Fibrinolytic and coagulant responses to regional limb perfusions of tumor necrosis factor, interferon-gamma, and/or melphalan.

Regional limb perfusion with antineoplastic agents stresses the local vasculature in a variety of ways. However, by monitoring the perfusates from limbs treated with melphalan alone or with melphalan plus tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma), we were able to distinguish the effect of the cytokines on the observed coagulant and fibrinolytic responses. We collected samples of effluent from a series of lower extremities that were perfused with the cytokines and/or melphalan as treatment for localized melanoma. Both regimens produced statistically significant evidence of coagulant and fibrinolytic activation. However, limbs receiving cytokines in addition to the melphalan responded with a sharper rise in tissue plasminogen activator (tPA) and plasmin (plasmin-antiplasmin complexes [PAP]) than limbs treated with melphalan alone. Evidence of thrombin formation (prothrombin fragment 1 + 2 [F1 + 2], thrombin-antithrombin complexes [TAT]) was also greater when the cytokines were included, although the response was delayed and less consistent than the fibrinolytic activation.

Endogenous D-factor activity partially mediates the toxic but not the therapeutic effects of tumor necrosis factor.

We have earlier shown that passive immunization against differentiation-inducing factor/leukemia-inhibitory factor (D factor) activity improves the survival of endotoxemic mice, suggesting that D factor may contribute to the systemic toxicity associated with tumor necrosis factor (TNF). In the current experiments, TNF induced D-factor gene expression in various tissues of non-tumor-bearing female C57BI/6 mice. Passive immunization against D-factor significantly improved survival after a lethal TNF challenge in both non-tumor-bearing (p2 < 0.02) and tumor-bearing mice (p2 < 0.01). In mice bearing 10-day s.c. MCA 105 sarcomas, D-factor antibody alone had no effect on tumor growth as compared with control IgG. Tumor regression and regrowth in mice treated i.v. with TNF was not affected by pre-treatment with D-factor antibody, as compared with pre-treatment with IgG. However, TNF-treatment-related mortality was abrogated by pre-treatment with D-factor antibody (0% vs. 36% for IgG-pre-treated controls). These results indicate that endogenous D-factor activity contributes to the toxicity but not to the anti-tumor effects of TNF therapy. With renewed interest in the use of TNF for the treatment of patients with cancer, improved understanding of the role of D factor in mediating the effects of TNF may have important clinical benefits.

Apparent lymph node primary gastrinoma.

BACKGROUND: The existence of lymph node (LN) primary gastrinoma as a cause of Zollinger-Ellison syndrome is controversial. We reviewed our experience with patients in whom gastrinomas were identified and excised only from LNs. METHODS: From 1982 to 1992, 110 patients with ZES underwent exploration for gastrinoma and 21 (19%) had disease limited to one or more LNs. Standardized exploration included intraoperative ultrasonography, intraoperative endoscopy with transillumination and exploratory duodenotomy in 86%, 67%, and 24% of patients, respectively. Each patient underwent yearly biochemical and radiologic follow-up. RESULTS: Thirteen patients (62%) with a median follow-up period of 5.8 years had an initial biochemical cure, whereas eight patients (38%) with a median follow-up period of 3.6 years had persistent disease. Of the 13 patients whose condition initially returned to normal, four have had biochemical recurrence, with a median time to recurrence of 4.2 years and a median follow-up period of 7.4 years. Nine patients (43%) remain biochemically cured, with a median follow-up period of 5.3 years. CONCLUSIONS: Resection of apparent LN primary gastrinoma is warranted, because 43% of those who underwent resection had no evidence of disease, with a median follow-up period of 5.3 years.

Experience with Vi typhoid capsular polysaccharide vaccine in the U.K.

Adult volunteers were immunised with a single dose of typhoid Vi capsular polysaccharide vaccine. After immunisation, 96% of the 103 subjects seroconverted and 94% had antibody levels above the protective threshold. Systemic reactions were uncommon, local reactions were mild and transient.

Typhoid Vi: a less reactogenic vaccine.

A typhoid vaccine derived from the purified Vi capsular polysaccharide (CPS) antigen of Salmonella typhi was compared with a heat-killed whole-cell typhoid vaccine in 637 healthy male volunteers. The individuals were placed in three groups: group 1 received two doses of heat-killed whole-cell typhoid vaccine, at an interval of 28 days; group 2 received a single dose of typhoid Vi CPS vaccine followed after 28 days by water for injection; and group 3 received water for injection on the first occasion and a single dose of typhoid Vi CPS vaccine 28 days later. Local and systemic adverse reactions were recorded for 5 days following each injection. Subjects receiving the typhoid Vi CPS vaccine complained of fewer local adverse reactions on each of the first 3 days following immunization: on day 1, 18.6% of subjects given typhoid Vi CPS vaccine reported local reactions compared with 59.7% of those receiving heat-killed whole-cell vaccine (P less than 0.001). The percentage of subjects receiving the heat-killed whole-cell vaccine who complained of systemic reactions was more than twice that of subjects receiving the Vi CPS vaccine (7.9% and 3.4%, respectively, on day 1; P less than 0.01).

[Sumatriptan--future development, alternative features and potential new indications]. / Sumatriptan--przyszly rozwój, alternatywne postacie i potencjalne nowe wskazania.

Sumatriptan is a highly selective 5 HT1 receptor subtype agonist. The efficacy and safety profiles of sumatriptan given by tablet or subcutaneous injection have been extensively investigated in the acute treatment of migraine attacks, where it has proved effective and well tolerated. A substantial proportion of patients with an acute attack of migraine suffer from once or more gastrointestinal symptom, including nausea, vomiting and occasionally diarrhoea. The presence of these symptoms may make the oral administration of acute treatments unsatisfactory. Subcutaneous administration is an alternative, but fear or dislike of injections or an inability to self inject makes subcutaneous treatment unacceptable to some patients. Alternative routes of administration are being investigated to overcome these difficulties including intranasal sprays and rectal suppositories. For those patients who experience difficulties swallowing whole tablets, an effervescent tablet is under development. Recent data have demonstrated that sumatriptan offers effective relief of cluster headache attacks, a condition where suffers experience repeated severe headache attacks, of short duration, during a cluster period. Further new indications are being investigated including the treatment of menstrual migraine, paediatric migraine and other headaches.

Influenza vaccine and anticoagulation control in patients receiving warfarin.

The effects of a trivalent split virion influenza vaccine on anticoagulation control were prospectively evaluated in a sample of well-controlled warfarin recipients. Vaccine-induced changes in prothrombin time ratios were not detected during one month of follow-up after immunisation. The results are supported by the findings of other studies conducted in this country and the USA, which have all refuted the conclusions of early reports that suggested a possible interaction between warfarin and influenza vaccine.

D1 dopamine agonist effects assessed in vivo with [14C]-2-deoxyglucose autoradiography.

In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra, the 2-deoxyglucose (2-DG) autoradiographic method of measuring regional cerebral glucose utilization (RCGU) was used to assess the effects of three systemically administered dopamine agonists: bromocriptine, pergolide and (+)-4-propyl-9-hydroxynaphoxazine (PHNO). Pergolide increased RCGU in the substantia nigra pars reticulata (SNr) ipsilateral to the lesion in a dose-dependent manner (0.04 mg/kg, up 52%; 0.4 mg/kg, up 111%), resulting in asymmetric glucose utilization on the dopamine-denervated and intact sides of the brain. Pretreatment with a selective D1 antagonist (SCH 23390, 0.5 mg/kg) blocked completely the RCGU increase elicited by pergolide (0.4 mg/kg) whereas pretreatment with a selective D2 antagonist (eticlopride, 1.0 mg/kg) only mildly attenuated this increase. The effect of drug treatments on RCGU in the entopeduncular nucleus (EP) paralleled that in the SNr. These results demonstrate that the RCGU increase in the EP and SNr after pergolide administration is dependent primarily on D1 receptor stimulation. Administration of bromocriptine and PHNO minimally altered RCGU in the ipsilateral EP and SNr and did not result in significant left/right RCGU asymmetry. Considered in the context of prior studies of selective D1 and D2 agonists, the results suggest that, in this model, the magnitude of the RCGU increase in the EP and SNr elicited by a dopamine agonist, above the modest effects produced by selective D2 stimulation, represents a measure of D1 agonist effect in vivo. The results support a nonselective D1/D2 stimulatory effect of pergolide (0.04-0.4 mg/kg) and a selective D2 action of both bromocriptine and PHNO.

Tuberculin testing: comparison of imotest with Heaf and Mantoux.

Immunisation against tuberculosis is still recommended for secondary school children in the UK. Only children who do not react to tuberculin tests are offered vaccination. We report the results of two studies, carried out to evaluate a new applicator of the disposable Imotest multiple puncture tuberculin test. The results demonstrate that Imotest is well tolerated and compares favourably with the Heaf and Mantoux tests. Imotest detected significantly more tuberculin responders than Heaf.

Mexiletine therapy for ventricular tachycardia.

We have described a patient with sustained ventricular tachycardia that could not be controlled by any of the readily available oral antiarrhythmic agents. Because of the patient's response to intravenous lidocaine, she was treated with mexiletine, which has given excellent results.