Association of polymorphisms in the paraoxonase 1 gene with breast cancer incidence in the CPS-II Nutrition Cohort.

Paraoxonase 1 (PON1) plays an important role in the high-density lipoprotein-mediated prevention of low-density lipoprotein oxidation and the metabolism of lipid-soluble radicals. In this study, we investigated the association of two common, nonsynonymous polymorphisms in the PON1 gene (Q192R and L55M) with breast cancer risk in postmenopausal women through a nested case-control study within the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Using conditional logistic regression of genotyping results from 502 cases and 502 cancer-free controls matched on age, race/ethnicity, and date of blood draw, we found that the L55M single nucleotide polymorphism (SNP) was associated with an increased risk of breast cancer [odds ratio (OR), 1.58; 95% confidence interval (95% CI), 1.05-2.37 for MM]. No association was found for the Q192R SNP. The L55M association with breast cancer was modified by nonsteroidal anti-inflammatory drug (NSAID) use. The association was limited to women who took NSAIDs and was somewhat stronger among women who reported regular (> or = 15 times per month) NSAID use (OR, 3.24; 95% CI, 1.17-9.00) than in those who reported any NSAID use (OR, 2.46; 95% CI, 1.39-4.36). These results suggest that genetic variation in PON1, particularly at the L55M SNP, may be associated with increased risk of breast cancer in postmenopausal women. Furthermore, NSAID use seems to modify this risk.     

Evaluation of treatment efficacy of Raynaud phenomenon by digital blood pressure response to cooling. Raynaud's Treatment Study Investigators

Our previous studies have suggested that digital blood pressure response to cooling could provide a measure of the efficacy of treatments that are administered to patients with Raynaud phenomenon (RP). This method was used on 158 primary RP patients participating in a multicenter, randomized clinical trial that compared the efficacy of sustained-release nifedipine with temperature biofeedback in the treatment of RP. A pill placebo and electromyography served as controls. The response to local finger cooling was measured at 30 degrees, 20 degrees, 15 degrees and 10 degrees C in a temperature-controlled room under standardized conditions. The results showed that, at the 15 degrees C and 10 degrees C local cooling temperatures, the patients in the nifedipine group had a higher mean digital systolic blood pressure, a higher relative digital systolic blood pressure (RDSP), a smaller proportion of subjects with RDSP < 70% and a smaller proportion of subjects with a zero reopening pressure than the patients in the three other treatment groups. These results were statistically significant at 10 degrees C, the nifedipine group being significantly different from all others (p < 0.05); no significant difference was found between the three other treatment groups.     

The contraceptive potential of ZP3 and ZP3 peptides in a primate model.

It has been known for some time that antibodies raised against ZP3, the major component of the glycoprotein shell that surrounds all mammalian oocytes, can successfully inhibit sperm-egg interaction in vitro. In our own studies using the non-human primate Callithrix jacchus, active immunisation was successfully achieved when homologous or heterologous ZP3 was used as an immunogen. However this long-term suppression of fertility was at the expense of ovarian function. An ovarian pathology was observed which was characterised by a disruption of folliculogenesis and depletion of the primordial follicle pool. Adverse auto-immune reactions have also been observed in mice following induction of immunity to mouse ZP3. Following careful selection of B-cell epitopes on mouse ZP3, peptide vaccines were formulated which could circumvent these adverse side effects and induce reversible infertility in actively immunised mice. To identify similar epitopes on primate ZP3, epitope mapping studies were performed and several candidate regions of the molecule were identified. These were incorporated into chimeric peptide vaccines and administered as single or triple peptide vaccines. Active immunisation successfully induced antibodies that bound exclusively to the zona pellucida of marmoset and human ovarian sections. These antibodies were able to suppress human sperm-egg binding by up to 60% in vitro. Encouragingly, no adverse side effects on ovarian function were observed following long-term immunisation however, no loss of fertility was consistently observed in vivo. Thus considerable research is still required to identify a combination of ZP epitopes that will induce reversible infertility in the absence of any ovarian dysfunction.     

Establishment and characterization of acquired resistance to the farnesyl protein transferase inhibitor R115777 in a human colon cancer cell line.

R115777 (Zarnestra) is a farnesyl protein transferase inhibitor currently undergoing worldwide clinical trials. As acquired drug resistance may limit the efficacy of the drug, a model of acquired resistance has been established in vitro by continuous drug exposure of the human colon cancer cell line KM12. A stably resistant cell line possessing 13-fold resistance to R115777 was generated. The resistant cells showed cross-resistance to another, structurally different farnesyl transferase inhibitor-277, but not to GGTI-298. A lack of cross-resistance was observed to a variety of other agents, which included clinically used drugs, such as doxorubicin, etoposide, cisplatin, and paclitaxel, as well as signal transduction blockers, such as the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor UO126, the phosphatidylinositol 3'-kinase inhibitor LY294002, and the epidermal growth factor receptor tyrosine kinase inhibitor PD153035. Resistance did not appear to be related to differences in drug efflux pumps, such as P-glycoprotein or in drug accumulation. Total levels of farnesyl transferase protein subunits were similar in the parent and resistant cells, but, notably, the enzyme activity was markedly reduced in the resistant cell line compared with the parent cells. This was not because of a mutation in the enzyme or a difference in activation of the alpha-subunit of farnesyl transferase by phosphorylation. Hence, resistance to R115777 was generated; the mechanism of resistance in this model may be associated with the enzyme target of the inhibitor. The results suggest that the development of clinical resistance may occur with farnesyl protein transferase inhibitors.     

Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics.

PURPOSE: Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.     

Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non-small-cell lung cancer.

PURPOSE: Preclinical studies suggested that the antiangiogenic agent TNP-470 was synergistic with cytotoxic therapy. TNP-470 was administered with paclitaxel to adults with solid tumors to define the safety and optimal dose of the combination regimen and to assess pharmacokinetic interactions. PATIENTS AND METHODS: Thirty-two patients were enrolled chronologically onto one of two treatment arms. Arm A involved a fixed TNP-470 dose with escalating doses of paclitaxel, and Arm B involved a fixed paclitaxel dose with escalating doses of TNP-470. Paclitaxel and TNP-470 pharmacokinetics were evaluated along with toxicity. RESULTS: The combination of TNP-470 administered at 60 mg/m(2) three times per week and paclitaxel 225 mg/m(2) administered over 3 hours every 3 weeks was defined as both the maximum-tolerated dose and the optimal dose. Myelosuppression was similar to that expected with paclitaxel alone. Mild to moderate neurocognitive impairment was observed; however, the majority of changes were subclinical and reversible as determined by prestudy and poststudy neuropsychiatric test results. A clinically insignificant decrease of paclitaxel clearance was observed for the combination. Median survival for all patients was 14.1 months. Partial responses were reported in eight (25%) of 32 patients and in six (38%) of 16 patients with NSCLC, 60% of whom had received prior chemotherapy. CONCLUSION: The combination of TNP-470 and paclitaxel, each at full single-agent dose, seems well tolerated, with minimal pharmacokinetic interaction between the two agents. Further studies of TNP-470 with chemotherapy regimens are warranted in NSCLC and other solid tumors.     

Computed tomography fluoroscopy‐guided chemical lumbar sympathectomy: Simple,safe and effective

Demographic, clinical and laboratory data were retrospectively collected from records of 146 cases of CT fluoroscopy‐guided chemical lumbar sympathectomy for the palliation of inoperable peripheral vascular disease (PVD) between January 1997 and August 1999. Of these, 16% had claudication, 39% had rest pain and 44% had ischaemic ulcers or gangrene. Seventy‐three percent of elective cases were outpatients. At 3 months, 27 cases were lost to follow up, leaving 119 cases. Within 3 months, improvement, defined as doubling of the walking distance, cessation of rest pain or healing of ulcers, occurred in 30.3% of cases. No change was observed in 45.4% of cases and 24.3% of cases deteriorated. Patients with ulcers or gangrene had significantly poorer results than those without any ischaemic lesions, as only 19% versus 39% of patients improved (P < 0.05). The presence of hypertension, diabetes mellitus, hyperlipidaemia and smoking had no value in predicting clinical outcome (P > 0.05). There were no major complications noted. CT fluoroscopy‐guided chemical lumbar sympathectomy is safe and effective, with a complication rate of less than 1%, and efficacy of at least 30% measured within 3 months. It is a simple and minimally invasive procedure, easily performed on an outpatient basis. CT fluoroscopy‐guided chemical lumbar sympathectomy should be considered for all patients in the early stages of inoperable PVD.     

Comparison of ketamine and morphine for analgesia after tonsillectomy in children

In a double blind study we compared the effects of i.m. ketaminewith morphine on postoperative analgesia in children undergoingtonsillectomy. Eighty children (aged 6–15 yr) were randomizedto receive either i.m. morphine 0.1–0.15 mg kg^–1or ketamine 0.5–0.6 mg kg^–1, after induction ofa standard general anaesthetic. Pain scores 30 min after extubationwere higher (P<0.05) in the ketamine group, but were similarthereafter to the morphine group. Mean () times to recovery from anaesthesia were 20.1 ( 6.5) min in the ketamine group compared to 14.2 (5.6) min inthe morphine group (P<0.01). There were no differences insupplemental analgesia requirements, or the incidence of vomitingor dreaming between the groups. We conclude that ketamine 0.5mg kg^–1 i.m. may be an alternative analgesic for childrenundergoing tonsillectomy.