The pharmacokinetics of plasminogen activator inhibitor-1 in the rabbit

The pharmacokinetics of the activated and latent forms of plasminogen activator inhibitor-1 (PAI-1) isolated from HT1080 fibrosarcoma cells (HT1080 PAI-1) and a nonglycosylated form of human PAI-1 isolated from a yeast expression system (rPAI-1) were followed in the rabbit. As assessed by an immunologic assay specific for human PAI-1, guanidine HCI activated HT1080 PAI-1 and rPAI-1 entered the total plasma volume following intravenous bolus administration and exhibited a biphasic clearance pattern. The t1/2s of HT1080 PAI-1 for the initial and beta phases equalled 6.0 and 24.8 minutes, respectively. The t1/2s of rPAI-1 for the initial and beta phases equalled 8.8 and 34.0 minutes, respectively. Similar results were obtained by measuring PAI-1 activity in plasma and with trace amounts of 125I-rPAI-1, suggesting that the above pharmacokinetic behavior could also apply to endogenous PAI-1. The liver was the main site of rPAI-1 clearance. Unactivated, latent PAI-1 exhibited a very different pharmacokinetic profile. Over 80% of latent rPAI-1 cleared from the circulation within 10 minutes (t1/2 = 1.7 minutes). The difference in clearance behavior between activated and latent PAI-1 may be related to the ability of activated PAI-1, but not latent PAI-1, to rapidly form high-molecular-weight complexes with plasma binding factors which were observed in vitro and in vivo. Because PAI-1 could potentially tilt the fibrinolytic balance toward a prothrombotic state, its rapid clearance may represent an important control mechanism governing the circulating levels of this key component of the fibrinolytic pathway.     

Evaluation of AMSA in previously treated patients with acute leukemia: results of therapy in 109 adults

AMSA was evaluated in the treatment of 109 adults with previously treated acute leukemia. Of the 102 evaluable patients, 82 had AML, 17 ALL, and 3 CML in blastic phase. A number of different dose schedules of AMSA were explored, and we conclude that the optimum dose of AMSA for remission induction in acute leukemia is 120 mg/sq m/day for 5 days. Complete remissions were observed in 23 (28%) patients with AML and in 1 patient with ALL. Patients who achieved complete remission were maintained on AMSA using a dose of 30-40 mg/sq m/day for 5 days repeated at 4-wk intervals. The median duration of complete remission was 12 wk (3-59 wk), and the responders survived significantly longer than the failures (27 wk versus 8 wk, p = 0.002). The side effects associated with AMSA therapy included mild nausea and vomiting, stomatitis, diarrhea, phlebitis, alopecia, and myelosuppression-related infections. Our results indicate that AMSA is a useful new antileukemic agent for the treatment of relapsed acute leukemia and appears to have activity comparable to that of the currently available drugs, such as cytarabine and the anthracycline antibiotics.     

IMVP-16: an effective regimen for patients with lymphoma who have relapsed after initial combination chemotherapy

Results of second-line chemotherapy regimens against lymphoma have usually been poor. In this study, we used a combination of ifosfamide, methotrexate, and VP-16 to treat 52 patients with lymphoma who had either relapsed or who had failed to attain a complete remission on front-line treatment. Thirty-two patients (62%) responded (CR 37%, PR 25%) and 10 (19%) had a minor response. The median relapse-free interval of the responding patients was 12 mo, and the median survival of the whole group was 15 mo. Of the 18 patients who achieved complete remission, 10 still remain free of any evidence of disease. The factor that best predicted for response to IMVP-16 was the quality of the remission achieved on front-line therapy. In view of the poor prognosis associated with recurrent lymphoma, the results obtained with this study are considered most encouraging. Patients with recurrent lymphoma can be successfully salvaged by the use of this combination regimen, especially if introduced early after relapse or preferably before progressive disease develops.     

Electrocardiographic predictive factors of long-term clinical improvement with multisite biventricular pacing in advanced heart failure

Biventricular pacing has recently been proposed for treating patients with drug refractory heart failure and intraventricular conduction delay. The purpose is to restore ventricular relaxation and contraction sequences as homogeneously as possible. The aim of this study was to determine if some factors could predict the long-term clinical effectiveness of that new treatment. This study included 26 patients, aged 66 ± 7 years, with drug refractory heart failure and wide QRS. Patients were implanted with a biventricular pacemaker. The left ventricle was paced through a coronary sinus tributary. New York Heart Association functional class, exercise tolerance, and left ventricular (LV) ejection fraction were collected at baseline and after pacemaker implantation. Patients were divided into 2 groups: group I = responders; group II = nonresponders. QRS duration and axis at baseline and during biventricular pacing, interventricular conduction time, and LV and right ventricular lead positions were compared between the 2 groups. Group I patients (n = 19) had a mean reduction of 1.3 in functional class and an increase in peak oxygen consumption rate by a mean of 50%. The only parameter that differed between the 2 groups was the QRS duration during biventricular pacing, with a significantly shorter value in group I than in group II (154 ± 17 vs 177 ± 26 ms; p = 0.016). Thus, a positive response to biventricular pacing is correlated with the quality of electrical resynchronization. The optimal positions of the right and LV leads would be those that could induce the greatest shortening of QRS duration.     

Anti-inhibitor Coagulant Complex (Autoplex) for treatment of factor VIII inhibitors in hemophilia

Fourteen individuals with severe hemophilia complicated by factor VIII inhibitors (1 to 132 Bethesda Units) were treated for 33 bleeding episodes with a new activated prothrombin complex concentrate, Anti- Inhibitor Coagulant Complex (Autoplex, Hyland, Glendale, Calif.). Excellent or good results were observed in 21 of 25 minor bleeding episodes treated, which included joint, soft tissue, and mucous membrane hemorrhages. Eight major bleeding problems (an epidural bleed, a puncture wound, 2 serious soft tissue hemorrhages, 2 lacerations, and 2 major surgical procedures) were treated with excellent (6) or good (2) results. No serious complications were encountered, but two children developed transient hypofibrinogenemia following Autoplex infusion. Although some shortening of the prothrombin time and activated partial thromboplastin time was noted after infusion of Autoplex, there is no useful laboratory test for monitoring therapy. Despite the unknown mechanism of action for bypassing factor VIII, Autoplex appears to be a useful and needed interim product and is safe and effective. In view of the possible potentiation of thrombosis concurrent use of fibrinolytic inhibitors should be avoided.     

ParticipACTION: Awareness of the participACTION campaign among Canadian adults - Examining the knowledge gap hypothesis and a hierarchy-of-effects model

Background  

ParticipACTION was a pervasive communication campaign that promoted physical activity in the Canadian population for three decades. According to McGuire's hierarchy-of-effects model (HOEM), this campaign should influence physical activity through intermediate mediators such as beliefs and intention. Also, when such media campaigns occur, knowledge gaps often develop within the population about the messages being conveyed. The purposes of this study were to (a) determine the current awareness of ParticipACTION campaigns among Canadians; (b) confirm if awareness of the ParticipACTION initiative varied as a function of levels of education and household income; and, (c) to examine whether awareness of ParticipACTION was associated with physical activity related beliefs, intentions, and leisure-time physical activity (LTPA) as suggested by the HOEM. Specifically, we tested a model including awareness of ParticipACTION (unprompted, prompted), outcome expectations, self-efficacy, intention, and physical activity status.     

Gastrointestinal safety and therapeutic efficacy of parenterally administered phosphatidylcholine-associated indomethacin in rodent model systems

Background and purpose

Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that is limited in its enteral or parenteral use by side effects of gastroduodenal bleeding and ulceration. We have investigated the ability of phosphatidylcholine associated with indomethacin to form a therapeutically effective drug (INDO-PC) with reduced gastrointestinal (GI) toxicity for parenteral use.

Experimental approach

Rats were treated acutely by intravenous or chronically with subcutaneous injection of vehicle, indomethacin or INDO-PC using three related protocols. We then evaluated the following properties of these parenterally administered test drugs: (i) GI toxicity (luminal and faecal haemoglobin; intestinal perforations and adhesions; and haematocrit); (ii) bioavailability (plasma indomethacin); and (iii) therapeutic efficacy (analgesia from sensitivity to pressure; anti-inflammatory from ankle thickness; cyclo-oxygenase (COX) inhibition from synovial fluid prostaglandin E₂ concentration) in rats with adjuvant-induced joint inflammation.

Key results

Acute and chronic dosing with INDO-PC produced less GI bleeding and intestinal injury than indomethacin alone, whereas the bioavailability, analgesic, anti-inflammatory and COX inhibitory activity of INDO-PC were comparable to indomethacin.

Conclusions and implications

The chemical association of phosphatidylcholine with indomethacin appears to markedly reduce the GI toxicity of the NSAID while providing equivalent therapeutic efficacy in a parenteral INDO-PC formulation.     

LASSBio-881: an N-acylhydrazone transient receptor potential vanilloid subfamily type 1 antagonist orally effective against the hypernociception induced by capsaicin or partial sciatic ligation

Background and purpose:

Compound LASSBio-881 is an orally effective antinociceptive that binds to cannabinoid receptors and is active mainly on the neurogenic component of pain models. We investigated whether transient receptor potential vanilloid subfamily type 1 (TRPV1) channels are involved in the effects of LASSBio-881.

Experimental approach:

Modulation of capsaicin (CAP)- and low pH-induced currents was evaluated in TRPV1-expressing Xenopus oocytes. In vivo effects were evaluated in CAP-induced acute and inflammatory changes in nociception, as well as in partial sciatic ligation-induced thermal hypernociception.

Key results:

LASSBio-881 inhibited TRPV1 currents elicited by CAP with an IC₅₀ of 14 µM, and inhibited proton-gated currents by 70% at 20 µM. Functional interaction with CAP was surmountable. Locally applied LASSBio-881 decreased time spent in CAP-elicited nocifensive behaviour by 30%, and given orally it reduced measures of CAP- or carrageenan-evoked thermal hypernociception by 60 and 40% respectively. In addition, LASSBio-881 decreased the paw withdrawal responses to thermal stimuli of animals with sciatic neuropathy 7–11 days after nerve ligation, at a dose of 300 µmol·kg⁻¹·day⁻¹ p.o. At this dose, hyperthermia was not observed within 4 h following oral administration.

Conclusions and implications:

LASSBio-881 is a TRPV1 antagonist that apparently competes with CAP. Accordingly, LASSBio-881 inhibited nociception in models of acute, inflammatory and neuropathic pain presumed to involve TRPV1 signalling. These in vivo actions were not hindered by hyperthermia, a common side effect of other TRPV1 antagonists. We propose that the antinociceptive properties of LASSBio-881 are due to TRPV1 antagonism, although other molecular interactions may contribute to the effects of this multi-target drug candidate.     

Oral health‐related quality of life among rural‐dwelling Indigenous Australians

Background: There is limited information on the impact of poor oral health on Indigenous Australian quality of life. This study aimed to determine the prevalence, extent and severity of, and to calculate risk indicators for, poor oral health‐related quality of life among a convenience sample of rural‐dwelling Indigenous Australians. Methods: Participants (n = 468) completed a questionnaire that included socio‐demographic, lifestyle, dental service utilization, dental self‐care and oral health‐related quality of life (OHIP‐14) factors. Results: The prevalence of having experienced one or more of OHIP‐14 items ‘fairly often’ or ‘very often’ was 34.8%. The extent of OHIP‐14 scores was 1.88, while the severity was 15.0. Risk indicators for having experienced one or more of OHIP‐14 items ‘fairly often’ or ‘very often’ included problem‐based dental attendance, avoiding dental care because of cost, difficulty paying a $100 dental bill and non‐ownership of a toothbrush. An additional risk indicator for OHIP‐14 extent was healthcare card ownership, while additional indicators for OHIP‐14 severity were healthcare card ownership and having had 5+ teeth extracted. Conclusions: Risk indicators for poor oral health‐related quality of life among this marginalized population included socio‐economic factors, dentate status factors, dental service utilization patterns, financial factors and dental self‐care factors.     

Treatment of periodontal disease for glycaemic control in people with diabetes

Background: Glycaemic control is a key issue in the care of people with diabetes mellitus (DM). Some studies have suggested a bidirectional relationship between glycaemic control and periodontal disease. Objectives: To investigate the relationship between periodontal therapy and glycaemic control in people with diabetes and to identify the appropriate future strategy for this question. Search strategy: A comprehensive approach was adopted employing handsearching; searching of electronic databases including the Cochrane Oral Health Group’s Trials Register, CENTRAL, MEDLINE, EMBASE, CINAHL, ZETOC, ISI Web of Knowledge and LILACS; contact with appropriate non‐English language healthcare professionals; authors and organizations. The final date for searching for studies was 24 March 2010. Selection criteria: This review studied randomized controlled trials of people with Type 1 or 2 diabetes mellitus (DM) with a diagnosis of periodontitis. Suitable interventions included mechanical periodontal therapy with or without adjunctives and oral hygiene education. Data collection and analysis: The titles and abstracts of 690 papers were examined by two review authors independently. Ultimately, seven studies were included and 19 excluded after full text scrutiny. All trials were assessed for risk of bias. Main results: Three studies had results pooled into a meta‐analysis. The effect for the mean percentage difference in HbA1c for scaling/root planing and oral hygiene (+/? antibiotic therapy) versus no treatment/usual treatment after 3–4 months was ?0.40% (95% confidence interval (CI) fixed effect ?0.78% to ?0.01%), representing a statistically significant reduction in HbA1c (P = 0.04) for scaling/root planing. One study was assessed as being at low risk of bias with the other two at moderate to high risk of bias. A subgroup analysis examined studies without adjunctive antibiotics ?0.80% (one study: 95% CI ?1.73% to 0.13%; P = 0.09), with adjunctive antibiotics in the test group ?0.36% (one study: 95% CI ?0.83% to 0.11%; P = 0.14), and with antibiotics in both test and control groups after 3/4 months ?0.15% (one study: 95% CI ?1.04% to 0.74%; P = 0.74). Authors’ conclusions: There is some evidence of improvement in metabolic control in people with diabetes, after treating periodontal disease. There are few studies available and individually these lacked the power to detect a significant effect. Most of the participants in the study had poorly controlled Type 2 DM with little data from randomized trials on the effects on people with Type 1 DM.