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Biomedical subjects

J Cassidy

Publications and source records attributed to J Cassidy.

At least 19 recordsLinked to original sources
PubMed1995

Phase I clinical and pharmacokinetic study of 3'-deamino-3'-(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762).

Methoxymorpholinyldoxorubicin (FCE 23762) is a novel, highly lipophilic doxorubicin analogue. It possesses potent in vitro and in vivo antitumor activity including efficacy in multidrug-resistant tumor cell lines. It is also metabolically activated in vivo resulting in an 80-fold increase in potency over the parent drug. In this phase I study the drug was administered by i.v. bolus injection at 3-week intervals. Fifty-three patients with refractory solid tumors were treated; 133 courses of FCE 23762 were administered at doses ranging from 30 to 2250 micrograms/m2. The dose limiting toxicity was reversible myelo-suppression (granulocytopenia and thrombocytopenia), demonstrating a delayed nadir and recovery in comparison to doxorubicin. Other toxicities included transient elevation of hepatic transaminases, delayed and prolonged nausea and vomiting, mucositis, anorexia, fatigue, and diarrhea. Heavily pretreated patients demonstrated more myelosuppression than previously untreated patients at 1250 micrograms/m2. No cardiotoxicity was observed. Four objective tumor responses were seen: one complete response in a patient with pelvic recurrence of cervical cancer; one partial response in a patient with cutaneous and lymph gland metastases from head and neck cancer; and two minor responses in patients with liver metastases from colorectal cancer. Plasma concentrations of FCE 23762 and its 13-dihydro metabolite, FCE 26176, were measured in 20 patients at doses > or = 675 micrograms/m2, using HPLC with fluorescence detection. The area under the plasma concentration-time curve ranged from 30 to 80 ng/h/ml; plasma data suggested linear kinetics in the range of tested doses (although there was considerable interpatient variability). The maximum tolerated dose defined in this study using this schedule is 1500 micrograms/m2. A safe phase II dose for previously untreated patients using this schedule is 1250 micrograms/m2; however, this may actually be below the optimal dose for this patient population.

Adult↗
PubMed1994

Detection of Mycobacterium bovis infection in skin test-negative cattle with an assay for bovine interferon-gamma.

Mycobacterium bovis was isolated from respiratory secretions and lymph nodes from 15 skin test-negative cattle which exhibited interferon-gamma responses. These field cases, identified by blood testing, constituted a significant proportion of skin test-negative cattle which had been subjected to extensive post mortem examinations. Typical tuberculous lesions were found in seven of them. The consequences of cattle with early tuberculosis infection not being detected by traditional tuberculin testing are considered.

Animals↗
PubMed1994

A phase I-II study of N-(phosphonacetyl)-L-aspartic acid (PALA) added to 5-fluorouracil and folinic acid in advanced colorectal cancer.

N-(phosphonacetyl)-L-aspartic acid (PALA) inhibits the enzyme L-aspartic acid transcarbamoylase (ATCase) which is important in de novo pyrimidine synthesis. Low dosages of PALA modulate the in vitro activity of 5-fluorouracil (5-FU) and PALA (250 mg/m2) inhibits pyrimidine synthesis in patients. PALA (250 mg/m2 day 1) was combined with an established 5-FU/folinic acid (FA) regimen [FA (200 mg/m2 over 2 h days 2 + 3) and bolus and 22 h infusional 5-FU (300-500 mg/m2 days 2 + 3)] without the need for dose reduction of 5-FU or FA. 35 patients were entered. Treatment was well tolerated; 4/27 patients experienced > or = ECOG grade 3 toxicity at full 5-FU dosage (500 mg/m2 bolus/infusion). However, the response rate in 33 evaluable patients was only 6.1% [95% confidence intervals (C.I.) 0.2-21.8%]. Median response duration was short (4 months, 95% C.I. 3-6 months) and overall median survival was 10 months (95% C.I. 7-16 months). Although PALA (250 mg/m2) can be combined with full dosage 5-FU/FA, the combination has poor activity in colorectal cancer.

Adolescent↗
PubMed1994

Bolus/infusional 5-fluorouracil and folinic acid for metastatic colorectal carcinoma: are suboptimal dosages being used in the UK?

Bolus/infusional 5-fluorouracil (5-FU) and folinic acid (FA) is reported to be highly active [partial response (PR) = 54%, median survival 18 months] in patients with metastatic colorectal carcinoma (MCCa). To confirm this level of activity, we conducted a retrospective analysis of 95 previously untreated patients with MCCa treated with FA by 2 h i.v. infusion (200 mg m-2) followed by 5-FU bolus/22 h i.v. infusion (300-500 mg m-2) on days 1 and 2 every 2 weeks. Thirty patients also received N-(phosphonacetyl)-L-aspartate (PALA), 250 mg m-2, 24 h prior to 5-FU/FA. In 81 evaluable patients, the response rate was low: PR = 11%, stable disease (SD) = 36% and median survival = 8 months. There was an improvement in survival with increased 5-FU dosage (500 mg m-2) [relative hazard (RH) = 0.38, 95% CI 0.21-0.70], controlled for age, primary site, PALA, liver function and performance status. Good performance status (PS 0 or 1) was also associated with improved survival (RH = 0.21, 95% CI 0.10-0.46). Response, survival and toxicity were not altered by the co-administration of PALA. Bolus/infusional 5-FU (500 mg m-2) and FA was well tolerated. WHO toxicities (grade 3) were: mucositis, 2%; diarrhoea, 14%; nausea and vomiting, 5%. In light of the apparent dose effect, poor response and low toxicity, we recommend that regimes incorporating higher 5-FU dosages are explored and prospectively validated before bolus/infusional 5-FU becomes accepted standard practice.

Adult↗
PubMed1994

Chemotherapy administration: doses, infusions and choice of schedule.

BACKGROUND: Oncologists are trained to make the best use of all available modes of therapy for patients with cancer. Our current armamentarium of cytotoxic drugs is, however, far from ideal, resulting in therapeutic failure in some of the common solid tumours. To make the best use of available drugs, optimum doses, schedules and routes of administration should be used for each individual patient and disease state. Existing drugs: Traditional methods of drug development have produced some active anticancer drugs, though the inflexibility and empiricism evident in the early-phase clinical trials of some drugs has seriously delayed the definition of optimum doses, schedules and routes of administration. This is illustrated by the anticancer agents, etoposide and 5-fluorouracil, both of which are still not used optimally, despite more than 20 years of clinical investigation. New drugs: It could be argued that these drugs were developed prior to our improved understanding of drug actions, pharmacokinetics and pharmacodynamics, and that such problems do not arise with new agents today. However, examples of the camptothecin derivatives (topotecan and CPT-II) show that we have progressed, but that we still have a long way to travel. This paper highlights the problems inherent in the development of new anticancer drugs. Strategies for avoiding these problems include: adoption of biological endpoints for phase I studies; the use of modern pharmacokinetic techniques to develop pharmacodynamic models; adaptive control of drug dosing.

Antineoplastic Agents↗
PubMed1994

The insecure/ambivalent pattern of attachment: theory and research.

Relatively little has been written about one group of infants identified with Ainsworth's "Strange Situation" assessment of infant-parent attachment, those classified insecure/ambivalent. Although virtually all samples contain some insecure/ambivalent infants, these infants are uncommon, comprising 7%-15% of most American samples. Recently developed assessments of attachment in children and adults have identified attachment groups of older individuals thought to parallel the insecure/ambivalent infant group. Empirical work in which insecure/ambivalent individuals are examined as a separate group is reviewed within the context of attachment theory, and a coherent picture emerges of the antecedents (relatively low or inconsistent maternal availability; biological vulnerability) and sequelae (limited exploratory competence) of this group. This picture is used as the basis for additional theoretical proposals, and suggestions for future research are presented.

Adaptation, Psychological↗
PubMed1994

Emotion regulation: influences of attachment relationships.

Emotion regulation and quality of attachment are closely linked. It has been proposed here that one influence on individual differences in emotion regulation may be a child's attachment history. Individuals characterized by the flexible ability to accept and integrate both positive and negative emotions are generally securely attached; on the other hand, individuals characterized by either limited or heightened negative affect are more likely to be insecurely attached. While acknowledging the role of infant temperament, I have focused on the role of social factors in examining the link between emotion regulation and attachment. The approach to emotion regulation taken here--that emotion regulation is adaptive in helping a child attain her goals--is esentially a functionalist approach (Bretherton et al., 1986; Campos et al., 1983), consistent with earlier views of emotions as important regulators of interpersonal relationships (Charlesworth, 1982; Izard, 1977). It has been proposed that patterns of emotion regulation serve an important function for the infant: the function of maintaining the relationship with the attachment figure. Emotion regulation has been described as serving this function in two ways. First, the function of maintaining the relationship is thought to be served when infant emotion regulation contributes to the infant's more generalized regulation of the attachment system in response to experiences with the caregiver. Infants who have experienced rejection (insecure/avoidant infants) are thought to minimize negative affect in order to avoid the risk of further rejection. Infants whose mothers have been relatively unavailable or inconsistently available (insecure/ambivalent infants) are thought to maximize negative affect in order to increase the likelihood of gaining the attention of a frequently unavailable caregiver. Both these patterns of emotion regulation help ensure that the child will remain close to the parent and thereby be protected. Second, the function of maintaining the attachment relationship is thought to be served when the infant signals to the parent that she will cooperate in helping maintain the parent's own state of mind in relation to attachment. The minimizing of negative affect of the avoidant infant signals that the infant will not seek caregiving that would interfere with the parent's dismissal of attachment. The heightened negative emotionality of the ambivalent infant signals to the parent that the infant needs her and thus helps maintain a state of mind in which attachment is emphasized. The approach to emotion regulation presented here is congruent with much work examining the socialization of emotions (Lewis & Saarni, 1985; Thompson, 1990).

Affect↗
PubMed1994

New drugs in clinical development in Europe.

This article deals with new antitumor agents currently in Phase I or II evaluation in various European centers. Drugs reviewed in this article include Taxotere, Camptothecin analogues, CPT-11, and Topotecan. Rhizoxin, D1694, and Bryostatin are among other agents reviewed in this article.

Antineoplastic Agents↗
PubMed1993

Phase I and pharmacokinetic study of taxotere (RP 56976) administered as a 24-hour infusion.

N-Debenzoyl-N-tert-butoxycarbonyl-10-deacytyl taxol (Taxotere, RP 56976) is a semisynthetic analogue of taxol, prepared from a noncytotoxic precursor extracted from the needles of the European yew tree (Taxus baccata L.). It has a broad spectrum of antitumor activity against a variety of transplantable tumors in mice. In vitro cytotoxicity assays suggest that it is 2-5-fold more potent than taxol. In this phase I study Taxotere was administered by 24 h i.v. infusion at 3-week intervals. Thirty patients with solid tumors refractory to conventional therapy were treated; 70 courses of Taxotere were administered at doses ranging from 10 to 90 mg/m2. Grade 4 neutropenia and grade 3 mucositis were dose limiting but reversible at 90 mg/m2. The pattern and grade of toxicity at this dose were similar in 3 heavily pretreated patients compared with 7 patients who had received a maximum of one previous chemotherapy regimen. Alopecia occurred at 55 mg/m2 and above. Other mild toxicities included phlebitis, diarrhea, emesis, and sensory peripheral neuropathy, but these were neither dose-limiting nor clearly dose-related. One patient treated at 70 mg/m2 had an anaphylactoid reaction following the second dose of Taxotere. No cardiovascular toxicity was observed. No partial or complete responses were documented. Plasma concentrations of Taxotere were determined by high-performance liquid chromatography, and end-of-fusion levels at the maximum tolerated dose exceeded drug concentrations which are cytotoxic in vitro. The maximum tolerated dose for Taxotere administered as a 24-h infusion is 90 mg/m2.

Adult↗
PubMed1993

Phase I clinical study of LL-D49194 alpha 1 with retrospective pharmacokinetic investigations in mice and humans. The EORTC ECTG.

LL-D49194 alpha 1 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-D49194 alpha 1 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.

Aged↗
PubMed1993

Human transbuccal absorption of diclofenac sodium from a prototype hydrogel delivery device.

The buccal delivery of the nonsteroidal antiinflammatory drug, diclofenac sodium (Voltaren), from a prototype hydrogel was studied in man in a randomized crossover design of buccal delivery and i.v. infusion. After a 30-min delay, plasma levels of diclofenac increased to near steady-state levels of 100 ng/ml by 3 hr. With each subject serving as his own control, the i.v. infusion data facilitated the calculation of a mean steady-state flux of diclofenac sodium of 2.1 +/- 0.6 mg/cm2-hr across human buccal mucosa and a time lag of 1.0 +/- 0.5 hr. The large flux of this ionized species indicates that the traditional lipoidal model of buccal permeation based on the partition coefficient is inadequate.

Absorption↗
PubMed1993

Pharmacokinetics of high molecular weight agents.

The various high molecular weight agents discussed in this chapter are at different stages of gestation, but as yet none have had a clear clinical impact despite many years of scientific effort. The problems that have been encountered along the way for many agents are similar: how to avoid reticuloendothelial trapping and how to achieve adequate penetration of a macromolecule into a solid tumour. The solutions offered to these problems are as diverse as the agents themselves, and, as a spin-off, our understanding of tumour cell behaviour (eg endocytosis) has improved. For many of the systems discussed, it remains unclear whether this approach is just a complex way of administering a continuous low dose infusion of the cytotoxic component. Advances in this field appear to have accelerated over the last 2-3 years, and it should not be much longer before these scientifically pleasing and elegant systems are shown to have clinical advantages over conventional cytotoxic drug delivery.

Antineoplastic Agents↗
PubMed1993

Pharmacokinetics and early clinical studies of selected new drugs.

The five examples given here illustrate new cytotoxic agents at different stages of evaluation. In all cases, considerable effort has gone into detailed pharmacokinetic studies conducted before and during the clinical phase I studies. Has this effort contributed significantly to the development of these agents? At present, it has to be said that the contribution made in the case of these particular agents has been modest. For the anthrapyrazoles, the availability of the pharmacokinetic data did not permit a pharmacokinetically guided dose escalation to be performed because of non-linear kinetics, and a similar comment can be made for rhizoxin, since the human plasma AUC values at the MTD were much lower than in the mouse. For the camptothecin analogues, a detailed knowledge of the kinetics of the closed and open forms of the various agents did not influence the way in which the studies were conducted, nor did pharmacokinetic information appreciably do so for EO9, although some comfort was gained by clinical investigators when the short half-life seen in preclinical species was also observed in humans. For suramin, therapeutic drug monitoring is clearly essential, although toxicity remains a problem. Of course, a proper understanding of the pharmacokinetics and metabolism of these agents greatly improves the interpretation of the clinical observations made and is often critical in planning the next stages of development. This is more clearly seen with agents that have unusual forms of toxicity, such as flavone acetic acid, for which the achievement of notional target concentrations is a key element in clinical trials (Kerr et al, 1987; Maughan et al, 1992). Moreover, as reviewed elsewhere (Graham and Workman, 1992; see also Graham and Kaye, this volume), there are several other instances where pharmacokinetically guided dose escalation has greatly improved the conduct of a phase I study. Good examples of this are iododoxorubicin (Gianni et al, 1990), mitotic inhibitor CI-980 (Brodfuehrer et al, 1992) and DNA intercalator CI-958 (Whitfield et al, 1992). Not surprisingly then, pharmacokinetics can help guide early clinical studies of some compounds but not others and whether they will be of value can only be determined by carrying out the pharmacokinetic measurements. The real value of the pharmacokinetic studies for the five compounds reviewed may not yet have been seen. Interpatient variations in drug handling can play a major part in determining levels of anti-tumour activity as well as toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

The role of the data manager in clinical cancer research. An opportunity for nurses.

A clinical trial is a research study conducted in humans and designed to answer specific questions using scientifically controlled methods. These trials require considerable effort to assure that the data obtained are reliable, reproducible, and readily available. Data managers play a key role in this research effort. A nurse with a clinical background, computer knowledge, and some experience in the research environment is well suited for the role of data manager. The data manager performs a variety of tasks in this position that will enhance the quality of the data gathered in a research study. These responsibilities include designing forms, monitoring protocol accrual, abstracting data, entering data onto protocol-specific forms and/or specifically designed computerized data-entry screens, assuring the quality and the integrity of the data, and providing investigators with interim and summary reports. In addition, the data manager can be responsible for the management of a computerized clinical data base system, including the training of users and the designing of basic reports for the investigators. A nurse, functioning as a data manager, who understands research methodology, is detail oriented, and is well organized, could be a valuable asset to the clinical trials team in the successful management of any clinical study.

Clinical Trials as Topic↗