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J T Douglas

Publications and source records attributed to J T Douglas.

At least 37 records · Page 2Linked to original sources
PubMed1998

Differential susceptibility of primary and established human glioma cells to adenovirus infection: targeting via the epidermal growth factor receptor achieves fiber receptor-independent gene transfer.

Adenovirus (Ad) vectors are promising for gene therapy of glioma due to their ability to achieve efficient gene transfer upon intratumoral administration. Yet in this context, Ad mediates widespread gene transfer to both tumor and surrounding parenchyma. Ad entry is dependent upon the expression of fiber receptors, such as coxsackie/adenovirus receptor, and alpha(v) integrins on the target cells for binding and internalization, respectively. We hypothesized that the susceptibility of human gliomas to Ad would likely be heterogeneous due to variable expression of these receptors. It was found that established human glioma cell lines exhibited differential susceptibility to Ad-mediated gene transfer, which correlated directly with the level of radiolabeled Ad binding and with the expression of coxsackie/adenovirus receptor but not with the expression of alpha(v) integrins. To circumvent the lack of fiber receptors and to target Ad gene transfer specifically to tumor cells, we used a bispecific antibody conjugate to ablate Ad binding to fiber receptors and retarget binding to the epidermal growth factor receptor (EGFR), a tumor-associated marker negligibly expressed in normal, mitotically quiescent neural tissues. The results demonstrate that EGFR-targeted Ad gene transfer was EGFR specific and independent of fiber-fiber receptor interactions. Furthermore, EGFR targeting significantly enhanced Ad gene delivery to 7 of 12 established glioma cell lines and to 6 of 8 cultured primary gliomas. Interestingly, EGFR-targeted Ad gene transfer did not correlate with EGFR expression across cell lines, suggesting the importance of other factors. This study establishes that fiber receptor expression limits the utility of Ad vectors for gene transfer to glioma cells and suggests that targeting Ad via EGFR may prove valuable for tumor-specific gene transfer to high-grade gliomas. These findings have key relevance in the context of Ad vector-based approaches for glioma gene therapy.

Adenoviruses, Human↗
PubMed1998

The potential role of cell adhesion molecules in the pathogenesis of diabetic neuropathy.

Cross-sectional studies have shown plasma cell adhesion molecules (CAMs) to be increased in patients with diabetes-related complications. In the first prospective study of CAMs, we have shown that plasma CAMs may be a predictor of the development of diabetic neuropathy. We followed up 28 diabetic patients (13 neuropathic) over a 5 year period, starting from 1991. All patients had peroneal nerve conduction velocity (PNCV), vibration perception threshold and plasma CAMs measured at baseline and follow-up. We found P-selectin and intercellular adhesion molecule-1 (ICAM-1) to be increased at baseline in patients with neuropathy compared to non-neuropathic patients. P-selectin and E-selectin were also found to be significantly higher at baseline in patients who at follow-up showed deterioration in PNCV of more than 3 m/s (p<0.05; p=0.01; respectively). P-selectin and ICAM-1 strongly correlated with PNCV. Univariate and multivariate regression analyses showed a significant inverse association between increasing log P-selectin, log E-selectin and log ICAM-1 with decreasing PNCV, and remained significant even after adjustment for glycaemic control. P-selectin and E-selectin, odds ratios of 8.8 (95% CI: 1.1-68.8; p=0.038) and 12.5 (95% CI: 1.2-132.1; p=0.036), respectively, were significantly associated with the risk of deterioration of PNCV after 5 years. This study suggests that plasma cell adhesion molecules may play an important role in the development and progression of peripheral neuropathy in diabetes mellitus.

Adult↗
PubMed1998

Imaging and tissue biodistribution of 99mTc-labeled adenovirus knob (serotype 5).

Hepatic sequestration of systemically administered adenoviral vectors reduces the number of viral particles available for delivery to other tissues. The biological basis of this phenomenon was investigated using a new in vivo technique which permitted imaging in real time. Recombinant adenovirus serotype 5 knob (Ad5K) was radiolabeled with the gamma-emitter 99mTc (half-life = 6 h). Scatchard analysis of the 99mTc-Ad5K showed specific, high-affinity binding to U293 cells (Kd = 1.4 +/- 0.5 nM), demonstrating that the radiolabeling process had no effect on receptor binding. In vivo dynamic imaging with an Anger gamma camera revealed that the liver binding followed an exponential rise to maximum, with a measured 100% extraction efficiency. Initially, the liver binding capacity was 3.1 +/- 0.4 micrograms Ad5K, equivalent to approximately 17,000 Ad5K molecules per liver cell. Liver binding was blocked by preincubation of Ad5K with neutralizing anti-Ad5K antibody; a 50% reduction in liver uptake was demonstrated by imaging. Unlabeled Ad5K was more effective in blocking liver uptake of 99mTc-Ad5K, whereas irrelevant unlabeled Ad3K had no effect. Imaging data for the liver uptake studies were in agreement with biodistribution determined by removing and measuring tissues. These data demonstrated that in vivo imaging is a sensitive tool for measuring changes to liver tropism. Similar imaging techniques can be applied to adenovirus vectors to measure specific targeting for gene therapy.

Adenoviridae↗
PubMed1998

Basic fibroblast growth factor enhancement of adenovirus-mediated delivery of the herpes simplex virus thymidine kinase gene results in augmented therapeutic benefit in a murine model of ovarian cancer.

A number of preclinical and human clinical gene therapy trials using adenoviral vectors have shown that the number of viral particles necessary to give adequate levels of gene transfer can be associated with significant vector-related toxicity. In an effort to reduce the number of adenoviral particles required for a given level of gene transfer, we sought to redirect adenoviral infection via a receptor that is highly expressed on the target cells. By using basic fibroblast growth factor (FGF2) as the targeting ligand, adenovirus-mediated gene transfer to the human ovarian cancer cell line SKOV3.ip1 was significantly enhanced, permitting the transduction of a greater number of target cells to be achieved by a given dose of virus. In a murine model of human ovarian carcinoma, an FGF2-redirected adenoviral vector carrying the gene for herpes simplex virus thymidine kinase (AdCMVHSV-TK) was shown to result in a significant prolongation of survival compared with the same number of particles of unmodified AdCMVHSV-TK. In addition, equivalent survival rates were achieved with a 10-fold lower dose of the FGF2-redirected AdCMVHSV-TK compared with the unmodified vector. To our knowledge, this is the first report demonstrating that strategies to enhance the efficiency of in vivo transduction of adenoviral vectors will be of clinical utility.

Adenoviridae↗
PubMed1997

Targeted gene delivery to Kaposi's sarcoma cells via the fibroblast growth factor receptor.

Kaposi's sarcoma (KS) is a major AIDS-related malignancy associated with significant morbidity and mortality. Current chemotherapeutic regimens are associated with a dismal prognosis. In an effort to develop a new approach to KS treatment, we devised a gene therapy-based adenovirus retargeting schema that redirects the adenovirus to fibroblast growth factor receptors endogenously present on the cell surface of KS cells. By using a bifunctional conjugate consisting of a blocking antiadenoviral knob Fab linked to basic fibroblast growth factor, FGF2, the gene transduction of KS cells was enhanced 7.7-44 fold; recombinant adenoviruses encoding either the firefly luciferase reporter gene, or the herpes simplex thymidine kinase gene, demonstrated quantitative enhancement of expression in the KS cell lines. In this regard, two KS cell lines that were previously refractory to native adenovirus transduction could be successfully transduced by the addition of the conjugate. This study thus addresses the utility of adenoviral retargeting to the FGF receptor in KS cells that are ordinarily transduction refractory to standardized approaches and allows practical development of gene therapy approaches for the treatment of human KS.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Strategies to accomplish targeted gene delivery to muscle cells employing tropism-modified adenoviral vectors.

We are developing strategies to modify the tropism of adenoviral vectors to accomplish targeted transduction of muscle cells for DMD gene therapy. In one approach, we have introduced targeting ligands into the adenovirus fibre, which mediates the binding of the virus Ad5 to the primary cellular receptor. In order to incorporate these fibre-ligand fusions into recombinant adenoviral vectors, we have employed a method based upon homologous DNA recombination between a fibre-deleted, propagation-defective rescue plasmid and a shuttle plasmid encoding a variant fibre. To date, we have generated an adenoviral vector containing chimeric fibres composed of the tail and shaft domains of adenovirus serotype 5 and the knob domain of serotype 3. This modification altered the receptor recognition profile of the virus containing the fibre chimera. In an alternative approach to the generation of a targeted adenoviral vector, we conjugated folate to the neutralising Fab fragment of an anti-fibre monoclonal antibody. This Fab-folate conjugate was shown to redirect adenoviral infection of target cells via the folate receptor at a high efficiency. These studies suggest that it will be possible to achieve our goal of deriving targeted adenoviral vectors for muscle cell-specific gene delivery in vivo.

Adenoviridae↗
PubMed1997

Use of a novel cross-linking method to modify adenovirus tropism.

Recombinant adenovirus (Ad) vectors can accomplish efficient in vivo gene transfer and thus are important in the context of a variety of gene therapy approaches. The cellular receptor for the Ad fiber knob is prevalent on a number of normal tissues which undermines the targeting of Ad to specific tumor cells. Therefore, the ablation of native Ad tropism and the introduction of novel Ad tropism are both necessary to target Ad vectors specifically to tumors. In this study, we have developed a flexible method for cross-linking the Fab fragment of a neutralizing anti-knob monoclonal antibody (1D6.14) to a cell receptor ligand. The cross-linking moieties are complementary low molecular weight recognition units, similar in concept to the avidin-biotin system. For proof of concept, we cross-linked 1D6.14 Fab to the basic fibroblast growth factor (FGF2). The Fab and FGF2 conjugates were synthesized and characterized both structurally and functionally. The conjugates were then complexed with an adenovirus vector carrying firefly luciferase (AdCMVLuc) and the resulting complex used to show infection of a number of tumor cell lines expressing FGF receptors. This cross-linking system should provide a rapid and convenient method of conjugating various ligands to the Fab fragment for targeting Ad vectors to different types of tumors.

Adenoviridae↗
PubMed1997

Epitope mapping of twelve monoclonal antibodies against the phenolic glycolipid-I of M. leprae.

Epitope mapping of 12 monoclonal antibodies (MAbs) directed to the trisaccharide part of the phenolic glycolipid-I (PGL-I) of Mycobacterium leprae was carried out by using the set of chemically synthesized sugar-BSA conjugates. The results can be summarized as follows: mAb (1-21), mAb (1-24) and mAb (1-25) recognized the outer (nonreducing end) monosaccharide of the trisaccharide chain of PGL-I. However, the affinity of these MAbs to the outer monosaccharide was weak. They required the contributions of some parts of the second sugar for enough affinity. MAbs ml 6A12, ml 8A2, ml 8B2, and PG2 B8F recognized the outer disaccharide. MAb F47-21-3 recognized the outer disaccharide and some parts of the third sugar. MAb SF 1 recognized the trisaccharide of PGL-I. MAb 3D1-A9 recognized the phenol group and the structure around the branching point on the carrier protein in addition to the trisaccharide. MAbs DZ 1 and 2G3-A8 had unique characters which recognized the inner part of the sugar chain. MAb DZ 1 recognized the inner (reducing end) disaccharide. MAb 2G3-A8 recognized the inner monosaccharide, phenol group and the structure around the branching point on the carrier protein. All of the MAbs tested, except for ml 6A12, recognized the anomeric configurations in the sugar parts they recognized; ml 6A12 recognized the anomeric configuration only within the outer disaccharide. This set of MAbs, which were well defined on their binding specificity, promises to be an effective tool for the immunological study of PGL-I and the clinical assessment of leprosy.

Antibodies, Bacterial↗
PubMed1996

Targeted gene delivery by tropism-modified adenoviral vectors.

The utility of adenoviral vectors for gene therapy is currently limited due, in part, to the widespread distribution of the cellular receptor for the adenovirus fiber that precludes the targeting of specific cell types. In order to develop a targeted adenovirus, it is therefore necessary both to ablate endogenous viral tropism and to introduce novel tropism. We hypothesized that these two goals could be achieved by employing a neutralizing anti-fiber antibody, or antibody fragment, chemically conjugated to a cell-specific ligand. To test this concept, we chose to target the folate receptor, which is overexpressed on the surface of a variety of malignant cells. Therefore, we conjugated folate to the neutralizing Fab fragment of an anti-fiber monoclonal antibody. This Fab-folate conjugate was complexed with an adenoviral vector carrying the luciferase reporter gene and was shown to redirect adenoviral infection of target cells via the folate receptor at a high efficiency. Furthermore, when complexed with an adenoviral vector carrying the gene for herpes simplex virus thymidine kinase, the Fab-folate conjugate mediated the specific killing of cells that overexpress the folate receptor. This work thus represents the first demonstration of the retargeting of a recombinant adenoviral vector via a non-adenoviral cellular receptor.

Adenoviridae↗
PubMed1996

Rheological and microvascular parameters in diabetic peripheral neuropathy.

1. In order to determine whether rheological changes occur in neuropathic diabetic patients in the absence of smoking, proteinuria, retinopathy or other factors thought to influence haemorheology, three groups of subjects were studied; 24 non-diabetic control subjects (C), 24 non-neuropathic (D) and 24 neuropathic (N) diabetic patients. The groups were matched for age, sex, type and duration of diabetes. No patient or control was a current smoker. No patient had clinically detectable retinopathy or microalbuminuria. Neuropathy was defined as a peroneal conduction velocity < 40 ms-1. All subjects were tested resting semi-recumbent after a light breakfast. 2. There were no significant differences in rheological or microvascular parameters between uncomplicated diabetic patients and non-diabetic control subjects, although peroneal nerve motor conduction velocity was significantly reduced in otherwise uncomplicated diabetic patients [C 51.7 +/- 6.0 ms-1 (mean +/- SD) versus D 45.1 +/- 5.2 ms-1 (P < 0.05 C versus D)]. 3. Transcutaneous oxygen and laser Doppler flux measured at 44 degrees C were higher in control subjects than in neuropathic diabetic patients [C 76 +/- 16 mmHg versus D 71 +/- 10 mmHg versus N 63 +/- 9 mmHg, and C 72 +/- 40 flow units versus D 64 +/- 41 flow units versus N 50 +/- 26 flow units respectively (both P not significant C versus D, P < 0.05 N versus C). 4. Erythrocyte aggregation, plasma viscosity and plasma fibrinogen were all significantly higher in the neuropathic diabetic patients compared with non-diabetic control subjects (all P < 0.05 N versus C). Erythrocyte filtration was not significantly different between groups but was lower in diabetic patients. Whole-blood viscosity (corrected to 45% haematocrit) was significantly higher at both high (100 s-1) and low (1 s-1) shear rates in neuropathic diabetic patients than in non-diabetic control subjects (both P not significant C versus D, P < 0.05 N versus C). There were no significant differences in whole-blood viscosity at a shear rate of 0.01 s-1. 5. In summary, there were no significant differences in rheological or microvascular parameters between matched groups of uncomplicated diabetic patients and control subjects, but erythrocyte aggregation, fibrinogen and plasma and corrected whole-blood viscosity were all significantly different in neuropathic diabetic patients compared with control subjects, as were assessments of microvascular flow. These results suggest that haemorheological changes are associated with disturbances of microvascular flow and diabetic peripheral neuropathy in the absence of other diabetic complications.

Adult↗
PubMed1996

Generation of recombinant adenovirus vectors with modified fibers for altering viral tropism.

To expand the utility of recombinant adenovirus vectors for gene therapy applications, methods to alter native viral tropism to achieve cell-specific transduction would be beneficial. To this end, we are pursuing genetic methods to alter the cell recognition domain of the adenovirus fiber. To incorporate these modified fibers into mature virions, we have developed a method based on homologous DNA recombination between two plasmids. A fiber-deleted, propagation-defective rescue plasmid has been designed for recombination with a shuttle plasmid encoding a variant fiber gene. Recombination between the two plasmids results in the derivation of recombinant viruses containing the variant fiber gene. To establish the utility of this method, we constructed a recombinant adenovirus containing a fiber gene with a silent mutation. In addition, we generated an adenovirus vector containing chimeric fibers composed of the tail and shaft domains of adenovirus serotype 5 and the knob domain of serotype 3. This modification was shown to alter the receptor recognition profile of the virus containing the fiber chimera. Thus, this two-plasmid system allows for the generation of adenovirus vectors containing variant fibers. This method provides a rapid and facile means of generating fiber-modified recombinant adenoviruses. In addition, it should be possible to use this system in the development of adenovirus vectors with modified tropism to allow cell-specific targeting.

Adenoviridae↗
PubMed1995

A novel method for treatment of abdominal aortic aneurysms using percutaneous implantation of a newly designed endovascular device.

BACKGROUND: Percutaneous implantation of a stent to bridge abdominal aortic aneurysm (AAA) may provide an alternative to surgical reconstruction in patients with this serious disorder. We developed a self-expandable, stainless steel, woven mesh endovascular device with a delivery catheter and studied its efficacy in a canine model of AAA. METHODS AND RESULTS: Infrarenal AAAs were created surgically in eight adult dogs using autologous tissue. Two types of endovascular stents were used in this study; a plain or uncovered stent, about 14 mm in diameter in the unconstrained configuration, and a covered stent, coated by porous polyurethane, about 16 mm in diameter. All stents were successfully placed on the first attempt. Aortograms revealed a mean aneurysm diameter of 1.86 +/- 0.47 cm, an average of 70% larger than the reference aortic lumen before stent placement. After stent placement, aortograms showed that the aneurysmal cavity disappeared completely in three dogs treated with a covered stent and that the aortic blood flow into the cavity markedly reduced, with faint contrast filling the cavity in the remaining five dogs treated with an uncovered stent. The uncovered stent was intentionally placed across the major arterial branches in two dogs. No acute complications were encountered at the time of stent placement. Two dogs were killed shortly after the procedure for immediate evaluation of the device, which was found to be in place and patent. One dog in which a covered stent was placed was euthanized 2 1/2 weeks later because of paraplegia secondary to a spinal cord infarction noted 48 hours after stent placement. Postmortem study revealed thrombus occluding the stent lumen. The remaining five dogs tolerated the devices well and completed 4 weeks of follow-up. Premortem aortograms showed no residual aneurysmal cavity in four dogs and only a small cavity in one dog that had received an uncovered stent. All stents were fully patent with no thrombus and were either completely or partially surfaced by neointima. Importantly, the major arterial branches over which the uncovered stents were placed were widely patent without obstruction by neointima. CONCLUSIONS: This study demonstrates the feasibility of percutaneous implantation of this new device and its effectiveness in the treatment of surgically created AAA in our canine model. The covered stent was able to exclude AAA immediately upon deployment and is of potential value in the emergency treatment of leaking AAAs. The uncovered stent appears to safely bridge branch arteries as well as significantly reduce the angiographic size of the aneurysm and may be useful in the elective therapy of AAAs. These results are promising, and future clinical trials to investigate the safety and efficacy of this device in humans are warranted.

Animals↗
PubMed1995

Systemic endotoxaemia and fibrinolysis during aortic surgery.

OBJECTIVE: To determine whether endotoxaemia and activation of the systemic fibrinolytic system occurs during and after aortic surgery. DESIGN: Prospective clinical study. SETTING: University Hospital. MATERIALS: 31 patients undergoing aortic surgery. CHIEF OUTCOME MEASURES: Venous blood assay for endotoxin and plasminogen activator inhibitor-1 (PAI-1). Samples were obtained preoperatively, immediately before and 5 minutes after cross-clamp application and removal, and at 2, 4, 6 and 24 hours postoperatively. Tonometric sigmoid intramural pH was monitored throughout this period as a means of detecting colonic mucosal ischaemia. MAIN RESULTS: Endotoxin levels increased after clamping of the aorta, peaking immediately before clamp removal, mean value 34.5 pg/ml, p < 0.01, but returning to preoperative levels by 24 hours. PAI-1 levels progressively increased after surgery, with persistently high levels remaining at 24 hours (p < 0.01). CONCLUSIONS: Endotoxaemia does occur during aortic surgery and appears to be associated with activation of the systemic fibrinolytic system.

Acidosis↗
PubMed1995

Predominance of a single genotype of Mycobacterium tuberculosis in countries of east Asia.

Analysis of the population structure of Mycobacterium tuberculosis strains from the People's Republic of China showed that the vast majority belong to a genetically closely related group. These strains shared the majority of their IS6110 DNA-containing restriction fragments, and also, the DNA polymorphism associated with other repetitive DNA elements, like the polymorphic GC-rich sequence and the direct repeat, was very limited. Because the majority of these strains originated from the province of Beijing, we designated this grouping the "Beijing family" of M. tuberculosis strains. Strains of this family were also found to dominate in neighboring countries such as Mongolia, South Korea, and Thailand, whereas a low prevalence of such strains was observed in countries on other continents. These data indicate that strains of the Beijing family recently expanded from a single ancestor which had a selective advantage. It is speculated that long-term Mycobacterium bovis BCG vaccination may be one of the selective forces implicated in the successful spread of the Beijing genotype.

China↗
PubMed1994

BALB/c mice infected with Brucella abortus express protracted polyclonal responses of both IgG2a and IgG3 isotypes.

A polyclonal IgG2a response dependent on the secretion of endogenous IFN-gamma has been demonstrated in BALB/c mice injected with killed whole cells of Brucella abortus [1]. Here we report intense and protracted polyclonal responses of IgG2a and also of IgG3 isotypes in BALB/c mice undergoing primary infections with B. abortus attenuated vaccine strain 19 or virulent strain 2308. Ratios of total serum Ig levels between infected mice and age matched controls were greater than 38 for IgG3 and greater than 12 for IgG2a between weeks 4 and 8 post-infection. Polyclonal increases of IgM and IgG1 that were proportionally much lower (ratios < 2 and < or = 3, respectively) also occurred in infected mice during this time. It is hypothesized that both IgG3 and IgG2a polyclonal responses required IFN-gamma, which was induced by B. abortus primarily in a T cell-independent fashion during the first weeks of infection, and from T cells thereafter.

Animals↗
PubMed1994

Antibody-mediated protection against Brucella abortus in BALB/c mice at successive periods after infection: variation between virulent strain 2308 and attenuated vaccine strain 19.

In BALB/c mice antibodies specific for the O polysaccharide (OPS) as well as T lymphocytes mediate protective immunity to Brucella abortus. We performed quantitative analyses of isotypes of OPS antibodies generated during primary infections, and tested the protective qualities of antisera at successive stages of infection against B. abortus strain 2308, representative of the wild type, and attenuated vaccine strain 19. IgM antibodies predominated during the first 3-4 weeks of infection. IgG3 antibodies increased slowly for the first 3 weeks but then rose rapidly and persisted at high levels (> 300 micrograms/ml). IgG1, IgG2a and IgG2b antibodies had increased slightly by week 4 and then remained at low to moderate levels (< 70 micrograms/ml). Week 2 serum pools (IgM high, IgG3 low or undetectable) transferred substantial protection against 2308 (> or = 1 log unit) which increased relatively little (to 1.2-1.5 log units) with later sera that were high in IgG antibodies. In contrast, week 2 sera conferred low levels of protection against 19 (< 0.6 log units), but protection was dramatically increased (to > or = 2.3 log units) with sera obtained 1 week later that had slightly increased IgG antibodies. Monoclonal IgM antibodies also provided better protection against 2308 than 19, while monoclonal IgG3 antibodies protected much better against 19. Strain 19 opsonized with antibodies taken at any stage of infection was killed within normal macrophages, whereas comparably opsonized 2308 underwent intracellular replication. Phagocytosis of 2308 was better than of 19 when brucellae were opsonized with either polyclonal IgM or IgG3 antibodies, and the difference between strains was more extreme following IgM opsonization. The data suggest an explanation for differences in the growth curves of 2308 and 19 in spleens of BALB/c mice. Higher numbers achieved by 19 at week 2 could result from extracellular replication owing to ineffectual opsonization by IgM antibodies, while the precipitous decline of 19 beginning at week 3 could be caused by the increase in more effective IgG3 opsonins that facilitate its rapid intracellular destruction.

Animals↗
PubMed1993

The incidence and mechanism of hypotension following thrombolytic therapy for acute myocardial infarction with streptokinase-containing agents--lack of relationship to pretreatment streptokinase resistance.

The incidence, amplitude, mechanism and relationship to prior exposure to streptococcal antigen of blood pressure changes to streptokinase-containing thrombolytic agents were investigated in 125 patients treated with either 1.5 x 10(6) IU streptokinase over 60 min or 30 U anistreplase over 5 min, within 6 h of onset of acute myocardial infarction. Twenty-one of 52 patients with anterior and 34 of 73 with inferior myocardial infarction had a hypotensive response. There were no significant differences in the incidence, duration or amplitude of hypotension between the two treatment groups. The maximum mean fall in systolic blood pressure was 16.9 mmHg (95% confidence limits, CL 12.2 to 24.5 mmHg), and the maximum mean fall in diastolic blood pressure was 13.7 mmHg (CL 10.3 to 17.1 mmHg), starting 4 min after start of therapy and resolving within 34 min. Blood pressure changes were well tolerated. Hypotension was not related to pretreatment streptokinase resistance titre, or anti-SK IgG concentration, to changes in plasma fibrinogen, B-beta 15-42 peptide, D-dimer--as indices of thrombin activation and fibrin (-ogen) breakdown--to plasma viscosity. The blood pressure changes following treatment with streptokinase-containing thrombolytic agents in acute myocardial infarction are frequent but well tolerated. The mechanism of hypotension remains unclear, but is not related to prior exposure to streptococcal antigen.

Anistreplase↗