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Biomedical subjects

B Wonke

Publications and source records attributed to B Wonke.

At least 55 records · Page 3Linked to original sources
PubMed1994

Effect of different treatment regimes on linear growth and final height in beta-thalassaemia major.

OBJECTIVE: The clinical picture of thalassaemia major has changed progressively over the years. Our study is a retrospective analysis of data on growth in a group of patients who have completed puberty spontaneously and have attained their adult height. Our objective was to evaluate the effect of different transfusion regimes and desferrioxamine administration on the growth pattern in beta-thalassaemia major. DESIGN AND PATIENTS: We studied 64 patients (28 males and 36 females). The patients were divided into three groups (A, B and C) according to the different transfusion regimes and the schedules of chelating therapy. Group A consisted of 16 patients who were transfused regularly at low haemoglobin levels (on average 8.5 g/dl) from an early age and started subcutaneous chelation therapy during adolescence. Group B consisted of 19 patients who were transfused regularly at high haemoglobin levels (on average 10 g/dl) from an early age and started subcutaneous therapy during childhood. Group C consisted of 29 patients who were transfused regularly at high haemoglobin levels (on average 10.5 g/dl) from an early age and started subcutaneous chelation therapy very early, at a mean age of 2 years. Standard auxological measurements were made at 3-monthly intervals throughout childhood and puberty until adult height was achieved. For group C patients the data on linear growth are provided only until the age of 12 years. RESULTS: Our study indicates that group A male and female patients did not grow significantly better than those in group B. Group C male and female patients, surprisingly, grew no faster than those who started chelation therapy late in childhood (group A). The most striking feature in the majority of both group A and B patients was reduced spurt in height at puberty. In addition, in both groups, a reduced sitting height due to spinal growth abnormality was found. An inverse correlation between sitting height and serum ferritin levels was observed in group A patients (r = -0.55, P < 0.05), whereas there was a direct correlation in group B patients (r = 0.42, P < 0.05). CONCLUSIONS: These data suggest that an ideal therapeutic regime has yet to be found which avoids the toxic effect of iron overload and on the other hand avoids interference with growth, secondary to desferrioxamine. Therefore we recommend that the growth of thalassaemia patients be monitored routinely at every follow-up visit and documented on growth velocity charts in order to detect early changes in their growth pattern and to establish an appropriate protocol for investigation and treatment.

Adult↗
PubMed1994

Deferiprone-associated myelotoxicity.

Agranulocytosis developed in a 63-year-old patient with myelodysplasia 6 weeks after commencing treatment with the oral iron chelator deferiprone (L1, 1,2-dimethyl-3-hydroxypyrid-4-one, CP20) at a daily dose of 79 mg/kg. This was the 3rd case of agranulocytosis (neutrophils 0 x 10(9)/l) in clinical trials of L1 at the Royal Free Hospital. The neutrophil count recovered 7 days after stopping L1 and commencing G-CSF at a dose of 300 micrograms daily. Three other patients with milder degrees of neutropenia (neutrophils < 1.5 x 10(9)/l) have also been observed in our trials. The case histories of these 4 patients are described here; other reported cases of neutropenia or agranulocytosis are reviewed. Based on worldwide long-term clinical trials the incidence of agranulocytosis is about 1.6% and of neutropenia 2%.

Adult↗
PubMed1994

Effect of alpha thalassaemia trait and enhanced gamma chain production on disease severity in beta thalassaemia major and intermedia.

One hundred and twenty patients with homozygous beta thalassaemia were selected to determine the clinical effects of certain genetic factors which may modify disease severity. Genetic analysis defined specific beta thalassaemia mutations, the alpha thalassaemia genotype, and the presence of an XmnI restriction enzyme site, associated with increased fetal haemoglobin (HbF) production under certain conditions. Genotypic data with globin chain synthesis were related to the age when regular transfusions began and subsequent pubertal development. This study showed that the major determinants of disease severity in beta thalassaemia were the beta thalassaemia mutations, with co-inheritance of alpha thalassaemia trait and coinheritance of a high HbF determinant acting as ameliorating factors. The presence of an alpha thalassaemia deletion significantly reduced initial disease severity, although the effect on pubertal development was less clear. It is concluded that detailed genetic analysis should be performed in all newly diagnosed patients with thalassaemia. This, in conjunction with clinical assessment, will help to predict disease severity and prognosis.

Adolescent↗
PubMed1994

Zinc concentration in patients with iron overload receiving oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one or desferrioxamine.

AIMS: To determine the changes in serum zinc concentration and the extent of urinary zinc excretion in patients with iron overload receiving the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) or desferrioxamine (DFX), and to correlate these results with blood glucose concentration. METHODS: Serum zinc and ferritin concentrations, urinary zinc and iron excretion were regularly assayed in 39 patients and the glucose tolerance test (GTT) was performed in each patient. Patients were segregated according to their GTT into normal, diabetic, and those with an abnormal GTT. The mean of L1- or DFX associated urinary zinc excretion for each group was determined and compared with the other two groups and with normal value. L1 associated urinary zinc excretion was also compared with L1 dose, serum ferritin values, and urinary iron excretion. RESULTS: Both DFX and L1 were associated with a significantly increased urinary zinc excretion (15.1 (7.3) mumol/24 hours, 11.1 (6.0) mumol/24 hours, respectively) compared with normal subjects. In patients receiving DFX this increase only occurred in patients with diabetes mellitus. Both diabetic and non-diabetic patients receiving L1 treatment excreted more zinc than normal. Diabetic patients receiving L1 or DFX excreted more zinc than non-diabetics receiving the same treatment. No correlation was found between urinary zinc excretion and L1 dose or patients' serum ferritin concentrations. In seven patients receiving long term L1 treatment a fall in serum zinc was observed from an initial 13.6 (1.6) mumol/l to a final 9.6 (0.8) mumol/l. In one patient this was associated with symptoms of dry skin and itchy skin patches requiring treatment with oral zinc sulphate. CONCLUSIONS: In contrast to DFX, L1 treatment is associated with increased zinc loss. This, however, is modest and does not lead in most patients to subnormal serum zinc concentrations. In a few patients whose negative zinc balance may give rise to symptoms, zinc supplementation rapidly corrects the deficit.

Adolescent↗
PubMed1994

Assessment of hepatic iron overload in thalassemic patients by magnetic resonance spectroscopy.

The transverse relaxation time of water protons is shortened by the presence of iron. This shortening depends on the amount and the environment of iron in the sample. We have developed a method for measuring short transverse relaxation time noninvasively by magnetic resonance spectroscopy. To evaluate magnetic resonance spectroscopy as a means of assessing hepatic iron content in patients with transfusional iron overload, we compared the results obtained with this method with those obtained by other means of assessing total body iron content. The correlation between the liver biopsy iron concentration and 1/transverse relaxation time was highly significant (r = 0.95, p < 0.004, n = 6) for iron loads up to 3% dry weight. The correlation between serum ferritin and 1/transverse relaxation time was also significant, but the correlation coefficient was much lower (r = 0.67, p < 0.002, n = 20). The correlation between 24-hr urinary iron excretion and 1/transverse relaxation time was not significant, nor was that between AST and 1/transverse relaxation time. We conclude that magnetic resonance spectroscopic determination of the transverse relaxation time of hepatic water is an accurate method of measuring liver iron content, especially when the iron content is below 3%. Because it is a noninvasive method that is associated with negligible side effects, it could provide clinicians with an excellent means of assessing the effectiveness of the various therapeutic strategies used in the management of patients with iron overload.

Adolescent↗
PubMed1993

Alpha interferon in the treatment of chronic hepatitis C infection in thalassaemia major.

Hepatitis C virus (HCV) is responsible for the majority of cases of post transfusion non-A non-B (NANB) hepatitis in thalassaemia major (TM). Twelve multi-transfused TM patients with serological, biochemical, histological and molecular biological evidence of HCV infection have been treated for 6 months with recombinant alpha-interferon (IFN). Ten (83%) responded as assessed by a fall of at least 50% of pre-treatment serum transaminase levels. Histological improvement was observed in 6/7 responders tested. Natural killer (NK) cell activity 24 h after the first dose of IFN was significantly increased in responders as compared to non-responders (P < 0.05). HCV RNA disappeared from serum in 5/12 and from liver tissue in 2/5 of the responders. The degree of induction of peripheral blood mononuclear cell 2'5' oligoadenylate synthetase messenger RNA (2-5 OAS mRNA), an enzyme induced by IFN, after the first dose of IFN did not correlate with response. IFN was generally well tolerated. We conclude that the response rate in multi-transfused TM patients infected with HCV and treated with IFN is similar to that in non-multi-transfused patients.

Adolescent↗
PubMed1993

Pharmacokinetics of sex steroids in patients with beta thalassaemia major.

AIMS: To assess the pharmacokinetics of oral, intramuscular, or transdermal hormone replacement in patients with beta thalassaemia major. METHODS: Oral (testosterone undecanoate 40 mg) and intramuscular (testosterone propionate 15 mg, phenylpropionate 30 mg, isocaproate 30 mg and decanoate 50 mg) testosterone and transdermal (17 beta oestradiol 25 micrograms and 50 micrograms) oestradiol were evaluated in 21 male (16-29 years) and 11 female (19-26 years) patients with beta thalassaemia major and various forms of hypogonadism. RESULTS: In male patients given oral testosterone, peak testosterone concentrations were observed either two to four hours or seven hours after administration; intramuscular testosterone produced peak values seven days after injection. Transdermal 17 beta oestradiol given to female patients produced a biphasic pattern with an initial peak concentration occurring at 36 hours and a secondary rise at 84 hours. CONCLUSIONS: The results indicate that oral androgens should be given twice daily in cases of hypogonadism, and where growth is incomplete, lower than recommended doses. If intramuscular testosterone is used, smaller doses of 10-25 mg should be given every one to two weeks. Transdermal administration of 25-50 micrograms 17 beta oestradiol generally produces a plasma E2 value in the early to mid-follicular phase range (100-300 pmol/l). This is appropriate in adults but excessive for prepubertal girls. Diffuse iron infiltration of tissues does not seem to interfere with the absorption of androgens and oestrogens from the gut, muscle, or skin.

Administration, Cutaneous↗
PubMed1993

Agranulocytosis in a patient with thalassaemia major during treatment with the oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one.

Agranulocytosis developed in a 20-year-old Greek patient with beta-thalassaemia major, 11 weeks after commencing chelation with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) and 6 weeks after receiving the drug at a total daily dose of 105 mg/kg. The patient presented with generalised weakness, low-grade fever and sore throat. The total white cell count was 2.0 x 10(9)/l with 0.1 x 10(9)/l neutrophils. The patient was admitted to hospital and successfully treated with intravenous broad-spectrum antibiotics. Neutrophil count recovered 7 weeks later. A number of immunological tests were performed in an attempt to elucidate the cause of agranulocytosis. These investigations gave inconclusive evidence for the presence of a weak IgM antibody to myeloid cells exposed to L1 in this patient. Further studies are required, however, to evaluate the mechanism in any other patient who develops agranulocytosis in association with L1 therapy.

Administration, Oral↗
PubMed1993

Recombinant alpha 2B interferon (IFN) in the treatment of chronic hepatitis C disease in thalassaemia major (TM).

Hepatitis C virus (HCV) is responsible for the majority of cases of post transfusion non-A non-B (NANB) hepatitis in thalassaemia major (TM). Fifteen multi-transfused TM patients with serological, biochemical, histological and molecular biological evidence of HCV infection have been treated for six months with recombinant alpha interferon (IFN). Eleven (73%) responded, 8 (53%) had complete response (CR), 3 (20%) partial response (PR) and 4 (27%) did not respond (NR) to IFN. Natural killer (NK) cell activity 24 hours after the first dose of IFN was significantly increased in responders as compared to non-responders. Liver histology showed an overall reduction of portal inflammation and periportal necrosis in the responding patients. HCV RNA disappeared from serum in 8 (15) responders and partial responders. Non responders remained positive. HCV RNA was tested and found to be positive in liver tissue material in 7 patients, five of those were re-tested after IFN treatment. Two became negative (both CR) 3 remained positive despite biochemical response to IFN. The degree of induction of peripheral blood mononuclear cell 2'5' oligoadenylate synthetase messenger RNA (2-5 OAS mRNA), an enzyme induced by IFN, after the first dose of IFN did not correlate with response neither was any significant interaction with cytokines observed; tumour necrosis factor (TNF), interleukin-1. (IL-1) and CD4:CD8 ratios did not change. We conclude that IFN should be given to all TM patients with chronic active hepatitis due to HCV.

Adolescent↗
PubMed1992

Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in thalassemia major.

Eleven patients with beta thalassemia major were entered into the trial of the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Their ages ranged from 17 to 26 years (mean +/- SD, 22.3 +/- 2.7). Six were male and five were female. L1 was administered at an initial daily dose of 42.5 to 60 mg/kg as a single dose. After 4 weeks, the dose was increased to 85 to 119 (102 +/- 10.7) mg/kg for 191 to 352 days divided into either two or four doses daily, except for one patient who developed agranulocytosis after 11 weeks and was taken off the trial. Initial serum ferritin values in the remaining 10 patients ranged between 1,000 and 9,580 (5,549 +/- 3,333) micrograms/L and at end of the trial their mean serum ferritin was significantly lower (4,126 +/- 2,278; P less than .05 using the paired t-test). Urinary iron excretion at a daily dose of 85 to 119 mg/kg administered as two divided doses ranged between 0.14 and 0.82 (0.44 +/- 0.26) mg/kg/24 h. In three patients, the four doses per day schedule caused substantially more iron excretion than the same total dose divided into two. During the course of the trial, several possible adverse effects have been encountered. One patient (female, aged 20) developed agranulocytosis 11 weeks after starting treatment and 6 weeks after beginning treatment with a daily dose of 105 mg/kg. This patient's neutrophil count recovered spontaneously 7 weeks after the discontinuation of L1. A decrease in serum zinc levels to subnormal levels was observed in four patients with symptoms of dry skin, with an itchy scaly rash in two that was associated with low serum zinc levels that responded to zinc therapy. Urinary zinc levels ranged from 4.7 to 23.4 (13 +/- 5.5) mumol/24 h and were above 9 mumol/24 h (upper limit of normal) in eight patients. Mild nausea occurred in three patients and transient diarrhea in a fourth. Mild musculoskeletal symptoms occurred in three patients but settled without discontinuation of L1 therapy in two and with temporary discontinuation of L1 in the third. A transient increase in serum aspartate transaminase was also noted in five patients, but serum aspartate transaminase levels subsequently decreased in all of them. No cardiovascular, neurologic, renal, or retinal toxicities were demonstrable. These results confirm that L1 is an effective oral iron chelator. Further clinical trials are needed to determine the incidence and severity of adverse effects.

Adult↗
PubMed1992

Serum non-transferrin-bound iron in beta-thalassaemia major patients treated with desferrioxamine and L1.

Non-transferrin-bound iron (NTBI) in plasma is toxic due to its ability to participate in free radical formation with resultant peroxidation and damage to cell membranes and other biomolecules. NTBI concentration was determined in serum in 12 normal volunteers and in 52 patients with beta-thalassaemia major by a modification of the method described by Singh et al (1990). There was no detectable NTBI in normal individuals. In the patients NTBI values ranged from -1.5 to 9.0 mumol/l (mean +/- SD: 3.6 +/- 2.3). The patients' serum ferritin concentrations ranged from 207 to 11,400 micrograms/l (2674 +/- 2538), total serum iron from 20 to 61 mumol/l (39.5 +/- 9.6) and transferrin saturation from 44 to 110% (84.5 +/- 13.8). The NTBI correlated significantly with serum ferritin (r = 0.467, P < 0.001), total serum iron (r = 0.608, P < 0.001) and transferrin saturation (r = 0.481, P < 0.005). When patients were grouped according to their compliance with desferrioxamine (DFX) therapy, the good compliers had significantly lower NTBI concentrations compared to the poor compliers (poor: 5.4 +/- 1.8 mumol/l v good: 2.7 +/- 1.7 mumol/l, P < 0.001). There was also a significant difference between the level of NTBI and whether or not the patients had complications of iron overload (5.2 +/- 1.7 mumol/l v 2.9 +/- 1.6 mumol/l, P < 0.001). During this study 10 patients were entered into a trial of the oral iron chelator 1,2- dimethyl-3-hydroxypyrid-4-one (L1). Their NTBI values were observed during the first 6 months of the trial and showed a significant fall (paired t-test: P = 0.007). These results suggest that the level of NTBI may prove helpful in assessing the efficiency of chelation in patients with transfusion dependent anaemia and help to predict organ damage.

Adolescent↗
PubMed1992

A study of hepatitis B and C prevalence and liver function in multiply transfused thalassemic and their parents.

A series of clinics were conducted in Delhi, India, in January, 1990. Of 54 patients with beta thalassemia major (mean age 7.6 years), 11.1% (6 out of 54) tested positive for antibodies to hepatitis C virus (anti HCV antibodies) and 66.6% (36 out of 54) showed evidence of hepatitis B virus (HBV) infection. Only 7.4% (4 out of 54) were hepatitis B surface antigen (HBsAg) positive. Of their parents, 2.2% (2 out of 90) tested positive for anti HCV antibodies, 28.9% (26 out of 90) showed evidence of previous HBV infection and 11.1% (10 out of 90) were HBsAg positive. We argue that HCV constitutes a greater long term threat than HBV in these patients due to the higher incidence of chronic liver disease. We would advocate the introduction of HCV screening of donated blood as well as reinforcing the importance of HBV screening and immunization.

Adolescent↗
PubMed1991

A novel delta 0 mutation in cis with Hb Knossos: a study of different genetic interactions in three Egyptian families.

We have defined the molecular basis of normal HbA2 beta-thalassaemia associated with Hb Knossos. DNA sequence analysis of the delta globin gene in cis with beta Knossos showed deletion of a single A in codon 59 leading to a premature termination at codon 60. This delta 0/beta Knossos allele has been observed in three unrelated Egyptian families and associated with a single beta haplotype (+----++). One individual who was homozygous for the delta 0/beta Knossos allele as well as heterozygous for a non-deletional alpha thalassaemia, was completely clinically asymptomatic, while others have coinherited the delta 0/beta Knossos allele with different beta and alpha thalassaemia determinants. A study of the different genetic interactions giving rise to a spectrum of clinical phenotypes is reported.

Adult↗
PubMed1990

Antilymphocyte globulin therapy enhances impaired function of natural killer cells and lymphokine activated killer cells in aplastic anaemia.

MHC-unrestricted cytotoxic lymphocytes, namely natural killer (NK) and lymphokine activated killer (LAK) cells, have been implicated in the regulation of haemopoiesis. To investigate the possible role of these lymphocytes in the pathogenesis of aplastic anaemia (AA), we studied their functions in the peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) of patients with AA treated with antilymphocyte globulin (ALG). Before treatment, both NK and LAK activities in the PBMC of 25 patients were low (NK = 1.9 +/- 2.1 x 10(3) LU/l) LAK = 4.7 +/- 3.6 x 10(3) LU/l) compared to normal (NK = 6.0 +/- 3.0 x 10(3) LU/l, LAK = 10.0 +/- 3.5 x 10(3) LU/l) or multiply transfused (NK = 7.8 +/- 6.6 x 10(3) LU/l, LAK = 25.2 +/- 13.6 x 10(3) LU/l) controls. The NK and LAK activities in the BMMC in AA patients were not significantly different from those in PBMC. In all patients with low LAK and NK activities pre ALG there was an increase in activity 2-24 weeks after therapy which eventually reached normal levels and which was maintained for up to 2 years. Analysis of lymphocyte phenotypes in AA patients before treatment showed both significantly low mean proportion and absolute numbers of CD16+ cells compared to normals, which increased after therapy. Changes in MHC-unrestricted cytotoxicity and lymphocyte phenotypes post therapy were not correlated with haemopoietic recovery. These data suggest that ALG treatment can enhance the functions of MHC-unrestricted lymphocytes independently from haemopoiesis. It is unlikely that these cells play a role in the pathogenesis of AA.

Adolescent↗