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Biomedical subjects

D A Warrell

Publications and source records attributed to D A Warrell.

At least 163 records · Page 9Linked to original sources
PubMed1986

Intramuscular loading dose of quinine for falciparum malaria: pharmacokinetics and toxicity.

In a study of intramuscular injection of quinine eight adults with moderately severe falciparum malaria resistant to chloroquine were treated with quinine dihydrochloride, being given a loading dose of 20 mg salt (16.7 mg base)/kg followed by three or four eight hourly maintenance doses of 10 mg salt (8.3 mg base)/kg injected into the anterior thigh. All patients responded to treatment. Fever and parasite clearance times (mean (SD) 60 (23) h and 53 (22) h respectively) were comparable with those obtained with intravenous quinine. The mean peak plasma quinine concentration of 11.0 mg/l (34.4 mu mol/l) [corrected] was reached a median of five hours after administration of the loading dose. In all patients plasma quinine concentrations exceeded the high minimum inhibitory concentration for Plasmodium falciparum malaria prevalent in Thailand within four hours of the start of treatment but did not cause toxicity other than mild cinchonism. When intravenous infusion is not possible an intramuscular quinine loading dose is an effective means of starting treatment in patients with moderately severe falciparum malaria who cannot swallow tablets.

Adult↗
PubMed1986

Divided dose intramuscular regimen and single dose subcutaneous regimen for chloroquine: plasma concentrations and toxicity in patients with malaria.

Adults with malaria in Sri Lanka were treated with parenteral chloroquine diphosphate, either 2.5 mg base/kg intramuscularly at 0, 1, 12, 13, 24, and 25 hours or 5 mg base/kg subcutaneously at 0, 12, and 24 hours. Both regimens were completed with oral chloroquine phosphate, 5 mg base/kg, at 36 and 48 hours. Mean peak chloroquine concentrations in the first 12 hours, which were 0.5 (range 0.3-0.6) mg/l (1.4 (0.9-1.7) mu mol/l) [corrected] with the intramuscular regimen and 0.3 (0.2-0.4) mg/l (1.0 (0.7-1.3) mu mol/l) [corrected] with the subcutaneous regimen (p less than 0.05), were reached in median times of 90 (65-90) minutes and 30 (30-60) minutes respectively (p less than 0.05) after the start of treatment. The mean area under the plasma concentration curve for the first 12 hours was 1.4 (0.9-2.1) mg/l.h (4.5 (2.8-6.4) mu mol/l.h) [corrected] after intramuscular administration and 1.8 (0.8-2.3) mg/l.h (5.7 (2.7-7.2) mu mol/l.h) [corrected] after subcutaneous administration (p greater than 0.1). Mean maximum plasma concentrations were higher after intramuscular administration (0.6 (0.4-0.8) mg/l (1.7 (1.3-2.5) mu mol/l)) [corrected] than after subcutaneous administration (0.4 (0.4-0.5) mg/l (1.3 (1.3-1.5) mu mol/l)) [corrected] (p less than 0.05), but both regimens produced satisfactory plasma profiles. Chloroquine resistance was found in the only case of Plasmodium falciparum malaria. Chloroquine is absorbed rapidly after divided dose intramuscular injection and single dose subcutaneous injection and does not cause hypotension or neurotoxicity in adults. Similar regimens should be evaluated in children before the parenteral use of this drug is abandoned.

Adolescent↗
PubMed1986

Hypoglycaemia and antimalarial drugs: quinidine and release of insulin.

Life threatening hypoglycaemia has been closely associated with the use of quinine, but the effect of quinidine and the synthetic antimalarials on the homoeostasis of glucose has not been investigated. In volunteers given a fixed dose of 500 mg base and patients with malaria given a quinidine loading dose (15 mg base/kg) mean (SEM) plasma insulin concentrations rose from 6.1 (1.5) mU/l to 10.9 (4.4) mU/l (p less than 0.02) and 10.4 (2.0) mU/l to 18.5 (5.3) mU/l (p less than 0.04), respectively. Plasma glucose concentrations fell from 4.5 (1.1) mmol/l (81 (20) mg/100 ml) to 4.0 (0.3) mmol/l (72 (5) mg/100 ml) in volunteers (p less than 0.04) and from 5.7 (1.3) mmol/l (102 (23) mg/100 ml) to 4.8 (1.6) mmol/l (86 (29) mg/100 ml) in patients (p less than 0.05). One of two patients with cerebral malaria and acute renal failure became profoundly hypoglycaemic (plasma glucose concentration 1.4 mmol/l (25 mg/100 ml), plasma insulin concentration 3.1 mU/l). Hypoglycaemia may occur in any severely ill fasting patient given parenteral quinidine. The other antimalarials tested, chloroquine, amodiaquine, mefloquine, and halofantrine, did not stimulate the release of insulin, an important advantage that should be taken into account when treatment is chosen for Plasmodium falciparum malaria.

Amodiaquine↗
PubMed1986

Effectiveness of SMS 201-995, a synthetic, long-acting somatostatin analogue, in treatment of quinine-induced hyperinsulinaemia.

SMS 201-995, a new long-acting, synthetic somatostatin analogue, dose 50 micrograms/h, given as a continuous intravenous infusion, completely abolished quinine-induced insulin release in 9 healthy Thai volunteers. Hyperinsulinaemia, which caused sustained hypoglycaemia in a 32-year-old post-partum Thai patient who was receiving intravenous quinine for falciparum malaria, was suppressed within 30 min of starting SMS 201-995, and the patient became fully conscious. This octapeptide antagonises the stimulatory effect of quinine on the pancreatic beta cell and is a specific therapy for life-threatening hyperinsulinaemic hypoglycaemia complicating falciparum malaria.

Adult↗
PubMed1986

Prediction, prevention, and mechanism of early (anaphylactic) antivenom reactions in victims of snake bites.

Victims of snake bites are often subjected to cutaneous or conjunctival hypersensitivity testing before being given antivenom. None of 12 early (anaphylactic) reactions was predicted by these tests in 25 Nigerian and Thai patients. The incidence and severity of early reactions was the same whether antivenom was given by intravenous injection over 10 minutes or diluted and given as an intravenous infusion over 30 minutes. Although antivenom activated complement in vitro, there was no evidence of complement activation or formation of immune complexes in patients bitten by snakes who were treated with antivenom, whether or not they developed early reactions. Higher doses of antivenom might induce the complement activation and formation of immune complexes (aggregates) that have been observed during the clinically more severe reactions associated with homologous immunoglobulin treatment.

Anaphylaxis↗
PubMed1986

A critical reappraisal of the use of enzyme-linked immunosorbent assays in the study of snake bite.

The enzyme-linked immunosorbent assay (ELISA) has been the most widely used serological test in snake bite immunodiagnosis and epidemiology. The technique has been applied, however, without due consideration of the many factors which would affect an inherently sensitive test system, especially in tropical rural areas where large scale snake bite studies are usually carried out. This review discusses the effects of non-specific reactivity, cross reactivity and the quality of reagents on both the sensitivity and specificity of venom antigen and antibody detection assays. Simple laboratory modifications to optimize the assays are described. The importance of using the predictive value to assess the validity of applying the same test system in different circumstances is stressed. To fulfil its potential as the most versatile immunoassay technique in snake bite research, the test conditions of the ELISA will have to be much more stringently controlled in future.

Antibodies↗
PubMed1986

The pathophysiology of severe falciparum malaria.

By the end of the 1940s, the clinical and pathological features of severe falciparum malaria had been well described by military physicians and pathologists working in theatres of war where the disease was endemic. From that time serious efforts were made to discover the pathophysiology of the severe manifestations of malaria because an understanding of these mechanisms forms an important basis for the clinical management of affected patients. Recently, after a period of neglect, there has been a revival of interest in malaria as a subject for clinical and laboratory research. In this article, Rodney Phillips and David Warrell review aspects of that work and attempt to unravel the mysteries of the pathophysiology of severe malaria in man.

Journal Article↗
PubMed1986

Antigen-specific immunosuppression in human malaria due to Plasmodium falciparum.

Proliferative responses of T lymphocytes to antigens specific and not specific for malaria were investigated in 32 adult patients in eastern Thailand during acute infection with Plasmodium falciparum malaria and during their convalescence. Immune unresponsiveness to malarial antigen, which persisted for more than four weeks in 37.5% of the individuals, was present in all patients, irrespective of parasitemia or severity of clinical illness. Suppression of responses to nonspecific antigens was less profound and observed only in patients with moderately severe or cerebral malaria. The depressed functional responses were associated with a loss of T lymphocytes--both helper and suppressor subsets--from the peripheral blood; these responses were recovered once parasites were cleared. These results indicate that blood-stage plasmodial infections may suppress responses important for immunity to malaria and so allow the parasite to survive. They further suggest that patients acutely or even recently infected with P. falciparum may not respond as well to a malaria vaccine as would uninfected individuals.

Adolescent↗
PubMed1986

Cardiovascular toxicity and distribution kinetics of intravenous chloroquine.

Chloroquine diphosphate (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to 12 healthy adult male volunteers. Plasma concentrations of chloroquine and the principal metabolite desethylchloroquine, electrocardiograph intervals, and arterial blood pressure were measured at frequent intervals to determine the relationship between cardiovascular effects and plasma concentrations. Peak plasma concentrations ranged between 784 and 6649 (mean 2913) ng ml-1. The decline in plasma concentrations was multiexponential with an initial rapid distribution phase; mean (+/- s.d.) first order rate constant 0.65 +/- 0.14 min-1, and an estimated apparent volume of the central compartment of 0.18 +/- 0.15 l kg-1. There was no serious toxicity, but subjective side effects were reported in all patients and there was a significant fall in systolic blood pressure (110 +/- 9.5 to 101 +/- 12.5 mm Hg; P = 0.03) and rise in heart rate which paralleled the change in plasma chloroquine concentrations. Coincident with changes in blood pressure, there was a significant prolongation of the electrocardiograph QRS interval; 81 +/- 15 to 92 +/- 13 ms (P less than 0.01) but no change in the QTc interval. These findings suggest that the cardiovascular toxicity of parenteral chloroquine is related to transiently high plasma concentrations occurring early in the distribution phase. This results from incomplete distribution from a central compartment that is approximately one thousand times smaller than the eventual total apparent volume of distribution at steady state. Rate of administration is therefore a major determinant of toxicity.

Adolescent↗
PubMed1986

Quinine pharmacokinetics and toxicity in pregnant and lactating women with falciparum malaria.

Quinine dihydrochloride (10 mg or, in two patients, a loading dose of 20 mg kg-1) was infused intravenously over 4 h in ten severely ill but conscious women with falciparum malaria complicating the third trimester of pregnancy. Plasma quinine concentrations, measured spectrophotofluorimetrically after benzene extraction, fitted closely a single exponential decline after the intravenous infusion. These data were therefore fitted to a one compartment model: total apparent volume of distribution, V, 0.96 +/- 0.27 l kg-1 (+/- s.d.), elimination half-time (t1/2,z), 11.3 +/- 4.3 h, total clearance, 1.22 +/- 0.77 ml min-1 kg-1. There was no relationship between arterial blood pressure and plasma quinine concentrations. Eight women delivered of live infants while taking quinine, had placental cord plasma quinine concentrations from 1.0 to 4.6 mg l-1 (mean 2.4) which correlated significantly with maternal plasma quinine concentrations (r = 0.78, t = 3.06, P less than 0.05). The mean (+/- s.d.) ratio of cord plasma to maternal plasma quinine concentration was 0.32 +/- 0.14. Heart blood from a foetus aborted at term had a plasma quinine concentration of 2.8 mg l-1; simultaneous maternal plasma quinine was 7.1 mg l-1 (ratio 0.39). Breast milk quinine concentrations and milk to plasma ratios were 0.5-3.6 mg l-1 (mean 2.6) and 0.11-0.53 (mean 0.31) in twenty-five women who were breast-feeding and had taken oral quinine sulphate for 1-10 days (mean 4.0). Five women with more serious infections received intravenous quinine; breast milk quinine concentrations ranged between 0.5 and 8.0 mg l-1 (mean 3.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Evidence against immune haemolysis in falciparum malaria in Thailand.

Evidence of immune mediated haemolysis was sought in 83 patients with P. falciparum malaria in eastern Thailand. Amongst 73 patients with uncomplicated infection 12 (16.4%) had a weakly positive direct antiglobulin test (DAT). The incidence in 32 children aged 8-16 years was similar to that in adults. Of 10 patients with cerebral malaria, six adults, all of whom were in unrousable coma, had a positive DAT. Erythrocyte-bound IgG1 accounted for the positive DAT in all cases; sensitization with complement or other IgG subclasses was not found. Patients with uncomplicated malaria had a median value of 70 IgG molecules per erythrocyte compared with 65 molecules per cell in 67 healthy controls. This difference was not statistically significant but could account for the lower incidence of a positive DAT in control subjects (4.5%). There was no correlation between the number of IgG molecules per cell and the degree of anaemia during the acute or convalescent phases of the infection. There is no evidence from this study that an immunohaemolytic process contributes to the anaemia of falciparum malaria in eastern Thailand.

Adolescent↗
PubMed1986

Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in southern Thailand: clinical and laboratory correlations.

Three monospecific antivenoms for Malayan pit viper (MPV) (Calloselasma rhodostoma) were compared in Southern Thailand, where this species is the most common cause of snake bite morbidity. Forty-six patients with proved MPV bites and incoagulable blood, indicating systemic envenoming, were randomly allocated for treatment with Thai Red Cross (TRC), Thai Government Pharmaceutical Organization (GPO), or Twyford Pharmaceutical monospecific antivenoms. Both GPO and Twyford antivenoms produced rapid and permanent restoration of blood coagulability, but TRC antivenom failed in 2/15 cases. Patients in the GPO group showed the greatest increase in plasma fibrinogen concentration during the first 24 hr and had fewer early anaphylactic reactions (6/15) compared with Twyford 8/16 and with TRC 13/15. Pyrogenic reactions occurred more frequently after TRC antivenom (8/15) than GPO (1/15) or Twyford (0/16). Patients requiring more than one dose of antivenom were identifiably more severely envenomed on admission. In an accompanying laboratory study the antivenoms were assessed in rodents using five WHO standard tests of neutralizing activity. Compared with the other two antivenoms TRC was significantly inferior in anti-lethal potency, GPO was superior in anti-hemorrhagic and anti-necrotic potency and Twyford was superior in anti-procoagulant and anti-defibrinogenating potency. The clinical efficacy of these antivenoms against local necrosis remains equivocal. GPO and Twyford antivenoms are recommended for the treatment of systemic envenoming by MPV in an initial dose of 5 ampoules.

Adult↗
PubMed1986

ELISA confirmation of acute and past envenoming by the monocellate Thai cobra (Naja kaouthia).

The monocellate Thai cobra (Naja kaouthia) is a major cause of snake bite mortality and morbidity throughout Thailand, but neither the local nor the systemic effects of its venom are diagnostic. Species diagnosis is important because only monospecific antivenoms are available for treatment in Thailand. We tested the ability of the ELISA technique to detect venom antigen in the sera of 58 acute snake bite cases including 4 fatalities, and venom antibody in 51 patients bitten between 1 month and 19 years previously. N. kaouthia venom antigen was found in 8 of 33 patients with only local envenoming and in 14 of 20 with local plus systemic (neurotoxic) envenoming, but the mean venom concentration was 33 times greater in the latter group. The serum of 1 fatal case contained banded krait (Bungarus fasciatus) but no cobra venom antigen. N. kaouthia venom antibody was present in sera of patients bitten between 1 month and 7 years previously. Antibody was found in 6 of 8 patients who had had local envenoming alone but in only 19 of 41 who had had systemic envenoming treated by antivenom. The titer of antibody declined with an approximate half time of 2-3 years. One patient had a significant titer of B. fasciatus venom antibody. This study confirms the value of ELISA-immunodiagnosis and the predominance of N. kaouthia as a cause of neurotoxic envenoming in the Bang Phli area. However, the attribution of 1 fatal case to B. fasciatus bite suggests that patients with neurotoxic signs should be given B. fasciatus antivenom if they fail to respond to cobra antivenom.

Animals↗
PubMed1986

Clinical significance of venom antigen levels in patients envenomed by the Malayan pit viper (Calloselasma rhodostoma).

Serial venom antigen levels were measured by enzyme-linked immunosorbent assay (ELISA) in 46 patients with systemic envenoming by the Malayan pit viper (Calloselasma rhodostoma), a major cause of snake bite in Southeast Asia. The principal effects of the venom are defibrination, hemorrhage and local tissue necrosis. Admission venom levels, which varied between 0 and 595 ng/ml, correlated with the incidence of spontaneous systemic bleeding, blood incoagulability and concentrations of plasma fibrinogen and serum fibrin degradation products. The presence or absence of nonclotting blood also correlated with the time elapsed between the bite and hospital admission. The development of nonclotting blood may be delayed by up to 72 hr after the bite even though circulating venom and raised FDP may be detected at presentation. This is probably explained by a temporary equilibrium between synthesis and consumption of fibrinogen. Venom antigenemia recurred in 12 patients (26%) suggesting continuous absorption of venom from the wound or saturation of extravascular binding sites. Admission venom levels also correlated with the extent of local swelling and the occurrence of tissue necrosis at the site of the bite. Venom was detected in 87% of wound aspirates and 88% of urine specimens taken on admission. Tourniquets, of the type used in rural Thailand, did not delay the absorption of venom into the circulation.

Adolescent↗
PubMed1986

Function of the blood-cerebrospinal fluid barrier in human cerebral malaria: rejection of the permeability hypothesis.

We tested the hypothesis that cerebral malaria is caused by blood-brain barrier inflammation and cerebral edema. In a group of 157 Thai patients with strictly defined cerebral malaria, cerebrospinal fluid (CSF) opening pressures were normal in 79% and were lower in fatal cases than in survivors (means +/- 1 SD, 144 +/- 58 and 167 +/- 51 mm CSF, respectively, P = 0.051). CSF: serum albumin ratios (X 10(3)) in 39 of them were significantly higher than in 61 British controls (medians 8.5 and 5.5, respectively, P = 0.04), but were no higher in 7 fatal cases. In a group of 12 patients this ratio was not significantly higher during coma than after full recovery (means +/- 1 SD, 9.0 +/- 6.2 and 6.7 +/- 4.2, respectively, P greater than 0.1). CSF alpha 2-macroglobulin concentrations were always normal. CSF : serum 77Br- ratios were elevated in 11/19 comatose cases but fell to normal 4 to 9 days later in 11/11 cases. Dexamethasone treatment had no significant effect on bromide partition. The percentage of an intravenously administered dose of 125I-human serum albumin detectable per ml of CSF 6 hr after intravenous injection was 2.4 +/- 1.3 X 10(-5) in 14 comatose patients and 4.4 +/- 4.0 X 10(-5) in 9 of them during convalescence (P greater than 0.1). These results demonstrate that the blood-CSF barrier is essentially intact in patients with cerebral malaria and give no support to the idea that cerebral edema is the cause of coma.

Blood-Brain Barrier↗
PubMed1986

Effect of inosiplex on the humoral and cell-mediated immune responses to intradermal human diploid cell rabies vaccine.

Antigen-stimulated lymphocyte transformation was studied in recipients of intradermal human diploid cell rabies vaccine (HDCV). HDCV was administered intradermally at 8 different anatomical sites, 0.1 ml each, on day 0; followed by another 4-site injection on day 7. Rabies antigen-stimulated in vitro proliferative response was evident as early as 7 days after starting immunization. It reached a peak on day 14 and had declined by day 28. The cellular proliferative response preceded and roughly correlated with the antirabies antibody response. Simultaneous administration of inosiplex, an antiviral and immunopotentiating drug, during the first 10 days of intradermal HDCV immunization did not result in heightened antibody titres or cell-mediated immune response to the vaccine. The number of T cells and the lymphocyte proliferative response to phytohaemagglutinin in inosiplex-treated vaccinees were similarly not significantly different from untreated controls. Our results confirm other previous findings that a specific cell-mediated immune response can be consistently and rapidly induced by an intradermal regimen of HDCV immunization. The addition of inosiplex to this regimen did not enhance the humoral or cell-mediated immune responses to the vaccine. The apparent lack of immunostimulating effect of inosiplex in this setting may be the result of several factors such as the immunization schedule and the immunologic parameters examined.

Adult↗
PubMed1986

The importance of anaemia in cerebral and uncomplicated falciparum malaria: role of complications, dyserythropoiesis and iron sequestration.

Ninety-four per cent of 169 patients with cerebral malaria developed anaemia (haematocrit less than 35 per cent) and 30 per cent required blood transfusion to maintain the haematocrit at more than 21 per cent. Anaemia was at its worst on admission in 58 patients (34 per cent); in the rest the haematocrit fell further, reaching its nadir one to 17 days later (mean 2.3 days). The mean lowest haematocrit was 24.3 +/- 7.2 per cent (+/- 1 SD) and the mean maximum fall was 7.9 +/- 5.6 per cent. Anaemia was more severe in patients with bacterial infection, retinal haemorrhages, schizontaemia and in pregnancy. The lowest haematocrit correlated with admission parasitaemia (r = -0.33, p less than 0.001), total serum bilirubin (r = -0.25, p less than 0.01) and serum creatinine (r = -0.22, p less than 0.01). In 23 patients with uncomplicated falciparum malaria the mean serum iron on admission was 53 micrograms/dl (range 16-157) and the mean serum ferritin 1773 ng/ml (range 170-10 000). There was a significant (p less than 0.001) rise in serum iron 96 h after starting antimalarial treatment; the serum ferritin declined slowly over several weeks. Stainable iron was present in all marrows examined and in eight patients the characteristic pattern of the anaemia of chronic disorders was seen. Seventy-three per cent of patients had dyserythropoiesis which was moderate to gross in 36 per cent. Dyserythropoiesis and erythrophagocytosis were often present on admission but sometimes appeared after the parasitaemia had cleared and persisted for at least three weeks into convalescence. These disturbances in iron metabolism and haemopoiesis are not completely explicable by red blood cell parasitisation. They may contribute more to the anaemia than has previously been recognised.

Adolescent↗