001) were not associated with increased factor VII levels or reduced need for postoperative blood products. However, lack of a standardized intraoperative resuscitation plan may contribute to postoperative coagulopathy and is a major study limitation.

Efficacy of intramuscular meperidine hydrochloride versus placebo in experimental foot lameness in horses

There are no peer reviewed, blinded controlled studies regarding the skeletal analgesic efficacy of intramuscularly administered meperidine in horses. Using an adjustable heart bar shoe model of equine foot pain, the objective of this study was to test the hypothesis that meperidine (pethidine) administered intramuscularly would prove more efficacious in alleviating lameness than a saline placebo. Crossover pharmacodynamic experiment. Eight healthy adult Thoroughbred horses randomly underwent weekly i.m. treatments 1 h after lameness induction: saline placebo (1 ml/45 kg bwt) or meperidine hydrochloride (1 mg/kg bwt i.m.). Heart rate (HR) and lameness score (LS) responses were assessed by a blinded observer every 20 min for 5 h after lameness induction and then hourly through 12 h after treatment. Jugular venous blood samples were obtained at -1, 0, 0:05, 1, 2, 4, 6, 8, 10 and 12 h and were subsequently analysed for drug concentrations (lower limit of detection, 1 ng/ml). Repeated measures ANOVA and post hoc Tukey's test were used to identify analgesic effects at a significance level of P<0.05. Mean (± s.e.) HR were lower in meperidine trials at 2.3, 3.3 and 3.7 h post administration (P<0.05). Mean LS were lower in meperidine trials at 2.0, 2.3 and 3.3 h post administration (P<0.05). Mean plasma (meperidine) peaked at 227 ± 52 ng/ml at 1 h post administration and decreased to 2.7 ± 0.3 ng/ml at 12 h post administration. In 3 of 8 subjects, plasma (meperidine) was below the lower limit of detection at 12 h after administration. Intramuscular meperidine was more effective than the saline placebo but only for 2.0-3.7 h post administration compared with the 8-12 h durations of efficacy reported previously using this same model when horses were treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Meperidine may be a suitable nonNSAID alternative analgesic for acute foot pain with efficacy lasting from 2-3 h after a single i.m. dose.

Activity Restriction Among Women With a Short Cervix

Preterm birth remains a leading cause of perinatal morbidity and mortality, and prophylactic and therapeutic strategies have not reduced its frequency. Activity restriction specifically has not been beneficial and is associated with adverse social, economic, and health outcomes. This present secondary analysis of data from the Short Cervix and Nulliparity Trial was designed to estimate the determinants and outcomes of activity restriction in parturients with a short cervix. In the original randomized placebo-controlled trial, asymptomatic nulliparous women with singleton gestations and cervices of less than 30 mm received either weekly intramuscular 17-α hydroxyprogesterone caproate or placebo. During the weekly study visits, participants were asked whether pelvic rest (no sexual activity), reduction of work activity, or reduction of nonwork activity had been recommended. Women who had reductions in either pelvic, work, or nonwork activity were considered as having had “any” activity restriction. The association between activity restriction and preterm birth was determined at less than 37 and less than 34 weeks’ gestation. Multivariable analyses were performed with multiple logistic regression with odds ratios (ORs), adjusted ORs (aORs), and 95% confidence intervals (CIs) reported. All tests were 2 tailed, and P < 0.05 defined statistical significance. All analyses were performed with SAS version 9.2. Of the 657 women in the randomized trial, 646 (98%) responded to questions regarding activity restriction. Nearly 40% of women with a short cervix were placed on some activity restriction, usually in the midsecond to early third trimester, soon after the diagnosis of a short cervix was made. In 171 (68%) of 252 patients, all 3 types of activity restriction were combined. Compared with women without activity restriction, women who received recommendations for activity restriction were older (P < 0.001), more likely to have private insurance (P = 0.01), and less likely to be Hispanic white (P < 0.001); they also had shorter cervical lengths and were more likely to have cervical funneling or intra-amniotic debris. Preterm birth at less than 37 weeks’ gestation was significantly more common among women placed on any activity restriction (37% vs 17%, P < 0.001; OR, 2.91; 95% CI, 2.0–4.21). No significant interactions were found between activity restriction and treatment with 17-α hydroxyprogesterone caproate, cervical length of less than 15 mm, or gestational age at screening. After controlling for treatment group and demographic and ultrasonographic differences among those with and without activity restriction, preterm birth at less than 37 or less than 34 weeks’ gestation remained significantly more common among those placed on any activity restriction (aOR, 2.37; 95% CI 1.60–3.53 and aOR, 2.28, 95% CI, 1.36–3.80, respectively). Results were similar when only women prescribed limitation of work and nonwork activities were included in the restriction group (<37 weeks’ gestation: aOR, 2.44; 95% CI, 1.63–3.65; <34 weeks gestation: aOR, 2.70; 95% CI, 1.62–4.52). Some form of activity restriction was prescribed for more than 1 in every 3 nulliparous women with a short cervix. Activity restriction affected patients’ work and home life, and yet, they were still significantly more likely to deliver preterm. Activity restriction has been associated with increased stress and anxiety and increased chances of venous thromboembolism, bone loss, deconditioning, and financial difficulties. These complications and risk of preterm birth suggest that this intervention should be proven beneficial before it is used routinely for preterm birth prophylaxis.

Aggressive relapsing multiple sclerosis characterized by rapid disability progression

BackgroundCriteria for identifying relapsing multiple sclerosis (RMS) patients with aggressive disease, which would be useful for clinical decision making, are currently unavailable. ObjectiveIdentify RMS patients with aggressive disease characterized by rapid disability progression. MethodsData from a 2-year, phase 3, double-blind, placebo-controlled trial with long-term follow-up evaluations of RMS patients taking either intramuscular interferon beta-1a (IM IFNβ-1a, 30μg) or placebo with baseline Expanded Disability Status Scale (EDSS) scores of 1.0–3.5 were retrospectively analyzed. Patients with a ≥2.0-point increase in EDSS score, resulting in a score ≥4.0 by study end, were considered to have aggressive RMS. The risk of a poor long-term outcome, defined as an EDSS score ≥8.0 at 8 years of follow-up, was calculated as an odds ratio from a logistic regression model comparing patients with and without aggressive RMS. ResultsOnly 25 patients met the criteria for aggressive RMS. Among these patients, mean disease duration was 5.1±3.85 years, mean baseline age was 37.2±6.35 years, and mean baseline EDSS score was 2.8±0.74. Fewer IM IFNβ-1a-treated than placebo-treated patients met the criteria for aggressive RMS at 2 years (7% vs 22% on placebo, p=0.0072). Thirteen patients reached the EDSS milestone of ≥8.0 by the end of the 8-year follow-up. The odds ratio for attaining severe disability was 86.4 (95% CI, 10.3–726.4; p<0.0001) for patients with aggressive RMS compared to patients without aggressive RMS. ConclusionsDefining aggressive RMS based on rapid EDSS progression was useful in identifying patients at risk for more severe disease course.

Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study [Supplementary Cholecalciferol in recovery from tuberculosis]. A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis’

BackgroundVitamin D enhances host protective immune responses to Mycobacterium tuberculosis by suppressing Interferon-gamma (IFN-g) and reducing disease associated inflammation in the host. The objectives of this study were to determine whether vitamin D supplementation to patients with tuberculosis (TB) could influence recovery.MethodsTwo hundred and fifty nine patients with pulmonary TB were randomized to receive either 600,000 IU of Intramuscular vitamin D3 or placebo for 2 doses. Assessments were performed at 4, 8 and 12 weeks. Early secreted and T cell activated 6 kDa (ESAT6) and Mycobacterium tuberculosis sonicate (MTBs) antigen induced whole blood stimulated IFN-g responses were measured at 0 and 12 weeks. Statistical comparisons between outcome variables at 0 and 12 weeks were performed using Student’s t-test and Chi2 tests.ResultsAfter 12 weeks, the vitamin D supplemented arm demonstrated significantly greater mean weight gain (kg) + 3.75, (3.16 – 4.34) versus + 2.61 (95% CI 1.99 – 3.23) p 0.009 and lesser residual disease by chest radiograph; number of zones involved 1.35 v/s 1.82 p 0.004 (95% CI 0.15, 0.79) and 50% or greater reduction in cavity size 106 (89.8%) v/s 111 (94.8%), p 0.035. Vitamin D supplementation led to significant increase in MTBs-induced IFN-g secretion in patients with baseline ‘Deficient’ 25-hydroxyvitamin D serum levels (p 0.021).ConclusionsSupplementation with high doses of vitamin D accelerated clinical, radiographic improvement in all TB patients and increased host immune activation in patients with baseline ‘Deficient’ serum vitamin D levels. These results suggest a therapeutic role for vitamin D in the treatment of TB.Trial registrationClinicalTrials.gov; No. NCT01130311; URL: clinicaltrials.gov