Regional lung deposition of a technetium 99m-labeled formulation of mometasone furoate administered by hydrofluoroalkane 227 metered-dose inhaler.

BACKGROUND: A new inhaled suspension formulation of mometasone furoate (MF), a potent corticosteroid with minimal systemic availability, has been developed for the treatment of asthma. This formulation is delivered by metered-dose inhaler (MDI) using the nonchlorofluorocarbon propellant hydrofluoroalkane 227 (HFA-227). OBJECTIVE: The primary goal of this study was to determine the respiratory tract deposition of this formulation of MF. A secondary objective was to measure plasma concentrations of MF and a putative metabolite, 6-X-OH MF, to determine the systemic exposure to corticosteroid. METHODS: This was a single-dose, open-label study in which 200 microg of technetium 99m (99mTc)-radiolabeled MF was administered to patients with asthma. Gamma scintigraphy was used to quantify lung, oropharyngeal, stomach, and MDI mouthpiece deposition patterns of MF. RESULTS: Eleven patients, aged 21 to 47 years, with a history of asthma were enrolled in and completed the study. The mean (+/- SD) whole lung deposition of MF was 13.9%+/-5.7% of the metered (ex-valve) dose. The central lung zone received 5.3%+/-2.8% of the dose; the intermediate zone received 4.7%+/-1.9%; and peripheral lung deposition was 4.0%+/-1.5%. The mean (+/- SD) ratio of peripheral to central lung deposition was 0.8+/-0.2. Oropharyngeal deposition was 79.1%+/-8.7% of the ex-valve dose, with 6.3%+/-7.8% deposited on the MDI mouthpiece and 0.7%+/-0.5% exhaled. The majority of plasma samples taken for analysis of MF and 6-13-OH MF concentrations were below the limit of quantification (50 pg/mL) in all patients after inhalation of 200 microg 99mTc-labeled ME CONCLUSION: The lung deposition of MF when administered via HFA-227 MDI is comparable to the 10 to 20% lung deposition seen with other corticosteroid suspension for- mulations administered by MDI that have demonstrated effectiveness in the treatment of asthma.

A comparison of the lung deposition of budesonide from Easyhaler, Turbuhaler and pMDI plus spacer in asthmatic patients.

Inhaled corticosteroids in pressurized metered does inhalers (pMDIs) are often delivered via a large volume spacer device, but these are bulky and inconvenient. Dry powder inhalers (DPIs) provide a highly portable and convenient propellant-free alternative to pMDIs for asthma maintenance therapy However, each DPI could have unique in vivo delivery characteristcs. In order to quantify the total and regional lung deposition of budesonide (200 microg) from (a) Easyhaler, (b) Turbuhaler and (c) pMDI plus Nebuhaler 750 ml spacer, a three-way randomized cross-over study was carried out in 12 mild to moderate asthmatic patients. Deposition was quantified by the imaging technique of gamma scintigraphy Optimal inhalation techniques were used throughout. Mean (SD) whole lung deposition (% metered dose) was similar for Easyhaler [18.5 (7.8) %] and Turbuhaler [21.8 (8.2) %], but was significantly higher for pMDI plus Nebuhaler [44.1 (10.0) %, P < 0.01]. The regional distribution patterns in the lungs were predominantly central for all three devices. Nebuhaler reduced oropharyngeal deposition significantly compared with the two DPIs. Easyhaler showed comparable deposition to Turbuhaler and hence drugs delivered by Easyhaler would be expected to have a similar clinical effect to those delivered by Turbuhaler in asthma maintenance therapy.

Soft tissue infections of the extremities in an orthopaedic centre in the UK.

OBJECTIVES: To determine the spectrum, and clinical impact of acute extremity soft tissue infections, encountered in the Orthopaedic service of an inner city hospital in UK. METHODS: Patients requiring admission for an acute limb soft tissue infection to the Orthopaedic unit of the Manchester Royal Infirmary, UK, between July 1996 and 2001 were identified from our database. Infections involving the groin and axilla, those developing within 30 days of a surgical procedure, and patients with chronic soft tissue ulcers or infections were not considered. RESULTS: Of 142 infections the majority were cellulitis (50%) and superficial abscesses (34.5%). Most were secondary to trauma (31.6%), human or animal bites (20%) and intravenous drug abuse (17.6%). Although most patients were young and otherwise healthy, ten developed significant complications: myonecrosis requiring below knee amputation (1), acute carpal tunnel syndrome (1), osteomyelitis (6), extensive skin loss requiring reconstruction (1), deep vein thrombosis (1). Seven hundred and eighty four hospital inpatient days and 143 operative interventions were devoted to these patients. The estimated cost for each episode of soft tissue infection was pound 1011. In 25% of cases earlier referral to a surgical service would have been more appropriate. CONCLUSIONS: Soft tissue infections of the extremities confer significant morbidity and impose an important burden on medical resources.

Synthesis and iron binding studies of myo-inositol 1,2,3-trisphosphate and (+/-)-myo-inositol 1,2-bisphosphate, and iron binding studies of all myo-inositol tetrakisphosphates.

The first syntheses of the natural products myo-inositol 1,2,3-trisphosphate and (+/-)-myo-inositol 1,2-bisphosphate are described. The protected key intermediates 4,5,6-tri-O-benzoyl-myo-inositol and (+/-)-3,4,5,6-tetra-O-benzyl-myo-inositol were phosphorylated with dibenzyl N,N-di-isopropylphosphoramidite in the presence of 1H-tetrazole and subsequent oxidation of the phosphite. The crystal structures of the synthetic intermediates (+/-)-1-O-(tert-butyldiphenylsilyl)-2,3,O-cyclohexylidene-myo-inos itol and (+/-)-4,5,6-tri-O-benzoyl-1-O-(tert-butyldiphenylsilyl)-2,3-O-cycl ohexylidene- myo-inositol are reported. myo-Inositol 1,2,3-trisphosphate, (+/-)-myo-inositol 1,2-bisphosphate, and all isomeric myo-inositol tetrakisphosphates were evaluated for their ability to alter HO. production in the iron-catalysed Haber-Weiss reaction. The results demonstrated that a 1,2,3-grouping of phosphates in myo-inositol was necessary for inhibition, also that (+/-)-myo-inositol 1,2-bisphosphate potentiated HO. production. myo-Inositol 1,2,3-trisphosphate resembled myo-inositol hexakisphosphate (phytic acid) in its ability to act as a siderophore by promoting iron-uptake into Pseudomonas aeruginosa.

Human lung deposition data: the bridge between in vitro and clinical evaluations for inhaled drug products?

Regulatory dossiers for new inhaled drug products generally contain in vitro data, which assess delivered dose and particle size distribution, together with clinical efficacy and safety data. Human lung deposition data may be generated using radionuclide imaging techniques or appropriate pharmacokinetic methods, and can act as a 'bridge' via which a seamless transition can be made between in vitro testing in the laboratory and efficacy/safety testing in the clinic. By enabling informed decisions to be made about the evaluation of new devices or formulations in man, lung deposition data permit a long and expensive clinical trials programme to be commenced with much greater certainty of a successful outcome. Human lung deposition data should be considered for supplementing the information required for regulatory dossiers.

Bone grafting for protrusio acetabuli during total hip replacement. A review of the Wrightington method in 61 hips.

Total hip replacement has been very successful in patients with painful, stiff hips associated with protrusio acetabuli, but the heat of polymerisation of methylmethacrylate cement may cause necrosis of the thin medial wall with consequent danger of migration of the cup. Since 1968 at Wrightington, thin slices of the head of the femur have been used as bone grafts to reinforce the acetabulum. We have reviewed 61 hips in 51 patients at an average of 4 years 3 months after operation. Grading for severity is discussed and the degree of physiological remodelling of the medial wall of the acetabulum after grafting assessed. There was an average of about 4 mm of remodelling, but this varied considerably; most took place within the first year. In no case was there relapse of the protrusio.

Septic arthritis following intra-articular steroid injection of the knee--a survey of current practice regarding antiseptic technique used during intra-articular steroid injection of the knee.

Septic arthritis is a potential catastrophic complication of intra-articular steroid injection. There is lack of evidence regarding the precautions that should be taken to avoid such a complication, as well as how often it is encountered. The aim of this study was to evaluate the antiseptic precautions taken during intra-articular steroid injection of the knee in the United Kingdom (UK), and estimate how often septic arthritis is encountered by health professionals in the UK following steroid injection of the knee. A questionnaire was posted to 100 orthopaedic surgeons, 100 rheumatologists and 50 general practitioners (GPs), asking them about the cases of septic arthritis following intra-articular steroid injection of the knee that they encountered during their practice and the precautions they take when injecting knees. The response rate was 76.4%; 57.6% of the respondents used alcohol swabs to clean the skin, and the remaining 42.4% used chlorhexidine or Betadine. Only 16.3% used sterile towels to isolate the injection site. There were 32.5% of respondents who routinely used sterile gloves when injecting, and a total of 46.6% used either sterile or non-sterile gloves. Also, 91.1% changed needles between drawing the steroid and injecting it into the joint. Only 24 respondents (12.6%) had encountered septic arthritis after steroid injection of the knee (18 once, 3 twice, 2 three times, 1 several times). We concluded that septic arthritis post intra-articular steroid injection of the knee is probably rare. There is a wide variation in the precautions taken to avoid such a complication. However, the trend seems to be towards minimal use of antiseptic techniques. Further large prospective studies are needed to determine how frequently septic arthritis of the knee is encountered post steroid injection, and the exact precautions that should be taken to avoid it.

Is tourniquet use necessary for knee arthroscopy?

PURPOSE: With several studies identifying the tourniquet as a factor for increased risk of complications in knee arthroscopy, we wished to identify whether its use is necessary. TYPE OF STUDY: We performed a prospective randomized trial on 109 patients undergoing knee arthroscopy. MATERIALS AND METHODS: All patients had a tourniquet placed on the thigh and were assigned to either have it inflated or not inflated. Personal information, operative details, postoperative pain scores, analgesic requirements, and complications were recorded. RESULTS: The 2 groups were comparable. There was no significant difference between the 2 groups with respect to operative view, duration of operation, pain scores, analgesic requirements, or complications. The tourniquet required intraoperative inflation in 4 patients assigned not to have it inflated; in 1 patient, the tourniquet made no difference to the operative view. CONCLUSIONS: Many orthopaedic units continue to use a tourniquet routinely for knee arthroscopy, probably in the belief that a clear operative view can only be achieved with one. However, the findings in our trial indicate that knee arthroscopy may be performed adequately without the use of a tourniquet. Therefore, we recommend that its routine use for this procedure is discontinued.

Xenogenous fertilization of laboratory and domestic animals in the oviduct of the pseudopregnant rabbit.

Xenogenous fertilization was accomplished using bovine, porcine, and hamster follicular oocytes. The xenogenous fertilization rates for bovine and porcine follicular oocytes in the oviduct of the pseudopregnant rabbit were 13.4% and 2.0%, respectively. Temperatures of ovary, during transport to the laboratory, of 0 degrees or 37 degrees C had no effect on xenogenous fertilization rates of bovine oocytes. In vitro culture in 50 mug/ml FSH did not alter the xenogenous fertilization rates of bovine oocytes. Fertilization was observed with oocytes recovered 40 to 75 hr after insemination. Two cell embryos were recovered 70 to 75 hr after insemination. Ligation of the rabbit oviduct, number of ova deposited and sperm concentration did not affect the xenogenous fertilization rates of hamster ova. Cleavage of xenogenously fertilized hamster oocytes occurred between 28 and 29 hours after insemination.

A brief history of gamma scintigraphy.

Gamma scintigraphy involves the radiolabeling of inhaled drug formulations, followed by in vivo imaging of deposition in two dimensions. This permits whole lung deposition to be quantified as mass of drug or percentage of the dose, and regional deposition patterns to be assessed. Gamma scintigraphy is the method by which the majority of inhaled drug deposition data have been obtained, and scintigraphic studies have become viewed as milestone assessments in the development of new pulmonary drug products. Lung deposition data are used to show "proof of concept" in vivo for these products, and act as a bridge between in vitro laboratory testing and a clinical trials program. Gamma scintigraphy is likely to remain the method of choice for assessing inhaled drug deposition for some time to come.

Deposition and pharmacokinetics of flunisolide delivered from pressurized inhalers containing non-CFC and CFC propellants.

Our objective was to assess the deposition and pharmacokinetics of a novel formulation of flunisolide (Aerobid, Forest Laboratories) in hydrofluoroalkane (HFA) 134a delivered by pressurized metered dose inhaler (pMDI). The design was a two-way crossover investigation in 12 healthy male subjects comparing HFA-134a flunisolide by pMDI versus pMDI plus 50 mL spacer device. Four of these subjects also took part in a two-way crossover investigation comparing chlorofluorocarbon (CFC) flunisolide pMDI versus pMDI plus Aerochamber holding chamber. The imaging technique of gamma scintigraphy was used to quantify total and regional lung deposition of flunisolide. Plasma levels of flunisolide and its major metabolite (6beta-OH flunisolide) were also determined. The spacer and Aerochamber reduced oropharyngeal deposition dramatically for both the HFA and CFC products (mean 59.8 to 14.9% (p < 0.01) of ex-valve (metered) dose for HFA product; 66.3 to 12.3% (p < 0.01) of ex-valve dose for CFC product) owing to deposition of part of the dose on the walls of the add-on devices themselves. Lung deposition averaged 22.6 and 40.4% (p < 0.01) of the ex-valve dose for the HFA formulation used with pMDI alone and with pMDI plus spacer. Mean lung deposition of the CFC formulation delivered via the Aerochamber (mean 23.4%) was higher than that for the CFC pMDI alone (mean 17.0%), but this difference was not statistically significant. Lung deposition expressed as percentage ex-device (delivered) dose averaged 68.3% for HFA pMDI plus spacer and 19.7% for CFC pMDI. Plasma levels of flunisolide were higher for the pMDI plus spacer than for pMDI alone, reflecting higher lung deposition via the spacer, but plasma levels of the 6beta-OH flunisolide metabolite were higher for the pMDI alone as a consequence of higher oropharyngeal deposition. When delivered via the spacer, pulmonary targeting of the flunisolide HFA formulation was improved compared with the CFC formulation, which should benefit patients by providing satisfactory asthma therapy from a much-reduced delivered dose of flunisolide.

Deposition and pharmacokinetics of an HFA formulation of triamcinolone acetonide delivered by pressurized metered dose inhaler.

Novel formulations of asthma drugs contained in pressurized metered dose inhalers (pMDIs) are being developed containing hydrofluoroalkane (HFA) propellants. The objectives of this study were to assess the deposition in the lungs and oropharynx of triamcinolone acetonide (TAA; Azmacort, Aventis Pharma, Collegeville, PA) delivered by pMDI formulated with HFA-134a, together with the pharmacokinetic profile of TAA, and to determine the extent to which the Azmacort spacer improves targeting of TAA to the lungs. The deposition of TAA, labelled with 99mTc, was assessed by gamma scintigraphy in 10 patients with mild to moderate asthma (mean forced expiratory volume in one second [FEV1] 76% predicted), who received in randomized order three delivered (ex-device) doses of 75 microg TAA via pMDI coupled to an Azmacort spacer (TAA-spacer), and three delivered doses of 230 microg TAA via the same device, but with the spacer removed (TAA-no spacer). Mean lung deposition expressed as mass of drug was similar for each regimen (TAA-no spacer 175 microg; TAA-spacer 188 microg), but when expressed as percentage delivered dose, lung deposition was higher for TAA-spacer (53.8%) versus TAA-no spacer (26.0%), indicating superior drug targeting for TAA-spacer. The spacer reduced oropharyngeal deposition. The pharmacokinetic data showed higher plasma levels of drug for TAA-no spacer, resulting from higher oropharyngeal deposition. "Pharmacoscintigraphic" data showed proof of concept for a novel HFA delivery system for an inhaled corticosteroid based on pulmonary targeting of drug.

Frozen autografts: an alternative to graft disposal.

The use of fresh frozen tendon allografts is a well-documented surgical technique. We present a case where a harvested semitendinosus autograft was preserved by deep-freezing, having abandoned the initial procedure due to infection. After treatment of the infection the graft was subsequently used to reconstruct the postero-lateral corner complex with no deleterious effect at 1 year.

Infected total knee replacement following a dental procedure in a severe haemophiliac.

This article documents the late infection of a total knee replacement in a haemophiliac following a dental procedure. It underlines the need for reconsideration of the current British guidelines regarding antibiotic prophylaxis for dental procedures in patients with total joint replacement.

Patellar instability following total knee replacement -- the dangers of constant design evolution.

Patellar instability following total knee replacement although infrequent can cause disabling symptoms. We report a case of symptomatic patellar instability caused by insertion of left femoral component into a right knee. We highlight that all members of the surgical and theatre team need to be familiar both with the implant equipment and of any recent design modifications, particularly if they have been used to using one system for a long time, in order to prevent surgical errors. In addition this possibility should be born in mind by surgeons looking for causes of post-operative patellar instability.

The development of a protocol in using day surgery for minor orthopaedic trauma patients.

We examined all minor orthopaedic trauma patients requiring surgical intervention at Manchester Royal Infirmary over a 6-month period to determine whether minor trauma patients meet the day surgery requirements in terms of medical fitness, analgesia requirements and postoperative complications. A total of 83 patients had surgery for minor orthopaedic trauma in the defined period. Of these patients, 79 (95.2%) were medically fit, 45 (70%) were admitted to a hospital ward and 19 (30%) were brought back to day surgery. None of the patients attending day surgery developed postoperative complications or required return to hospital. The majority of patients admitted to a ward required simple or no analgesia pre- (95.5%) and postoperatively (100%), and most were discharged on the same (55.6%) or next (35.6%) day of their operation. We suggest a protocol whereby patients with minor trauma are brought back to day surgery. This could potentially reduce pressures on bed availability.

Factors delaying surgical treatment of hip fractures in elderly patients.

BACKGROUND: Published guidelines recommend early surgical treatment of hip fractures in elderly patients. Understanding the factors that delay surgical intervention is essential in order to introduce changes that will facilitate early treatment. AIM: To determine the factors delaying surgical treatment of hip fractures in elderly patients for more than 24 h. PATIENTS AND METHODS: Assessment of 163 consecutive patients undergoing surgery for hip fractures at the trauma unit of Manchester Royal Infirmary. RESULTS: Only 72/163 (44.2%) patients had their operation within 24 h of presenting to hospital. The remaining 91 patients had a total of 239 days delay (in excess of the initial 24 h) for surgical treatment. Active medical problems (56.5%) and a wait for medical investigations (19.7%) caused most delays. Lack of operating theatre time and Sunday trauma lists caused 23.8% of delays. CONCLUSIONS: Medical problems account for most delays of surgical treatment of hip fractures. A multidisciplinary approach, with early input by medical and anaesthetic teams, is essential in managing such patients. Established protocols may reduce waiting times for essential investigations.

Reduced delays in A&E for elderly patients with hip fractures.

Published guidelines recommend early transfer of patients with hip fractures to hospital wards and avoidance of unnecessary delays in A&E. We describe a protocol whereby the liaison of an orthopaedic trauma co-ordinator with A&E reduced A&E-to-ward transfer times by 43%. Following introduction of the new protocol, 39% of hip fracture patients were in a ward bed within 3 h of admission to A&E compared to 4% previously. The new protocol also reduces administrative workload for the on-call orthopaedic SHOs.

Unusual mechanical complications of unicompartmental low contact stress mobile bearing patellofemoral arthroplasty: a cause for concern?

The Low Contact Stress Patellofemoral Arthroplasty (LCS PFA) is a newer design belonging to the second generation of inlay type implants, addressing the problems encountered in the first generation models (Lubinus & Richard's). The cemented mobile bearing metal backed patellar component in this system is "modular"; allowing interchangeable usage with either the trochlear component in a PFA or the femoral component of a total knee arthroplasty, thus obviating the need for patellar revision during conversion of PFA to TKA. The younger active patient with a PFA may exert extreme joint reaction forces on their patellar implant, rendering early loosening of the patellar implant. The endurance of this implant with repeated flexion beyond 90 degrees is also a concern. We describe a series of three unusual mechanical failures associated with this particular design of metal backed patellar component of the unicompartmental LCS patellofemoral arthroplasty.