Efficacy and Safety of Donidalorsen for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25. RESULTS: A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity. CONCLUSIONS: Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.).

A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381). METHODS: In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments. RESULTS: Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen. CONCLUSION: The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.

Clinical Progress in Hepatic Targeting for Novel Prophylactic Therapies in Hereditary Angioedema.

Hereditary angioedema (HAE) is typically caused by a deficiency of the protease inhibitor C1 inhibitor (C1INH). The absence of C1INH activity on plasma kallikrein and factor XIIa leads to overproduction of the vasoactive peptide bradykinin, with resulting angioedema. As the primary site of C1INH and prekallikrein production, the liver is recognized as an important therapeutic target in HAE, leading to the development of hepatic-focused treatment strategies such as GalNAc-conjugated antisense technology and gene modification. This report reviews currently available data on hepatic-focused interventions for HAE that have advanced into human trials. Donidalorsen is an investigational GalNAc3-conjugated antisense oligonucleotide that binds to prekallikrein mRNA in the liver and reduces the expression of prekallikrein. Phase 2 data with subcutaneous donidalorsen demonstrated a significant reduction in HAE attack rate compared with placebo. Phase 3 trials are underway. ADX-324 is a GalNAc3-conjugated short-interfering RNA being investigated in HAE. BMN 331 is an investigational AAV5-based gene therapy vector that expresses wild-type human C1INH and is targeted to hepatocytes. A single intravenous dose of BMN 331 is intended to replace the defective SERPING1 gene and enable patients to produce functional C1INH. A first-in-human phase 1/2 study is ongoing with BMN 331. NTLA-2002 is an investigational in vivo clustered regularly interspaced short palindromic repeats/Cas9-based therapy designed to knock out the prekallikrein-coding KLKB1 gene in hepatocytes; a phase 1/2 study is ongoing. Findings from these and other ongoing studies are highly anticipated with the expectation of expanding the array of treatment options in HAE.

A thrombophilic allele of clotting Factor VII/VIIa promoting recurrent pulmonary emboli, clinical details, and a structural model of the altered protein: a case report.

BACKGROUND: The clotting or hemostasis system is a meticulously regulated set of enzymatic reactions that occur in the blood and culminate in formation of a fibrin clot. The precisely calibrated signaling system that prevents or initiates clotting originates with the activated Factor Seven (FVIIa) complexed with tissue factor (TF) formed in the endothelium. Here we describe a rare inherited mutation in the FVII gene which is associated with pathological clotting. CASE PRESENTATION: The 52-year-old patient, with European, Cherokee and African American origins, FS was identified as having low FVII (10%) prior to elective surgery for an umbilical hernia. He was given low doses of NovoSeven (therapeutic Factor VIIa) and had no unusual bleeding or clotting during the surgery. In fact, during his entire clinical course he had no unprovoked bleeding. Bleeding instances occurred with hemostatic stresses such as gastritis, kidney calculus, orthopedic surgery, or tooth extraction, and these were handled without factor replacement. On the other hand, FS sustained two unprovoked and life-threatening instances of pulmonary emboli, although he was not treated with NovoSeven at any time close to the events. Since 2020, he has been placed on a DOAC (Direct Oral Anticoagulant, producing Factor Xa inhibition) and has sustained no further clots. POSSIBLE MECHANISM OF (UNAUTHORIZED) FVII ACTIVATION: FS has a congenitally mutated FVII/FVIIa gene, which carries a R315W missense mutation in one allele and a mutated start codon (ATG to ACG) in the other allele, thus rendering the patient effectively homozygous for the missense FVII. Structure based comparisons with known crystal structures of TF-VIIa indicate that the patient's missense mutation is predicted to induce a conformational shift of the C170's loop due to crowding of the bulky tryptophan to a distorted "out" position (Fig. 1). This mobile loop likely forms new interactions with activation loop 3, stabilizing a more active conformation of the FVII and FVIIa protein. The mutant form of FVIIa may be better able to interact with TF, displaying a modified serine protease active site with enhanced activity for downstream substrates such as Factor X. CONCLUSIONS: Factor VII can be considered the gatekeeper of the coagulation system. Here we describe an inherited mutation in which the gatekeeper function is altered. Instead of the expected bleeding manifestations resulting from a clotting factor deficiency, the patient FS suffered clotting episodes. The efficacy of the DOAC in treating and preventing clots in this unusual situation is due to its target site of inhibition (anti-Xa), which lies downstream of the site of action of FVIIa/TF.

Inhibition of Prekallikrein for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is characterized by recurrent and unpredictable swellings that are disabling and potentially fatal. Selective inhibition of plasma prekallikrein production by antisense oligonucleotide treatment (donidalorsen) may reduce the frequency of attacks and the burden of disease. METHODS: In this phase 2 trial, we randomly assigned, in a 2:1 ratio, patients with hereditary angioedema with C1 inhibitor deficiency to receive four subcutaneous doses of either donidalorsen (80 mg) or placebo, with one dose administered every 4 weeks. The primary end point was the time-normalized number of investigator-confirmed angioedema attacks per month (attack rate) between week 1 (baseline) and week 17. Secondary end points included quality of life, as measured with the Angioedema Quality of Life Questionnaire (scores range from 0 to 100, with higher scores indicating worse quality of life), and safety. RESULTS: A total of 20 patients were enrolled, of whom 14 were randomly assigned to receive donidalorsen and 6 to receive placebo. The mean monthly rate of investigator-confirmed angioedema attacks was 0.23 (95% confidence interval [CI], 0.08 to 0.39) among patients receiving donidalorsen and 2.21 (95% CI, 0.58 to 3.85) among patients receiving placebo (mean difference, -90%; 95% CI, -96 to -76; P<0.001). The mean change from baseline to week 17 in the Angioedema Quality of Life Questionnaire score was -26.8 points in the donidalorsen group and -6.2 points in the placebo group (mean difference, -20.7 points; 95% CI, -32.7 to -8.7). The incidence of mild-to-moderate adverse events was 71% among patients receiving donidalorsen and 83% among those receiving placebo. CONCLUSIONS: Among patients with hereditary angioedema, donidalorsen treatment resulted in a significantly lower rate of angioedema attacks than placebo in this small, phase 2 trial. (Funded by Ionis Pharmaceuticals; ISIS 721744-CS2 ClinicalTrials.gov number, NCT04030598.).

Efficacy and safety of a first-in-class inhaled PDE3/4 inhibitor (ensifentrine) vs salbutamol in asthma.

INTRODUCTION: This study aimed to investigate the dose-response and pharmacology of a range of single doses of nebulised ensifentrine (RPL554), an inhaled dual phosphodiesterase (PDE) 3/4 inhibitor in patients with asthma. METHODS: In this randomised, placebo-controlled, double-blind crossover study, patients received single nebulised doses of ensifentrine 0.4, 1.5, 6 and 24 mg, salbutamol 2.5 and 7.5 mg, and placebo. Eligible patients were adults with asthma, pre-bronchodilator forced expiratory volume in 1 s (FEV1) 60-90% predicted and ≥1.5 L, with post-salbutamol FEV1 increase ≥15%. The co-primary objectives were peak and average FEV1 over 12 h for ensifentrine vs placebo and salbutamol. Secondary endpoints included: peak and average systolic and diastolic blood pressure, pulse rate and ECG heart rate; and safety and tolerability (adverse events [AEs], and serum potassium). ClinicalTrials.gov: NCT02427165. RESULTS: A total of 29 patients were randomised, with 25 (89%) completing the study. For the two co-primary endpoints there was a clear ensifentrine dose-response relationship, with all treatments superior to placebo (p < 0.001). There was no relationship between the ensifentrine dose and AE incidence or blood pressure. Ensifentrine 0.4, 1.5 and 6 mg had significantly lower effects than both salbutamol doses on pulse and heart rates. Ensifentrine did not impact potassium, whereas there was a was a dose-related reduction for salbutamol. Inhalation of ensifentrine resulted in a dose-related increase in plasma exposure. CONCLUSIONS: Single-dose ensifentrine demonstrated dose-dependent bronchodilation, and was as effective as a therapeutic dose of nebulised salbutamol. All ensifentrine doses were similarly well tolerated, and did not show the characteristic ß2-agonist systemic adverse effects.

The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD.

We investigated the short-term bronchodilator effects of RPL554 (an inhaled dual phosphodiesterase 3 and 4 inhibitor) combined with other bronchodilators in chronic obstructive pulmonary disease patients with reversibility (>150 mL to short-acting bronchodilators).Study 1 was a six-way, placebo-controlled crossover study (n=36) with single doses of RPL554 (6 mg), salbutamol (200 µg), ipratropium (40 µg), RPL554 (6 mg)+salbutamol (200 µg), RPL554 (6 mg)+ipratropium (40 µg) or placebo. Study 2 was a three-way crossover study (n=30) of tiotropium (18 µg) combined with RPL554 (1.5 or 6 mg) or placebo for 3 days. Forced expiratory volume in 1 s (FEV1), lung volumes and specific airway conductance (sG aw) were measured.In study 1, peak FEV1 change compared with placebo was similar with RPL554, ipratropium and salbutamol (mean 223, 199 and 187 mL, respectively). The peak FEV1 was higher for RPL554+ipratropium versus ipratropium (mean difference 94 mL; p<0.0001) and RPL554+salbutamol versus salbutamol (mean difference 108 mL; p<0.0001). In study 2 (day 3), both RPL554 doses caused greater peak FEV1 effects than placebo. The average FEV1 (0-12 h) increase was greater with RPL554 6 mg only versus placebo (mean difference 65 mL; p=0.0009). In both studies, lung volumes and sG aw showed greater RPL554 combination treatment effects versus monotherapy.RPL554 combined with standard bronchodilators caused additional bronchodilation and hyperinflation reduction.

Therapeutic equivalence of triamcinolone acetonide hydrofluoroalkane and chlorofluorocarbon nasal inhalers in patients with seasonal allergic rhinitis.

BACKGROUND: Triamcinolone acetonide (TAA) has been reformulated as an hydrofluoroalkane (HFA) aerosol for intranasal use in patients with seasonal allergic rhinitis (SAR). This study compared the TAA HFA formulation with the previously available chlorofluorocarbon (CFC) nasal inhaler in a dose-ranging study. METHODS: This was a double-blind, parallel-group, multicenter study in 780 adults with SAR. Patients had a history of fall seasonal rhinitis and positive skin tests to ragweed. After meeting minimum symptom requirements during the run-in phase, patients were randomized to one of eight groups: TAA CFC or HFA at 14, 110, or 440 micrograms once daily or matching placebo. Treatment was continued for two weeks and patient completed a daily diary for reflective and instantaneous rating of nasal and ocular allergy symptoms. RESULTS: All active treatment groups were statistically superior to placebo with respect to the primary outcome variable, total nasal symptoms. Furthermore, the TAA HFA and TAA CFC formulations were statistically comparable over the dose range. Within each formulation, there was a significant mean reduction from baseline in the symptoms of rhinitis that increased with increasing dose. Ocular symptoms were also reduced with both formulations. Both preparations were well tolerated without any safety concerns. CONCLUSION: In conclusion, a new formulation of TAA with a HFA propellant was found to be effective in the treatment of SAR and comparable with the previously available TAA CFC formulation. There was a dose response to TAA, with doses as low as 7 micrograms per nostril once daily producing statistically significant improvement in rhinitis symptoms.

Linear growth and bone maturation are unaffected by 1 year of therapy with inhaled flunisolide hydrofluoroalkane in prepubescent children with mild persistent asthma: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Inhaled corticosteroids (ICS) are the preferred long-term therapy for subjects with persistent asthma. However, concerns remain about potential effects of long-term ICS use on growth in children. OBJECTIVE: To determine the effect of 1 year of inhalation therapy with flunisolide hydrofluoroalkane (HFA) on growth velocity and bone maturation in children with mild persistent asthma. METHODS: In this double-blind, placebo-controlled study, 218 prepubescent (Tanner Stage 1) children with mild persistent asthma ranging in age from 4 to 10 years were evaluated. After a 2-week run-in period, subjects were randomized (1:1) to 2 puffs flunisolide HFA twice daily (85 µg/puff) or placebo for 52 weeks. Height was assessed by stadiometry at each visit. Growth velocity (cm/52 weeks) was estimated by the slope of the linear regression of height over time. An independent assessor scored hand and wrist radiographs for bone development pretreatment and at week 52. Analysis of covariance was used for all efficacy endpoints. RESULTS: The 2 treatment groups were similar at baseline for sex, race, age, weight, and height. At the end of double-blind treatment, mean growth velocity was 6.01 ± 1.84 cm/52 weeks for flunisolide HFA (n = 106) and 6.19 ± 1.30 cm/52 weeks for placebo (n = 112) (P = .425). Mean advancement in bone age during the 1-year study was similar for the 2 groups: 0.93 ± 0.46 years for flunisolide HFA (n = 70) and 1.01 ± 0.41 years for placebo (n = 75) (P = .128). CONCLUSIONS: In this study, flunisolide HFA did not suppress growth or bone maturation at the highest approved dose for children with persistent asthma.

Gastrointestinal surgery in alpacas and llamas.

The clinical signs associated with acute abdominal pain in South American camelids tend to be subtle and less frequent (similar to ruminants) as compared with that of horses. Abdominocentesis and transabdominal ultrasound are useful tools in determining the necessity of an exploratory laparotomy. Preoperative anticipation of the lesion location helps determine the surgical approach to the abdomen. Perioperative management is vital to improve chances for survival. Timely surgical intervention for correctable gastrointestinal lesions is expected to minimize postoperative complications and improve outcomes.

Fracture management in alpacas and llamas.

Camelids are considered to be excellent patients for the treatment of orthopedic injuries. Clients will usually opt for treatment because of the relative high commercial value of most camelids. For these reasons, the veterinary surgeon has a full repertoire of internal and external fixation techniques to choose from when determining the ideal repair option. Complications to fracture repair are frequent and include lameness, osteomyelitis, malunion, delayed union, nonunion, sequestrum formation, and implant failure. When irreversible damage to the neurovascular bundle has occurred, limb amputation, with or without a prosthetic device, may be an alternative to euthanizing the patient.

Bovine cesarean section in the field.

Cesarean section is perhaps one of the more challenging surgical procedures performed on the farm; the veterinarian often has far less control over the patient, availability of assistance, and environmental contaminants. A number of variables may affect the successful outcome of this procedure for both the calf and cow; case selection is the most important and often overlooked variable. In addition, patient and surgeon preparation, surgical technique, calf viability at the time of surgery, and exteriorizing the uterus can affect outcome. Good surgical technique including gentle tissue handling, appropriate suture materials and patterns, adequate infolding of the uterine incision to prevent leakage, combined with antibiotics and anti-inflammatory medication when indicated can help minimize detrimental adhesions that may adversely affect the future reproductive efficiency of the cow.

Minimally invasive field abomasopexy techniques for correction and fixation of left displacement of the abomasum in dairy cows.

To reduce the potential drawbacks associated with laparotomy techniques for correction and fixation of left displaced abomasums (LDA), minimally invasive techniques have been developed. This chapter reviews the toggle pin suture (TPS) and the laparoscopic abomasopexy procedures used in the field for correction and fixation of the abomasum for correction of left-displacement of the abomasum in dairy cows. The importance of case selection cannot be overestimated. By combining laparoscopy with the principle of the TPS procedure, the lack of visual control associated with the TPS procedure is eliminated, while the advantage of the speed of completion and minimal invasiveness provided by both procedures are maintained. Successful LDA treatment includes not only early detection and treatment of the LDA, but also the prevention of secondary ketosis and aggressive treatment of concurrent disease.

Humerus fractures in llamas and alpacas: seven cases (1998-2004).

OBJECTIVE: To describe treatment and outcome of humerus fractures in llamas and alpacas. STUDY DESIGN: Retrospective study. ANIMALS: Llamas (n=4) and alpacas (3) with humerus fracture. METHODS: Medical records (January 1, 1998-August 1, 2004) were reviewed for small camelids with a humeral fracture. Retrieved data were signalment, history, physical examination and radiographic findings, surgical and medical treatment, and outcome. RESULTS: Humeral fracture occurred in 7 of 38 (18%) camelids admitted with fractures. Affected animals were aged from 1 month to 3 years old. Fracture configuration included long-oblique (n=4), short-oblique (2), and Salter-Harris Type II fracture of the proximal physis (1). One adult llama was managed by stall confinement and surgical repair was attempted in the other camelids: fixation by screws inserted in lag fashion (n=3), intramedullary pinning and fixation by screws inserted in lag fashion (1), rush pinning (1), and bone plating (1). A Velpeau sling was used for additional support in 3 animals. All fractures healed but temporary radial nerve paresis occurred in 3 animals. Limb shortening and permanent lameness occurred in the llama managed conservatively. CONCLUSIONS: Humerus fractures in small camelids are amenable to surgical repair which may offer better long-term outcome than medical treatment alone. CLINICAL RELEVANCE: Surgical treatment of humerus fractures should have a good prognosis in llamas and alpacas. In select cases, minimally invasive techniques, such as rush pinning or fixation by screws inserted in lag fashion are sufficient for fracture healing.

Therapeutic action in self psychology.

The author summarizes Kohut's principal theories and their implications for understanding therapeutic action. He notes that Kohut's model of self development can be applied to both healthy and pathological outcomes, and that this model necessitates modifications in classical psychoanalytic technique. A discussion of some of the many variations within self psychology includes elaborations of Kohut's beliefs that have been contributed by more recent theorists. The author also discusses the centrality of affects in the formation of psychic structure and the implications for technique of this theoretical construct.

Small airways response to naturalistic cat allergen exposure in subjects with asthma.

BACKGROUND: It is currently unclear whether the small airways (diameter <2 microm) contribute significantly to late asthmatic reactions to inhaled allergen. OBJECTIVES: We sought to determine whether naturalistic exposure to cat allergen induced late responses in the small airways as measured by pulmonary function testing and high-resolution computed tomography (HRCT) of the chest performed at end-expiration. METHODS: In a group of 10 subjects with cat-induced asthma, physiologic studies (spirometry and lung volumes, including closing volume) and HRCT were performed before and 6 and 23 hours after a cat room challenge that caused a 20% or greater acute fall in FEV(1). RESULTS: There was no significant decline in FEV(1) at 6 or 23 hours after cat exposure. Forced expiratory flow at 25% to 75% of forced vital capacity was significantly decreased at 6 hours after the challenge and returned to normal by 23 hours. HRCT image analysis as well as closing volume demonstrated increased air trapping from baseline at both 6 and 23 hours after the challenge. In addition, image analysis demonstrated a significant increase in small airways hyperresponsiveness to methacholine at 23 hours after the challenge. No significant mean changes were noted in lung volumes at either 6 or 23 hours or in PC(20) FEV(1) at 23 hours postchallenge. CONCLUSION: These findings demonstrate that naturalistic exposure to cat allergen results in significant small airways obstruction and hyperresponsiveness persisting for at least 23 hours, at which time these changes cannot be detected by conventional physiologic measures. CLINICAL IMPLICATIONS: Physiologically silent distal lung inflammation persists after an antigenic challenge.

Evidence of remodeling in peripheral airways of patients with mild to moderate asthma: effect of hydrofluoroalkane-flunisolide.

BACKGROUND: We have shown previously that inflammation in asthma is not restricted to central airways but can also be demonstrated in peripheral airways. It is not clear whether inflammation of the peripheral airways is associated with structural changes and whether this remodeling process can be modulated by deposition of inhaled corticosteroids (ICSs). OBJECTIVES: To compare remodeling in peripheral and central airways and to investigate the effects of hydrofluoroalkane (HFA)-ICS on remodeling at these sites. METHODS: Transbronchial and endobronchial biopsies were obtained from 12 patients with mild to moderate asthma before and after a 6-week course of HFA-ICS (flunisolide). Total collagen deposition, expression of collagen III, TGF-beta, and alpha-smooth muscle actin were examined by using Van Gieson staining and immunocytochemistry, respectively. RESULTS: Total collagen occupied 37.7% of the wall area of peripheral airways, compared with 54.5% of the wall area of central airways (P = .04). There was no significant difference in central versus peripheral airways for collagen III or alpha-smooth muscle actin immunoreactivity and in the number of TGF-beta(+) cells in the submucosa. The only significant effect of HFA-flunisolide was a decrease in alpha-smooth muscle actin area in peripheral airways (13.4% vs 4.6%; P = .01) that correlated with the percentage increase in forced expiratory flow at 25% to 75% of vital capacity (r(s) = -1.00; P = .00). CONCLUSION: Our data show that there is a considerable degree of airway remodeling in peripheral airways in patients with asthma and confirm the inability of ICS to modulate collagen deposition and TGF-beta expression. Treatment with HFA-flunisolide is associated with a significant decrease in the expression of alpha-smooth muscle actin in peripheral airways, which correlated with improvement in peripheral airway function.

One-step laparoscopic abomasopexy for correction of left-sided displacement of the abomasum in dairy cows.

Four adult dairy cows in which a diagnosis of left-displaced abomasum (LDA) had been made underwent a 1-step laparoscopic abomasopexy (LA). The technique was performed with each cow positioned in dorsal recumbency. Two laparoscopic portals were created in the right paramedian area to identify the abomasum and direct insertion of the steel trocar and cannula into the abomasal lumen. A stainless steel toggle pin (with 2 lengths of suture attached to its midpoint) was inserted via the cannula into the abomasal lumen while the excess suture material remained exterior to the abdomen. The abomasum was deflated, and the excess suture material was withdrawn up to a preset marker on the suture to position the abomasum adjacent to the body wall. The suture was then tied to secure the abomasum in place. By use of this 1-step LA technique, LDA was successfully corrected in all 4 cows. The procedure is minimally invasive and allows viewing of the abomasum for correct positioning and fixation; it can be accomplished with the speed associated with the blind roll-and-tack technique. The 1-step LA technique may reduce the incidence of complications associated with traditional laparotomy and the blind roll-and-tack technique and could be a useful alternative procedure for the treatment of LDA in dairy cows.

Analgesic efficacy and tolerability of oxycodone 5 mg/ibuprofen 400 mg compared with those of oxycodone 5 mg/acetaminophen 325 mg and hydrocodone 7.5 mg/acetaminophen 500 mg in patients with moderate to severe postoperative pain: a randomized, double-blind, placebo-controlled, single-dose, parallel-group study in a dental pain model.

BACKGROUND: Combination therapy has been widely used for the clinical management of acute pain. By combining 2 drugs with different mechanisms of action, such therapy provides additive analgesic effects while reducing the risk for adverse effects. OBJECTIVE: This study compared the efficacy and tolerability of oxycodone 5 mg/ibuprofen 400 mg with those of oxycodone 5 mg/acetaminophen 325 mg, hydrocodone 7.5 mg/acetaminophen 500 mg, and placebo in a dental pain model. METHODS: This was a multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group, single-dose study in patients experiencing moderate to severe pain after surgical removal of > or = 2 ipsilateral impacted third molars. Patients were randomly assigned to receive oxycodone 5 mg/ibuprofen 400 mg, oxycodone 5 mg/acetaminophen 325 mg, hydrocodone 7.5 mg/acetaminophen 500 mg, or placebo. The primary outcome measures were total pain relief through 6 hours after dosing (TOTPAR6), sum of pain intensity differences through 6 hours (SPID6), and adverse events. Secondary efficacy measures included SPID3 and TOTPAR3, peak pain relief, peak pain intensity difference, time to onset of pain relief, time to use of rescue medication, proportion of patients reporting pain half gone, and the patient's global evaluation. RESULTS: Two hundred forty-nine patients (43.5% male; 87.5% white; mean age, 19.1 years; mean body weight, 153.6 pounds) were randomized to treatment as follows: 62 to oxycodone 5 mg/ibuprofen 400 mg, 61 to oxycodone 5 mg/acetaminophen 325 mg, 63 to hydrocodone 7.5 mg/acetaminophen 500 mg, and 63 to placebo. Oxycodone 5 mg/ibuprofen 400 mg provided significantly greater analgesia compared with oxycodone 5 mg/acetaminophen 325 mg, hydrocodone 7.5 mg/acetaminophen 500 mg, and placebo (mean [SD] TOTPAR6, 14.98 [5.37], 9.53 [6.77], 8.36 [6.68], and 5.05 [6.49], respectively; P < 0.001, oxycodone 5 mg/ibuprofen 400 mg vs all other treatments). SPID6 values also differed significantly for oxycodone 5 mg/ibuprofen 400 mg compared with all other treatments (mean: 7.78 [4.11], 3.58 [4.64], 3.32 [4.73], and 0.69 [4.85]; P < 0.001). Oxycodone 5 mg/ibuprofen 400 mg was significantly more effective compared with the other treatments on all secondary end points (P < 0.001, all variables except peak PID vs oxycodone 5 mg/acetaminophen 325 mg [P = 0.006]), with the exception of the time to onset of analgesia. The lowest frequency of nausea and vomiting occurred in the groups that received oxycodone 5 mg/ibuprofen 400 mg (6.5% and 3.2%, respectively) and placebo (3.2% and 1.6%). Rates of nausea and vomiting were significantly lower with oxycodone 5 mg/ibuprofen 400 mg compared with oxycodone 5 mg/acetaminophen 325 mg (P = 0.011 and P = 0.009, respectively) but not with hydrocodone 7.5 mg/acetaminophen 500 mg. CONCLUSIONS: In this study in patients with moderate to severe pain after surgery to remove impacted third molars, oxycodone 5 mg/ibuprofen 400 mg provided significantly better analgesia throughout the 6-hour study compared with the other opioid/nonopioid combinations tested, and was associated with fewer adverse events.