Clinical pharmacology of cyclooxygenase inhibition and pharmacodynamic interaction with aspirin by floctafenine in Thai healthy subjects.

Floctafenine, a hydroxyquinoline derivative with analgesic properties, is widely used in Thailand and many other countries. The objectives of this study were to evaluate in Thai healthy volunteers: i) the inhibition of whole blood cyclooxygenase(COX)-2 and COX-1 activity by floctafenine and its metabolite floctafenic acid in vitro and ex vivo after dosing with floctafenine; ii) the possible interference of floctafenine administration with aspirin antiplatelet effects. We performed an open-label, cross-over, 3-period study, on 11 healthy Thai volunteers, who received consecutively floctafenine(200mg/TID), low-dose aspirin(81mg/daily) or their combination for 4 days, separated by washout periods. Floctafenine and floctafenic acid resulted potent inhibitors of COX-1 and COX-2 in vitro (floctafenic acid was more potent than floctafenine) showing a slight preference for COX-1. After dosing with floctafenine alone, whole blood COX-1 and COX-2 activities were inhibited ex vivo in a time-dependent fashion which paralleled floctafenic acid plasma concentrations. Aspirin alone inhibited profoundly and persistently platelet COX-1 activity and AA-induced platelet aggregation throughout 24-h dosing interval which was affected by the co-administration of floctafenine. At 24 h after dosing with aspirin and floctafenine, the inhibition of platelet thromboxane(TX)B2 generation and aggregation were significantly(P less than 0.05) lower than that caused by aspirin alone. Therapeutic dosing with floctafenine profoundly inhibited prostanoid biosynthesis through the rapid conversion to floctafenic acid. Floctafenine interfered with the antiplatelet effect of aspirin. Our results suggest that floctafenine should be avoided in patients with cardiovascular disease under treatment with low-dose aspirin.

Pilot Study: effects of parenteral glutamine dipeptide supplementation on neutrophil functions and prevention of chemotherapy-induced side-effects in acute myeloid leukaemia patients.

The effect of parenteral glutamine dipeptide (Gln) supplementation on neutrophil phagocytosis, superoxide anion generation (SAG), prevention of chemotherapy-induced side-effects and cost-effectiveness was examined in a pilot study of acute myeloid leukaemia (AML) patients receiving chemotherapy. Sixteen AML patients were randomized to receive intravenous supplementation with Gln (30 g/day) or an equivalent quantity (25 g/day) of a standard amino acid mixture (control) on days 1 - 5 of chemotherapy. Complete blood count was evaluated twice a week until hospital discharge, and neutrophil phagocytosis and SAG were measured when absolute neutrophil count reached > 500 /microl. Patients were observed for development of infection, mucositis and diarrhoea. In Gln-treated patients, the percentage of neutrophil phagocytosis and the SAG levels were significantly higher than in control patients (20.5 +/- 6.0% and 18.9 +/- 2.9 nmol/10(6) neutrophils per 10 min, respectively). The Gln-treated patients lost significantly less weight, tended to have shorter in-patient duration and had less severe oral mucositis than controls. This pilot study provides preliminary indication that parenteral Gln supplementation enhances neutrophil phagocytic function, maintains nutritional status and is cost effective. Parenteral Gln may also prevent oral mucositis, although further studies involving more patients need to be undertaken to confirm this and the other results.

Effects of n-3 fatty acids on serum interleukin-6, tumour necrosis factor-alpha and soluble tumour necrosis factor receptor p55 in active rheumatoid arthritis.

We investigated the effects of a low n-6 fatty acid (FA) diet supplemented with fish oil on serum pro-inflammatory cytokine concentrations and clinical variables in patients with active rheumatoid arthritis (RA). Sixty patients were randomly assigned to receive a diet low in n-6 FAs and n-3 FAs supplement (fish oil group), a diet low in n-6 FAs and placebo (placebo group), or no special diet or intervention (control group). Serum cytokines and clinical and biochemical variables were evaluated at baseline and various timepoints. At week 18 the fish oil group had significant reductions in linoleic acid, C-reactive protein (CRP) and soluble tumour necrosis factor receptor p55 (sTNF-R p55), and significant elevations in eicosapentaenoic acid and docosahexaenoic acid compared with baseline. There were no significant differences in the clinical variables between the three groups. At week 24 there were significant reductions in interleukin-6 and TNF-alpha in the fish oil and placebo groups. Supplementation with n-3 FA and a low n-6 FA intake decreased serum sTNF-R p55 and CRP levels in patients with RA.

Serum C-reactive protein level in postsplenectomized thalassemic patients.

C-reactive protein is an established marker for the detection of acute and chronic inflammatory processes. The most potent stimulator for the hepatic synthesis of this protein is interleukin 6. Previous studies have shown that inflammatory cells and inflammatory cytokines, such as interleukin 6, interferon gamma, etc were elevated in postsplenectomized thalassemic patients. The aim of this study was to determine serum C-reactive protein concentration in postsplenectomized beta thalassemic patients (beta thal/HbE postsplenec), and to compare them with those in nonsplenectomized beta thalassemic patients (beta thal/HbE), postsplenectomized non thalassemic patients (postsplenec), reactive thrombocytosis (RT), chronic myeloproliferative disorders (MPD) and normal adult volunteers. Serum C-reactive protein concentration as determined by an automatic Behring Nephelometer was carried out in 28 beta thal/HbE postsplenec, 22 beta thal/HbE, 12 postsplenec, 23 RT, 21 MPD, and 26 healthy adult volunteers. The values of CRP in beta thal/HbE postsplenec were significantly higher when compared with beta thal/HbE, and normal volunteers (4.1 +/- 0.7 vs 1.6 +/- 0.4 mg/L P = 0.006, and 4.1 +/- 0.7 vs 0.45 +/- 0.09 mg/L, P < 0.001). CRP levels in beta thal/HbE postsplenec were also higher than the postsplenec group (4.1 +/- 0.7 vs 0.19 +/- 0.7 mg/L P = 0.095). On the contrary, they were significantly lower than those in RT (4.1 +/- 0.7 vs 55.4 +/- 14.8 mg/L, P = 0.002). However, when compared to those with MPD, the values were not statistically different (4.1 +/- 0.7 vs 17.1 +/- 12.3 mg/L, P = 0.871). Interestingly, there was a trend towards increasing C-reactive protein levels in beta thal/HbE postsplenec patients with higher platelet count, although no correlation was observed. Besides the inflammatory process, platelet and/or factor(s) that control(s) thrombopoiesis seem(s) to play a role in the high serum C-reactive protein levels in the studied population.

Etiology and incidence of thrombotic and hemorrhagic disorders in Thai patients with extreme thrombocytosis.

A retrospective study of 126 patients with extreme thrombocytosis (defined as a platelet count > or = 1,000 x 10(9)/L) was performed during a five-year period (June 1994-June 1999). The aim of this study was to determine the etiology and to evaluate the clinical consequences of extreme thrombocytosis. Seventy patients (55.5%) had reactive thrombocytosis (RT) with an age range of 43 +/- 2.2 years, 56 (44.5%) had chronic myeloproliferative disorders (MPD) with an age range of 53 +/- 2.4 years. Underlying causes of RT were malignancy (25/70 or 35.7%), infection (16/70 or 22.9%), postsplenectomized beta-thalassemia/Hb E (11/70 or 15.7%), inflammation (12/70 or 17.1%), iron deficiency anemia (6/70 or 8.6%). Duration post splenectomy in our beta-thalassemia/Hb E patients ranged from 4 months to 21 years, with a median of 10 years. Subtypes of our MPD cases were chronic myeloid leukemia (30/56 or 53.6%), essential thrombocytosis (18/56 or 32.1%), polycythemia vera (4/56 or 7.1%), agnogenic myeloid metaplasia (3/56 or 5.4%) and unclassified MPD (1/56 or 1.8%). Bleeding and thrombotic tendency were respectively noted in 7 (12.5%) and 2 (3.6%) of MPD patients. Two patients of the MPD group (3.6%) experienced both bleeding and thrombotic episodes. One patient (1.4%) of the RT group developed vasculitis-associated thrombosis. However, none of the patients in the RT group had bleeding complications. Extreme thrombocytosis was not a rare condition in a university hospital population, and bleeding and/or thrombotic complication was more common in the MPD group.

Levels of serum tumor necrosis factor alpha in relation to clinical involvement and treatment among Thai adults with Plasmodium falciparum malaria.

UNLABELLED: Concentrations of tumor necrosis factor alpha (TNF-alpha) in serum were measured in 17 Thai men infected with Plasmodium falciparum malarial infections to determine whether they were affected by severity of infections or exchange transfusions. Twelve patients were considered having complicated malarial infections, eight of whom had cerebral malaria. Five patients had uncomplicated malarial infections. The results showed that malarial infection markedly raised TNF-alpha level above normal values (mean +/- SEM 406 +/- 38 vs 15 +/- 5, p = 0.004). In complicated malaria, cerebral involvement appeared to significantly increase concentration of TNF-alpha when compared to values in uncomplicated malaria (mean +/- SEM 496 +/- 64 vs 339 +/- 12, p = 0.01). Degree of parasitemia, intravenous quinine (day 0 value vs day 7 value) and exchange transfusion did not significantly affect TNF-alpha levels. CONCLUSION: Serum level of TNF-alpha is increased in Plasmodium falciparum malarial infections and may be a useful index to predict severity of malarial infection, cerebral malaria in particular.

Levels of serum interleukin-6 and tumor necrosis factor in postsplenectomized thalassemic patients.

Levels of serum interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were studied in 34 nonsplenectomized thalassemic patients (Thal/nonsplenec), 43 postsplenectomized thalassemic patients (Thal/postsplenec), 13 splenectomized non-thalassemic patients (nonThal/ postsplenec) and 18 normal control by enzyme linked immunosorbent assay method. Serum IL-6 concentration in Thal/postsplenec was significantly increased when compared with Thal/ nonsplenec and normal volunteers (3.55 +/- 2.47 pg/ml vs 2.38 +/- 2.31 pg/ml, p = 0.036 and 3.55 +/- 2.47 pg/ml vs 2.66 +/- 0.45 pg/ml, p = 0.028, respectively). This study also demonstrated that TNF-alpha value in Thal/postsplenec was drastically increased above normal control level (15.8 +/- 4.86 pg/ml vs 9.16 +/- 2.18 pg/ml, p = 0.001) and the level was statistically significantly higher than that in Thal/ nonsplenec (15.5 +/- 4.86 pg/ml vs 9.96 +/- 5.19 pg/ml, p = 0.001). There was a trend toward increasing of cytokine levels in Thal/postsplenec with higher platelet count although no correlation was observed. This study addresses the possible role of IL-6 and TNF-alpha in the pathogenesis of reactive thrombocytosis in Thal/postsplenec.

Effect of dialyzer membranes on beta-2 microglobulin production in Thai hemodialysis patients.

UNLABELLED: Responses to different types of dialyzer membranes in an Asian population may differ from those of a Caucasian population. Comparative studies on the effects of different dialyzer membranes on beta-2 microglobulin production are also limited. Therefore, we conducted this study to determine the effects of different dialyzer membranes on in vitro mononuclear cell production of beta-2 microglobulin in 9 Thai hemodialysis patients. Each patient was dialysed with 4 different types of dialyzer, including cuprophane (CUP), cellulose diacetate (CD), polysulphone (PS), and polyacrylonitrile membrane (PAN), each for a 1-month period in a randomized sequence. Mononuclear cell culture was done by taking an immediate post-dialysis blood sample at the end of the 1-month period. Beta-2 microglobulin production from cell culture was determined 24 hours later. Mononuclear cell culture and determination of beta-2 microglobulin production from the culture were also done in 10 normal controls and 10 predialysis ESRD patients. The beta-2 microglobulin productions (microgram/L) were shown as follows; Control CUP CD PS PAN [table: see text] (*p < 0.05 compared to cuprophane membrane). CONCLUSION: polysulphone and polyacrylonitrile membrane induced significantly less beta-2 microglobulin production compared to cuprophane and slightly less compared to cellulose diacetate membrane.

Standardization of platelet aggregation test in normal Thai adults.

Platelet aggregation test was assessed by the turbidimetric method in 52 normal Thai adults consisting of 24 males and 28 females with ages ranging from 20 to 50 years. The aggregating agents used were adenosine diphosphate (ADP), adrenaline and collagen. It was found that the ranges of threshold concentration of ADP, adrenaline and collagen which gave maximal induction of platelet aggregation were 5-10 microM, 2.5-10 microM and 0.14-0.28 mg/mL, respectively. Collagen at the above concentration, showed lag phase within 2 minutes. This corresponds to that described in the reference method. Moreover, when induced by ADP and adrenaline 53-65 per cent and 81-87 per cent of the subjects, respectively, showed biphasic curve. The above concentration of ADP, adrenaline and collagen are suitable for the study of platelet aggregation in normal Thai adults.

Blood cell production and hemostatic mechanism in Thai vegetarians.

The activity of hemostatic mechanism and blood cell production of 50 Thai vegetarians and 30 nonvegetarians were compared. The hemostatic mechanism of both vegetarians and nonvegetarians showed no significant difference, whereas, a significant decrease in hemoglobin, hematocrit and red blood cell count with significant increase in hypersegmented neutrophils were found in vegetarians who had taken vegetarian diets for over 4 years.

Chronic immunologic thrombocytopenic purpura: results of cyclophosphamide therapy before splenectomy.

Corticosteroids, cyclophosphamide, and splenectomy were employed in the treatment of 43 patients with immunologic thrombocytopenic purpura. All received corticosteroids initially; 22 patients received corticosteroids and cyclophosphamide, and six received drug treatment and underwent splenectomy. Of those receiving corticosteroids alone, 11 had excellent responses and ten had good responses. Of those receiving corticosteroids and cyclophosphamide, responses to treatment were excellent in six, good in eight, and fair in two. Of those receiving drug treatment and undergoing splenectomy, the responses to treatment were excellent in four, good in one, and fair in one. The duration required for induction of remission indicated the prognosis for patients; excellent responses were observed at 1, 2.4, and 4 months in groups treated, respectively, with corticosteroids, corticosteroids and cyclophosphamide, and drugs plus splenectomy.

Histamine changes in Plasmodium falciparum malaria.

Histamine, serum complement factor 3 (C'3) and platelets were studied in 33 Plasmodium falciparum patients. Elevation of histamine level in the blood was found during acute infection but was more marked in the group of patients with systemic complications. A correlation between histamine changes, clinical complications, reduction of C'3 and degree of thrombocytopenia was observed. The possible role of histamine in the development of complications in P. falciparum infection and the possible release of this substance through the activation of complement system and immune destruction of platelets were discussed.