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Biomedical subjects

S J Machin

Publications and source records attributed to S J Machin.

At least 127 records · Page 7Linked to original sources
PubMed1991

Platelet aggregation is inhibited by a nitric oxide-like factor released from human neutrophils in vitro.

Thrombin-induced platelet aggregation was inhibited in vitro by washed human neutrophils. Aggregation was inhibited in a neutrophil concentration dependent manner but glutaraldehyde fixed neutrophils had no significant effect on platelet aggregation. The neutrophil-derived inhibitory factor had the pharmacological profile of nitric oxide. Its action was potentiated by both superoxide dismutase and M&B22, 948, a selective cyclic guanosine monophosphate (cyclic GMP) phosphodiesterase inhibitor. Haemoglobin lessened this inhibitory action of neutrophils. L-Arginine, the substrate for nitric oxide formation, enhanced inhibition, whereas, L-canavanine, a structural analogue of L-arginine, prevented it. Nitric oxide release by neutrophils antagonized platelet ATP secretion and thromboxane B2 release. Inhibition was mediated by nitric oxide activation of guanylate cyclase with a subsequent rise in cyclic GMP. When neutrophils were stimulated with formyl-met-leu-phe, there was a further increase in platelet cyclic GMP. This was enhanced by superoxide dismutase, but lessened by haemoglobin. Leukotriene B4 stimulation of neutrophils promoted inhibition of platelet aggregation. Leukotriene B4 alone had no direct effect on thrombin-induced aggregation of platelets. Platelets, when incubated with neutrophils and stimulated with calcium ionophore A23187, increased leukotriene B4 production by neutrophils in a platelet concentration dependent manner. Platelets alone were unable to release leukotriene B4. The action of platelets in haemostasis is modified as they come into contact with neutrophils. This may be an important physiological mechanism.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Antibiotic treatment and associated prolonged prothrombin time.

The incidence and type of pathology causing a prolonged prothrombin time and clinical bleeding episodes were assessed in a multicentre study of 1109 patients receiving cefotetan, a N-methyl-thiotetrazole (NMTT), or equivalent antibiotics. There was no significant difference in the incidence of a prolonged prothrombin time (9.9% with cefotetan, 8.0% with comparable antibiotics) of clinical bleeding episodes. However, prothrombin time increases of greater than 12 seconds were significantly (p = 0.002) greater with cefotetan (3.8%) than with comparators (0.8%). In both antibiotic groups increases in prothrombin time were more likely following surgery and in patients who were older, with a high platelet count, low albumin, or higher urea and creatinine concentrations. All antibiotic treatment can be associated with prolonged prothrombin times and new agents should always be assessed in a large multicentre study before the practical, clinical importance of haemostatic defects can be defined.

Adolescent↗
PubMed1991

Exchange transfusion of a patient with fulminant Lassa fever.

We report a patient with fulminant Lassa fever who responded dramatically to a 2.5-litre exchange transfusion of whole blood. On admission he was semicomatose with facial oedema and oral haemorrhage; his platelets showed markedly depressed aggregation to ADP; and his plasma inhibited the aggregation responses of normal platelets in vitro. Exchange transfusion resulted in rapid clinical improvement, recovery of platelet function, and disappearance of platelet-inhibitory activity in plasma. The patient died 2 weeks later from an acute encephalopathy. His initial response was sufficiently impressive to suggest that further evaluation of this therapeutic approach is justified in selected patients with overwhelming Lassa virus infection.

Adult↗
PubMed1990

Demonstration of viraemia patterns in haemophiliacs treated with hepatitis-C-virus-contaminated factor VIII concentrates.

Sequential serum samples from previously untreated haemophiliacs in whom non-A, non-B hepatitis (NANBH) developed after they received factor VIII concentrate contaminated with hepatitis C virus (HCV) were tested by a commercial assay for the presence of antibodies to the C100 protein of HCV (anti-C100) and by "nested" PCR for the presence of HCV RNA sequences. Three temporal patterns of viraemia were observed: transient viraemia in acute resolving NANBH; viraemia lasting for several years in chronic NANBH; and intermittent viraemia in chronic NANBH, with an initial transient phase followed by recurrence after many months. In three of five cases the initial detection of serum HCV RNA was made before the onset of liver function test abnormality, many weeks or months before anti-C100 seroconversion. Diagnosis of acute HCV infection may therefore be possible much earlier by PCR than by existing serological techniques, but the timing of samples may be critical.

Acute Disease↗
PubMed1990

Changes in metabolism induced by oral contraceptives containing desogestrel and gestodene in older women.

Forty women aged 35-45 years were investigated to determine changes in haemostasis, lipids and lipoproteins whilst taking combined contraceptive pills containing the new third generation progestogens, desogestrel and gestodene. There was no statistically significant difference between the two preparations in any of the parameters studied. Women taking the combined pill showed increases in fibrinogen and factor X and a reduction in antithrombin III when compared with their control values. There were also small but significant increases in triglycerides and triglyceride-rich lipoproteins. Total high density lipoprotein cholesterol (HDL), high density lipoprotein-2 cholesterol (HDL2), high density lipoprotein-3 cholesterol (HDL3) and apolipoprotein A-1 were all increased at some stages of the treatment cycle, whereas low density lipoprotein cholesterol (LDL) showed a reduction in the first cycle of treatment. The changes in lipids and lipoproteins would not appear to increase the risk of cardiovascular disease, however the effects of the increase in the pro-coagulant factors are uncertain.

Adult↗
PubMed1990

Ceftazidime monotherapy is as effective as ceftazidime combined with gentamicin in the treatment of febrile neutropenic patients.

To evaluate the efficacy of ceftazidime monotherapy in the empirical treatment of febrile neutropenic patients, a randomized trial was performed of ceftazidime (C) vs. ceftazidime and gentamicin (C + G) with the addition of teicoplanin (T) for those patients with a long intravenous line-associated infection. Success without modification at the end of treatment was seen in 32.7% (C), 28.3% (C + G), 52.4% (C + T) and 65.2% (C + G + T). Monotherapy with ceftazidime is as effective as when used in combination with an aminoglycoside in neutropenia.

Agranulocytosis↗
PubMed1990

Multiple transient ischaemic attacks and a mild thrombotic stroke in a HIV-positive patient with anticardiolipin antibodies.

Antiphospholipid antibodies (APA) have been reported to be associated with thrombosis in systemic lupus erythematosus (SLE) and in many other clinical groups. However, although these antibodies have been identified in a substantial number of patients infected with the human immunodeficiency virus (HIV), in this case an association with thrombosis has not been evident. We describe a patient with HIV infection who had anticardiolipin antibodies (ACA) but no lupus anticoagulant (LA) who had recurrent transient ischaemic attacks (TIAs) and a mild stroke.

Adult↗
PubMed1990

Basal and induced prothrombinase expression in platelets from patients with essential thrombocythaemia (ET).

Both the basal and the collagen plus thrombin-stimulated prothrombinase activities have been measured in platelets from eight patients with essential thrombocythaemia (ET). On a mean basis these activities were significantly lower than the values recorded for a group of age and sex matched control subjects. When the Ca2+ ionophore A23187 was substituted for the agonist mixture the induced expression of prothrombinase activity was essentially the same for the patient and control groups. It is suggested that the defect in prothrombinase expression seen with ET platelets may reside in either membrane signal transduction processes concerned with Ca2+ mobilization or in Ca2+ sensitive cytoskeletal control of membrane phospholipid topography.

Adult↗
PubMed1990

Prophylactic teicoplanin during insertion of Hickman catheters.

With the extensive use of Hickman catheters in patients requiring cytotoxic chemotherapy there is now a resurgence of Gram-positive septicaemia among these patients during the neutropenic periods. We are currently running a prospective randomized study of prophylactic teicoplanin during insertion of Hickman catheters to determine if it reduces the incidence of Gram-positive septicaemia. A total of 44 patients have completed the study (23 in the teicoplanin group and 21 in the control group). The diagnoses were: acute myelogenous leukaemia (13), non-Hodgkin's lymphoma (16), Hodgkin's disease (11), chronic granulocytic leukaemia (3) and acute lymphoblastic leukaemia (1). The number of days between insertion of Hickman catheters and the development of neutropenia was: teicoplanin group: mean 14.7, median 11, range 0-53; control group: mean 11.8, median 10, range 0-37. In the treated patients, there were four episodes of line-associated Gram-positive septicaemia and a total of four organisms were isolated. In the control group, 10 organisms were isolated from a total of nine episodes of line-associated Gram-positive septicaemia. The organisms were: coagulase-negative staphylococci (8), Streptococcus B, (1), Strep. faecalis (1), Strep. mitis (1), alpha streptococcus (1), diphtheriods (1) and Staphylococcus aureus (1). All organisms were sensitive to teicoplanin. No adverse reaction was observed in any patient. Prophylactic teicoplanin during insertion of Hickman catheters may therefore reduce the incidence of line-associated Gram-positive septicaemia in neutropenic patients.

Anti-Bacterial Agents↗
PubMed1990

A randomized prospective study of ceftazidime and ciprofloxacin with or without teicoplanin as an empiric antibiotic regimen for febrile neutropenic patients.

Febrile neutropenic patients were randomized to receive ceftazidime and ciprofloxacin with the addition of teicoplanin in cases with clinical suspicion of a Hickman line-associated infection. At 48 h both clinical and bacteriological analyses were made. Patients were categorized as: success, in cases of improvement or stability in the clinical condition; failure, if there was a deterioration of the clinical condition; and non-evaluable, in cases of protocol violation or death due to other causes. A total of 86 patients have completed the study so far; 43 patients were randomized to the ceftazidime and 43 to the ciprofloxacin group. Teicoplanin was added to the monotherapy in 12 patients in the ceftazidime group and 15 in the ciprofloxacin group. The diagnoses were: acute myelogenous leukaemia (25), non-Hodgkin's lymphoma (34), Hodgkin's disease (17); acute lymphoblastic leukaemia (9) and chronic granulocytic leukaemia (1). Forty-eight hour clinical assessment showed a response rate in the ceftazidime group of: success 18/31 (58%), failure 13/31 (42%); in the ceftazidime and teicoplanin group: success 8/12 (67%), failure 4/12 (33%); in the ciprofloxacin group: success 23/28 (82%), failure 5/28 (18%); and in the ciprofloxacin and teicoplanin group: success 11/15 (73%), failure 4/15 (27%). Blood cultures were positive in 48/86 (56%) cases, with more than one organism isolated in seven of these 48 cases. Organisms isolated were: coagulase-negative staphylococci (20), Escherichia coli (13), Pseudomonas aeruginosa (4), Staphylococcus aureus (3), diphtheroids (3), Klebsiella sp. (3), Enterobacter cloacae (2), Streptococcus faecalis (2), Ent. adenocarboxylata (1), Clostridium septicum (1). Strept. B (1), alpha streptococcus (1) and P. fluorescens (1), In-vitro testing showed that all Gram-positive organisms were sensitive to teicoplanin, and Gram-negative organisms to ciprofloxacin or ceftazidime. There were seven cases of superimposed infections with eight organisms isolated, all cases occurring in patients receiving ciprofloxacin alone: coagulase-negative staphylococci (4), Strep. sangius (1), Strep. viridans (1), diphtheroids (1) and P. maltophilia (1). Both ciprofloxacin and ceftazidime are comparable in efficacy as empirical monotherapy for febrile neutropenic patients. There is, however, a significant increase in the incidence of superimposed infection in patients receiving only ciprofloxacin. In view of the very high incidence of Gram-positive septicaemia, we suggest that teicoplanin should be added as part of the initial empiric antibiotic regimen in all febrile neutropenic patients.

Anti-Bacterial Agents↗
PubMed1990

A plasma inhibitor of platelet aggregation in patients with Argentine hemorrhagic fever.

Hemorrhage in patients with Lassa fever is associated with the presence of a circulating plasma inhibitor of platelet aggregation. This study was to determine whether patients with Argentine hemorrhagic fever (AHF) develop a similar inhibitor. Normal platelets showed significantly weaker aggregation responses to a sub-maximal dose of adenosine diphosphate (ADP) when mixed with plasma from 10 patients with AHF (mean percent of control +/- 1 SE = 57.2 +/- 6.7%) compared to those mixed with plasma from 9 viral control patients (79.5 +/- 4.1%; P less than 0.05) and 9 febrile patients with septicemia (103.8 +/- 3%; P less than 0.001). Plasma from 3 patients with severe AHF inhibited in a dose-dependent fashion the aggregation responses of normal platelets to collagen, sodium arachidonate, a calcium ionophore (A23187), and ristocetin; none of 4 samples from convalescent AHF patients showed this inhibitory activity. The platelet inhibition was sudden in onset and unaffected by a 30 min pre-incubation, not neutralized by convalescent plasma with high titer antibody to Junin virus, and abolished after heating plasma from an AHF patient at 56 degrees C for 30 min. Hemorrhage in AHF is associated with the presence of a circulating inhibitor of platelet aggregation, and disturbed hemostasis in arenavirus-induced hemorrhagic fevers may have a common basis.

Adenosine Diphosphate↗
PubMed1990

Heparin cofactor II levels are increased by the use of combined oral contraceptives.

Heparin cofactor II (HCII) was assayed by a microtitre amidolytic substrate technique. A linear response was obtained up to 1.5 U/ml and HCII levels were not affected by freezing and thawing the plasma. The assay was validated by comparing HCII and antithrombin III (AT III) levels in AT-III-deficient plasmas and samples from critically ill patients. Higher HCII levels were found in healthy normal women than in healthy normal men (means 1.16 and 0.97 U/ml, respectively, P less than 0.01). A significant increase in HCII levels from 0.86 to 1.10 U/ml (mean values) was seen in healthy normal women starting on combined oral contraceptive (COC) preparations (P less than 0.001). Increased HCII levels were maintained over a 6-month period, but fell towards normal 14 days after stopping COC, although they were still significantly higher than before starting COCs. The discrepancy in HCII level between normal men and women may be due to COC use. In clinical studies, different reference ranges should be used for men and women, and the need for careful questioning about the use of COCs is emphasized.

Adolescent↗
PubMed1990

The in-vitro and ex-vivo effects of chloroquine sulphate on platelet function: implications for malaria prophylaxis in patients with impaired haemostasis.

Platelet aggregation responses were studied in platelet-rich plasma from six healthy volunteers before and 2 and 6 h after ingestion of 600 mg chloroquine sulphate. Apart from a mild reduction in height of aggregation response to 1 microgram ml-1 collagen 2 h post-drug ingestion (mean percentage of pre-drug values +/- s.e.m. = 87.8% +/- 4.0%; P = 0.04), no significant differences were observed in platelet responses to ADP (1 and 5 microM) or collagen (1 and 4 micrograms ml-1) at 2 or 6 h post-chloroquine compared to the pre-drug values. In vitro, drug concentrations approximately 1000 times greater than those used therapeutically were required for 50% inhibition of platelet aggregation and ATP release in response to 5 microM ADP, 1 microgram ml-1 collagen and 4 micrograms ml-1 collagen (IC50 concentrations +/- s.e.m. for inhibition of aggregation = 98.5 +/- 3.7, 53.5 +/- 56.4 and 113.0 +/- 6.2 mg l-1 respectively; IC50s +/- s.e.m. for inhibition of ATP release = 0.9 +/- 0.2, 14.7 +/- 4.0 and 23.0 +/- 5.3 mg l-1 respectively). These data provide no cause for concern in using chloroquine for malaria prophylaxis in patients with impaired haemostasis.

Adenosine Diphosphate↗
PubMed1990

Nicotine and cigarette smoking: effects on the ultrastructure of aortic endothelium.

The aortic endothelium from rats has been examined by scanning (SEM) and transmission electron microscopy (TEM) following nicotine administration or cigarette smoking. Nicotine was administered to rats by subcutaneous injections at concentrations of 1, 5, 10 and 20 mg/kg or by continuous subcutaneous pumps delivering a solution of 0.54 g/ml of nicotine at the rate of 1 microliter/h for 7 days. Animals were exposed to fresh smoke from eight cigarettes, each yielding 19 mg tar and 1.5 mg nicotine. Twenty minutes after subcutaneous injections, no endothelial abnormalities were evident by SEM, apart from at the high dose where minimal endothelial damage was seen. Limited endothelial damage was discerned following nicotine infusion and this consisted of microvillus formation, platelet adhesion and some cell separation. TEM revealed no endothelial changes in any of the animals. Cigarette smoking, however, resulted in considerable endothelial morphological changes consisting of the formation of blebs, microvillus-like projections, increased numbers of plasmalemmal vesicles and an increase in the numbers of Weibel-Palade bodies. The results suggest that components of cigarette smoke other than nicotine are responsible for the endothelial cell changes associated with smoking.

Animals↗