"Cost-effectiveness of ACL treatment is dependent on age and activity level: a systematic review".

PURPOSE: To systematically review the literature on health-economic evaluations of anterior cruciate ligament (ACL) injury between reconstruction surgery (ACLR) and non-operative treatment (NO) and suggest the most cost-effective strategy between the two. METHODS: All economic studies related to ACLR versus NO post-ACL injury, either trial based or model based, published until April 2022, were identified using PubMed and Embase. The methodology of the health-economic analysis for each included study was categorized according to the four approaches: cost-minimization analysis (CMA), cost-effectiveness analysis (CEA), cost-benefit analysis (CBA), and cost-utility analysis (CUA). The quality of each included study was assessed using the Consensus on Health Economic Criteria (CHEC) list. RESULTS: Of the seven included studies, two compared the strategies of early ACLR and NO alone, and five compared early ACLR and NO with optional delayed ACLR. All studies performed a CUA, and one study performed a CBA additionally. The CHEC scores of the included studies can be considered good, ranging from 15 to 18 from a maximum of 19. Applying the common standard threshold of $50,000 per QALY, six studies in young people with high-activity levels or athletes showed that early ACLR would be preferred over either NO alone or delayed ACLR. Of six studies, two even showed early ACLR to be the dominant strategy over either NO alone or delayed ACLR, with per-patient cost savings of $5,164 and $1,803 and incremental per-patient QALY gains of 0.18 and 0.28, respectively. The one study in the middle-aged people with a moderate activity level showed that early ACLR was not more cost-effective than delayed ACLR, with ICER $101,939/QALY using the societal perspective and ICER $63,188/QALY using the healthcare system perspective. CONCLUSION: Early ACLR is likely the more cost-effective strategy for ACL injury cases in athletes and young populations with high-activity levels. On the other hand, non-operative treatment with optional delayed ACLR may be the more cost-effective strategy in the middle age population with moderate activity levels. LEVEL OF EVIDENCE: Systematic review of level III studies.

Anterolateral proximal tibial opening wedge osteotomy for biplanar correction in genu valgum recurvatum using patient specific instrumentation (PSI). A technical note.

BACKGROUND: Biplanar anterolateral proximal tibial opening wedge osteotomy has been described as successful for patients with combined recurvatum and valgus alignment. As it is a correction in two planes, it is a technically demanding procedure. We report the use of a novel technique with patient specific instrumentation (PSI) guides for different steps, aiming to reduce the complexity of this procedure. METHODS: One patient was treated for genu valgum recurvatum. A virtual surgical plan was made. A two-step PSI approach was used, consisting of an osteotomy guide and a repositioning guide and a custom trial wedges. RESULTS: Follow-up showed full function and improved VAS and KOOS scores. A neutral alignment was achieved. There was 2.76 degrees less varus compared to pre-operative planning, 1.24 degrees of excess slope and a rotational difference of 0.10 degrees. Saw plane accuracy was within 1 mm. CONCLUSIONS: PSI is a recent technical addition to HTOs as a modality to improve accuracy and reduce surgical complexity. Pre-planning and PSI use in an anterolateral opening wedge PTO allowed for an accurate and reproducible biplanar correction in genu valgum recurvatum. Accuracy was comparable to PSI use in lateral open wedge high tibial osteotomies.

Isolated lateral extra-articular tenodesis enhance better rotatory knee joint stability post-primary ACL repair: Four cases report and literature review.

INTRODUCTION AND IMPORTANCE: Residual rotatory instability has been reported to occur after primary anterior cruciate ligament reconstruction. The anterolateral ligament complex of the knee has gained attention for its role in rotational instability of the knee, especially in association with anterior cruciate ligament injuries. The role of an isolated lateral extra-articular tenodesis procedure among those patients presenting with residual rotatory instability after primary anterior cruciate ligament reconstruction has not been reported on. CASE PRESENTATION: Four patients (Tegner level 4) presenting with residual rotatory instability after primary anterior cruciate ligament reconstruction without signs of graft failure, underwent an isolated lateral extra-articular tenodesis with modified Lemaire procedure. Pre- and postoperative outcome scores were assessed. At one-year follow-up, all patients reported functional knee stability. Pivot shift tests were negative and postoperative Lysholm scores were increased with a mean of 19.75 points. Tegner scores equaled the preinjury level. CLINICAL DISCUSSION: This case report showed that our four patients where successfully treated with an isolated secondary modified Lemaire procedure for residual anterolateral rotatory instability after primary anterior cruciate ligament reconstruction. CONCLUSION: An isolated secondary lateral extra-articular tenodesis procedure can be a valuable treatment option for moderate active patients with residual rotatory instability after a primary anterior cruciate ligament reconstruction without signs of graft failure.

Intraoperative ultrasound guidance in breast-conserving surgery shows superiority in oncological outcome, long-term cosmetic and patient-reported outcomes: Final outcomes of a randomized controlled trial (COBALT).

BACKGROUND: The multicenter randomized controlled COBALT trial demonstrated that ultrasound-guided breast-conserving surgery (USS) results in a significant reduction of margin involvement (3.1% vs. 13%) and excision volumes compared to palpation-guided surgery (PGS). The aim of the present study was to determine long term oncological and patient-reported outcomes including quality of life (QoL), together with their progress over time. METHODS: 134 patients with T1-T2 breast cancer were randomized to USS (N = 65) or PGS (N = 69). Cosmetic outcomes were assessed with the Breast Cancer Conservative Treatment cosmetic results (BCCT.core) software, panel-evaluation and patient self-evaluation on a 4-point Likert-scale. QoL was measured using the EORTC QLQ-C30/-BR23 questionnaire. RESULTS: No locoregional recurrences were reported after mean follow-up of 41 months. Seven patients (5%) developed distant metastatic disease (USS 6.3%, PGS 4.4%, p = 0.466), of whom six died of disease (95.5% overall survival). USS achieved better cosmetic outcomes compared to PGS, with poor outcomes of 11% and 21% respectively, a result mainly attributable to mastectomies due to involved margins following PGS. There was no difference after 1 and 3 years in cosmetic outcome. Dissatisfied patients included those with larger excision volumes, additional local therapies and worse QoL. Patients with poor/fair cosmetic outcomes scored significantly lower on aspects of QoL, including breast-symptoms, body image and sexual enjoyment. CONCLUSION: By significantly reducing positive margin status and lowering resection volumes, USS improves the rate of good cosmetic outcomes and increases patient-satisfaction. Considering the large impact of cosmetic outcome on QoL, USS has great potential to improve QoL following breast-conserving therapy.

Pseudotumour incidence, cobalt levels and clinical outcome after large head metal-on-metal and conventional metal-on-polyethylene total hip arthroplasty: mid-term results of a randomised controlled trial.

We compared the incidence of pseudotumours after large head metal-on-metal (MoM) total hip arthroplasty (THA) with that after conventional metal-on-polyethylene (MoP) THA and assessed the predisposing factors to pseudotumour formation. From a previous randomised controlled trial which compared large head (38 mm to 60 mm) cementless MoM THA with conventional head (28 mm) cementless MoP THA, 93 patients (96 THAs: 41 MoM (21 males, 20 females, mean age of 64 years, standard deviation (sd) 4) and 55 MoP (25 males, 30 females, mean age of 65 years, sd 5) were recruited after a mean follow-up of 50 months (36 to 64). The incidence of pseudotumours, measured using a standardised CT protocol was 22 (53.7%) after MoM THA and 12 (21.8%) after MoP THA. Women with a MoM THA were more likely to develop a pseudotumour than those with a MoP THA (15 vs 7, odds ratio (OR) = 13.4, p < 0.001). There was a similar incidence of pseudotumours in men with MoM THAs and those with MoP THAs (7 vs 5, OR = 2.1, p = 0.30). Elevated cobalt levels (≥ 5 microgram/L) were only associated with pseudotumours in women with a MoM THA. There was no difference in mean Oxford and Harris hip scores between patients with a pseudotumour and those without. Contrary to popular belief, pseudotumours occur frequently around MoP THAs. Women with a MoM THA and an elevated cobalt level are at greatest risk. In this study, pseudotumours had no effect on the functional outcome after either large head MoM or conventional MoP THA.

Intramodality and intermodality agreement in radiography and computed tomography of equine distal limb fractures.

REASONS FOR PERFORMING STUDY: Computed tomography (CT) is increasingly accessible in equine referral hospitals. OBJECTIVES: To document the level of agreement within and between radiography and CT in characterising equine distal limb fractures. STUDY DESIGN: Retrospective descriptive study. METHODS: Images from horses that underwent radiographic and CT evaluation for suspected distal limb fractures were reviewed, including 27 horses and 3 negative controls. Using Cohen's kappa and weighted kappa analysis, the level of agreement among 4 observers for a predefined set of diagnostic characteristics for radiography and CT separately and for the level of agreement between the 2 imaging modalities were documented. RESULTS AND CONCLUSIONS: Both CT and radiography had very good intramodality agreement in identifying fractures, but intermodality agreement was lower. There was good intermodality and intramodality agreement for anatomical localisation and the identification of fracture displacement. Agreement for articular involvement, fracture comminution and fracture fragment number was towards the lower limit of good agreement. There was poor to fair intermodality agreement regarding fracture orientation, fracture width and coalescing cracks; intramodality agreement was higher for CT than for radiography for these features. POTENTIAL RELEVANCE: Further studies, including comparisons with surgical and/or post mortem findings, are required to determine the sensitivity and specificity of CT and radiography in the diagnosis and characterisation of equine distal limb fractures.

Morphology of distal border synovial invaginations of the equine distal sesamoid bone: comparison between computed tomography and a hoof-specific radiographic projection.

OBJECTIVES: To compare the difference and agreement of the morphology of distal border synovial invaginations on a dorsoproximal-palmarodistal oblique (DPr-PaDiO) projection with hoof-specific angle versus computed tomography. METHODS: Computed tomography (CT) images and a DPr-PaDiO radiographic projection with hoof-specific angle were obtained on 50 cadaveric forefeet from 25 Warmblood horses. Computed tomography was assumed to be the gold standard. The number, shape and depth of penetration of distal border synovial invaginations into the distal sesamoid bone were evaluated with both methods, and the comparison of their measurements was statistically described. RESULTS: Significantly more invaginations were seen on CT compared to radiography, with an observed average difference of 1.2. In none of the cases did radiography have a higher number than that observed with CT. No statistically significant difference for depth between CT and the DPr-PaDiO projection was seen, however, there was quite a large variation of the actual difference of measurements against their mean found. Radiography was underestimated when high mean values applied. The agreement between both modalities for shape was moderate to good. A very high specificity of the specific DPr-PaDiO projection for shape was found (97%). CLINICAL SIGNIFICANCE: The radiographic projection with hoof-specific angle differs significantly from CT concerning the number and depth of the distal border synovial invaginations. Therefore, this specific view may not be considered useful in the evaluation of these invaginations.

Differences in the morphology of distal border synovial invaginations of the distal sesamoid bone in the horse as evaluated by computed tomography compared with radiography.

REASONS FOR PERFORMING STUDY: Distal border synovial invaginations of the distal sesamoid bone are radiographically assessed during the selection process of horses admitted as breeding stallions or in purchase examinations. Nowadays, many moderately or some deeply penetrating proximally enlarged synovial invaginations are considered as moderate or severe radiographic findings. OBJECTIVE: To measure the difference between and agreement of the morphology of distal border synovial invaginations on radiography vs. computed tomography (CT). It was hypothesised that the morphology of distal border synovial invaginations would be better evaluable on CT compared with radiography. METHODS: Computed tomography scans and 3 dorsoproximal-palmarodistal oblique (DPr-PaDiO) radiographs were obtained on 50 cadaver forefeet from 25 Warmblood horses. Computed tomography was assumed to be the gold standard. The number, shape and depth of penetration of distal border synovial invaginations into the distal sesamoid bone were evaluated with both methods, and the comparison of their measurements was statistically described. RESULTS: A statistically significant mean difference for number of distal synovial invaginations between CT and all 3 DPr-PaDiO projections was found and was approximately equal to 2, meaning that CT permits visualisation of an average of 2 more invaginations than radiography. In none of the cases did radiography have a higher number observed than CT. A large variation in the difference of measurements for depth of penetration against their mean difference between CT and the 3 radiographic projections was seen. Radiography underestimated the depth of invaginations, and more so when these were deeper. There was no statistically significant mean difference found between the techniques for depth. A moderate to good agreement between measurements on CT and the three DPr-PaDiO projections for shape was seen, in which the D55°Pr-PaDiO projection showed the best agreement. A high specificity (90-99%) and low sensitivity (65%) for all projections for shape were found. CONCLUSIONS AND POTENTIAL RELEVANCE: Radiography differs considerably from CT concerning the morphology of distal navicular border synovial invaginations. For the evaluation of the number, depth and shape of distal synovial invaginations in the distal sesamoid bone, radiography shows only partially the morphology seen on CT.

A comparison of three methods for nonpalpable breast cancer excision.

AIMS: To evaluate the efficacy of three methods of breast-conserving surgery (BCS) for nonpalpable invasive breast cancer in obtaining adequate resection margins and volumes of resection. MATERIALS AND METHODS: A total of 201 consecutive patients undergoing BCS for nonpalpable invasive breast cancer between January 2006 and 2009 in four affiliated institutions was retrospectively analysed. Patients with pre-operatively diagnosed primary or associated ductal carcinoma in situ (DCIS), multifocal disease, or a history of breast surgery or neo-adjuvant treatment were excluded from the study. The resections were guided by wire localisation (WL), ultrasound (US), or radio-guided occult lesion localisation (ROLL). The pathology reports were reviewed to determine oncological margin status, as well as tumour and surgical specimen sizes. The optimal resection volume (ORV), defined as the spherical tumour volume with an added 1.0-cm margin, and the total resection volume (TRV), defined as the corresponding ellipsoid, were calculated. By dividing the TRV by the ORV, a calculated resection ratio (CRR) was determined to indicate the excess tissue resection. RESULTS: Of all 201 excisions, 117 (58%) were guided by WL, 52 (26%) by US, and 32 (16%) by ROLL. The rate of focally positive and positive margins for invasive carcinoma was significantly lower in the US group (N = 2 (3.7%)) compared to the WL (N = 25 (21.3%)) and ROLL (N = 8 (25%)) groups (p = 0.023). The median CRRs were 3.2 (US), 2.8 (WL) and 3.8 (ROLL) (WL versus ROLL, p < 0.05), representing a median excess tissue resection of 3.1 times the optimal resection volume. CONCLUSION: US-guided BCS for nonpalpable invasive breast cancer was more accurate than WL- and ROLL-guided surgery because it optimised the surgeon's ability to obtain adequate margins. The excision volumes were large in all excision groups, especially in the ROLL group.

Computed tomographic morphology of the synovial invaginations of the distal sesamoid bone of the horse.

The morphological features of the distal border synovial invaginations (SI) of the distal sesamoid bone (DSB) in horses were described by the use of computed tomography (CT). Transverse CT images were obtained on 50 cadaver forefeet from 25 Warmblood horses. Dorsal and sagittal planes were reformatted. The CT images allowed the evaluation of the number, shape, depth of penetration and direction of the SI into the bone. The total number of SI was 295 (mean 5.9). The number of invaginations in a particular DSB ranged from 3 (n = 3), 4 (n = 6), 5 (n = 11), 6 (n = 12), 7 (n = 13), 8 (n = 3), 9 (n = 1) to 11 (n = 1). The shape of the SI was 'conical' (n = 118), 'linear' (n = 109), 'lollipop' (n = 38) or 'branched' (n = 30). Penetration of the SI into the DSB was 'mild' in 195 cases, 'moderate' in 67 cases and 'deep' in 33 cases. The SI ran in a 'straight', 'dorsoproximal' and 'palmaroproximal' direction in 187, 28 and 80 cases, respectively. In only six DSBs, all SI ran in the same direction. The images obtained in this study may serve as reference for the radiographic evaluation of these SI.

[Two patients with an isolated traumatic rupture of the subscapular tendon]. / Twee patiënten met een geïsoleerde traumatische subscapularispeesruptuur.

A man aged 65 and a woman aged 55 were referred to the orthopaedic clinic because of persistent pain in the right shoulder following a fall, 5 and 16 months earlier respectively. On physical examination they were found to have a painful shoulder and loss of strength on endorotation of the right arm. Ultrasound examination of the shoulder revealed subscapular tendon rupture in both patients, this was confirmed by MRI scan in the first patient. Treatment was operative repair of the tendon by a deltopectoral approach, followed by wearing a exorotation-limiting sling. After six months the first patient was free of complaints and the second patient was still experiencing pain when laying on the right shoulder. An isolated traumatic rupture of the subscapular tendon is uncommon and is often misdiagnosed or only discovered later. This diagnostic delay negatively influences the success of operative treatment. Focusing attention on the typical trauma mechanism, the character of the symptoms and the use of simple physical examination such as the lift-offtest or the belly press test can lead to the correct diagnosis.

Instillation of taurolidine/heparin after laparotomy reduces intraperitoneal tumour growth in a colon cancer rat model.

OBJECTIVE: To investigate whether irrigation of the abdominal cavity after laparotomy for caecum resection with taurolidine/heparin or adhesion prophylactic substances reduces intraperitoneal tumour growth or the local recurrence rate in a colon carcinoma rat model. METHODS: 60 BDIX rats underwent caecum resection after intraperitoneal inoculation of 1 x 10(4) colon carcinoma cells (DHD/K12/TRb). Intergel, Interceed, taurolidine/heparin or NaCl 0.9% were intraperitoneally applied after randomisation. Finally, the total number and total weight of intraperitoneal metastases were determined as well as the adhesion score according to Moreno. Metastatic tissue was examined histologically and immunohistochemically (E-cadherin, CD44, beta(1)-integrin). RESULTS: Taurolidine/heparin significantly reduced not only the total number (3 vs. 11 in the control group) but also the total weight (65 vs. 330 mg) of intraperitoneal metastases in comparison to the control group (p = 0.003 and p = 0.005). E-Cadherin expression in the metastatic tissue of animals treated with taurolidine/heparin was significantly decreased (p = 0.016). CONCLUSION: Taurolidine/heparin effectively reduces intraperitoneal tumour growth when used as an intraoperative lavage. These results represent a good rationale for intraoperative adjuvant irrigation with taurolidine/heparin during resection of colon cancer.

The influence of adhesion prophylactic substances and taurolidine/heparin on local recurrence and intraperitoneal tumor growth after laparoscopic-assisted bowel resection of colon carcinoma in a rat model.

BACKGROUND: The goal of the study was to investigate the influence of adhesion prophylactic substances (Interceed/lntergel) as well as taurolidine/heparin on intraperitoneal tumor growth and the local recurrence rate after laparoscopic cecum resection in a rat tumor model. METHODS: Sixty BDIX rats were randomized in three therapy groups and one control group. A laparoscopic-assisted cecum resection was performed via three-trocar method after intraperitoneal tumor cell application (10,000 cells) of a colon carcinoma cell line (DHD/K1/TRb) in all animals. According to the randomization, the cecum suture and a 1 x 1-cm peritoneal defect were either covered with Intergel/Interceed or 1 ml of 0.5% taurolidine 10 IU heparin. The control group underwent instillation of 1 ml 0.9% NaCl solution. After 4 weeks the animals were euthanized and intraperitoneal tumor growth, local recurrence rate, and the number of intraperitoneal adhesions were determined. RESULTS: The local recurrence rate was not significantly affected by any of the substances. Nevertheless, taurolidine/heparin significantly reduced the total number and weight of intraperitoneal metastases. The formation of adhesions was not significantly influenced by adhesion prophylaxis substances or by taurolidine/heparin. CONCLUSIONS: Taurolidine/heparin led to a significant reduction of intraperitoneal tumor growth after intraperitoneal application, whereas local tumor recurrence was not significantly influenced. This might be due to the number of injected tumor cells in this cell suspension model. Interceed and Intergel did not reduce intraperitoneal tumor growth. Furthermore, adhesion formation was not reduced by any of the substances.

[Colic surgery in the horse: a retrospective study of 272 patients]. / Koliekchirurgie bij het paard: een retrospectief onderzoek van 272 patiënten.

In the period from January 1995 until December 2000, 272 horses underwent a laparotomy for gastrointestinal disorders. The results of these surgeries were evaluated. From these 272 patients 176 (= 65%) were discharged in good health from the hospital. When the patients that were euthanized immediately after the start of the surgery, because of a fatal deterioration, were not taken into account, the short time survival rate was 77%. Strangulated small and large intestinal obstructions (48%) had a lower short time survival rate than non-strangulated obstructions (87%). Fatal postoperative complications occurred in 18% of the patients in which the surgery was completed. Postoperative shock was the most common cause. Non-fatal complications were found in 16% of the patients which survived surgery. The major non-fatal complications were incisional hernia and thrombophlebitis of the jugular vein. From the patients that survived the surgery 81% returned to their former level of performance. Early referral may decrease the percentage of fatal complications and improve the prognoses of surgery.

Role of nitric oxide in the airway response to exercise in healthy and asthmatic subjects.

A role of nitric oxide (NO) has been suggested in the airway response to exercise. However, it is unclear whether NO may act as a protective or a stimulatory factor. Therefore, we examined the role of NO in the airway response to exercise by using N-monomethyl-L-arginine (L-NMMA, an NO synthase inhibitor), L-arginine (the NO synthase substrate), or placebo as pretreatment to exercise challenge in 12 healthy nonsmoking, nonatopic subjects and 12 nonsmoking, atopic asthmatic patients in a double-blind, crossover study. Fifteen minutes after inhalation of L-NMMA (10 mg), L-arginine (375 mg), or placebo, standardized bicycle ergometry was performed for 6 min using dry air, while ventilation was kept constant. The forced expiratory volume in 1-s response was expressed as area under the time-response curve (AUC) over 30 min. In healthy subjects, there was no significant change in AUC between L-NMMA and placebo treatment [28.6 +/- 17.0 and 1.3 +/- 20.4 (SE) for placebo and L-NMMA, respectively, P = 0.2]. In the asthmatic group, L-NMMA and L-arginine induced significant changes in exhaled NO (P < 0.01) but had no significant effect on AUC compared with placebo (geometric mean +/- SE: -204.3 +/- 1.5, -186.9 +/- 1.4, and -318.1 +/- 1.2%. h for placebo, L-NMMA, and L-arginine, respectively, P > 0.2). However, there was a borderline significant difference in AUC between L-NMMA and L-arginine treatment (P = 0.052). We conclude that modulation of NO synthesis has no effect on the airway response to exercise in healthy subjects but that NO synthesis inhibition slightly attenuates exercise-induced bronchoconstriction compared with NO synthase substrate supplementation in asthma. These data suggest that the net effect of endogenous NO is not inhibitory during exercise-induced bronchoconstriction in asthma.

The effect of inhaled leukotriene D4 and methacholine on sputum cell differentials in asthma.

The cysteinyl leukotriene LTE4 has been shown to induce airway eosinophilia in asthmatics in vivo. This phenomenon has not yet been reported for LTD4. Hence, we examined the effect of inhaled LTD4 and a control bronchoconstrictor agent, methacholine, on cell differentials in hypertonic saline-induced whole sputum samples of 12 nonsmoking atopic asthmatic subjects (three women, nine men; 21 to 29 yr of age; FEV1, 74 to 120% pred; PC20FEV1 methacholine < 9.6 mg/ml). The study had a cross-over, placebo-controlled design consisting of 4 d separated by > or = 1 wk. On each randomized study day, the subjects inhaled five serial doses of either LTD4 (mean cumulative concentration: 95.7 microM) or methacholine (mean cumulative concentration: 542 mM) or five doses of their respective diluents (PBS/ethanol or PBS). The airway response was measured by FEV1, followed by sputum induction with 4.5% NaCl, 4 h postchallenge. Inflammatory cells (> or = 250) were counted twice on coded cytospins and expressed as percentages of nonsquamous cells. There was no significant difference in the maximal percent fall in FEV1 from baseline between LTD4 (mean +/- SEM, 49.5 +/- 4.4% fall) and methacholine (mean +/- SEM, 55.9 +/- 3.4% fall) (p = 0.11). LTD4 induced a significant increase in the percentage of sputum eosinophils as compared with its diluent (mean +/- SD, 26.6 +/- 21.3% and 10.2 +/- 8.8%, respectively; p = 0.025), whereas a similar trend for methacholine failed to reach significance (mean +/- SD, 19.1 +/- 22.9% and 7.8 +/- 5.8%, respectively; p = 0.11). There was no significant difference in the changes in the percentage of sputum eosinophils between LTD4 and methacholine (mean difference +/- SD, 7.5 +/- 12.5% eosinophils; p = 0.09). We conclude that LTD4 induces eosinophilia in sputum of asthmatic subjects 4 h after inhalation. Our data suggest that LTD4 recruits eosinophils into the airways of asthmatics in vivo, possibly by virtue of direct or indirect chemotactic properties, whereas an additional effect of vigourous airway narrowing per se cannot be excluded.

Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma.

Heparin possesses anti-inflammatory properties, which appeared to be dependent on the dose, timing, and the route of administration in animal studies. In asthma, a single dose of inhaled heparin only slightly reduced the early asthmatic response (EAR) but failed to protect against the late asthmatic response (LAR) to inhaled allergen. We studied the effect of multiple doses of inhaled heparin on the EAR and LAR to inhaled house-dust mite extract in eight stable asthmatics in a two-period, randomized, double-blind, crossover study. During both study periods, a standardized allergen challenge was performed and PC20 histamine was measured 24 h before and 24 h postallergen. Five doses of unfractionated heparin sodium (1,000 U/kg/dose) or placebo were inhaled 90 and 30 min preallergen, and 2, 4, and 6 h postallergen. Airway response was measured by FEV1, and the EAR (0-3 h) and LAR (3-10 h) were expressed as corresponding areas under the time-response curves (AUC). The acute effects of heparin and placebo on baseline FEV1 were not different (p > 0.07). Although not reaching significance, heparin attenuated the EAR by an average of 40% (mean AUC(0-3) +/- SEM: 29.5 +/- 6.0 [placebo] and 17.8 +/- 5.5% fall x h [heparin]; p = 0.08), while it significantly reduced the LAR by an average of 36% (AUC(3-10) +/- SEM: 169.3 +/- 20.0 [placebo] and 109.1 +/- 23.6% fall x h [heparin]; p = 0.005). We conclude that inhaled heparin reduces the LAR to allergen in asthmatic subjects, which may be due to its anti-inflammatory activity. Our finding suggests that heparin may have potential as anti-asthma therapy.

The effect of inhaled thiorphan on allergen-induced airway responses in asthmatic subjects.

BACKGROUND: Neuropeptides are likely to be implicated in the pathophysiology of allergen-induced airway responses. However, upon release in the airways, neuropeptides are potentially inactivated by neutral endopeptidase (NEP). OBJECTIVE: We hypothesized that NEP-inhibition by inhaled thiorphan (TH) would increase allergen-induced early (EAR) and late (LAR) asthmatic responses, and allergen-induced airway hyperresponsiveness to histamine in asthmatic subjects in vivo. The dose and dosing intervals of TH were derived from previous pharmacokinetic and dose-finding studies. METHODS: Nine non-smoking, atopic, asthmatic men with dual asthmatic responses to inhaled house-dust mite extract participated in a double-blind, placebo-controlled, cross-over study. During each study period PC20 histamine was measured 24 h before, and 3 and 24 h post-allergen. TH (1.25 mg/mL, 0.5 mL) or placebo (P) were aerosolized pre-allergen, and three times at 2 h intervals post-allergen (total dose of TH: 2.5 mg). Forced expiratory volume in one second (FEV1) was recorded and expressed as percentage fall from baseline. The EAR (0-3 h) and the LAR (3-8 h) were defined as maximum percentage fall from the pre-allergen baseline and as corresponding areas under the time-response curves (AUC). RESULTS: As compared with P, TH failed to induce an acute effect on FEV1 at any of the timepoints (P > 0.08). There was no significant difference between P and TH in the EAR and the LAR: neither in terms of maximum percentage fall from baseline (mean +/- SEM: EAR: 22.3 +/- 4.7% (P) and 20.4 +/- 4.1% (TH), P = 0.75; LAR: 25.2 +/- 4.7% (P) and 26.4 +/- 5.8% (TH), P = 0.77) nor in terms of AUC (P = 0.76). Correspondingly, the changes in PC20 histamine were not different between the two treatments (P > 0.40). CONCLUSION: We conclude that four adequate doses of the inhaled NEP-inhibitor, thiorphan, failed to potentiate allergen-induced airway responses in asthma. These results suggest that either neuropeptides do not play a predominant role in allergen-induced airway responses, or that allergen challenge induces NEP-dysfunction in humans in vivo.

The effect of MK-0591, a novel 5-lipoxygenase activating protein inhibitor, on leukotriene biosynthesis and allergen-induced airway responses in asthmatic subjects in vivo.

BACKGROUND: The 5-lipoxygenase metabolites of arachidonic acid are likely to be involved in the pathophysiology of atopic asthma. We investigated the effect of pretreatment with MK-0591, a novel 5-lipoxygenase activating protein inhibitor, on allergen-induced early asthmatic reactions (EARs) and late asthmatic reactions (LARs), and subsequent airway hyperresponsiveness to histamine. METHODS: Eight atopic men with mild to moderate asthma aged 19 to 31 years, (forced expiratory volume in 1 second [FEV1] > or = 67% of predicted value, histamine provocative concentration causing a 20% fall in FEV1 [PC20] < 4 mg/ml) and documented EAR and LAR to house dust mite extract participated in a two-period, double-blind, placebo-controlled, crossover study. During each study period histamine PC20 was measured 2 days before and 1 day after a standardized allergen inhalation challenge test. MK-0591 was administered in 3 oral doses of 250 mg each at 24, 12, and 1.5 hours before inhalation of allergen. Biochemical activity of MK-0591 was determined by calcium ionophore A-23187-stimulated leukotriene (LT)B4 biosynthesis in whole blood ex vivo and by urinary LTE4 excretion. Airway response to allergen was measured by FEV1 (percent fall from baseline). The EAR (0 to 3 hours) and the LAR (3 to 8 hours) were expressed as corresponding areas under the time-response curves. RESULTS: MK-0591 and placebo did not differ in their effects on prechallenge FEV1 (p = 0.10). As compared with the value before pretreatment, MK-0591 blocked LTB4 biosynthesis and LTE4 excretion by a mean of 98% (range, 96% to 99%; p < 0.002) and 87% (range, 84% to 96%; p < 0.046), respectively, from 0 to 24 hours after allergen challenge. Both the EAR and the LAR were significantly reduced after administration of MK-0591 as compared with placebo, with a mean inhibition of 79% (p = 0.011) and 39% (p = 0.040), respectively. Allergen-induced airway hyperresponsiveness was not significantly different between the two pretreatment periods (p = 0.37). CONCLUSIONS: In this study oral MK-0591 prevented leukotriene biosynthesis after allergen challenge in patients with mild to moderate asthma. The results of our study indicate that 5-lipoxygenase products play an important role during the EAR, whereas their contribution to the pathophysiology of the LAR seems to be of less importance.