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Biomedical subjects

R E Phillips

Publications and source records attributed to R E Phillips.

At least 127 records · Page 7Linked to original sources
PubMed1987

Plasma concentrations and toxicity of chloroquine after slow intravenous infusion in patients with falciparum malaria.

Five male patients with acute Plasmodium falciparum or Plasmodium vivax infections were infused with chloroquine diphosphate (15 mg kg-1) over four hours. Further does of chloroquine diphosphate (5 mg kg-1) were given at 12, 24, 36 and 60 hours. Plasma chloroquine concentrations were determined before and four hours after each dose and then daily until discharge. No serious cardiovascular toxicity was observed, and plasma chloroquine concentrations exceeding the putative minimum inhibitory concentration (MIC) of sensitive P. falciparum strains were reached within four hours of starting treatment. Further doses produced plasma concentrations which were sustained above the putative MIC, but showed no rapid increase into the range associated with toxicity.

Adolescent↗
PubMed1987

Pharmacokinetics of intravenous amodiaquine.

Amodiaquine hydrochloride (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to seven healthy adult male volunteers, and by constant rate infusion (10 mg base kg-1) over 4 h to 10 adult patients admitted to hospital with falciparum malaria. After intravenous injection in volunteers there was considerable variation in plasma concentration profiles between subjects; peak plasma concentrations ranged between 65 and 1921 ng ml-1. A biexponential equation was fitted to the plasma concentration time data and the following estimated pharmacokinetic parameters (geometric mean; range) were derived; lambda 1 = 24.4 (7.6-95.0) h-1, lambda 2 = 0.33 (0.12-0.79) h-1, V1:1.1 (0.3-3.6) 1 kg-1, Vss: 17.4 (2.3-95.9) 1 kg-1 and systemic clearance 13.0 (4.7-56.6) 1 kg-1 h-1. After intravenous infusion there was also considerable variability between patients with post-infusion plasma concentrations ranging between 82 and 836 ng ml-1. The plasma concentration-time profiles were biphasic with the following estimated pharmacokinetic parameters (geometric mean; range) alpha = 1.87 (0.60-8.52) h-1, beta = 0.069 (0.021-0.265) h-1, V1: 4.6 (0.5-29.3) 1 kg-1, Vss: 38.3 (3.7-127.9) 1 kg-1 and systemic clearance CL (1.6-17.3) 1 kg-1 h-1. There was no measurable long terminal elimination phase, and the principal metabolite desethyl amodiaquine was not detected in the plasma samples. There was no serious toxicity in either group. During intravenous injection there was a significant fall in systolic blood pressure in four subjects (mean fall 16 mm Hg) but there was no significant change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Plasma and whole blood mefloquine concentrations during treatment of chloroquine-resistant falciparum malaria with the combination mefloquine-sulphadoxine-pyrimethamine.

Mefloquine-sulphadoxine-pyrimethamine (MSP) in combination has proved effective against multiple-drug-resistant falciparum malaria, but nothing is known about mefloquine absorption when it is given in this formulation. Nine Thai patients, aged 15-51 years with uncomplicated chloroquine-resistant falciparum malaria, took 11.2-16.7 mg of mefloquine base per kilogram bodyweight as MSP tablets. All patients responded to treatment with fever and parasite clearance times of 61 +/- 29 h (mean +/- s.d.) and 52 +/- 24 h, respectively. The mean apparent absorption half-time (t1/2abs) of mefloquine was 4.89 h (range 2.25-9.72) and mean peak plasma concentration was 1815 ng ml-1 (range 725-3368). Peak plasma mefloquine concentrations in three patients who vomited within 2 h of treatment were 725, 956 and 1972 ng ml-1. There was no significant difference between plasma and whole blood mefloquine concentrations during the first 48 h of treatment. Based on the elimination of parasitaemia, the plasma mefloquine concentrations are adequate for therapy of uncomplicated falciparum malaria although the relationship between plasma concentrations and therapeutic efficacy of mefloquine requires further study.

Adolescent↗
PubMed1987

Evolution of coagulation abnormalities following Russell's viper bite in Burma.

The evolution of coagulation abnormalities was studied in Russell's viper bite victims who, on admission to hospital, showed no clinical signs of systemic envenoming. Based on the laboratory results and subsequent clinical course, three groups were distinguished. The first group, consisting of five cases, showed no activation of coagulation at any stage. The second group, consisting of six cases, developed mild to moderate abnormalities in some tests, particularly in the aPTT and factor V assay, which corrected to normal without treatment. The third group, consisting of nine patients, developed haemostatic abnormalities as early as 1-2 h after the bite, which progressed to severe defibrination 4-8 h later at which time antivenom was given. Comparison of the haemostatic abnormalities in the three groups suggested that serial monitoring of the serum FDP concentration may be of value in predicting the likelihood of systemic envenoming and progression to complete defibrination.

Adolescent↗
PubMed1987

Reduced erythrocyte survival following clearance of malarial parasitaemia in Thai patients.

Erythrocyte survival times were measured in healthy Thai controls and in patients following clearance of asexual P. falciparum or P. vivax parasitaemia. In five controls the mean cell life (MCL) of compatible donor erythrocytes was 89.6 d (mean range 73-101 d) compared with a mean MCL of 56.8 d (range 30-66 d) for autologous erythrocytes in 12 falciparum patients. In one of these patients the survival curve was biphasic with a rapid loss of some labelled cells. The survival of compatible donor erythrocytes was also studied in 10 patients and two types of survival curve could be distinguished. In five patients the cells had a mean MCL of 64.4 d (range 42-90 d). In the others survival curves were curvilinear, suggesting a complex mechanism of cell clearance or the presence of more than one cell population. There was initially a more rapid rate of destruction. In P. vivax malaria the MCL of autologous erythrocytes in seven patients was a mean of 67.2 d (range 34-74 d) and that of compatible donor cells in six patients was 66.8 d (range 54-76 d). In all except one of these patients both autologous and donor cell survival curves could be fitted to straight lines. No increase in cell-bound IgG or C3 was evident in 12 patients tested. The differences between the mean MCL in all the groups of patients and the controls were statistically significant at the 5% level. This indicates an increased rate of erythrocyte destruction following clearance of P. falciparum or P. vivax parasites which is not antibody or complement mediated. The mechanism is unknown, but appears to be extrinsic to the erythrocytes themselves and may result from nonspecific activation of the reticuloendothelial function associated with the parasitic infection.

Adult↗
PubMed1987

The bone marrow in human cerebral malaria: parasite sequestration within sinusoids.

Bone marrow aspirates from patients with cerebral malaria were studied with the light and electron microscopes. Various abnormalities were found including: (1) an increase in plasma cells and macrophages, sometimes to a marked degree; (2) phagocytosis of parasitized red cells by macrophages and of merozoites by neutrophil metamyelocytes, neutrophil granulocytes and macrophages; (3) an increase in the proportion of eosinophil granulocytes and their precursors; (4) the presence of giant metamyelocytes; and (5) morphological abnormalities of erythroblasts, particularly irregularly-shaped nuclei and karyorrhexis. A high percentage of the red cells within marrow sinusoids were parasitized and the parasitized cells were attached to the endothelium. Some marrow sinusoids were packed with and completely obstructed by parasitized cells. Strands of electron-dense material were sometimes found connecting the knobs of parasitized red cells to endothelial cells or to the knobs of adjacent parasitized red cells. A striking finding was a complex interdigitation between cytoplasmic processes developed by some of the parasitized red cells and those developed by the endothelial cells to which they were attached. Occasionally, cytoplasmic processes arising from marginated parasitized red cells completely penetrated the endothelial cell and emerged extravascularly. Several parasitized red cells were also found extravascularly between haemopoietic cells. Sequestration of parasitized red cells within small blood vessels may play a part in the pathogenesis not only of the encephalopathy of cerebral malaria but also of the bone marrow dysfunction in severe malaria.

Adolescent↗
PubMed1987

Demand oxygen delivery during exercise.

Nine hypoxemic patients with COLD, whose hypoxemia is aggravated by minimal exercise, volunteered for this study. Each subject underwent two treadmill exercise trials at two oxygen delivery settings, each on the DODS and SF delivery systems for a total of four exercise trials. We measured SaO2 via ear oximetry and recorded oxygen usage per minute. We compared the oxygen usage required for the two techniques to achieve an SaO2 of 90 percent. The results indicate that the mean oxygen requirement using the DODS to achieve an SaO2 of 90 percent was 211.4 ml/min as compared to SF delivery which required 1,610.9 ml/min. This implies an oxygen savings advantage of the DODS over SF of 7:1. The fact that the DODS oxygen savings extends to exercise conditions lends support to its use in portable oxygen therapy. Widespread use of this and other oxygen savings techniques could result in significant cost savings while maintaining the desired benefits of supplemental oxygen administration.

Aged↗
PubMed1987

Intrathecal immunoglobulin synthesis in cerebral malaria.

Local synthesis of immunoglobulin within the central nervous system has been evaluated in 37 patients with acute cerebral malaria; seven patients were also studied in the convalescent phase. There was evidence in the cerebrospinal fluid (CSF) of 21 patients that intrathecal IgG synthesis occurs in the acute phase. There were raised IgG: albumin ratios in 43% of acute patients. Oligoclonal IgG bands or cathodal IgG was seen in the CSF of 43% of patients tested by polyacrylamide electrophoresis. Only eight out of 37 acute patients (22%) had no evidence of intrathecal IgG synthesis by either method. The serial studies showed that most patients had IgG-CSF abnormalities when tested in convalescence. These studies suggest that an immune stimulus (perhaps malarial antigens or mitogens) may be present in the brain in acute cerebral malaria.

Acute Disease↗
PubMed1986

Unilateral kainic acid lesions reveal dominance of right archistriatum in avian fear behavior.

Unilateral injections of 1 microgram of kainic acid in the archistriatum of 5-day-old domestic chicks reduced fear, as expressed by distress calls (peeps), significantly more than did identical injections in the same structure on the left side. This result adds affective behavior to the growing list of functions that have been shown to be differentially controlled by the right and left hemispheres in birds. The directions of the specializations are intriguingly similar to those for verbal and affective functions in human beings.

Animals↗
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

Giardiasis in Mount Isa, north-west Queensland.

A random survey of 680 dwellings was undertaken to determine the prevalence and mode of transmission of Giardia intestinalis in Mount Isa. Of the population, 4.5% were shown to have cysts in their stools; the highest prevalence rate of 12.0% occurred in children aged one to five years. Epidemiological studies strongly suggest that the disease, which is endemic in the city, is being transmitted by hand-to-mouth contamination; schools, preschools, kindergartens and play groups are important foci of transmission. No evidence was found that the parasite was being brought into the city from outside, or that people were acquiring it from water or domestic pets. Symptoms consistent with giardiasis were more commonly present in children than in adults. Approximately two-thirds of infected persons were asymptomatic. The diagnosis of giardiasis as based on symptoms alone was inadequate, although more likely to be correct in children than in adults.

Adolescent↗
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

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

Chemotherapy in giardiasis: clinical responses and in vitro drug sensitivity of human isolates in axenic culture.

To investigate drug sensitivities of human Giardia isolates, we developed a reproducible in vitro 3H-thymidine uptake assay to compare drug potencies. Among 13 Giardia intestinalis stocks obtained from the culture of trophozoites isolated from duodenal juice, considerable variation in susceptibility to a range of currently used drugs was found. The population doubling time of these stocks also varied widely. Clinical features in patients ranged in severity from mild chronic diarrhea to a celiac-like syndrome, with a similar variation in the degree of histologic change in the mucosa. Brush-border enzyme activities were universally reduced in children younger than 5 years of age. The two isolates with the highest ID50 values for furazolidone in vitro were from patients who had persistent symptoms after treatment with this drug; these patients subsequently responded to treatment with a nitroimidazole with greater in vitro potency. These studies suggest that biologic variants of G. intestinalis exist in humans and may in part account for the variable clinical manifestations and for some treatment failures.

Animals↗
PubMed1986

Purified Vero cell rabies vaccine and human diploid cell strain vaccine: comparison of neutralizing antibody responses to post-exposure regimens.

Neutralizing antibody responses to conventional rabies post-exposure regimens of human diploid cell strain vaccine (HDCSV) and the new purified Vero cell rabies vaccine (PVRV) were compared in 58 healthy Thai veterinary students. The geometric mean titres (GMTs) of the group given HDCSV were slightly higher than those given PVRV, but on day 28 the peak GMTs of the two groups were statistically similar. The early antibody response to PVRV was unaffected by the addition of passive immunization, whereas the level of HDCSV response was reduced on day 14, so that there was no difference on that day between the GMTs of the two vaccine groups given HRIG. However, by day 91 the GMT of those given PVRV and HRIG was lower than in those given HDCSV alone or with HRIG. The appearance of antibody was less rapid than was observed in previous studies using multiple-site intradermal vaccination. Side effects were trivial. Our results confirm the promise of this new, potentially more economical tissue culture vaccine, but they suggest that the regimen could be improved.

Adolescent↗