A phase I/II study of continuous infusion suramin in patients with hormone-refractory prostate cancer : toxicity and response

 Introduction: Suramin is a synthetic polysulfonated naphthylurea which has been used for the treatment of African trypanosomiasis and onchocerciasis, but since the mid-1980s has received attention as a possible antiretroviral and antineoplastic agent. Objective: This clinical trial of suramin was undertaken as a phase I/II study in patients with hormone-refractory prostate cancer, with the hypothesis that the intensity of therapy with suramin could be increased significantly if measures were undertaken to maintain the plasma concentrations of the drug under 300 μg/ml. Methods: We report the clinical results of this trial, wherein patients were treated at three different targeted plasma suramin concentrations (275, 215 and 175 μg/ml) for varying periods of time (2, 4 or 8 weeks), with delivery of the drug by continuous intravenous infusion. Results: The major toxicity observed in this trial was neurologic, consisting of a motor and sensory peripheral neuropathy that resulted in both paresis and paralysis of the limbs. Nearly all of this severe (CTEP grade III, IV) neurologic toxicity was observed in the patients treated at a plasma suramin concentration of 275 μg/ml for 4 or more weeks. A single patient treated at 215 μg/ml for 8 weeks developed moderate (CTEP grade III) proximal lower extremity weakness, and no patient treated at 175 μg/ml developed this toxicity. The second most common toxicity observed was infection of the central venous catheter. The overall response rate for all of the evaluable patients was 17% (13 of 75 patients). In addition, prostate-specific antigen (PSA)-defined responses were observed in six patients receiving therapy at 175 μg/ml, but these responses were confounded by cessation of therapy with flutamide during suramin treatment. Conclusions: In summary, although plasma suramin concentrations were maintained below 300 μg/ml, neurologic toxicity nonetheless occurred with high frequency in patients treated at 275 μg/ml for 4 or more weeks. Therapy at 215 and 175 μg/ml was in general well tolerated, but central venous catheter-related infection, as well as the inconvenience and expense of continuous infusional therapy, make this method of drug delivery impractical. Only moderate antitumor activity was observed during this trial, but it is possible that both continuation of flutamide and flutamide withdrawal during suramin therapy confounded the assessment of suramin’s activity in hormone-refractory prostate cancer. Received: 9 June 1995/Accepted: 18 March 1996     

Association analysis of genes in the renin‐angiotensin system with subclinical cardiovascular disease in families with Type 2 diabetes mellitus: The Diabetes Heart Study

Aims Cardiovascular disease (CVD) is a major complication of Type 2 diabetes mellitus. The renin‐angiotensin system (RAS) and nitric oxide production are both important regulators of vascular function and blood pressure. Genes encoding proteins involved in these pathways are candidates for a contribution to CVD in diabetic patients. We have investigated variants of the angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin type 1 receptor (AT1R) and endothelial nitric oxide synthase (NOS3) genes for association with subclinical measures of CVD in families with Type 2 diabetes mellitus (T2DM). Methods Atherosclerosis was measured by carotid intima‐media thickness and calcification of the carotid and coronary arteries in 620 European Americans and 117 African Americans in the Diabetes Heart Study. Because of the role of these systems in blood pressure regulation, blood pressure was also investigated. Results Compelling evidence of association was not detected with any of the SNPs with any outcome measures after adjustments for covariates despite sufficient power to detect relatively small differences in traits for specific genotype combinations. Conclusions Genetic variation of the RAS and NOS3 genes do not appear to strongly influence subclinical cardiovascular disease or blood pressure in this diabetic population.     

Vasoactive intestinal peptide and neuropeptide Y coexist in non-noradrenergic sympathetic neurons to guinea pig trachea.

Vasoactive intestinal peptide (VIP) has been suggested to be a mediator of vagal inhibition of airway tone and it has been assumed that VIP-containing nerve fibres in the airway arise from intrinsic ganglia. We have used a combination of double- and triple-labelling immunohistochemistry, retrograde axonal tracing, organotypic culture and nerve lesion studies, to identify the origin and distribution of neurons containing immunoreactivity (IR) to VIP in guinea pig airway smooth muscle. We also investigated whether immunoreactivity to other neuropeptides coexisted with VIP-IR within these neurons. We found that all VIP-IR nerve fibres in guinea pig tracheal smooth muscle also contained IR to neuropeptide Y (NPY) but not to tyrosine hydroxylase (TH), a marker for noradrenergic neurons. Both VIP-IR and NPY-IR were absent from nerve cell bodies in the tracheal plexus. After maintenance of isolated trachea in organotypic culture for 4 days, to allow degeneration of extrinsic nerve fibres, nerve fibres containing VIP-IR or NPY-IR were almost completely absent from tracheal smooth muscle. Of ganglia known to supply the trachea, coexistence of VIP-IR and NPY-IR was found only in cell bodies of the stellate ganglion. Retrograde tracing studies using the fluorescent tracer, DiI, confirmed that the stellate ganglion was the site of origin of neurons containing VIP-IR and NPY-IR supplying the airways. These neurons projected to the airways from the stellate ganglion both directly through the mediastinum, and via the cervical sympathetic trunk and vagus nerves. These results suggest that nerve fibres containing both VIP-IR and NPY-IR in the tracheal smooth muscle of the guinea pig are derived from non-noradrenergic cell bodies in the stellate ganglion. The absence of VIP-IR from vagal post-ganglionic neurons suggests that VIP cannot be a mediator of vagal inhibitory transmission in tracheal smooth muscle of this species.     

Peribursal fat plane of the shoulder: anatomic study and clinical experience

A comprehensive anatomic and radiographic analysis of the peribursal fat plane in 12 cadavers confirmed that the fat plane seen on radiographs represents extrasynovial fat lining the subacromial bursa and documented the anatomic relations of the bursa. A three-part retrospective clinical evaluation of rotator cuff tears, calcific tendinitis, and rheumatoid arthritis was performed. Two osteoradiologists blindly graded the appearance of the peribursal fat plane with the shoulder in external versus internal rotation in 21 patients with arthrographically intact rotator cuffs and 21 patients with disrupted rotator cuffs. The peribursal fat plane was seen better with disrupted rotator cuffs. The peribursal fat plane was seen better with the shoulder in internal rotation and was seen in 60% of control subjects but only 21% of patients with rotator cuff tears. Partial or complete obliteration of this fat plane is a sensitive (79%) but less specific (60%) indicator of rotator cuff tears. Obliteration of the peribursal fat plane by inflammatory processes in adjacent tissues, including calcific tendinitis and rheumatoid arthritis, occurred with a high frequency.     

Hormone replacement therapy is associated with increased C-reactive protein in women with Type 2 diabetes in the Diabetes Heart Study.

AIMS: Increased levels of inflammatory biomarkers, especially C-reactive protein (CRP), are associated with increased risk for cardiovascular disease (CVD) events, such as myocardial infarction, stroke, peripheral vascular disease, and sudden cardiac death. Medical interventions that increase CRP levels, such as hormone replacement therapy (HRT) in post-menopausal women, are under increasing scrutiny. The effect of HRT on CRP levels in women with Type 2 diabetes (T2DM) is not well documented, and conflicting conclusions have been reported. The aim of this study was to determine the influence of HRT on women with diabetes in a large cross-sectional study. METHODS: Three hundred and twenty-seven post-menopausal women with T2DM from the Diabetes Heart Study participated. Current use of HRT was determined and serum CRP levels were measured using a high-sensitivity ELISA kit. Generalized estimating equation methods were used to assess the relationship of multiple clinical and lifestyle (e.g. smoking) measures on CRP levels including differences between women taking HRT (HRT+) and not taking HRT (HRT-). RESULTS: Overall serum CRP levels were strongly associated with body mass index (P < 0.0001) and age (P < 0.0001). Of the women, 243 were not using HRT and 84 were using HRT. HRT+ and HRT- women did not differ significantly in measures of clinical traits, with the exception of higher mean low-density lipoprotein cholesterol in HRT- women (P = 0.004). In all models tested, HRT+ women had significantly higher circulating CRP levels, with P-values ranging from 0.0045 to 0.010. CONCLUSIONS: In this study of serum CRP concentration as a function of HRT in women with Type 2 diabetes, there was consistent evidence for increased circulating CRP levels in women receiving oestrogen-containing HRT. Whether HRT-induced increases in CRP can account for the adverse cardiovascular effects of HRT remains to be established; however, based on these data, there is little reason to believe that diabetic women would be spared from such an effect.     

Effect upon the EEG of acute injury to the brain stem activating system

The effect upon the EEG in the unanesthetized "ecéphale isolé" of acute brain stem lesions in a position to involve the ascending reticular activating system has been studied. Elimination of the bulbar segment was without marked effect. Some synchronization followed elimination of the pons, but the most pronounced and prolonged changes occurred as a result of mesencephalic transection, or of discrete injury to the midbrain tegmentum or basal diencephalon, following which the EEG activation pattern of low voltage fast activity was reduced or abolished and the cortical record became dominated by recurring bursts or spindles of high voltage slow waves like those of normal sleep or barbiturate anesthesia. Bursts could be recorded from the intralaminar and other nuclei of the thalamus and these thalamic bursts were abolished by acute decortication. Conversely, cortical bursts were abolished by acute thalamic lesions. Possible interrelations of these regions in this activity is discussed. These results offer an explanation for the clinical observation of somnolence following basal injury to the brain, and suggest that a maintained influence of the ascending brain stem activating system underlies wakefulness, while absence of this influence precipitates sleep.