Phase I clinical study of LL-D49194α1 with retrospective pharmacokinetic investigations in mice and humans

Summary LL-D491941 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m². One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D491941 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial.     

Mechanism of tolerance development to 2,5-dimethoxy-4-iodoamphetamine in rats: down-regulation of the 5-HT2A, but not 5-HT2C, receptor

  Rationale: Defining the mechanism of tolerance development to hallucinogenic drugs will help to explain their mechanism of action. Objectives: The present study was conducted to determine first, if tolerance develops to the discriminative stimulus (DS) properties of the hallucinogen, 2,5 dimethoxy-4-iodo-amphetamine (DOI) and second, the mechanism mediating tolerance. Methods: Rats were trained to discriminate 0.75 mg/kg DOI from saline on a concurrent VI-30-min schedule of reinforcement with a 15-min time-out for incorrect responses. To evaluate tolerance development, rats were assigned to one of four groups and treated with either chronic saline or chronic DOI. Prior to chronic treatment, two groups were tested for choice behavior following vehicle administration while the remaining two groups were tested following the administration of 0.375 mg/kg DOI. One group from each pre-test condition was injected with either saline or DOI (1 mg/kg) for 8 days. Twenty-four hours after the last chronic injection the pre-test treatments were replicated. Using receptor autoradiography, the density of 5-HT_2A and 5-HT_2C receptors was measured in independent groups of rats that had received identical treatment conditions. Results: Animals receiving chronic DOI showed a 60% decrease in DOI lever responding (from 100% to 40%) when tested on 0.375 mg/kg DOI, while animals receiving chronic saline showed no change in percent choice (100%) on the DOI lever. Significant changes in binding were observed in 5-HT_2A receptors but not 5-HT_2C receptors. The results of tests with antagonists were consistent with the changes in binding. Conclusions: These results suggest that behavioral tolerance to DOI reflects neuroadaptive changes in 5-HT_2A receptors. Received: 17 July 1998 / Final version: 19 January 1999     

Equity and extramarital sexuality

Equity theory has recently been found to be a useful framework for under-standing the effects of imbalances in intimate contractual relationships such as marriage. Equitable couples seem to be happier, more satisfied with their relationship, and more confident that it will last than are their more mismatched, i.e., inequitable, counterparts. Furthermore, inequitable couples predictably act to set things right in their marriage. They either restore actual equity to the relationship or psychologically set their relationship in balance. If neither works, they may leave the field. Extramarital sex may be viewed as an equity restoration mechanism in that (1) it may be used by the deprived partner to achieve actual equity, (2) it may indicate a partner's readiness to leave the relationship because he feels he can do better, or (3) it may represent a desire to achieve equity in an alternative relationship(s) when inequity pervades the primary one. The hypothesis that the inequitable/underbenefited group should be more likely than the equitable group or the inequitable/overbenefited group to have engaged in extramarital sex was tested using data from a large-scale Psychology Todayquestionnaire. The results indicated that men and women in inequitable/under-benefited relationships had more extramarital affairs and began their extramarital activities earlier than did men and women in equitable and inequitable/over-benefited relationships. Alternative explanations of this finding, sex-role demands and length of the relationship, are explored and discarded as untenable. Research supported in part by National Institute of Mental Health Grant MH 26681.     

Human autologous tumor-specific T-cell responses induced by liposomal delivery of a lymphoma antigen.

PURPOSE: The idiotype (Id) of the immunoglobulin on a given B-cell malignancy is a clonal marker that can serve as a tumor-specific antigen. We developed a novel vaccine formulation by incorporating Id protein with liposomal lymphokine that was more potent than a prototype, carrier-conjugated Id protein vaccine in preclinical studies. In the present study, we evaluated the safety and immunogenicity of this vaccine in follicular lymphoma patients. EXPERIMENTAL DESIGN: Ten patients with advanced-stage follicular lymphoma were treated with five doses of this second generation vaccine after chemotherapy-induced clinical remission. All patients were evaluated for cellular and humoral immune responses. RESULTS: Autologous tumor and Id-specific type I cytokine responses were induced by vaccination in 10 and 9 patients, respectively. Antitumor immune responses were mediated by both CD4+ and CD8+ T cells, were human lymphocyte antigen class I and II associated, and persisted 18 months beyond the completion of vaccination. Specific anti-Id antibody responses were detected in four patients. After a median follow-up of 50 months, 6 of the 10 patients remain in continuous first complete remission. CONCLUSIONS: This first clinical report of a liposomal cancer vaccine demonstrates that liposomal delivery is safe, induces sustained tumor-specific CD4+ and CD8+ T-cell responses in lymphoma patients, and may serve as a model for vaccine development against other human cancers and infectious pathogens.     

Smoking among participants in the childhood cancer survivors cohort: the Partnership for Health Study.

PURPOSE: This article describes baseline data collection and the intervention design of Partnership for Health, a smoking cessation intervention for smokers in the Childhood Cancer Survivors Study. The purpose of this article is to evaluate demographic, psychosocial, and cancer-related factors that are associated with smoking behavior and mediators of smoking cessation. PATIENTS AND METHODS: This study includes 796 smokers from the Childhood Cancer Survivors Study database who were diagnosed with cancer before the age of 21, had survived at least 5 years, and were at least 18 years of age at the time of the baseline survey. Correlates of smoking behaviors included smoking rate, number of recent quit attempts, and nicotine dependence; two key mediators of smoking cessation, readiness to quit smoking and self-efficacy, were also assessed. RESULTS: Participants smoked, on average, 14 cigarettes/day; 53.2% were nicotine dependent, and 58% had made at least one quit attempt in the past year. Smoking behaviors were primarily associated with demographic variables; mediators of cessation were primarily associated with age at cancer diagnosis and perceived vulnerability to smoking-related illnesses. Severity of psychologic symptoms was associated with increased smoking rate, high nicotine dependence, and low self-efficacy. Support for quitting was related to smoking rate, number of quit attempts, readiness to quit smoking, and self-efficacy. CONCLUSION: These findings indicate that many cancer survivors who smoke are receptive to smoking cessation interventions. Factors related to mediators of smoking cessation might be particularly good targets for intervention.     

Urogenital ageing and its effect on sexual health in older British women

Objective To provide information on the extent of problems of urogenital ageing in older British women.
Design A MORI survey of a representative population sample of older British women.
Setting Home interviews.
Participants Two thousand and forty-five women aged 55–85+.
Results Urogenital symptoms had affected 48.8% of the women at some time, but no more than 11% were currently affected by individual symptoms; however, these were often of long duration. The majority (73%) were not sexually active, with lack of a partner being a factor for many. There was also a decreasing prevalence of sexual activity with increasing age. Those sexually active in the 65–74 year old age group (   n = 148  ) tended to have a similar sexual frequency (at least once per month) compared with the younger women studied. Approximately 12% of those who reported dyspareunia and/or vaginal dryness claimed a severe problem; 33% did not seek professional advice and 36% resorted to an over the counter remedy. Use of hormone replacement therapy was generally of relatively short duration. There was a declining gradient of ever-use with age.
Conclusions The extent of significant urogenital symptoms is relatively low, but some women are seriously affected and use self-help as well as professional assistance. The extent of sexual activity in older women and factors affecting this have been defined, and the effect of urogenital symptoms on sexual activity demonstrated.     

Cancer Patterns in the Middle East Special Report from the Middle East Cancer Society

To update its cancer statistics, the newly established Middle East Cancer Society examined the cancer frequency patterns in Egypt and the Gaza Strip. The results revealed differing overall patterns. For men the highest frequencies were found for lymphoma, bladder cancer and cancers of the oral cavity and pharynx in Egypt, and for lung cancer, leukaemia and lymphoma in Gaza. For women, breast cancer had the highest frequency in both areas, followed by cancers of the oral cavity and pharynx in Egypt, and leukaemia and lymphoma in Gaza. The distribution of cancer occurrence by organ system also varied. In the light of the different ethnicities, lifestyles, socioeconomic levels and carcinogenic exposure among the countries of the Middle East, this kind of comparison can provide the background for more sophisticated approaches for discerning risk factors in cancer. We believe that further cooperation among participating countries will overcome the present limitations in data collection, registration and access.     

Quality improvement in immunization delivery following an unsuccessful immunization recall.

OBJECTIVES: Within a clinic serving disadvantaged children, 1) to evaluate a multifaceted quality improvement (QI) project to improve immunization (IZ) up-to-date (UTD) rates and 2) to assess the efficacy of IZ reminder/recall performed following QI. METHODS: A year-long QI project followed by a trial of reminder/recall. QI interventions were targeted at previously identified barriers to IZ and were designed specifically to improve the efficacy of reminder/recall. QI interventions were designed to 1) increase the use of medical record releases to document IZs received elsewhere; 2) improve the accuracy of parental contact information; and 3) reduce missed opportunities by utilizing chart prompts, provider education, and provider reminders. Following QI, we conducted a randomized trial of reminder/recall. RESULTS: UTD rates for 7-11 month olds increased from 21% before the QI project to 52% after (P <.0001); rates for 12-18 month olds increased from 16% before QI to 44% after (P <.0001); 19-25 month olds 18% before to 33% after (P <.001). After QI, an average of 61 records per month were updated with IZs received elsewhere. However, the accuracy of parental contact information worsened (29% unreachable before QI vs 44% after, P <.001) and missed opportunities did not improve (8% before vs 6% after, P = not significant [NS]). A subsequent trial of reminder/recall did not increase UTD rates, with 17% of recalled children brought UTD vs 16% of controls (P = NS). CONCLUSIONS: Clinic-based QI increased documented UTD rates in a disadvantaged patient population. However, IZ reminder/recall did not further increase UTD rates above the rates achieved by the QI process.