Biomedical subjects
Publications and source records attributed to M L Lee.
Cutaneous involvement in giant cell arteritis is quite uncommon. A patient is described who presented with pretibial skin lesions clinically indistinguishable from erythema nodosum which, on biopsy, showed subcutaneous pannicular giant cell vasculitis. Cutaneous manifestations of giant cell arteritis are subsequently reviewed.
Several groups including ours at Hyland have studied the incidence of HTLV-III/LAV seroconversion and non-A, non-B hepatitis (NANBH) in recipients of products made from unscreened plasma. Of 18 previously untreated patients who received heat-treated factor VIII concentrate (HEMOFIL T), none seroconverted for HTLV-III/LAV. However, 11 of 13 similarly treated patients showed aminotransferase elevations indicative of NANBH. None of 21 patients receiving anti-inhibitor coagulant complex (Autoplex) seroconverted for HTLV-III/LAV, while 28 of 50 patients receiving other forms of treatment did seroconvert. Of 30 recipients of AUTOPLEX, 9 had elevated aminotransferase levels. Since all patients had hepatitis B markers when the study began, a diagnosis of NANBH cannot be made. Of 16 patients who received large doses of immune globulin for intravenous administration (IGIV, GAMMAGARD), none seroconverted for HTLV-III/LAV. Retrospective and prospective studies of 157 recipients of GAMMAGARD did not reveal a single case of NANBH attributable to receipt of this product. In contrast, NANBH has occurred following administration of HEMOFIL T, indicating that heating in the dried state does not eliminate the NANBH agent(s). In spite of lingering concerns about NANBH infectivity, the available data strongly suggest that heat treatment and/or cold ethanol fractionation render these plasma products safe from HTLV-III infectivity.
A retrospective analysis of 18 patients who had received a human intravenous immunoglobulin (IGIV) preparation was undertaken to ascertain the safety of this preparation with respect to transmission of human immunodeficiency virus (HIV), the virus that causes the acquired immune deficiency syndrome (AIDS). Patients were followed up by means of periodic enzyme-linked immunosorbent assay (ELISA) for the presence of circulating antibodies against HIV; a negative ELISA was evidence that HIV had not been transmitted to the recipients of IGIV. Results in 16 patients were negative, and two patients were determined to have had false-positive ELISAs because the Western blot test was negative for seroconversion. It is thus concluded that the IGIV product tested has little or no potential for transmitting HIV.
Early clinical experience with anti-inhibitor coagulant complex in the treatment of bleeding in patients with factor VIII inhibitors is described. Sixty patients with a total of 120 bleeding episodes were studied. Satisfactory responses were obtained in 86.6% of bleeding episodes. Efficacy was slightly better in open bleeding than in closed bleeding. Higher doses were significantly better than lower doses in treating open bleeding. The incidence of adverse reactions was low. The results reported support the safety and efficacy of anti-inhibitor coagulant complex in the treatment of bleeding in patients with factor VIII inhibitors.
The safety and efficacy of a new second-generation intravenous immunoglobulin manufactured using ion-exchange chromatographic methods was studied in 17 patients with primary immunodeficiency. In assessing safety, the incidence of adverse reactions during the first 48 hours after each infusion and long-term changes in laboratory values were considered. Efficacy was determined by the number of acute and new chronic infections as well as by the number of prescriptions filled for antibiotics. These results were compared with those reported for similar preparations. Results showed a low (4.4%) incidence of acute adverse reactions, and no serious reactions or significant changes were noted in any of the laboratory test results. The incidences of infection and antibiotic usage were as low as or lower than those reported with other preparations. Thus we conclude that this new intravenous immunoglobulin product is a safe, effective prophylactic treatment for patients who have primary immunodeficiency.
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A blinded randomized multicenter trial of two non-activated prothrombin complex concentrates was carried out to determine the clinical effectivity in the treatment of acute hemarthrosis in hemophiliac patients with inhibitors. The one product was prepared via DEAE Sephadex chromatography, while the second was fractionated via various precipitation procedures including polyethylene glycol. Equivalence of the two products was established with less than 15% difference in efficacy rates.
We have reported a model of ischemic bowel necrosis produced in the rat by injecting platelet activating factor (PAF) or PAF with bacterial endotoxin (LPS) into the mesenteric vasculature. In the present study, we examined the protecting effects of three PAF antagonists, i.e. (R,S)-3-[2-[(2-octadecylaminocarbonyloxymethyltetrahydro-2-fura nylmethoxy) -hydroxyphosphinyloxy]-ethyl]-thiazolium hydroxide inner salt 4-oxide (SRI 63-072), (+/-)-3-[4-[3-octadecylaminocarbonyloxy-2-methoxy)-propoxy]-butyl] -thiazolium bromide (SRI 63-119) and 1-O-hexadecyl-2RS-O-ethyl-3-O -(7-thiazolinoheptyl)-glycerol-methanesulfonate (ONO-6240), on PAF-induced bowel necrosis. The antagonists were injected into the vein 10 min before PAF. Two microgram of PAF or 20 micrograms LPS with 1 microgram of PAF were injected into the aorta above the renal arteries. The parameters assessed included blood pressure, hematocrit, white blood cell count, extent of bowel perfusion and microscopic changes of the bowel. We found that SRI 63-072 (3 mg/kg), SRI 63-119 (3 mg/kg) and ONO-6240 (2 mg/kg) significantly improved the initial hypotension, hemoconcentration and leukopenia caused by PAF. All three drugs also corrected the sustained hypotension and hypoperfusion and gross lesions of the bowel, although microscopic examination still revealed focal mild lesions. SRI 63-072 was also active at a much lower dose (0.3 mg/kg).
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Platelet activating factor (paf) given intravenously produces systemic hypotension in the rat. Similar effects can be induced using endotoxin or heat-aggregated IgG challenges, which are thought to involve endogenous paf release. Extending this concept, we have examined the ability of the paf antagonist SRI 63-072 to inhibit or reverse systemic hypotension induced with paf, heat-aggregated IgG or endotoxin 0111-B4 in rats. At 100 ng kg-1 paf, there occurred a 38.6 +/- 5.1% decrease in carotid mean arterial pressure (MAP) followed by a 3.2 +/- 0.7 min recovery period (RP) to return to normal pressure values. The ED50 of SRI 63-072 was 0.16 mg kg-1 i.v. (MAP) and 0.25 mg kg-1 (RP) when given 1-5 min before the paf challenge. Endotoxin (15 mg kg-1 i.v.) produced a hypotensive response (54 +/- 8% decrease in MAP) and a corresponding 80% decrease in mesenteric artery blood flow. When given 2-8 min after endotoxin, 1.0 mg kg-1 i.v. SRI 63-072 totally restored blood pressure and artery blood flow. SRI 63-072 similarly reversed heat-aggregated IgG (10 mg kg-1) induced reduction of MAP, with an ED50 of 0.05 mg kg-1 i.v. The observations that SRI 63-072 can inhibit or reverse systemic vascular effects produced from paf and other provocators of endogenous paf release strongly implicates paf as a common final mediator of hypotension and shock. As SRI 63-072 is a competitive receptor antagonist, the hypotensive effects of these provocators appear to be mediated by vascular receptors for paf.
Essential thrombocytosis is a myeloproliferative disease not known to have consistent cytogenetic abnormalities. A 46-year-old black woman with essential thrombocytosis and a Philadelphia chromosome is reported. Iron deficiency and tuberculosis were present but when effectively treated did not result in resolution of thrombocytosis. Megakaryocytic hyperplasia of bone marrow, abnormal platelet function studies and a compatible clinical state suggested the diagnosis of essential thrombocytosis. The diagnostic criteria for other myeloproliferative diseases were not met. The Philadelphia chromosome was consistently obtained from bone marrow preparations. We conclude that the Philadelphia chromosome may be found in essential thrombocytosis as well as other, previously reported, myeloproliferative diseases.
Previous studies with synthetic platelet-activating factor (PAF) (AGEPC) showed that aerosol challenges in rhesus monkeys resulted in airway responses simulating acute antigen-induced responses and immediate-type skin reactions [1]. The current studies evaluated whether an antagonist of PAF (SRI 63-072) could inhibit the airway and cutaneous reactivity to PAF. Under the conditions of these experiments, the antagonist partially inhibited PAF activity in both experimental systems. Inhibition of endpoint cutaneous reactivity to PAF may be a suitable system for comparing potency of pharmacologic antagonists in primate skin.
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Each of a pair of identical twin brothers was independently remanded for mental health assessment. The results of the assessment reliably revealed schizophrenia in one twin and mania in the other. The implications for genetic models of mental disorder are discussed.
The ability of synthetic platelet-activating factor (PAF) given intravenously to produce loss (extravasation) of protein rich plasma (resulting in hemoconcentration) has been examined using guinea pigs. Hemoconcentration induced by PAF was not prevented by prior administration of inhibitors of thromboxane synthetase (7-(3-pyridyl)heptanoic acid, UK-37,248-01), PGI2, aspirin, indomethacin or antiserum induced thrombocytopenia. Calcium channel blockers (nifedipine, verapamil, diethylamino octyltrimethoxybenzoate, diltiazem), antihistamines (pyrilamine, cimetidine, diphenhydramine), or the elevator of cAMP IBMX were ineffective in blocking PAF-induced hemoconcentration. In contrast, CV-3988, reported to be a specific antagonist to PAF, was 98% inhibitory of PAF extravasation when given i.a. at 3.5 mg/kg. The ED50 was 0.14 mg/kg I.A. and 15 mg/kg p.o. against 75 ng/kg PAF. These data suggest that PAF-induced hemoconcentration involves receptor mediated alterations of vascular permeability that are inhibited by a specific PAF antagonist.
We concluded cytogenetic studies on a couple who had had several spontaneous abortions. The peripheral lymphocytes of the woman repeatedly showed a mosaic pattern with a structurally altered, apparently balanced, autosomal translocation between chromosomes 4 and 5. Various studies were reviewed and it was concluded that the true frequency of structural rearranged mosaics in recurrent pregnancy loss is not known.
When presterilized, closed canister, membrane filter units for sterility testing are validated for process, large volumes of therapeutic products for injection can be tested for sterility, recovered, and added to a subsequent bulk prior to sterile filtration. Intermittent positive pressure, applied to the canisters through the vent filters, makes possible the relatively rapid filtration, with minimal foaming, of viscous solutions such as 25% (w/v) normal serum albumin (human). Canister systems appear to be at least as effective as the standard membrane filter method, and the canisters are particularly suited to the sterility testing of bulks.