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     

Prevalence of Chlamydia trachomatis and Mycoplasma pneumoniae in children with and without pharyngitis

The prevalence of Chlamydia trachomatis, Mycoplasma pneumoniae, group A beta-hemolytic streptococcus, and other treatable organisms was studied in children with and without pharyngitis. Children aged 2 to 12 years were evaluated between November 1985 and April 1986 in three family practice offices in the Salt Lake City area. Chlamydia trachomatis was not detected in the pharynx of any of the children studied. Mycoplasma pneumoniae was cultured from 5 percent of the 242 children studied, group A beta-hemolytic streptococcus from 30 percent, non-group A beta-hemolytic streptococcus from 5 percent, Hemophilus influenzae from 4 percent, and Staphylococcus aureus from 14 percent. The symptoms reported were not statistically associated with any organism isolated, and clinical signs of pharyngitis were associated only with the presence of group A beta-hemolytic streptococcus. Based on these results, management of pharyngitis in children should continue to be based on the detection and treatment of group A beta-hemolytic streptococcus.     

Protein components specifically associated with prespliceosome and spliceosome complexes.

We have carried out a systematic analysis of the protein composition of highly purified mammalian spliceosomes. We show that > 30 distinct proteins, including 20 previously unidentified components [designated spliceosome-associated proteins (SAPs)], are specifically associated with the spliceosome in a salt-resistant complex. In contrast to these spliceosome-specific proteins, we show that hnRNP proteins are not tightly associated with purified prespliceosome and spliceosome complexes. The splicing factor U2AF65, U1 snRNP-specific proteins, and several SAPs are present in the earliest prespliceosome complex (E). A set of 10 proteins is then added to the first ATP-dependent prespliceosome complex (A), and concomitantly, a significant decrease in the level of U2AF65 is observed. The fully assembled spliceosome is formed by the addition of 12 proteins in a reaction that requires ATP and both the 5' and 3' splice sites.     

Role of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver

Studies were carried out to investigate the metabolism of senecionine by human liver microsomes and the role of human cytochrome P450IIIA4 in this process. Human liver microsomes metabolized senecionine to two major products, (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) and senecionine N-oxide. The rates of product formation (DHP and senecionine N-oxide) varied widely with the microsomal samples tested. There was a 30-fold difference in DHP formation and a 25-fold difference in N-oxidation between the poorest metabolizer and the highest metabolizer of senecionine. The conversion of senecionine to DHP and senecionine N-oxide in human liver microsomes was markedly inhibited by the mechanism-based inactivators of P450IIIA4, gestodene and triacetyloleandomycin. Anti-P450IIIA4 IgG, at a concentration of 1 mg/nmol of P450, was found to inhibit completely the formation of DHP and senecionine N-oxide in human liver microsomes (HL101) having low activity toward senecionine. At 5 mg IgG/nmol P450, anti-P450IIIA4 inhibited 90 and 84% respectively of the formation of DHP and senecionine N-oxide in liver microsomes (HL110) with the highest activity toward senecionine. The formation of DHP or senecionine N-oxide was highly correlated with the amount of P450IIIA4 measured in the microsomes using polyclonal anti-P450IIIA4 IgG. The rate of DHP production also had a strong correlation with the rate of senecionine N-oxide formation (r = 0.999) and with the rate of nifedipine oxidation (r = 0.998). Our present studies provide evidence that P450IIIA4 is the major enzyme catalyzing the bioactivation (DHP formation) and detoxication (senecionine N-oxide formation) of senecionine in human liver.     

Leukopenia, neutropenia, and reduced hemoglobin levels in healthy American blacks

Hematologic profiles of 462 persons, mostly active-duty service members, were studied to determine whether hematologic differences between blacks and whites exist in a healthy population. Whites had significantly greater mean concentrations of leukocytes (6.73 vs 5.95 x 10(9)/L), neutrophils (3.96 vs 3.16 x 10(9)/L), and hemoglobin (153 vs 135 g/L for men, 147 vs 125 g/L for women). The mean differences were largely due to relatively symmetric shifts in the frequency distributions for these cell concentrations. No significant correlation was found between neutrophil count and morbidity from infection as measured by a standardized questionnaire. The use of separate hematologic reference values for blacks and whites should be considered.     

Compound (primordial) adnexal carcinoma arising in a systematized compound epithelial nevus.

A distinctive systematized epithelial nevus and associated multifocal carcinomas of the microcystic and sclerosing sweat duct type affected the lower extremities of a 9-year-old girl. The carcinomas were well differentiated and were both adenosyringomatous and microcystic. They qualify as microcystic and compound. In both the epithelial nevi and the carcinoma, primordial potentials are recapitulated.     

Sensory blockade for difficult passage of transesophageal echocardiography probes.

During transesophageal echocardiography probe passage, airway reflexes are usually obtunded with topical local anesthetics. This technique meets with varying degrees of success. Even partially intact airway reflexes result in coughing, retching, and withdrawal, which may prevent transesophageal echocardiography examination or predispose to life-threatening tachycardia and hypertension. Proper preparation of the patient enhances comfort and helps protect against tachycardia and hypertension as well as reducing the time required for examination. This article outlines specific monitoring issues and offers precautions that are critical to transesophageal echocardiography probe passage. It suggests a premedication regimen and describes methods of sedation. Furthermore, it outlines the afferent innervation of the upper airway and specific techniques of temporary reflex interruption.     

A Bayesian approach to aid in formulary decision making: incorporating institution-specific cost-effectiveness data with clinical trial results.

Pharmacy and therapeutics committees commonly cite a lack of generalizability as a reason for not incorporating cost-effectiveness information into decision making. To address this concern, many committees undertake site-specific economic evaluations, which are often limited by small sample sizes and nonrandomized designs. We show how 2 complementary approaches were used to minimize these limitations in an economic evaluation of abciximab at 1 institution. Using a propensity score methodology, we selected patients who did not receive abciximab for the comparison cohort. Then, we adopted a Bayesian, hierarchical, random-effects model to integrate site-specific and clinical trial data. We applied the posterior distributions of effectiveness with local cost data in a traditional decision-analytic model. In 74% of the simulations, abciximab was cost-effective at 1 institution at the $50,000 per life year saved threshold, assuming a 50:50 split of patients undergoing coronary stenting and angioplasty. Among patients undergoing coronary stenting, the cost-effectiveness ratio of the addition of abciximab was at or below the $50,000 per life year saved threshold in 66.0% of the simulations.