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M Hoffman

Publications and source records attributed to M Hoffman.

At least 73 records · Page 4Linked to original sources
PubMed2000

Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations.

A small number of thromboembolic events, including deep venous thrombosis and myocardial infarction, have been reported in patients receiving IVIG. These events have primarily occurred in patients receiving high-dose IVIG and have been attributed to an increase in blood viscosity. To test the hypothesis that a procoagulant might be present in IgG preparations, twenty-nine samples of intravenous immunoglobulin (IVIG) from eight different manufacturers were assayed for procoagulant activity. Twenty-six of these samples shortened the clotting time of factor XI-deficient plasma. Of these, fourteen samples had factor XI activities greater than 0.001 U/ml of normal pooled plasma. The remaining samples possessed less than 0. 001 U/ml of normal plasma activity. The procoagulant activity in these samples could be inhibited by an anti-factor XI polyclonal antibody, suggesting that the procoagulant activity was factor XI. The procoagulant activity increased in two samples after storage at 4 degrees C for 4 weeks, likely as a result of factor XIa autoactivation. Additionally, activity in some IVIG samples was able to directly activate factor IX, indicating that activated factor XI was present in these samples. Finally, the degree of factor XI(a) contamination in the samples was correlated with the manufacturer, suggesting that variations in the manufacturing process or source plasma affect the level of factor XI in the IVIG product. Because addition of small amounts of factor XIa to plasma can lead to production of significant amounts of thrombin, we suggest that factor XIa present in some IVIG preparations could contribute to the in vivo risk of thrombosis after IVIG therapy.

Drug Contamination↗
PubMed2000

The factor VII-platelet interplay: effectiveness of recombinant factor VIIa in the treatment of bleeding in severe thrombocytopathia.

Recently, high-dose factor VIIa has been used to correct bleeding in patients with various thrombocytopathias including Glanzmann's thrombasthenia, Bernard-Soulier syndrome, and uremia. High-dose factor VIIa is postulated to act on platelets in the absence of tissue factor to activate factors IX and X and thus enhance thrombin generation. This enhanced thrombin generation might help provide hemostasis in patients with thrombocytopathias through several mechanisms. Enhanced thrombin generation would provide a strong signal for recruitment of other platelets. Also, enhanced fibrin deposition might provide mechanisms for bypassing the specific defect in thrombocytopathias. Thus, platelets from a patient with Bernard-Soulier syndrome might associate with fibrin by a glycoprotein IIb-IIIa-mediated mechanism. Also, platelets from a patient with Glanzmann's thrombasthenia might associate with fibrin through von Willebrand factor-mediated interactions with glycoprotein Ib-V-IX. Finally, enhanced thrombin generation on platelets would mean that fewer platelets are required for hemostasis.

Blood Platelet Disorders↗
PubMed2000

The effect of factor X level on thrombin generation and the procoagulant effect of activated factor VII in a cell-based model of coagulation.

We used a cell-based, in-vitro model of normal hemostasis and hemophilia to address the question of whether factor (F) X concentration affects the hemostatic response to high-dose activated factor VII (FVIIa). Under conditions designed to mimic normal tissue factor-initiated hemostasis in vivo, we found that only a very small amount of FX -- equivalent to about 3% of the normal plasma level -- was required to support a 'normal' level of thrombin generation. This suggests that, under normal conditions in vivo, the level of FX does not significantly affect hemostatic function. By contrast, in experiments designed to mimic the hemophilic condition, the level of FX had a significant effect on the level of thrombin generated in the presence of high-dose FVIIa. This finding suggests that the plasma level of FX could affect the hemostatic response of hemophilic patients to high-dose FVIIa therapy.

Blood Coagulation↗
PubMed2000

Transient antiislet autoantibodies: infrequent occurrence and lack of association with "genetic" risk factors.

We hypothesized that genetic determinants of expression of persistent antiislet autoantibodies would similarly influence the expression of transient autoantibodies. To test this hypothesis, we prospectively evaluated sera from 478 relatives (SOC: sibling-offspring cohort) of patients with type 1 diabetes as well as 793 newborns from the general population (NEC: newborn nonrelative cohort) selected for expression of specific human leukocyte antigen haplotypes. Eight relatives of 478 (1.7% of SOC) expressed a transient autoantibody, and none had the high risk genotype DR3/4(DQ2/8). In contrast, 28 relatives (5.9%) had persistent antiislet autoantibodies, and 14 (50%) were DR3/4(DQ2/8) heterozygotes. Thirteen children of 793 (1.6% of NEC) expressed a transient autoantibody, and none had the high risk genotype DR3/4(DQ2/8). Seven of the NEC (0.9%) had persistent antiislet autoantibodies, and 4 (57.1%) were DR3/4(DQ2/8) heterozygous. Expression of persistent autoantibodies was strongly related to human leukocyte antigen status and family history of type 1 diabetes. In contrast, the expression of transient antiislet autoantibodies did not differ by family history of diabetes, and none of the DR3/4(DQ2/8) relatives and DR3/4(DQ2/8) newborns expressed transient autoantibodies. Our results indicate that children can express transient antiislet autoantibodies, but such transient autoantibodies are relatively infrequent and are not correlated with known genetic risk factors for type 1 diabetes.

Aging↗
PubMed2000

Links between the immune and coagulation systems: how do "antiphospholipid antibodies" cause thrombosis?

Inflammation and immune activation have been associated with thrombosis in a number of settings. We have been interested in the question of how the presence of a type of autoantibody, so-called "antiphospholipid" antibody, leads to thrombosis. Several mechanisms have been proposed including modulation of tissue factor expression, enhancement of procoagulant binding to platelets, and interference with antithrombotic mechanisms. We developed a cell-based model of coagulation that, unlike current coagulation assays, reflects some of the in vivo activities of "antiphospholipid" antibodies. "Antiphospholipid" antibodies against the phospholipid-binding protein beta-2-glycoprotein-1 enhance thrombin generation in this model system, primarily by enhancing procoagulant reactions on tissue factor-bearing cells.

Antibodies, Antiphospholipid↗
PubMed2000

[Ways to improve ocular bioavailability for topical applications].

The anatomical, physiological and pharmacological properties of the eye explain the short pre-corneal residence time and the poor bioavailability of most eye-drop solutions. Many approaches have been proposed to increase ocular bioavailability of drugs. Most eye-drops include a viscosity agent in their formulation to significantly prolong residence time although the increased viscosity is limited due to patient discomfort. More recent developments include biodegradable inserts, eye-drop based on cyclodextrins, liposomes or nanoparticles.

Biological Availability↗
PubMed2000

Breast cancer incidence and determinants of cancer stage in the Western Cape.

OBJECTIVE: To describe the overall and age-specific incidence rates for breast cancer and determinants of the stage of breast cancer at the time of diagnosis in the Western Cape, South Africa. METHODS: Data were derived from a case-control study of the association between injectable progestagen contraceptives and breast cancer conducted over a 4-year period from January 1994 to December 1997. In all, 485 cases were drawn from a study population consisting of coloured and black women under the age of 55 years, who presented with a first occurrence of invasive breast cancer at two tertiary hospitals in Cape Town. A questionnaire was administered and information on a large number of variables was recorded. RESULTS: The 249 cases who were interviewed during the first 2 years of the study constituted the numerator for estimates of incidence rates. The overall incidence rate was 23.1 per 100,000 women per year. The incidence rate for coloured women was 25.6 per 100,000, almost twice that for black women (14.7 per 100,000). The incidence rate in urban areas was 26.6 per 100,000, almost twice that in the rural areas (16.3 per 100,000). Stages 1 and 2 accounted for 57.8% of the cases. Early stage at diagnosis was significantly associated with a higher educational level, membership of a medical aid, residence in an urban area and a positive family history. CONCLUSION: The data suggest that there is scope for improvement in the detection of the disease through education and access to diagnostic measures, particularly in rural and disadvantaged populations.

Adult↗
PubMed1999

Lactation and breast carcinoma risk in a South African population.

BACKGROUND: A number of epidemiologic studies have reported a reduced risk of breast carcinoma among women who have lactated but others have not. The current study presents data regarding lactation and breast carcinoma risk from a hospital-based case-control study of black and colored South African women. METHODS: Incident breast carcinoma cases treated between January 1994 and October 1997 (n = 446) at 2 major hospitals in Cape Town and hospital patients admitted for conditions unrelated to breast carcinoma (controls, n = 1471) were queried regarding the duration of breast-feeding each liveborn child and breast carcinoma risk factors. Multivariate logistic regression models were used to calculate odds ratios (ORs) for various categories of lactation compared with a reference category of never having breast-fed among women who had had at least one full term live birth. RESULTS: Approximately 83% of cases and 85% of controls had ever breast-fed (OR = 0.9; 95% confidence interval [95% CI], 0.7-1.3). Among all subjects, the ORs for those who lactated for <3 years were near or at unity. Beyond 3 years, ORs extending up to >/=7 years were less than unity, but the 95% CIs included 1.0 (OR for duration of >/=7 years = 0.7; 95% CI, 0.4-1.3). ORs did not vary by menopausal status. Breast carcinoma risk was not found to be related to the duration of breast-feeding the first child, the number of children breast-fed, or the patient's age at first lactation. CONCLUSIONS: The results of the current study suggest lactation has little or no protective effect on breast carcinoma risk.

Age Factors↗
PubMed1999

Biodegradable monodispersed nanoparticles prepared by pressure homogenization-emulsification.

The aim of the present work was to investigate the preparation of nanoparticles (NP) as potential drug carriers for proteins. The hydrophilic protein bovine serum albumin (BSA) was chosen as the model drug to be incorporated within NP. Owing to the high solubility of the protein in water, the double emulsion technique has been chosen as one of the most appropriate method. In order to reach submicron size we used a microfluidizer as a homogenization device with a view to obtaining NP with a very high grade of monodispersity. Two different biodegradable polymers, poly[D, L-lactic-co-glycolic acid] 50/50 (PLGA) and poly[epsilon-caprolactone] (PCL) has been used for the preparation of the NP. The drug loading has been optimized by varying the concentration of the protein in the inner aqueous phase, the polymer in the organic phase, the surfactant in the external aqueous phase, as well as the volume of the external aqueous phase. The BSA encapsulation efficiency was high (>80%) and release profiles were characterized by a substantial initial burst release for both PLGA and PCL NP. A higher release was obtained at the end of the dissolution study for PLGA NP (92%) compared with PCL NP (72%).

Biocompatible Materials↗
PubMed1999

Evaluation of peroral silicone dosage forms in humans by gamma-scintigraphy.

Gastric emptying of oral silicone dosage forms was studied in humans by gamma-scintigraphy. To achieve a constant and predictable residence time in the stomach, three different formulations based on known concepts such as controlled swelling were investigated. The importance of physical parameters such as size or shape were also examined to assess the feasibility of designing a dosage form for gastric retention. Three shapes: minimatrices, extruded rods and moulded slabs were screened. To label the silicone polymer, two isotopes, used routinely in nuclear medicine departments, were selected: iodine-123 and indium-111. To select the most suitable isotope, the yield and the stability of the labelling were determined in vitro on the pharmaceutical dosage forms. The residence time of these silicone formulations, labelled with iodine and administered in hard gelatine capsules, was monitored in 12 subjects with a gamma camera. The study was performed under fed conditions after ingestion of a standardised meal labelled with indium. The minimatrices provided at least 3 h retention, slabs exhibited 4 h 40 min retention. For the rods the mean residence time in the stomach was around 4 h 20 min. In addition, a correlation was established between the gastric emptying of rods and the half-gastric residence time of meal. On the contrary, such a correlation was not observed for the slabs.

Administration, Oral↗
PubMed1999

Effect of the formulation on the in-vitro release of propranolol from gellan beads.

Gellan gum beads of propranolol hydrochloride, a hydrophilic model drug, were prepared by solubilising the drug in a dispersion of gellan gum and then dropping the dispersion into calcium chloride solution. The droplets formed gelled beads instantaneously by ionotropic gelation. Major formulation and process variables which might influence the preparation of the beads and the drug release from gellan gum beads were studied. Very high entrapment efficiencies were obtained (92%) after modifying the pH of both the gellan gum dispersion and the calcium chloride solution. The beads could be stored for 3 weeks in a wet or dried state without modification of the drug release. Oven-dried beads released the drug somewhat more slowly than the wet or freeze-dried beads. The drug release from oven-dried beads was slightly affected by the pH of the dissolution medium. Gellan gum could be a useful carrier for the encapsulation of fragile drugs and provides new opportunities in the field of bioencapsulation.

Calcium Chloride↗
PubMed1999

Nickel release from orthodontic arch wires and cellular immune response to various nickel concentrations.

AIMS: Results from two previous clinical studies suggested that exposure to high nickel-containing orthodontic arch wires may induce hypersensitivity in certain individuals. The purpose of this study was to measure the amount of nickel released from three types of nickel-containing arch wires into a synthetic saliva in vitro, and determine if the concentrations were sufficient to elicit either cytotoxic (trypan blue exclusion test) or stimulatory (MTT test) responses in human peripheral blood mononuclear cells (PBMCs) derived from nickel-sensitive and nickel-nonsensitive individuals. PBMCs were exposed to five concentrations of nickel sulfate solutions ranging from 0-29 ppm, and results were compared, particularly at concentrations obtained from nickel release experiments. FINDINGS: The amount of nickel released into synthetic saliva ranged from 0.4-4.1 ppb. Wires subjected to a combination of soaking and cyclic straining released significantly more nickel than those that were soaked only (p </= 0.05), and NiTi wires released significantly more nickel than did stainless steel or nitrogen-implanted NiTi wires (p </= 0.05). For PBMCs, significant increased cell proliferation was not observed for any nickel concentration. PBMC cell death rates were highest at nickel concentrations of 29 ppm when the cells were cultured without a cell growth promoter (p </= 0.05), and MTT test values were significantly reduced at both 2.9 and 29 ppm when a growth promoter was included (p </= 0.05). CONCLUSION: The maximum amount of nickel released from all tested arch wires was 700 times lower than the concentrations necessary to elicit cytotoxic reactions in human PBMCs.

Adult↗
PubMed1999

Comparison of the biodistribution in mice of 111indium oxine encapsulated into poly(lactic-co-glycolic)-D,L-85/15 and poly(epsilon caprolactone) nanocapsules.

Poly(lactic-co-glycolic)-D,L-85/15 (PLAGA) nanocapsules and poly(epsilon caprolactone) (PCL) nanocapsules were labeled with a relatively long half-life compound that is usually used in humans; that is, 111In-labelled oxine (111In oxine). This labeling technique led to a high 111In oxine entrapment efficiency and good stability during dialysis against phosphate buffer and phosphate buffered albumin solution. Because of these characteristics, the nanocapsules biodistribution was followed up after intravenous administration for up to 96 h by determining the gamma activity in the tissues after sampling. The administration of the PCL-encapsulated 111In oxine led to a decrease in the blood radioactivity and an increase in the liver radioactivity compared with the solution. This effect was even more pronounced with the PLAGA nanocapsules. Finally, the activity level in other tissues, such as the kidneys, the lungs, and the spleen, appeared to be rather low and only slightly affected by the encapsulation into one or the other polymer.

Animals↗
PubMed1999

Blood pressure and social support observations from Mamre, South Africa, during social and political transition.

OBJECTIVE: Social support, by moderating cardiovascular reactivity, has been demonstrated to attenuate the effects of stress on blood pressure in American communities. This is the first report to examine the relationship between social support and blood pressure in a South African context, during a period of infrastructure modernisation and political change. METHODS: A total of 1240 residents (542 men, 698 women) of mixed ethnic origin, older than 14 years and stratified by age and sex, participated in a survey to determine risk factors for hypertension and cardiovascular diseases. Social support was assessed by a questionnaire developed in consultation with the community. It was defined by interactions that may threaten family harmony (score 1) and by networking between relatives, friends, colleagues and neighbours (score 2). RESULTS: Mean blood pressure of the sample was 130/79 mm Hg (s.d. 25/14 mm Hg). Hypertension prevalence was 26.9%. Only 36% of women compared to 57.3% of men (P < 0.0001) were employed. More women (29%) than men (22%) reported threats to family harmony, but social support networks were similarly perceived by both sexes. Systolic and diastolic blood pressure correlated weakly with score 1 (r = 0.096, P < 0.0007) but no association was observed with score 2. Score 1 was not associated with blood pressure by multiple regression analysis, that included confounding by age, sex, BMI, alcohol consumption and smoking status. CONCLUSIONS: Neither threats to family harmony nor networking between relatives, friends or neighbours, significantly influences blood pressure in this community. Measures of social support thought to moderate blood pressure may have limited cross-cultural application. Attitudinal changes during socio-political transition may impact on the generalisability of instruments for measurement.

Adolescent↗
PubMed1999

Determination by capillary zone electrophoresis of mercaptopurine and thioguanine concentration in capsules for paediatric patients.

OBJECTIVE: Mercaptopurine monohydrate and thioguanine are two antineoplastic agents that inhibit purine metabolism. They are given by mouth in the treatment of acute leukaemias, usually for the maintenance of remission. In order to quantify these two antimetabolites into capsules for paediatric patients prepared in the pharmacy department, a capillary zone electrophoresis method (CZE) was developed. METHOD: The equipment and reagents used included: a P/ACE 5000 capillary electrophoresis system, a 37 cm x 75 microm silica capillary, a 22.2 mM borate buffer (pH 9.0), 5 s high pressure injections, direct UV detection at 280 nm, run 20 kV. Hypoxanthine was used as an internal standard. RESULTS: All compounds were separated in less than 3 min using a constant voltage of 20 kV. At a theoretical concentration of 100 microg/ml, the accuracy (average percentage of recovery = 98.9%, RSD = 0.45%, n = 6 for mercaptopurine and average percentage of recovery = 101.7%, RSD = 0.20%, n = 6 for thioguanine), the repeatability (RSD = 0.84%, n = 6 for mercaptopurine and RSD = 0.75%, n = 6 for thioguanine), the reproducibility (RSD = 0.58%, n = 18 for mercaptopurine and RSD = 1.55%, n = 18 for thioguanine) and the linearity of detection (range 50-150% of the studied concentration, r > 0.999 for mercaptopurine and r > 0.998 for thioguanine) were satisfactory. The capsule excipients did not interfere with quantification of the mercaptopurine or thioguanine peak. CONCLUSION: The two antineoplastic agents could be assayed rapidly by the same capillary zone electrophoretic method with acceptable accuracy and precision. This method is suitable for routine control of capsules prepared for paediatric patients.

Antimetabolites, Antineoplastic↗