Intermittent mydriasis associated with carotid vascular occlusion.

PurposeTo describe two cases of stereotyped, intermittent, neurologically isolated, unilateral mydriasis in patients with a history of acquired internal carotid artery (ICA) occlusive disease on the ipsilateral side.PatientsTwo patients with intermittent mydriasis.MethodsCase Series.ResultsCase one: A 78-year-old man experienced 10 episodes of intermittent, unilateral, and painless mydriasis in the left eye and had 100% occlusion of the left ICA artery due to atherosclerotic disease. Case two: A 26-year-old woman with history of migraine developed new painless, intermittent episodes of unilateral mydriasis after sustaining chest trauma and was diagnosed with subsequent dissection and 65% occlusion of the ipsilateral ICA. Neither patient developed permanent anisocoria.ConclusionBenign episodic unilateral mydriasis (BEUM) typically presents in young women with a history of migraine. To our knowledge, these are the first cases of episodic, unilateral, neurologically isolated mydriasis associated with occlusive disease of the ICA in the English language ophthalmic literature. We hypothesize that transient dysfunction of the autonomic nervous system related to the ICA disease may account for the intermittent mydriatic episodes in these patients and we recommend consideration for imaging of the ICA in patients with atypical features for BEUM (for example, old age or males, non-isolated mydriasis, or recent trauma).

The tissue distribution of the human beta3-adrenoceptor studied using a monoclonal antibody: direct evidence of the beta3-adrenoceptor in human adipose tissue, atrium and skeletal muscle.

OBJECTIVE: To develop a monoclonal antibody that recognises an epitope of the native beta3-adrenoceptor expressed on the extracellular surface of human cells and tissues. DESIGN: A high affinity monoclonal antibody, Mab72c, was raised against the human beta3-adrenoceptor expressed on a transfected mammalian cell line. RESULTS: In CHO (Chinese hamster ovary) cells transfected with beta3-adrenoceptor cDNA, antibody labelling was found to be proportional to receptor density measured by the binding of the radiolabelled beta-adrenoceptor antagonist, [125I]-iodocyanopindolol. The use of Mab 72c has demonstrated the expression of the beta3-adrenoceptor in a variety of human tissues, including gall bladder, prostate and colon, where a mRNA signal had been detected previously. This study also provides the first direct demonstration of the expression of beta3-adrenoceptors in human skeletal muscle, atrium and adipose tissue. CONCLUSION: The development of this antibody represents an important addition to the armentarium of reagents that are available to study the localisation of beta3-adrenoceptors in human tissues.

A recombinant, chimeric enzyme with a novel mechanism of action leading to greater potency and selectivity than tissue-type plasminogen activator.

BACKGROUND: Early intervention with thrombolytic agents has been shown unequivocally to reduce mortality after acute myocardial infarction. Presently used agents have disadvantages such as short half-life, immunogenicity, hypotension, and bleeding complications. Therefore, there is a need to develop improved thrombolytic drugs with novel mechanisms of action leading to improved properties. METHODS AND RESULTS: Hybrid plasminogen/tissue-type plasminogen activator (t-PA) complementary DNA was constructed and expressed in Chinese hamster ovary cells. The chimeric protein, comprising the fibrin-binding domains of plasminogen covalently linked to the catalytic domain of t-PA, was purified and evaluated in vitro and in vivo. The hybrid was inhibited rapidly in human and animal plasmas. The mediator of this rapid inhibition was shown to be alpha 2-antiplasmin. The active center of the hybrid could be protected by reversible active center acylation with a novel inverse acylating agent, 4'-amidinophenyl-4-chloroanthranilic acid (AP-CLAN). An acylated (CLAN-) hybrid was cleared from the bloodstream of guinea pigs at 0.35 +/- 0.02 ml/min.kg-1 compared with a clearance rate of 36 +/- 4 ml/min.kg-1 for t-PA. The CLAN-plasminogen/t-PA hybrid was evaluated in a quantitative, "humanized" guinea pig pulmonary embolism model and shown to be approximately threefold more potent when given by bolus than an infusion of t-PA. Furthermore, the acylated hybrid was more fibrin selective than t-PA as determined by the relation between clot lysis and fibrinogen degradation. CONCLUSIONS: An acylated, recombinant plasminogen/t-PA hybrid has sufficiently slow clearance to be administered by bolus and is more potent and fibrin selective than t-PA in vivo.

Effect of temocillin and moxalactam on platelet responsiveness and bleeding time in normal volunteers.

The effects of temocillin and moxalactam on platelet responsiveness and bleeding time were examined in healthy male volunteers. In the first study, moxalactam (4 g intravenously every 12 h) was given to six subjects; template bleeding times were at least doubled in five subjects 12 to 14 h after 7 doses (P = 0.008) and in all six subjects 12 to 14 h after 13 doses (P = 0.004). ADP-induced primary aggregation was approximately halved after 7 (P = 0.026) and 13 doses (P = 0.008), and there was a markedly increased tendency toward disaggregation. Collagen-induced aggregation was also halved, but the effect only reached statistical significance after 13 doses (P = 0.008). There was essentially no effect on primary aggregation in response to the thromboxane receptor agonist U46619 or to platelet activating factor. Temocillin (4 g intravenously every 12 h) was given to eight subjects, three of whom had participated in the moxalactam study 8 weeks earlier. Temocillin had no significant effect on template bleeding time 12 to 14 h after 7 or 13 doses. However, in four subjects, the endpoint may have been less abrupt. There was no significant effect on ADP-induced primary aggregation or responsiveness to collagen. Even after 13 doses of temocillin, secondary aggregation in response to normal concentrations of ADP was demonstrable in the platelet-rich plasma of all eight subjects. Neither antibiotic had any effect on prothrombin times. Thus, with methodology that readily detected the effects of moxalactam on hemostasis, we were unable to demonstrate any unequivocal deleterious effects of temocillin at its maximum recommended dose. Temocillin may therefore be particularly useful for the treatment of many gram-negative infections in patients at increased risk of clinical bleeding.

Further evidence against the validity of using an ADP-removing enzyme system (CP/CPK) for demonstrating the role of secreted ADP in platelet activation.

The ADP-removing enzyme system creatine phosphate-creatine phosphokinase (CP/CPK) selectively inhibited primary aggregation in response to the thromboxane receptor agonist, U46619, in mouse aspirin-treated platelet-rich plasma. Inhibition by CP/CPK has become accepted as evidence for mediation by secreted ADP, yet primary aggregation is not usually attributed to secreted ADP. Hence these results throw doubt on the assumed mechanism by which CP/CPK inhibits aggregation. The possibility that such inhibition was due to removal of extracellular ADP released prior to platelet stimulation and exerting a potentiating influence was investigated. Ths explanation appeared unlikely as further additions of creatine phosphokinase to platelet-rich plasma preincubated with CP/CPK caused further inhibition of primary aggregation. Moreover, low concentrations of CP/CPK that reduced responsiveness to U46619 had no effect on collagen-induced aggregation, which ADP is known to potentiate. The evidence presented is consistent with CP/CPK exerting a direct inhibitory effect on platelet membranes and so inhibiting a facet of platelet aggregation not mediated by secreted ADP. These data support the conclusion of a previous study (Huang, E.M. and Detwiler, T.C., J. Lab. Clin. Med.,95, 59-68, 1980) that inhibition by CP/CPK cannot be taken as evidence for the involvement of secreted ADP.

Effect of nabumetone (BRL 14777), a new anti-inflammatory drug, on human platelet reactivity ex vivo: comparison with naproxen.

The effect of nabumetone (BRL 14777) on human platelet reactivity ex vivo was compared with that of naproxen at equitherapeutic doses in the same six subjects. Nabumetone had only a weak and equivocal effect on collagen-induced and second phase aggregation in response to adenosine diphosphate and adrenaline. After nabumetone, platelets fully aggregated in response to sodium arachidonate, though approximately twice as much was needed as on control occasions. Sodium arachidonate was unable to elicit a full aggregation response after naproxen. These results suggest that nabumetone may cause less interference with haemostasis than other non-steroidal anti-inflammatory drugs.