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PubMed1990

Allatinhibin, a neurohormonal inhibitor of juvenile hormone biosynthesis in Manduca sexta.

The corpora allata (CA) of Manduca sexta larvae become incapable of synthesizing juvenile hormone (JH) early in the wandering stage of the last larval stadium. They then switch to the synthesis and release of JH acids. This change in CA activity is induced by an inhibitory factor--allatinhibin (AI)--from the brain. AI activity is present in the fifth (Vth) instar hemolymph from about Day 4 (day of wandering) until Day 7 (early prepupa). CA of early fifth instar larvae (uninhibited) incubated in vitro with brain-corpora cardiaca-corpora allata (Br-CC-CA) complexes or brain alone from wandering larvae are inhibited as demonstrated by bioassay. On the basis of these observations, an in vitro-in vivo assay for AI was developed. Br-CC-CA or Br alone were first incubated in tissue culture medium overnight. Day 0 (0d) Vth instar CA incubated for 16 hr in such medium will lose the ability to induce a larval molt in allatectomized 0d IVth instar larvae if the medium contained AI activity. The highest AI activity was exhibited by the medium obtained from incubations of brain from wandering larvae whereas the medium from incubation of 0d Vth and 0d pupal brains showed no AI activity. Dose-response data show that AI is active at 0.03 brain equivalents/200 microliters medium. CA must be exposed to AI for 12-16 hr for manifestation of inhibition. AI causes a stable inhibition of CA. AI is heat-labile, protease sensitive, has a molecular size between 1.0 and 3.5 kDa, and is clearly distinct from the allatostatins described by others.

Animals↗
PubMed2003

Fertility of ram semen frozen in Bioexcell and used for cervical artificial insemination.

The current use of ingredients of animal origin, such as egg yolk, in semen extenders presents a risk of microbial contamination, and has led to the search for alternatives. Such an extender is commercially available for bull semen (Bioexcell), IMV, L'Aigle, France), and it has previously been tested in vitro for freezing ram semen, with satisfactory results. The aim of the present study was to compare the fertility results of ewes in Uruguay, after cervical insemination with ram semen that was frozen in Bioexcell versus semen frozen in a conventional milk-egg yolk extender (control). Semen from five Corriedale rams was frozen, using a split sample design, in either milk-egg yolk or Bioexcell extender, using a two-step extension method. The sperm parameters assessed after thawing were subjective motility, membrane integrity (SYBR-14/PI), and capacitation status (CTC). Thawed semen was inseminated intracervically once during spontaneous estrus in 970 Corriedale ewes that grazed in natural pastures, under extensive management conditions. Fertility was recorded as nonreturn rates at 21 days (NRR-21) and 36 days (NRR-36) after artificial insemination (AI), as well as pregnancy rate (PR-US, diagnosed ultrasonographically 50 days after AI of the last ewe). Subjective motility was slightly higher in Bioexcell than in the milk extender (47 vs. 46.5%; NS), as was membrane integrity (38 vs. 37.7%; NS) and the percentage of uncapacitated spermatozoa (28.5 vs. 26.3%; NS). There were no statistically significant differences in fertility rates found between Bioexcell and the control extender: NRR-21 (35.9 vs. 33.2%), NRR-36 (34.8 vs. 32.6%), and PR-US (28.4 vs. 27.2%). In conclusion, Bioexcell appears to be an alternative to the conventional milk-egg yolk extender for freezing ram semen, and provides similar fertility results after cervical AI under extensive management conditions. Thus, Bioexcell, containing no additives of animal origin, can offer a safer alternative when frozen semen is used for introducing new genetic material into a flock or a country.

Animals↗
PubMed2003

Selective contribution of IFN-alpha/beta signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection.

A complex mechanism may be operational for dendritic cell (DC) maturation, wherein Toll-like receptor and other signaling pathways may be coordinated differently depending on the nature of the pathogens, in order for DC maturation to be most effective to a given threat. Here, we show that IFN-alpha/beta signaling is selectively required for the maturation of DCs induced by double-stranded RNA or viral infection in vitro. Interestingly, the maturation is still observed in the absence of either of the two target genes of IFN-alpha/beta, TLR3 and PKR (double-stranded-RNA-dependent protein kinase R), indicating the complexity of the IFN-alpha/beta-induced transcriptional program in DCs. We also show that the DCs stimulated in vivo by these agents can migrate into the T cell zone of the spleen but fail to mature without the IFN signal. The immune system may have acquired the selective utilization of this cytokine system, which is essential for innate antiviral immunity, to effectively couple with the induction of adaptive immunity.

Animals↗
PubMed2004

Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

This chapter about treatment and prevention of stroke is part of the 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading see Guyatt et al). Among the key recommendations in this chapter are the following: For patients with acute ischemic stroke (AIS), we recommend administration of i.v. tissue plasminogen activator (tPA), if treatment is initiated within 3 h of clearly defined symptom onset (Grade 1A). For patients with extensive and clearly identifiable hypodensity on CT, we recommend against thrombolytic therapy (Grade 1B). For unselected patients with AIS of > 3 h but < 6 h, we suggest clinicians not use i.v. tPA (Grade 2A). For patients with AIS, we recommend against streptokinase (Grade 1A) and suggest clinicians not use full-dose anticoagulation with i.v. or subcutaneous heparins or heparinoids (Grade 2B). For patients with AIS who are not receiving thrombolysis, we recommend early aspirin therapy, 160 to 325 mg qd (Grade 1A). For AIS patients with restricted mobility, we recommend prophylactic low-dose subcutaneous heparin or low molecular weight heparins or heparinoids (Grade 1A); and for patients who have contraindications to anticoagulants, we recommend use of intermittent pneumatic compression devices or elastic stockings (Grade 1C). In patients with acute intracerebral hematoma, we recommend the initial use of intermittent pneumatic compression (Grade 1C+). In patients with noncardioembolic stroke or transient ischemic attack (TIA) [ie, atherothrombotic, lacunar or cryptogenic], we recommend treatment with an antiplatelet agent (Grade 1A) including aspirin, 50 to 325 mg qd; the combination of aspirin and extended-release dipyridamole, 25 mg/200 mg bid; or clopidogrel, 75 mg qd. In these patients, we suggest use of the combination of aspirin and extended-release dipyridamole, 25/200 mg bid, over aspirin (Grade 2A) and clopidogrel over aspirin (Grade 2B). For patients who are allergic to aspirin, we recommend clopidogrel (Grade 1C+). In patients with atrial fibrillation and a recent stroke or TIA, we recommend long-term oral anticoagulation (target international normalized ratio, 2.5; range, 2.0 to 3.0) [Grade 1A]. In patients with venous sinus thrombosis, we recommend unfractionated heparin (Grade 1B) or low molecular weight heparin (Grade 1B) over no anticoagulant therapy during the acute phase.

Cerebral Infarction↗
PubMed1999

Two-year prospective and comparative study on the effects of tibolone on lipid pattern, behavior of apolipoproteins AI and B.

OBJECTIVE: To investigate long-term lipid and lipoprotein changes in postmenopausal women treated with tibolone in a prospective study using appropriate control groups. DESIGN: Seventy-six of 105 postmenopausal women initially selected for this study completed the 2-year follow-up. Patients were allocated into three groups. The first received 2.5 mg/day tibolone continuously (n = 27; group T), the second received 0.625 mg/day conjugated equine estrogen plus 2.5 mg/day of medroxyprogesterone (group E-P) continuously (n = 25), and a third group contained an additional 24 women who did not receive replacement therapy; these constituted the untreated control group (group C). Plasma lipids and lipoproteins were determined in all patients before joining the study and also at 12 and 24 months after being included. RESULTS: Women treated with tibolone experienced the greatest decreases in cholesterol, both total and high density lipoprotein (HDL), and triglycerides (TG), whereas the highest increase in HDL was observed in the group E-P. A decrease in low density lipoprotein levels was detected in both therapy groups, whereas a significant increase was observed in the control group. TG were increased after E-P therapy. In all the groups, apolipoprotein AI showed parallel trends to HDL and apolipoprotein B to low density lipoprotein. CONCLUSIONS: Both therapy groups, tibolone and E-P, induced changes in levels of plasma lipids, lipoproteins and apolipoproteins. Long-term tibolone treatment is associated with a marked and significant decrease in HDL apolipoprotein AI and TG, an effect that defines the major difference with standard HRT. Clearly, further studies are necessary to establish the definite risk/benefit ratio of tibolone with respect to its overall effect on lipid metabolism.

Anabolic Agents↗
PubMed2001

Correlation between spontaneous apoptosis and the expression of angiogenic factors in advanced gastric adenocarcinoma.

The aim of this study was to investigate whether angiogenic factors influence the occurrence of spontaneous apoptosis in advanced gastric cancer. The apoptotic indices (AIs) of 97 tumors from 97 patients with advanced gastric cancer (pT3, pN0, pM0, Stage II) were analyzed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL) method. Intratumoral microvessel densities (IMVDs) of tumors stained with anti-CD34 monoclonal antibody were quantified under x 200 magnification using computer-assisted image analysis. The expressions of angiogenic factors, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (dThdPase), transforming growth factor-alpha (TGF-alpha), and p53 were analyzed immunohistochemically and compared with IMVDs and AIs. The mean IMVD of the 97 tumors was 365/mm2 (range 147-990/mm2). The mean AI of tumors was 2.1% (range 0-11.3%). A significant inverse correlation between the AIs and the IMVDs was shown (p = -0.278, P = 0.0064). The mean IMVDs of tumors with high expressions of dThdPase, TGF-alpha, or p53 were significantly higher than those of tumors with low expressions of these factors. The mean AI of tumors with high expressions of dThdPase was significantly lower than that of tumors with low expressions of dThdPase (P = 0.023). However, no significant correlations were detected between AIs and the expression levels of VEGF, TGF-alpha, or p53. In gastric cancer, dThdPase may play an important role in tumor progression by increasing microvessels and by suppressing apoptosis of cancer cells.

Adenocarcinoma↗
PubMed2002

[Effect of erythromycin on apoptosis of eosinophils in nasal polyps in vitro].

OBJECTIVE: To study the effect of erythromycin on apoptosis of eosinophils in nasal polyps in vitro. METHODS: Fifteen nasal polyp biopsies were collected during nasal polypectomy. The specimens were cultured with erythromycin in RPMI1640, and cultured without erythromycin as control group. The explants in both groups were taken out at 1, 3, 5 day after culture. The apoptosis of cells was detected by terminal deoxynucleotidyl transferasemediated dUTP nick endlabeling(TUNEL), eosinophils were identified by morphology and serial sections stained with HE, then the apoptosis index (AI) of eosinophils was calculated. RESULTS: The AI of eosinophils in nasal polyps after cultured for 1,3,5 days with erythromycin were (31.77 +/- 9.52)%, (32.67 +/- 9.44)% and (50.34 +/- 8.78)% respectively. In control group, the AI of eosinophils were (29.18 +/- 7.31)%, (29.82 +/- 12.03)% and (42.25 +/- 8.08)% respectively. There were significant difference between two groups at 5 day after culture(P < 0.05). CONCLUSION: Erythromycin promoted apoptosis of eosinophils in nasal polyps in vitro.

Adolescent↗
PubMed2001

Alterations of epithelial permeability by Helicobacter and IL-1beta in vitro: protective effect of rebamipide.

Infection with Helicobacter increases the transcellular passage of macromolecules across the epithelium, and this effect can be prevented by a gastroprotective agent rebamipide. The aim was to gain insight into the mechanisms involved. The HT29-19A intestinal epithelial cells grown on microporous filters as monolayers were incubated in the presence or absence of rebamipide (1 or 2 mM) with: (1) suspension of a wild H. pylori strain, (2) IL-1beta (0.5 ng/ml) + IFN-gamma (2 units/ml). After incubation, the monolayers were submitted to evaluation of apoptosis by using the apoptotic cell death detection ELISA kit and to assessment of epithelial permeability in Ussing chamber where the ionic conductance (G), fluxes of mannitol (J(Man)) and of horseradish peroxidase in both intact (J(HRPi))- and degraded (J(D)) form, were measured. H. pylori increased the intact HRP fluxes across the barrier (J(HRPi) = 17 +/- 20 vs 97 +/- 70 ng/hr/cm2, P < 0.007), an effect prevented by rebamipide (J(HRPi) = 33 +/- 34 ng/hr/cm2, P < 0.006). IL-1beta increased the ionic conductance (G = 5.5 +/- 1.0 and 21.0 +/- 7.0 mS/cm2, P < 0.006), the intact HRP fluxes (J(HRPi) = 18 +/- 15 and 476 +/- 344 ng/hr/cm2, P < 0.006), and the apoptotic index of the cells (AI = 1 +/- 0 vs 3.7 +/- 0.8), all effects prevented by rebamipide (G = 12 +/- 4.9 mS/cm2, J(HRPi) = 79 +/- 38, AI = 1.6 +/- 0.6, P < 0.03 as compared to IL-beta-treated cells). In basal conditions, rebamipide increased the integrity of the barrier (G = 7.5 +/- 2.3 vs 6.0 +/- 1.8 mS/cm2 for controls, P < 0.007). In conclusion, H. pylori as well as IL-1beta, may alter epithelial permeability and rebamipide may exert its protective effect on gastric mucosa by reinforcing the epithelial barrier in normal conditions and by counteracting the deleterious effect of Helicobacter pylori and IL-1beta on macromolecular permeability.

Alanine↗
PubMed2005

Angiocidal effect of Cyclosporin A: a new therapeutic approach for pathogenic angiogenesis.

AIM: Angiogenesis is essential in the development of several disorders such as cancer, arthritis, and autoimmune diseases. Several agents prevent angiogenesis but only a few destroy established angiogenesis. In this study we tested whether local or systemic administration of Cyclosporin A (CyA) would inhibit as well as destroy established angiogenesis in an in vivo assay of angiogenesis. METHODS: We utilized an in vivo assay of angiogenesis in which an angiogenic mixture of Matrigel, FGF, VEGF, and heparin was injected subcutaneously into mice. Angiogenesis in the subcutaneous plugs was quantified by ANOVA. CyA or the vehicle for CyA was administered to the experimental or the control groups by three routes: by addition to the angiogenic mixture, by local injection into the angiogenic plug at various time points or by systemic administration at high doses. Angiogenesis was quantified by pointing method and expressed as an angiogenic index (AI). RESULTS: In control animals the subcutaneous plug of Matrigel with the angiogenic mixture revealed exuberant angiogenesis at day 4 and day 7. This angiogenesis was completely inhibited when CyA was included in the angiogenic mixture; the vehicle for CyA had no such effect. Angiogenesis that had progressed was found to regress after local subcutaneous injection of CyA at day 4 and 7. Similar regression of angiogenesis was noted when CyA was administered systemically after allowing angiogenesis to proceed for 4 days. CONCLUSIONS: Our experiments strongly suggest that CyA is both angiocidal and angiostatic in vivo. These results provide a basis for future therapy directed against established angiogenesis in malignancies and autoimmune diseases.

Animals↗
PubMed1999

Influence of low density lipoprotein (LDL) subfraction profile and LDL oxidation on endothelium-dependent and independent vasodilation in patients with type 2 diabetes.

Recent studies have suggested that hypercholesterolemia is associated with endothelial dysfunction. In patients with type 2 diabetes mellitus, dyslipidemia is mainly characterized by hypertriglyceridemia, low high density lipoprotein, and a preponderance of small dense low density lipoprotein (LDL) particles. We have examined the relationships among LDL subfractions, the susceptibility of LDL to oxidation in vitro, and endothelial function in type 2 diabetes mellitus. LDL subfractions were measured by density gradient ultracentrifugation. The susceptibility of LDL to oxidation was determined by measuring the kinetics of conjugated dienes formation during copper-mediated oxidation of LDL. Endothelium-dependent and independent vasodilation of the brachial artery were assessed by high resolution vascular ultrasound. Diabetic patients had a higher concentration of small dense LDL-III than matched controls (P < 0.01). The lag phase of conjugated dienes formation was shorter in the diabetic patients (P < 0.05), and the rate of LDL oxidation was faster (P < 0.05). Both endothelium-dependent (P < 0.01) and independent dilation of the brachial artery (P < 0.01) were impaired in the diabetic patients. On multivariate analysis, the rate of oxidation and LDL-III concentration accounted for 12% and 6%, respectively, of the variation in endothelium-dependent vasodilation (adjusted r2 = 0.18; P < 0.05), whereas LDL-III concentration and the maximum amount of conjugated dienes formed accounted for 27% and 5%, respectively, of the variation in endothelium-independent vasodilation (adjusted r2 = 0.32; P < 0.01) in the diabetic patients. In conclusion, endothelial and smooth muscle cell dysfunction in type 2 diabetes were related to abnormalities in LDL subfractions and in LDL oxidation.

Adult↗
PubMed2005

[Correlations of clinical symptoms and treatment efficacy in patients with rheumatoid arthritis treated with Chinese herbal drugs or Western medicine].

OBJECTIVE: To evaluate the correlations between clinical symptoms and treatment efficacy in patients with rheumatoid arthritis (RA). METHODS: Four hundred and thirteen patients were included in the clinical trial from 9 clinical centers. They were randomly divided into Western medicine-treated group with 204 cases and Chinese herbal drug-treated group with 209 cases. Eighteen clinical symptoms were evaluated before and after treatment. The Western medicine therapy included voltaren extended release tablets, methotrexate and sulfasalazine. The Chinese herbal drug therapy included glucosidorum Tripterygii totorum tablets and Yishen Juanbi Tablets combined with treatment based on syndrome differentiation. The American College of Rheumatology 20 (ACR20) was used as efficacy evaluation criteria. RESULTS: In the Chinese herbal drug-treated group, clinical symptoms such as arthralgia and tenderness of joints were positively correlated with the efficacy after 12-week treatment, while frequent urination at night was negatively correlated. In the same group, tenderness of joints and fever were positively correlated with the efficacy after 24-week treatment, while deep-colored and turbid urine was negatively correlated. In the Western medicine-treated group, tenderness of joints and thirst were positively correlated with the efficacy after 12-week treatment, while vertigo was negatively correlated. And in the same group, tenderness of joints was positively correlated with the efficacy after 24-week treatment, while heaviness of limbs was negatively correlated to the efficacy. The statistical results showed that the treatment efficacy was improved when the correlated symptoms were included in the indications. CONCLUSION: The treatment efficacy of RA is correlated with some symptoms, so further studies should proceed on these correlations in order to achieve better treatment outcome.

Adult↗
PubMedDate not supplied

Metabolic approach to the diagnosis and treatment of atherosclerotic peripheral vascular disease.

Metabolic and clinical peculiarities of patients with peripheral vascular disease (PVD) were evaluated in two studies. In the first study lipid and lipoprotein composition of 20 patients with PVD were examined. Twelve of these patients were normolipidemic, the other 8 hypertriglyceridemic. Ten normolipidemic and ten hyperlipidemic age-matched subjects served as controls. High density lipoprotein cholesterol (HDL-C) levels were markedly reduced in the hypertriglyceridemic, both with (35.1 +/- 5.0 mg/dl) and without (36.2 +/- 11.7 mg/dl) PVD as compared to the normolipidemic patients (47.0 +/- 6.3 mg/dl) and controls (48.1 +/- 10 mg/dl). All the PVD patients showed an increased apolipoprotein B content in the very low density lipoproteins (VLDL) as compared to controls (p less than 0.001). A significant correlation between VLDL-cholesterol and apo B levels was detected in both groups; however, two distinct populations could be clearly separated (slopes of the regression lines: PVD patients = 0.350; controls = 0.215, p less than 0.0001). These data suggest a possible discriminatory power of VLDL-apo B levels in PVD patients independent of other metabolic parameters. In the second study, the clinical activity of metformin (N, N-dimethylbiguanide) a widely used antidiabetic agent, on arterial blood flow was evaluated in 15 patients with PVD. Flow was determined by quantitative strain-gauge plethysmography during a cross-over trial, comparing 6 months of drug and placebo administration. Metformin (850 mg tid) significantly increased arterial flow after a standardized ischemia in both sequences. In spite of the minimal changes of plasma lipid levels during metformin, a highly significant increase of HDL-C levels (+8.3% during the whole treatment) was demonstrated. Plasma levels of isoprotein AI-1 were also raised during the metformin period. Although the mechanism/s of the beneficial effects of metformin on flow cannot, at present be defined, the reported results underline the significant therapeutic potential of this metabolic drug treatment in PVD.

Adult↗
PubMed2026

Intravenous thrombolysis for ischemic stroke in extended time window selected with CT perfusion: a systematic review and meta-analysis.

PURPOSE: Recent randomized controlled trials (RCTs) have provided new evidence regarding the efficacy and safety of intravenous thrombolysis (IVT) in patients with acute ischemic stroke (AIS) presenting within the extended time window (ETW). We performed a systematic review and meta-analysis to evaluate the efficacy and safety of IVT, in patients treated within the ETW and selected with perfusion imaging criteria, predominantly computed tomography perfusion (CTP). METHODS: A systematic review and meta-analysis, registered in PROSPERO, was conducted including all available RCTs comparing IVT with best medical treatment (BMT) in patients with AIS within the ETW, selected using advanced perfusion imaging criteria. The predefined efficacy outcomes were excellent functional outcome and good functional outcome at 3 months. The safety endpoints included symptomatic intracranial hemorrhage (sICH) and all-cause mortality at 90 days. RESULTS: Six RCTs, including 1182 patients treated with IVT and 1176 patients receiving BMT, were included. IVT was associated with a higher likelihood of achieving excellent and good functional outcomes at 3 months. Exploratory subgroup analyses by treatment timing suggested consistent findings up to 24 hours. No significant difference in 90-day mortality was observed between groups, whereas IVT was associated with an increased risk of sICH. CONCLUSION: Treatment with IVT in the ETW (4.5-24 h) in patients selected using advanced perfusion imaging, predominantly CTP, may be associated with improved functional outcomes in patients with AIS. Although IVT was associated with an increased risk of sICH, no significant increase in 90-day mortality was observed. PROSPERO REGISTRATION: CRD420261304314.

Aged↗
PubMed2006

Acute stroke management in the elderly.

BACKGROUND AND PURPOSE: Though the proportion of elderly stroke patients is increasing, patients >80 years are often excluded from clinical stroke trials. We reviewed the management of older patients presenting with acute ischemic stroke (AIS) and assessed the safety and efficacy of recombinant tissue plasminogen activator (rtPA) administration in a community-based setting. METHODS: A retrospective review of patients >80 years (n = 341) admitted to a community stroke center with AIS were compared to their younger counterparts (n = 690) using the stroke center database from April 2003 to December 2005. Parameters that were measured included admission and discharge NIH Stroke Scale (NIHSS), rate of thrombolytic treatment, the frequency and etiology of thrombolytic exclusion criteria and complications from rtPA for the different aged populations. Additional data were collected for Barthel Index at 12 months. RESULTS: A total of 166 patients underwent thrombolysis. Older patients were not delayed in reaching the hospital within 3 h of stroke onset (182/690, 26%, in the <80 cohort vs. 98/341, 29%, in the > or = 80 cohort). Although the overall rates of tPA use were similar in both the young and aged cohort, older patients were less likely to be treated with rtPA because of reasons not listed as exclusion criteria (17% in the <80 cohort vs. 32% in the > or = 80 cohort). The older group did not have an excess risk of intracranial hemorrhage following rtPA infusion despite equivalent NIHSS on admission (13.5 in the <80 cohort vs. 12.4 in the > or = 80 cohort). Both groups showed improvement in NIHSS following thrombolytic treatment with a drop of 7.7 points in the younger age group and 5.6 points in the older group. Elderly patients treated with rtPA had a comparable 12-month modified Barthel Index score to younger cohorts. CONCLUSIONS: Early treatment with rtPA in patients >80 years appears to be both safe and efficacious. Treated patients showed improvements both acutely (a decrease in NIHSS at 72 h) and chronically, as shown by a sustained improvement in the Barthel Index. A large number of elderly patients were excluded from rtPA treatment despite arriving within the time frame of treatment for reasons not considered as traditional exclusion criteria. Older patients with AIS can be treated safely with thrombolytic therapy in a community setting. This therapy should not be withheld on the basis of age.

Acute Disease↗
PubMed1988

Systemic effects resulting from topical ocular administration of SCH 33861, a novel ACE inhibitor ocular hypotensive agent.

SCH 33861 (7- N- 1(S)-(Carboxy)-3-phenylpropyl -(S)-alanyl 1,4-dithia-7-azaspiro 4.4 nonane-8(S)-carboxylic acid) is a novel, non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor with marked topical ocular hypotensive activity. The present study evaluated the degree of systemic ACE inhibition resulting from topical administration of 0.01 and 0.1% concentrations (10 and 100-fold greater than needed to lower IOP) of SCH 33861 in conscious rabbits. For reference purposes, captopril, a prototype ACE inhibitor, was examined at concentrations 5 and 20-fold greater than needed to lower IOP. Neither 0.01 nor 0.1% topical SCH 33861 led to inhibition of pressor responses to 0.3 micrograms/kg iv challenges with angiotensin I (AI) over a 4 hr period. Captopril, in contrast, caused significant attenuation of AI pressor responses. The magnitude and duration of systemic ACE inhibition following captopril administration was concentration related. Intravenous administration of the same dose administered topically did not cause any systemic ACE inhibition with 0.01% SCH 33861. Following iv 0.1% SCH 33861, 0.5 or 2.0% captopril, AI responses were inhibited 60-70% indicating the ability to inhibit ACE if any systemic absorption took place. Topical administration of 0.01% SCH 33861 twice daily for five days also did not produce systemic ACE inhibition. These findings indicate that topical amounts of SCH 33861 greatly in excess of those needed to effect reductions in IOP have an exceptionally low potential for producing systemic effects.

Administration, Topical↗
PubMed2005

Long-term use and tolerability of cyclooxygenase-2 inhibitors in patients with analgesic intolerance.

BACKGROUND: Cyclooxygenase-2 (COX-2) inhibitors are reported to be well tolerated in patients with analgesic intolerance (AI). However, limited data are available about the long-term tolerability of these drugs. OBJECTIVE: To determine the long-term tolerability of COX-2 inhibitors in patients with Al. METHODS: Patients with AI who previously underwent single-masked, placebo-controlled oral provocation tests and were found to tolerate nimesulide, meloxicam, rofecoxib, or celecoxib were interviewed regarding the long-term use and tolerability of these drugs. RESULTS: Of 87 patients, 61 (70%) had used the recommended COX-2 inhibitor(s). Of the 61 users, 54 (89%) tolerated the drug(s) well and 7 (11%) reported adverse events. Three patients reporting adverse events were rechallenged with the responsible COX-2 inhibitor, and their results were found to be negative. CONCLUSIONS: Long-term use of COX-2 inhibitors was tolerated well by most patients with AI, and placebo-controlled oral provocation tests, as a single test, seemed to predict tolerability. Furthermore, self-reported positive reactions in the long-term should also be confirmed with rechallenge tests for definite diagnosis.

Adult↗
PubMed2002

Lowered blood concentration of tacrolimus and its recovery with changes in expression of CYP3A and P-glycoprotein after high-dose steroid therapy.

BACKGROUND: In a living-donor liver transplant patient continuously receiving tacrolimus (FK506), pulse steroid therapy for 3 days caused the blood concentration of FK506 to decrease, followed by a gradual recovery to presteroid levels within 2 weeks. We conducted a study in rats to clarify the mechanism of the changes in the blood concentration of FK506 during and after steroid therapy. METHODS: Rats were intraperitoneally treated with a low dose (1 mg/kg per day) or a high dose (75 mg/kg per day) of dexamethasone (DEX) for 4 days and, at 1.5 hours after the last dose, were given FK506 (2 mg/kg) intravenously (IV) or orally (PO). Blood concentrations of FK506 and changes in the expression levels of P-glycoprotein and CYP3A2 in the liver and intestine were monitored. RESULTS: In the low-dose DEX group, the blood concentrations of FK506 after PO administration of FK506 were significantly lowered compared with those in the untreated group, while there was no such difference after IV administration. In the high-dose DEX group, the blood concentrations of FK506 after either IV or PO administration were significantly lowered. Consequently, the bioavailability of FK506 was decreased by DEX treatment, and the total clearance was significantly increased by high-dose DEX treatment. The pharmacokinetic parameters gradually recovered within 2 weeks after high-dose DEX treatment. In the high-dose DEX group, the protein levels of P-glycoprotein and CYP3A2 in the liver and intestine increased just after the treatment then decreased to normal levels within 2 weeks. CONCLUSION: Our results indicate that the decrease in the blood FK506 concentration caused by high-dose steroid therapy is a consequence of the induction of P-glycoprotein and CYP3A in the liver and intestine, and these changes were reversed within 2 weeks after cessation of steroid therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1985

Haemodynamic conditions for renal PGE2 and renin release during alpha- and beta-adrenergic stimulation in dogs.

Constriction of the renal artery and infusion of an alpha-adrenergic agonist induce autoregulated vasodilation and increase prostaglandin E2 (PGE2) and renin release. The enhancement of renin release during autoregulated vasodilation might be mediated by prostaglandins. To examine this hypothesis, experiments were performed in three groups of anaesthetized dogs. In six dogs constriction of the renal artery to a perfusion pressure below the range of autoregulation raised renin release from 2 +/- 1 to 27 +/- 6 micrograms AI X min-1 and PGE2 release from 1 +/- 1 to 10 +/- 2 pmol X min-1. After administration of indomethacin (10 mg X kg-1 b.wt), PGE2 release was effectively blocked and constriction of the renal artery raised renin release only from 0.1 +/- 0.1 to 6 +/- 1 micrograms AI X min-1. During subsequent continuous infusion of a beta-adrenergic agonist, isoproterenol (0.2 micrograms X kg-1 X min-1), constriction of the renal artery raised renin release from 0.1 +/- 0.1 to 52 +/- 11 micrograms AI X min-1, although there was no rise in PGE2 release. In six dogs, intrarenal infusion of phenylephrine, an alpha- adrenergic agonist, increased PGE2 and renin release before, but not after, indomethacin administration. In six other dogs, phenylephrine infused during isoproterenol infusion increased renin release equally before and after indomethacin administration. Thus the enhancing effect of constricting the renal artery or infusing an alpha-adrenergic agonist is not dependent upon prostaglandins. We propose that autoregulated dilation enhances renin release whether the stimulatory agent is a prostaglandin or a beta-adrenergic agonist.

Adrenergic alpha-Agonists↗