Tezepelumab Pharmacokinetics,Safety, and Tolerability After Administration via Vial-and-syringe,Accessorized Prefilled Syringe,or Autoinjector: A Randomized Trial in Healthy Volunteers

PurposeTezepelumab is an anti–thymic stromal lymphopoietin monoclonal antibody therapeutic in development for patients with severe, uncontrolled asthma. In ongoing Phase III studies, tezepelumab is administered via subcutaneous (SC) injections using a vial-and-syringe (V–S). This study compared the pharmacokinetic (PK) parameters, safety, and tolerability of tezepelumab administered subcutaneously via V–S versus via an accessorized prefilled syringe (APFS) or autoinjector (AI).MethodsThis single-center, randomized, open-label, parallel-group study was conducted in healthy volunteers aged 18–65 years. Participants, stratified according to weight (50 to <70 kg, 70 to <80 kg, or 80–90 kg), were randomized evenly to 9 groups representing injections to the abdomen, thigh, or upper arm via V–S, APFS, or AI. Tezepelumab PK parameters over 113 days were evaluated after a single 210-mg SC dose. The primary end points were comparison of C_max and AUC_0–∞ between device groups. Further PK parameters, immunogenicity, safety (including injection site reactions [ISRs] and injection site pain [visual analog scale]) were also assessed.FindingsA total of 315 adults were randomized to treatment. Geometric mean ratios for comparisons between device groups of C_max, AUC_0–∞, and AUC_0–last were close to 1, with 90% CIs all within the range of 0.8–1.25, meeting bioequivalence criteria. PK variables were also similar between devices across injection sites and weight categories. Across devices, thigh injection resulted in slightly higher exposure than upper arm injection, and abdomen injection resulted in exposure similar to or slightly lower than thigh injection; however, these differences were not clinically meaningful. Treatment-emergent anti-tezepelumab antibodies were present in 3 (2.9%), 1 (1.0%), and 0 participants in the V–S, APFS, and AI groups, respectively. Treatment-related adverse events were reported in 15.0% of participants overall (V–S, 10.7%; APFS, 18.1%; AI, 16.0%), including ISRs in 1 (1.0%), 3 (2.9%), and 3 (2.8%) participants in the V–S, APFS, and AI groups. Median visual analog scale pain score (0–100 mm scale) was 2 mm immediately after injection and was 0 mm at 30 min for all groups.ImplicationsTezepelumab PK parameters after a single 210-mg SC dose were comparable when administered via V–S, APFS, or AI. In all groups, immunogenicity rate and injection site pain were low, and ISRs were uncommon. These findings support administration of tezepelumab via APFS or AI, in addition to V–S, providing patients and physicians with greater choice and the potential convenience of at-home use. ClinicalTrials.gov identifier: NCT03989544.     

Double-blind, randomized, controlled trial of local anesthetic use for iliac crest donor site pain.

Autogenous iliac crest bone grafts are often used for persons undergoing anterior cervical fusion (ACF). Study findings have shown that pain at the iliac crest donor site can often be more severe than that at the primary operation site. A method used to eliminate pain after bone harvesting involves infiltration of a local anesthetic directly into the site. This study examined the efficacy of local anesthetic infiltration in the control of donor site pain, utilizing a randomized, double-blind, placebo-conrolled design. All participants received standard postoperative intravenous and oral analgesic. Those in the study group also received six injections of bupivacaine hydrochloride 0.25% into the donor site, while participants in the placebo group received normal saline injections. Participants receiving bupivacaine (n = 14) consistently reported lower hip pain scores than participants receiving the placebo (n = 8), with significant differences noted 3 hours after the first and second doses of the study drug. The bupivacaine group's mean morphine intake for the first 24 hours after surgery was found to be lower (32 mg; placebo 44 mg), whereas participants younger than 49 years who received bupivacaine were found, on average, to have stayed in the hospital one day less (3.6 days) than placebo group participants (4.5 days). Younger participants receiving bupivacaine required less morphine and had, on average, a reduced length of stay. The clinical implication of using local anesthetic for the relief of donor site pain suggests that it is a safe and efficacious technique.     

The effect of injection speed on the perception of intramuscular injection pain. A clinical update.

Injections are frequently administered by occupational health nurses in worksite health promotion programs. The purpose of this study was to examine the effect of varying injection speed on the perception of pain. Fifty workers were given intramuscular (i.m.) hepatitis B vaccine at injection speeds of 10 and 30 seconds per cubic centimeter (s/cc). The perception of pain was measured on a visual analogue scale and reported post-injection at three different time intervals. The results showed that no difference in pain was perceived by participants between the two injection speeds. Results also revealed that women consistently had higher mean pain scores than men and significantly more pain at the 0 hour measurement of the 10 s/cc injection. While the results of this study indicate no need to administer an i.m. injection slower than 10 s/cc, occupational health nurses will need to consider gender differences in pain perception when administering injections.     

Intradermal injections: Traditional bevel up versus bevel down

This study used qualitative and quantitative methods to examine differences regarding correct placement of injectate, leaking or bleeding, time to administer injection, and comfort of person administering, and receiving an intradermal injection. Each (N = 98) administered and received two injections. Subjects evaluated their comfort on a Likert scale. After second injection, each reported which was better. Most of the time (82%), a wheal was produced. Leaking or bleeding occurred a fourth of the time. Subjects rated the first injection better (p < 0.05) with no preference regarding technique. Subjects administering injections reported bevel up more comfortable (p < 0.01). Bevel up was significantly faster.     

Organophosphate antidote auto-injectors vs. traditional administration: a time motion study

Organophosphates may be used as weapons in chemical attacks on civilian or military populations. Antidotes are available to counter the effects of organophosphates, but they must be administered shortly after exposure. Timing required to administer organophosphate antidotes using traditional equipment vs. auto-injectors has not been studied. This study is intended to quantify and compare the time required to administer organophosphate antidotes using traditional equipment vs. auto-injectors in different treatment conditions. The study was a randomized, un-blinded design. There were 62 participants assigned to one of three groups: Mark I, ATNAA (antidote treatment nerve agent auto-injector), and traditional needle/syringe; however, the results from only 56 participants could be analyzed. Injection trials were videotaped. Subjects also completed a 14-item survey containing demographic questions, perceived ease of injection, receipt of prior training, and preferred training format for organophosphate treatment. Injection time differentials were compared using one-way analysis of variance; post hoc evaluation was performed using the Scheffe test with Bonferroni correction. Fifty-six subjects completed this study. The ATNAA required less time to administer than the Mark I or traditional needle/syringe devices (p < .001). There was no difference in time to administer the Mark I auto-injectors vs. a traditional needle/syringe. There were no differences between injection time and occupation, receipt of prior training, wearing of personal protective equipment, or perceived ease of injection device use. The use of auto-injectors shortens response time for administering organophosphate antidote treatment. An ATNAA auto-injector can be administered in less than half the time it takes to administer a single injection using a needle and syringe or two injections using a Mark I. Mark I can be administered in approximately the same amount of time it takes to administer a single injection using a needle and syringe. The difference between injection time for the ATNAA and needle and syringe would have been even larger if two injections were given with the needle and syringe. The wearing or absence of personal protective equipment does not affect injection time.     

A Phase I Study to Assess the Effect of Speed of Injection on Pain,Tolerability, and Pharmacokinetics After High-volume Subcutaneous Administration of Gantenerumab in Healthy Volunteers

PurposeGantenerumab, a fully human anti–amyloid-β IgG1 monoclonal antibody that binds to aggregated forms of amyloid-β, is being investigated as a potential disease-modifying treatment for early (prodromal to mild) Alzheimer disease (AD). Our study compared the pain associated with 5- and 15-s subcutaneous injections of gantenerumab and evaluated the tolerability and pharmacokinetic properties of subcutaneous gantenerumab.MethodsThis randomized, open-label, single-active-dose, placebo-controlled crossover study was conducted in 50 healthy volunteers aged 40–80 years with no history of clinically significant disorders, drug or alcohol abuse, familial history of early-onset AD, or prior gantenerumab exposure. Eligible participants were randomized to a sequence of one 300-mg SC gantenerumab injection into the abdomen and 2 SC placebo injections (1 into the abdomen and 1 into the thigh) during 5 or 15 s. All injections were administered at least 90 min apart. Participants were assessed for local pain by visual analog scale (VAS) and verbal rating scale; safety profiles were assessed by recording adverse events (AEs), and plasma pharmacokinetic properties were also evaluated.FindingsImmediately after the subcutaneous gantenerumab injection, the pain VAS score was numerically higher without reaching statistical significance in the 5-s versus 15-s injection group (VAS least-squares mean difference, 7.492 mm; 95% CI, −4.439–19.423 mm). In both injection speed groups, the mean pain VAS score was comparable after subcutaneous gantenerumab and placebo injections into the abdomen. Pain was reported after needle insertion and immediately after dosing, subsiding within 5 min after the dose. The pain VAS score was numerically higher after SC placebo injection into the thigh versus abdomen (5-s injection group: mean [SD] VAS score, 26.68 [27.83] vs 19.20 [25.60] mm; 15-s injection group: mean [SD] VAS score, 14.16 [20.62] vs 9.48 [12.04] mm). No serious AEs were reported; no participants withdrew because of an AE. All AEs were of mild intensity, were transient, and had resolved without sequelae at follow-up. The most common AEs were injection site reactions; redness was the most frequently observed skin reactivity event after subcutaneous gantenerumab administration (5-s injection group: 36%; 15-s injection group: 32%). After subcutaneous administration, gantenerumab reached a peak plasma concentration at a median time of 119 h (approximately 5 days); plasma concentrations declined in a monoexponential manner. Comparable pharmacokinetic profiles were observed between the injection speed groups.ImplicationsSubcutaneous gantenerumab injections at speeds of 5 and 15 s were well tolerated in healthy volunteers and could enable at-home administration by patients with AD or their caregivers. ClinicalTrials.gov identifier: NCT02882009.     

Needle temperature effect on pain ratings after injection

OBJECTIVES: Little research regarding appropriate immunization administration technique for adults has been carried out. Pain is a leading cause of self-deferral from immunizations. The purpose of this study was to determine whether administering intramuscular injections using cold needles would decrease patients' perceived pain and have an effect on the immune response elicited by the vaccine. METHODS: Eighty participants received an injection of influenza vaccine in 1 arm and a saline injection in the other using a cold or room temperature needle in a double-blind fashion assigned at random. Participants rated their pain after each injection using a standard visual pain scale bounded by no pain and most painful injection ever. Vaccine antibody response was measured using hemagglutination inhibition assays. RESULTS: Overall, pain scores after influenza vaccine administration were quite low (34.2+/-2.5 mm). The mean pain score for influenza vaccine was not different using cold or room temperature needles (cold 32.2 mm+/-3.20 vs. room temperature 36.0 mm+/-3.80; t=0.76; P=0.450). The mean pain scores for saline injections did not differ (room temperature 23.7 mm+/-3.19 vs. cold 25.2+/-2.95; t=-0.34; P=0.73). Individuals receiving injections with cold needles had less bruising (0/40 vs. 5/40; P<0.02) at the injection site, but incidences of pain and erythema were similar. The use of cold needles for vaccine administration had no effect on antibody response. CONCLUSIONS: Pain after influenza vaccine administration is generally mild. Use of cold needles may not be worth pursuing for injections associated with mild pain. However, it may be worthwhile to explore using cold needles as an analgesic with more painful injections.     

Accuracy and Feasibility of Ultrasound-Guided Intra-articular Injection of the Rat Hip Joint

Intra-articular injection is frequently used as an effective diagnostic and treatment tool for hip joint diseases. However, the underlying treatment mechanism remains unclear because of a lack of experimental animal models. A challenge facing researchers is how to accurately and consistently perform injections involving animal hip joints. The purpose of this study, then, was to establish an ultrasound (US)-guided intra-articular (IA) injection technique using rat hip joints and to evaluate its accuracy and feasibility versus a fluoroscopy (FL)-guided technique. For this study, 20 US-guided and 20 FL-guided IA injections were administered to separate groups of Sprague-Dawley rats. For each procedure, 50 μL of iohexol was injected into the hip joint using a 25G needle. The US-guided injections were performed using a linear probe, and the FL-guided IA injections were performed using C-arm X-ray fluoroscopy. All injections were verified by computed tomography imaging. The number of successful injections and needle repositions per injection, as well as operating times, were recorded, and the rats were observed for complications for 10 d after the injections. Statistical analysis was used to compare US-guided and FL-guided techniques with significance set at p < 0.05. The success rate was markedly higher for the US-guided interventions (90%) than for the FL-guided interventions (75%) (p<0.05). The intervention time was shorter in the US-guided group (95.95 ± 8.376 s) than in the FL-guided group (110.70 ± 20.236 s) (p < 0.05), and the median number of needles repositioned per injection in the US-guided group (1.20 ± 0.41) was notably less than that in the FL-guided group (1.60 ± 0.68) (p < 0.05). A puncture site hematoma was noted in two rat hips (10%) the day after injection in the FL-guided group. Overall, the study indicated that ultrasound-guided intra-articular injection of the hip is a feasible, accurate and safe method for use in rats. This makes it a promising tool for diagnosing coxofemoral pain, producing hip osteoarthritis animal models and administering intra-articular medication.     

Short needles (8 mm) reduce the risk of intramuscular injections in children with type 1 diabetes.

OBJECTIVE: To study whether 8-mm needles can reduce the frequency of intramuscular injections in diabetic children. RESEARCH DESIGN AND METHODS: We conducted a prospective crossover study in 50 children whose BMI was < or = 60th percentile to compare two lengths of needles (12.7 and 8 mm) regarding the occurrence of intramuscular injections as assessed by ultrasonography. RESULTS: The frequency of intramuscular injections was 86% with the 12.7-mm needles and 38% with the 8-mm needles. The frequency of intramuscular injections was significantly reduced when using the 8-mm needles in the arms (P < 0.01) and thighs (P < 0.001). The efficiency of 8-mm needles, as defined by an intramuscular injection with a 12.7-mm needle and a subcutaneous injection with an 8-mm needle, was found for half of the children who injected in the arm and for two-thirds of the children who injected in the thigh. The subcutaneous tissue (SQT) thickness measured by ultrasonography with a skinfold was significantly higher (9.8 +/- 2.2 mm) in the group in which the 8-mm needles were efficient than in the group in which they were not efficient (6.8 +/- 2.1 mm, P < 0.0001). The efficiency of the 8-mm needle was not related to age, sex, BMI, percentile of BMI, injection device, or injection site. The sensibility and specificity of SQT thickness in predicting the efficiency of the 8-mm needles were both 79%. CONCLUSIONS: Needles that are 8 mm long significantly reduce the risk of intramuscular insulin injection in slim or normal-weight (BMI < or = 60th percentile) diabetic children and adolescents.     

Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects.

OBJECTIVE: To study the pharmacokinetic and pharmacodynamic profile of insulin aspart (a new fast-acting human insulin analog) after subcutaneous administration in the deltoid, abdominal, and thigh sites and to compare this profile with regular human insulin (Novolin; Novo Nordisk A/S, Copenhagen). RESEARCH DESIGN AND METHODS: A total of 20 healthy subjects were studied in a single-center six-period double-blind randomized crossover trial with 6 study days and a washout period of 1 week between each single daily dose of the trial drug. Subjects were randomized to receive a single dose of 0.2 U/kg of insulin aspart or regular insulin on each of the 6 study days in three different sites (the deltoid, the abdomen, and the thigh) during a 10-h euglycemic clamp (two drugs and three injection sites). Pharmacokinetic and pharmacodynamic measurements were derived from blood sample measurements of glucose, insulin, and C-peptide during these clamps. RESULTS: The pharmacodynamic data from the euglycemic clamp study showed that, regardless of injection site, the maximal glucose infusion rate (GIR Cmax) was greater and occurred at an earlier time (GIR Tmax) after administration of insulin aspart than regular insulin (GIR Cmax: abdomen 813 vs. 708, deltoid 861 vs. 736, and thigh 857 vs. 720 g/min, P < 0.05 for all; GIR Tmax: abdomen 94 vs. 173, deltoid 111 vs. 192, and thigh 145 vs. 193 g/min, P < 0.05 for all). Pharmacokinetic parameters were also consistent with faster absorption and higher peak insulin concentrations after insulin aspart administration. From all sites, the peak insulin concentration (Cmax) was higher and occurred earlier (Tmax) after administration of insulin aspart than of regular insulin (Cmax: abdomen 501 vs. 260, deltoid 506 vs. 252, thigh 422 vs. 220 pmol/l, P < 0.001 for all sites; Tmax: abdomen 52 vs. 109, deltoid 54 vs. 98, and thigh 60 vs. 107 min, P < 0.01 for all sites). The absorption and glucose-lowering action of insulin aspart did not differ between sites (similar GIR Cmax, Tmax, and area under the curve parameters). However, the duration of the glucose-lowering effect was up to 34 min shorter (P < 0.01) for the abdomen injections than for the deltoid or thigh injections (lower time of 50% glucose disposal). In addition, the amount of glucose infused was significantly lower by 10-14% in the abdomen than in other sites. CONCLUSIONS: Subcutaneous administration of insulin aspart causes a more rapid and intense maximal effect compared with regular insulin during euglycemic clamp studies in nondiabetic subjects. Abdominal administration of insulin aspart has a shorter duration of glucose-lowering effect compared with administration in the deltoid or thigh.     

Evaluation of the Pharmacokinetic Profile of Ultra Rapid Lispro Administered Subcutaneously at Different Injection Sites

PurposeUltra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic profile and glucodynamic response of URLi when administered subcutaneously into the abdomen, upper arm, or thigh. An intravenous (IV) bolus administration was included to determine the absolute bioavailability at each injection site.MethodsIn this Phase I, randomized, open-label, 4-period, crossover study, healthy subjects received a single dose of 15 U URLi subcutaneously into the abdomen, upper arm, or thigh, or by intravenous injection. Serum insulin lispro concentrations and glucodynamic response during a 10-hour euglycemic clamp procedure were assessed after URLi administration.FindingsTotal insulin lispro exposure was similar for the abdomen, upper arm, and thigh, and absolute bioavailability was ～65% at each subcutaneous (SC) injection site. Total and peak insulin action were similar across these SC injection sites. The onset of appearance was <1 minute, and the time to early half-maximal drug concentration occurred at ～10 minutes across these three SC injection sites. Onset of insulin action occurred at ～22 minutes, and the early insulin action (for the first hour) was also similar across these SC injection sites. URLi was well tolerated after single SC injections and IV bolus administration.ImplicationsThe pharmacokinetic and glucodynamic profiles of URLi were similar after a single SC dose into the abdomen, upper arm, or thigh. The rate of insulin lispro absorption and early insulin action were maintained regardless of the SC injection site. The current study supports SC injection of URLi into the abdomen, upper arm, and thigh. ClinicalTrials.gov identifier: NCT03232983.     

A randomized, open-label, crossover study examining the effect of injection site on bioavailability of exenatide (synthetic exendin-4)

BACKGROUND: Exenatide (synthetic exendin-4;AC2993) is a 39-amino acid peptide in the new class of antidiabetic agents known as incretin mimetics. In clinical trials, exenatide exhibited glucoregulatory effects (glucose-dependent stimulation of insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying) in patients with type 2 diabetes mellitus (DM). OBJECTIVE: The goal of this study was to determine the relative bioavailability of exenatide injected subcutaneously into the abdomen, arm, or thigh. METHODS: Patients with type 2 DM were randomized in an open-label, crossover study to assess relative bioavailability of exenatide (10 microg) injected into the arm and thigh versus injection into the abdomen. Serial plasma exenatide concentrations were measured for 10 hours after injection. A sample size of >24 patients provided approximately 80% power to ensure that 90% CIs were within the 80% to 125% interval for the ratios (geometric least squares [LS] means) of AUC(0-infinity). RESULTS: Twenty-eight patients were randomized into the study (mean age, 56 [8] years; glycosylated hemoglobin, 8.0 [1.7]%; body mass index, 33 [5] kg/m2; all values given as mean [SD]). AUC(0-infinity) values (geometric LS mean SE for SC injections into the abdomen arm and thigh were 63,935 (6608), 59,573 (6157), and 62,148 (6424) pg./mL, respectively. The AUC (geometric LS mean ratio for relative bioavailability) for arm versus abdomen was 0.93 (geometric 90% CI, 0.82-1.05); for thigh versus abdomen it was 0.97 (geometric 90% CI, 0.86-1.10). Consistent with the observed data, intrasubject variability of AUC(0-infinity) was low among the 3 treatments (coefficient of variation, 26%). C(max) values (geometric LS mean [SE]) were 220 (24) pg/mL, abdomen; 218 (23) pg/mL, arm; and 193 (21) pg/mL, thigh. The C(max) (geometric LS mean ratio) for arm versus abdomen was 0.99 (geometric 90% CI, 0.85-1.15), and for thigh versus abdomen it was 0.88 (geometric 90% CI, 0.75-1.02). The most common treatment-emergent adverse events were mild to moderate nausea (36%), headache (25%), vomiting (21%), and dizziness (18%). Three patients received an inadvertent 10-fold overdose and were withdrawn from the study immediately. All experienced severe nausea and vomiting, and 1 patient experienced severe hypoglycemia requiring aid. All recovered without mishap and were excluded from statistical and tolerability results. There were no adverse events related to the injection or the injection site. CONCLUSION: In this study of patients with type 2DM, SC administration of exenatide into the abdomen, arm, or thigh resulted in comparable bioavailability.     

The abdomen, thigh, and arm as sites for subcutaneous sodium heparin injections.

The purpose of this study was to evaluate three subcutaneous injection sites for low-dose heparin therapy (5,000 units). One hundred and one subjects were randomly placed in one of three groups. Group A received injections in the abdomen, Group B, in the thigh, and Group C in the arm. Each subject received three injections at the one site. Activated partial thromboplastin time (APTT) was measured prior to initiation of heparin and again four hours after the first injection. Bruising was measured at 48, 60, and 72 hours postinjection. There were no statistically significant differences among groups for either changes in APTT or bruising at 60 and 72 hours postinjection. Thus the clinical practice of utilizing the abdomen as the only or preferred site for subcutaneous heparin injections was not supported.     

Evaluation of the comfort of Alphagan® P compared with Alphagan® in irritated eyes

The tolerability of brimonidine tartrate 0.15%--referred to as bromonidine-Purite 0.15% in this study--was compared with brimonidine tartrate 0.2% in irritated eyes of healthy volunteers as well as patients with glaucoma or ocular hypertension (N=20) in a 2-week, single-center, randomized, double-masked, crossover study. Participants were evaluated at days 0, 7, 11, and 15. At day 0, they were exposed to a controlled adverse environment (CAE), in which humidity, temperature, and airflow was regulated, for up to 90 minutes. Participants who reported a sufficient level of bilateral ocular discomfort during exposure to the CAE were enrolled in this study and received 1 drop of brimonidine-Purite 0.15% in 1 eye and 1 drop of brimonidine tartrate 0.2% in the contralateral eye. Immediately following instillation, participants were asked to indicate their preference for either study medication. The study medications were not used between days 0 and 7. From day 7 to 10, participants administered either drug bilaterally. On day 11, the treatment was crossed over, and participants were asked to compare the preferred medication with their previous regimen. They continued to administer the drug bilaterally twice daily until day 15, when the preferred medication was again compared with the previous regimen. Following CAE exposure at visit 1, 70.6% of the participants preferred brimonidine-Purite 0.15% over brimonidine tartrate 0.2% and indicated that it was significantly more comfortable than brimonidine tartrate 0.2% (P=.009). When given brimonidine-Purite 0.15% first before switching to brimonidine tartrate 0.2%, 80% of participants preferred brimonidine-Purite 0.15% (P=.012). When given brimonidine tartrate 0.2% first before switching to brimonidine-Purite 0.15%, 85% preferred brimonidine-Purite 0.15% (P=.001). The results of this study suggest that brimonidine-Purite 0.15% is significantly more comfortable than brimonidine tartrate 0.2% in patients with irritated eyes.     

Daptomycin lock therapy for grampositive long-term catheter-related bloodstream infections

Introduction: To evaluate the efficacy of Daptomycin (DPT) lock therapy in the treatment of Grampositive long‐term catheter‐related bloodstream infections (LT‐CRBI). Patients and methods: A retrospective review of all patients receiving DPT lock therapy for the treatment of LT‐CRBI from December 2009 to May 2010 was conducted. The primary endpoint used in this study was failure to cure the episode of LT‐CRBI. Cure was defined as fever disappearance, negative blood cultures within 1 month after the end of treatment, and catheter salvage. Results: Thirteen subjects (seven men, mean age 62 years) were evaluated. There were six Staphylococcus epidermidis, two Staphylococcus hominis, one Staphylococcus haemolyticus, two Enterococcus faecalis and two polymicrobial (S. epidermidis and S. hominis) bloodstream infections. DPT lock therapy was administered for a mean of 14 days (interquartilic range 10–14). Intravenous DPT was administered in nine patients for a mean of 10 days (interquartilic range 5–11). Clinical cure and blood culture sterilisation occurred in 11 of 13 patients (85%). Two patients had fever during treatment and catheters were removed. Median length of follow‐up in patients with therapeutic success was 67 days (interquartilic range 14–88). Conclusion: DPT lock therapy demonstrated good in vivo efficacy in LT‐CRBI caused by coagulase negative staphylococci and Enterococcus species.     

Spinal kappa receptor-mediated analgesia of E-2078, a systemically active dynorphin analog, in mice.

E-2078 ([N-methyl-Tyr1, N-methyl-Arg7, D-Leu8]dynorphin A (1-8) ethylamide) is a systematically active dynorphin analog. We examined the sites of action of analgesia induced by systemic application of E-2078 compared with morphine in mice. When administered either intracerebroventricularly or intrathecally, E-2078 produced maximal dose-dependent analgesia in the tail-pinch, tail-flick and formalin tests. Its peak effect was observed 15 min after both injections, contrasted with a slow peak (120 min) by subcutaneous injection. The intrathecal site was relatively more sensitive than the intracerebroventricular site and many times more sensitive than the subcutaneous route. In contrast, morphine was equipotent when given intracerebroventricularly and intrathecally. When E-2078 was administered subcutaneously and naloxone or nor-binaltorphine were given either intracerebroventricularly or intrathecally, the analgesic action of E-2078 was most potently and totally reversed by intrathecal injection of nor-binaltorphimine. Intracerebroventricular and intrathecal injections of naloxone were equally effective for antagonism of morphine-analgesia. These data indicate that systemically administered E-2078 produces analgesia via central actions, in which the activation of the spinal kappa receptors is most important.     

Comparison of upper arm and forearm blood pressure

The upper arm is the primary site used to obtain a blood pressure measurement (BPM); however, when it is not possible to use the upper arm, the forearm is a commonly used alternate site. This study determines if there is a significant difference between upper arm and forearm BPMs among adults and examines the relationship of participant characteristics to the BPM difference. A convenience sample was recruited from a low-income, independent-living, 104-apartment complex in the Midwest. Of the 106 participants, 64% were female and 89% were White. Ages ranged from 20 to 85 years (M = 50.7). The investigators calculated the BMIs (range = 18 to 42, M = 29.3, SD = 5.4) for the 89% (n = 94) of participants who reported their weight. The forearm tended to have higher BPMs than the upper arm (M difference = 4.0 mm Hg systolic, 2.3 mm Hg diastolic). However, site differences were greatest for men, obese adults, and middle aged (36 to 65) adults.     

Responses of tolerant and nontolerant Staphylococcus aureus strains to methicillin treatment in an experimental infection in mice.

Staphylococcus aureus strains can be divided into tolerant and nontolerant strains on the basis of their survival in vitro in the presence of high concentrations of methicillin (greater than or equal to 64 micrograms/ml). A strain is defined as tolerant if more than 2% of the inoculum survives under these conditions. The response of five susceptible and five tolerant S. aureus strains to treatment with methicillin was studied in an experimental thigh infection in mice. Animals were treated with one and two injections of methicillin (2.5 mg per mouse). At the end of treatment, the number of CFUs in the thigh muscles infected with the susceptible strains was found to be significantly lower than that in the thigh muscles infected with the tolerant