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Biomedical subjects

M A Graham

Publications and source records attributed to M A Graham.

At least 37 records · Page 2Linked to original sources
PubMed1997

Food allocation in rural Peruvian households: concepts and behavior regarding children.

Intrahousehold food allocation is an important determinant of child health and survival. In this paper I explore the ways in which food is distributed to young children in Ura Ayllu, a farming community located in the southern Peruvian highlands (Province of Sandia, Department of Puno, Peru). Quantitative data on energy intake and growth status are analyzed for two groups of children: toddlers (one through three years) and preschoolers (four through six years). The analyses indicate no gender differences in energy intake or growth among toddlers (one through three years) and preschoolers (four through six years) and that young children do not appear to be deprived of food relative to older household members, especially adults. Relative to standards specific to Andean populations, the mean caloric content of the toddler diet falls slightly below the estimated requirement for the age group while the preschooler diet is found to be calorically adequate. This paper also examines the ideological bases that shape food allocation within households. Regarding the local concepts and cultural rules that guide food allocation to children, Ura Ayllinos view young children as developmentally immature and believe their dietary and health needs are different from those of older children and adults. Infants and young children are considered weak (debil) and vulnerable to illness. Parents state that young children should not feel hunger which is thought to weaken a person and make him more susceptible to the natural and supernatural agents that cause illness. Certain dietary practices, such as on-demand breastfeeding and snacking between meals, suggest that parents try to avoid the experience of hunger and the potential for illness by making food available to their children. This study suggests that young Ura Ayllu children are viewed as having a right to food based on local concepts of child development, personhood, and general health maintenance.

Adult↗
PubMed1997

Criteria for the diagnosis of heat-related deaths: National Association of Medical Examiners. Position paper. National Association of Medical Examiners Ad Hoc Committee on the Definition of Heat-Related Fatalities.

The National Association of Medical Examiners Ad Hoc Committee on the Definition of Heat-Related Fatalities recommends the following definition of "heat-related death": a death in which exposure to high ambient temperature either caused the death or significantly contributed to it. The committee also recommends that the diagnosis of heat-related death be based on a history of exposure to high ambient temperature and the reasonable exclusion of other causes of hyperthermia. The diagnosis may be established from the circumstances surrounding the death, investigative reports concerning environmental temperature, and/or measured antemortem body temperature at the time of collapse. In cases where the measured antemortem body temperature at the time of collapse was > or = 105 degrees F (> or = 40.6 degrees C), the cause of death should be certified as heat stroke or hyperthermia. Deaths may also be certified as heat stroke or hyperthermia with lower body temperatures when cooling has been attempted prior to arrival at the hospital and/or when there is a clinical history of mental status changes and elevated liver and muscle enzymes. In cases where the antemortem body temperature cannot be established but the environmental temperature at the time of collapse was high, an appropriate heat-related diagnosis should be listed as the cause of death or as a significant contributing condition.

Adult↗
PubMed1997

Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors.

PURPOSE AND METHODS: Tirapazamine (SR4233, WIN 59075) is a benzotriazine-di-N-oxide bioreductive agent that is selectively activated to a reactive DNA-damaging species in hypoxic tumors. Preclinical studies show that synergistic antitumor activity results from a schedule-dependent interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tirapazamine (130 to 260 mg/m2) was administered as a 1-hour intravenous (IV) infusion beginning 3 hours before cisplatin (75 to 100 mg/m2). Thirteen patients received 41 courses of therapy. These patients had an excellent performance status and were not heavily pretreated. The predominant diagnosis was lung cancer. RESULTS: The major acute side effects were nausea and vomiting, which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, while with repeated dosing, anorexia and fatigue predominated. Full doses of each agent were well tolerated in combination, although in this previously treated population, fatigue increased markedly after three cycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a minor response occurred in a patient with mesothelioma. Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2. These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of tirapazamine are achievable in patients based on animal models. The mean cisplatin AUC was 285.6 +/- 46.4 microg/mL.min with mean Cmax values of 3.38 +/- 0.43 microg/mL at 75 mg/m2. The clearance of cisplatin was unaffected by coadministration with tirapazamine. CONCLUSION: This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapazamine up to 260 mg/m2. The observation of clinical responses in this trial supports the phase II investigation of this regimen.

Adult↗
PubMed1997

Phase I and pharmacokinetic study of tirapazamine (SR 4233) administered every three weeks.

Tirapazamine (SR 4233; 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide) is a bioreductive agent exhibiting up to 200 x greater toxicity for hypoxic cells as compared to oxygenated cells. In murine studies, a selective increase in tumor kill was observed when tirapazamine was coadministered with other agents, notably cisplatin. A Phase I study of single-agent tirapazamine administered i.v. every 3 weeks was conducted to determine the toxicity of a schedule for use with systemic chemotherapy. A total of 28 patients were given 50 courses of tirapazamine at doses ranging from 36-450 mg/m2. No tumor responses were observed. Reversible deafness and tinnitus were dose-limiting, with ototoxicity observed in 1 of 6 patients treated at 330 mg/m2, 1 of 4 patients treated at 390 mg/m2, and 3 of 3 patients treated at 450 mg/m2. Muscle cramps, nausea, and vomiting were also observed. Pharmacokinetic studies revealed a greater than dose-proportional increase in the area under the plasma concentration x time curve (AUCs) of the two major metabolites. Patients who developed ototoxicity generally showed higher plasma AUC values for the parent drug and metabolites. The mean plasma tirapazamine AUC at 330 mg/m2 was 1026.5 microgram/ml x min (range 863. 8-1252.3), but no pharmacokinetic data are available for the solitary patient who developed otoxicity at this dose level. These AUC values were in the (estimated) range required for therapeutic effect in murine studies. Ototoxicity was not observed when the AUC of tirapazamine was equal to or less than 1252 microgram/ml x min. The dose of 330 mg/m2 was therefore chosen as an appropriate level for combination chemotherapy studies.

Adult↗
PubMed1996

A comparison of methods for limited-sampling strategy design using data from a phase I trial of the anthrapyrazole DuP-941.

The pharmacokinetics of a drug in individual patients can be estimated using plasma samples collected at a limited number of time points. However, different methods for a limited-sampling strategy (LSS) design exist and the optimal method has not yet been defined. Plasma concentration data were available from 27 of 74 courses in a phase I study (dose range, 5-55 mg m-2) of the novel anthrapyrazole DuP-941. Three approaches to LSS development were compared. Firstly, forward stepwise regression (FSR) was used to derive equations to predict the DuP-941 area under the concentration-time curve (AUC) based on plasma concentrations measured at specified times. LSSs were developed using 14 randomly chosen data sets and were validated using the remaining 13 data sets. Secondly, "all subsets" regression (ASR) was used to develop LSSs. A jack-knife technique was also used to allow model development utilising 26 data sets and validation on the 27th data set. Thirdly, an LSS was developed using optimal sampling theory (OST), and the LSS was used in conjunction with a Bavesian algorithm. Selected sampling times for four-point LSSs were 10, 65, 185 and 485 min (FSR) and 10, 45, 200 and 480 min (OST). Ten candidate LSSs were developed using the ASR approach. ASR- and OST/Bayesian-derived four-point LSSs gave more precise (P < 0.05) estimates of AUC [mean absolute percentage of difference (MAD%) +/- SD: ASR, 6.4 +/- 3.7%; OST/Bayesian, 6.8 +/- 4.6%] than did FSR (MAD% = 15.1 +/- 9.9%). The OST/Bayesian approach is recommended because it allows estimation of all model parameters and is more flexible with regard to sample collection time and design variables.

Adult↗
PubMed1996

Phase I pharmacokinetics and limited sampling strategies for the bioreductive alkylating drug EO9. EORTC Early Clinical Trials Group.

EO9 is a synthetic indoloquinone which was designed to undergo redox cycling and formation of alkylating intermediates under bioreductive conditions. As part of a phase I clinical trial, EO9 plasma disposition was evaluated in 20 patients receiving 2.7-15 mg/m2i.v. weekly for 3 weeks. Pharmacokinetic studies were performed with the first and third dose of therapy and nine blood samples were obtained over 30 min postinfusion. Plasma EO9 was detected using HPLC UV and the disposition described by a two-compartment model. Wide variability in EO9 pharmacokinetics was observed. EO9 was rapidly eliminated from plasma with a median systemic clearance of 3.5 l/min/m2 (range 1.2-9.8), apparent volume of distribution of 6.2 l/m2 (1.0-34.9) and t 1/2 beta of 10.1 min (2.2-63.0). Substantial intrapatient variability was observed for all pharmacokinetic parameters. Linear regression and Bayesian methods were developed and validated for estimation of EO9 plasma AUC using up to three samples postinfusion. The use of two or three plasma samples provided precise estimation with acceptable prediction bias. In addition, a Bayesian algorithm offered more robust estimation of AUC and is preferable to linear regression models for future EO9 population pharmacokinetic analysis.

Adult↗
PubMed1996

In vivo pharmacology and anti-tumour evaluation of the tyrphostin tyrosine kinase inhibitor RG13022.

Amplification and increased expression of many growth factor receptors, including the epidermal growth factor receptor (EGFR), has been observed in human tumours. One therapeutic strategy for overcoming EGF autocrine control of tumour growth is inhibition of EGFR protein tyrosine kinase (PTK). A series of low molecular weight molecules have been identified which inhibit the EGFR PTK in vitro and demonstrate antiproliferative activity against human cancer cell lines with high expression of EGFR. A significant growth delay in squamous cancer xenografts has been reported for one of these compounds, the tyrphostin RG13022. Based on these encouraging results, we sought to confirm the activity of RG13022 in vivo and relate the effects to the in vivo plasma disposition. RG13022 and three additional peaks were detected by HPLC following intraperitoneal administration of 20 mg kg-1 RG13022 in MF1 nu/nu mice. RG13022 demonstrated rapid biexponential elimination from plasma with a terminal half-life of 50.4 min. RG13022 plasma concentrations were less than 1 microM by 20 min post injection. A primary product was identified as the geometrical isomer (E)-RG13022. Both RG13022 and its geometrical isomer inhibited DNA synthesis in HN5 cells after a 24 h in vitro incubation (IC50 = 11 microM and 38 microM respectively). Neither RG13022 nor its geometrical isomer displayed significant cytotoxicity. RG13022 had no influence on the growth of HN5 tumours when administered chronically, starting either on the day of tumour inoculation or after establishment of tumour xenografts. The rapid in vivo elimination of RG13022 has potential significance to the development of this and other related tyrphostin tyrosine kinase inhibitors, as plasma concentrations fell below that required for in vitro activity by 20 min post injection. The lack of in vivo tumour growth delay suggests that a more optimal administration schedule for RG13022 would include more frequent injections or continuous administration. An improved formulation for RG13022 is therefore required before further development of this or other similar protein tyrosine kinase inhibitors can be made. Alternative strategies should also be sought which display longer lasting in vivo exposures.

Animals↗
PubMed1996

Multicentre phase II pharmacological evaluation of rhizoxin. Eortc early clinical studies (ECSG)/pharmacology and molecular mechanisms (PAMM) groups.

Rhizoxin is a macrocyclic lactone compound that binds to tubulin and inhibits microtubule assembly. Rhizoxin demonstrated preclinical anti-tumour activity against a variety of human tumour cell lines and xenograft models. Phase I evaluation found a maximum tolerated rhizoxin dose of 2.6 mg m-2, with reversible, but dose-limiting, mucositis, leucopenia and diarrhoea. Clinical trials were then initiated by the EORTC ECSG in melanoma, breast, head and neck, and non-small-cell lung cancers with the recommended phase II rhizoxin dose of 2 mg m-2. Pharmacological studies were instituted with the phase II trials to complement the limited pharmacokinetic data available from the phase I trial. Blood samples were obtained from 69 of 103 eligible patients enrolled in phase II rhizoxin studies, and these were evaluable for pharmacokinetic analysis in 36 patients. Plasma rhizoxin concentrations were determined by high-performance liquid chromatography (HPLC), and post-distribution pharmacokinetic parameters were estimated by a one-compartment model. Rhizoxin was rapidly eliminated from plasma, with a median systemic clearance of 8.41 min-1 m-2 and an elimination half-life of 10.4 min. Rhizoxin area under the concentration-time curve (AUC) was higher in patients obtaining a partial response or stable disease than in those with progressive disease (median 314 vs 222 ng ml-1 min; P = 0.03). As predicted from previous studies, haematological and gastrointestinal toxicity was observed, but could not be shown to be related to rhizoxin AUC. This study demonstrated the rapid and variable elimination of rhizoxin from the systemic circulation. The presence of pharmacodynamic relationships and the low level of systemic toxicity suggest that future trials of rhizoxin with alternative dosage or treatment schedules are warranted.

Antibiotics, Antineoplastic↗
PubMed1996

Delayed rupture of the abdominal aorta in a child after a suspected handlebar injury.

Blunt abdominal trauma resulting in a laceration of the abdominal aorta is extremely rare. Only one previous example of this injury has been reported in a child. We present the clinical course and surgical management of blunt disruption of the infrarenal aorta in a 13-year-old boy with a subsequent delayed rupture of a third aortic laceration. This is the youngest patient to die from this type of injury after blunt abdominal trauma.

Abdominal Injuries↗
PubMed1996

The pharmacokinetics, bioavailability and biodistribution in mice of a rationally designed 2-nitroimidazole hypoxia probe SR-4554.

N-(2-Hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR-4554) is a fluorinated 2-nitroimidazole which has been rationally designed as a non-invasive probe for tumor hypoxia. The key selection criteria for this molecule were low central nervous system penetration and toxicity, high metabolic stability other than nitroreduction, good tumor uptake and high sensitivity for detection by magnetic resonance spectroscopy. As part of the pre-clinical development strategy, pharmacokinetic, bioavailability and biodistribution studies were performed in mice. Pharmacokinetic studies in mice demonstrated that SR-4554 was rapidly absorbed into plasma following i.p. administration and eliminated with a half-life of 42 min, similar to other 2-nitroimidazoles. By comparing the areas under the concentration-time curve (AUC), the tumor exposure towards SR-4554 was on average 84% of the value obtained for the plasma exposure. SR-4554 penetrated tumor tissue extremely well but, in contrast to misonidazole and certain other fluorinated analogues, its distribution into brain tissue was poor (AUCbrain/AUCplasma = 0.07), suggesting potentially lower toxicity in spite of its higher lipophilicity (P = 0.43 versus 0.63, respectively). The bioavailability of SR-4554 from i.p. and p.o. routes was 100 and 96% respectively. In non-tumor-bearing mice, SR-4554 was excreted mainly as unchanged drug. The percentage of the injected i.p. dose of SR-4554 excreted unchanged in the urine over 24 h was 68 +/- 8%. Neither SR-4554 nor its metabolites were detected in mouse feces. We propose that these favorable pharmacokinetic properties of SR-4554 are due to the hydrophilic character and hydrogen-bonding capability of the amide and hydroxyl functions in the compound.

Animals↗
PubMed1995

Development and validation of a solid-phase extraction and high-performance liquid chromatographic assay for a novel fluorinated 2-nitroimidazole hypoxia probe (SR-4554) in Balb/c mouse plasma.

N-(2-Hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide, a novel 2-nitroimidazole, is currently being developed as a non-invasive probe for tumour hypoxia. A sensitive (minimum quantifiable level = 25 ng/ml; C.V. = 6.01%) and selective assay has, therefore, been developed for the analysis of this compound in mouse plasma. The assay employed a solid-phase extraction followed by a rapid (10 min) HPLC analysis with UV-photodiode-array detection. No drug-related metabolites were observed in plasma when mice were treated with 180 mg/kg of the drug. The assay has proved to be suitable for studying the plasma pharmacokinetics of this fluorinated 2-nitroimidazole in mice.

Animals↗
PubMed1995

Development and validation of a sensitive solid-phase-extraction and high-performance liquid chromatography assay for the bioreductive agent tirapazamine and its major metabolites in mouse and human plasma for pharmacokinetically guided dose escalation.

A sensitive solid-phase-extraction and high-performance liquid chromatography (HPLC) method has been developed to investigate the pharmacokinetics and metabolism of the hypoxic-cell cytotoxic agent tirapazamine (1,2,4-benzotriazine-3-amine 1,4-di-N-oxide; WIN 59075, SR 4233), currently in phase I/II studies in the United Kingdom and United States. A sample extraction and concentration process was devised using strong cation-exchange Bond Elut cartridges. Tirapazamine, the mono and zero-N-oxide metabolites (WIN 64012, WIN 60109) were isocratically resolved using a microBondapak phenyl HPLC column and measured using photodiode-array detection. The minimal quantifiable level (MQL) of tirapazamine was 40 ng/ml in mouse plasma and 20 ng/ml in human plasma. Recovery was consistently greater than 80% for all compounds over the concentration range of 20 ng/ml to 20 micrograms/ml. No significant decomposition was observed following up to three freeze/thaw cycles and storage at -70 degrees C for 52 days. The assay was accurate and reproducible, with measured values lying within the limits of defined acceptance criteria. Additional studies to investigate the degree of plasma protein binding showed that tirapazamine did not bind extensively to plasma proteins (binding, 9.7% +/- 0.1% and 18.7% +/- 1.3% in mouse and human plasma, respectively). These small species differences in protein binding are unlikely to have any major impact on the extrapolation of pharmacokinetic data from mice to humans. The assay has now been successfully applied to investigate the pharmacokinetics and metabolism of tirapazamine in mice and patients as part of a pharmacokinetically guided dose-escalation strategy for phase I clinical trials.

Animals↗
PubMed1994

Lymphocyte profiles in patients with chronic low back pain enrolled in a clinical trial.

OBJECTIVE: Our earlier findings suggest that patients with musculoskeletal complaints have lower numbers and percentages of natural killer (NK) cells than asymptomatic subjects. This study examines patient lymphocyte profiles, as a secondary outcome measure, in a trial of manipulative therapies to treat chronic low back pain (LBP) of mechanical origin. DESIGN: The patients were compared in a randomized controlled trial. Baseline measures were collected at the initial visit; all patients were scheduled for 11 treatments in 14 days. Treatment consisted of either a high-force, high-velocity, low-amplitude manipulation procedure; a low-force, high-velocity, low-amplitude procedure or a series of educational lectures on lower back pain. Posttreatment measures were collected at the final treatment session; follow-up measures were obtained 2 wk later. SETTING: The study was conducted at a chiropractic teaching clinic in the suburban Chicago area. PARTICIPANTS: Individuals over 18 were eligible if they were new patients or repeat patients with a 6 month's hiatus, if the chief complaint was LBP of greater than 50 days' duration, if pain was elicited with palpation over one or more of the facet joints from the spinal levels between L1 and S1 and including the sacroiliac joints, and if there was absence of pain referral or if pain referral was only scleratogenous in nature. Criteria for excluding patients included hard neurologic signs, systemic disease potentially affecting the musculoskeletal system, contraindication to spinal manipulation such as osteoporosis, fracture or other bony pathology, or treatment with medication intended to relieve symptoms associated with their LBP. Eligibility was determined by a staff diagnostic team independent of the attending physician. Three hundred sixty-seven of 1,275 consecutive new patients met the eligibility criteria. Of these, 209 participated. These results are for 201 patients from whom flow cytometric data were obtained. OUTCOME MEASURES: Both absolute numbers and percentages of B-lymphocytes, T-lymphocytes, T-Helper (TH), T-Suppressor (TS) and NK lymphocytes were determined. Blood samples were collected at the same time that the primary outcome measures were obtained. Cells were stained with two-color monoclonal antibodies directed against specific cell surface antigens, and each lymphocyte subpopulation was quantified directly from lysed whole blood with a Coulter Epics Profile II flow cytometer. RESULTS: Thirty-five patients dropped out before the follow-up visit and technical problems resulted in the loss of data from 17 more and the exclusion of some subpopulation data. In all, 148 cases were analyzed for B cells, 146 for TH, TS and NK cells and 138 for cells that carried both the NK and TS marker. A one-way analysis of variance revealed no significant differences in the lymphocyte profiles at baseline among the three groups. All subpopulation baseline values were within reported reference ranges for normal adult populations. However, the percentage of NK cells (9.1%) was below the published minimum critical value. A repeated measures analysis of variance was used to determine whether treatment effects changed over time, that is, treatment-time interaction. The cell types for which the interaction tests were at or near statistical significance were: TH cells (p = .0208), total T cell percent (p = .0928) and absolute total T cells (p = .0908). Interaction tests for differences in either percent or absolute counts of B cells, TS cells, or NK cells were not statistically significant. CONCLUSIONS: This is the first report of lymphocyte profiles in patients with diagnosed chronic LBP. Our finding of a lower percentage of NK cells in these patients confirms our earlier finding that patients with musculoskeletal problems have a lower percentage of NK cells than do asymptomatic subjects. However, manipulative therapy was not shown to have a clinically significant effect on either the absolute n

Adult↗
PubMed1993

Initial characterization of the major mouse cytochrome P450 enzymes involved in the reductive metabolism of the hypoxic cytotoxin 3-amino-1,2,4-benzotriazine-1,4-di-N-oxide (tirapazamine, SR 4233, WIN 59075).

The benzotriazine di-N-oxide SR 4233 (tirapazamine, WIN 59075) is currently in phase I clinical trials as the lead compound in a series of novel and highly selective antitumour hypoxic cytotoxins. Reductive bioactivation is thought to proceed via a one-electron reduced, oxidizing nitroxide radical and also forms the inactive single N-oxide SR 4317 via radical disproportionation or a second one-electron reduction. In mouse liver microsomes reductive metabolism is catalysed predominantly by cytochrome P450 (70%) and cytochrome P450 reductase (30%). The aim of the present study was to examine which cytochrome P450 isozymes may be involved. Reduction of SR 4233 to SR 4317 was monitored by HPLC analysis. Metabolism by microsomes from both control and dexamethasone-induced BALB/c male mice was 70% inhibited by carbon monoxide. The cytochrome P450 inhibitor SKF 525A, following aerobic preincubation, also inhibited SR 4233 reduction by 58%. Reduction was induced 2-3-fold by dexamethasone and was not accountable by increases in cytochrome P450 reductase or DT-diaphorase. The induction data and the greater degree of inhibition of SR 4233 reduction by metyrapone compared to alpha-naphthoflavone suggested a possible involvement of Cyp2b, Cyp2c and Cyp3a cytochrome P450 subfamilies. Both Cyp3a (7.4-fold) and Cyp2b (1.8-fold) type enzymes were shown by western immunoblot analysis to be induced by dexamethasone, the latter correlating more closely with increased SR 4233 reductase activity and also with the 2-fold induction of benzphetamine N-demethylase, a Cyp2b-type enzyme. No inhibition of SR 4233 reduction was seen with erythromycin or cyclosporin A which act as substrates/inhibitors for Cyp3a-type enzymes, but inhibition was seen with p-nitrophenol and tolbutamide which are substrates for Cyp2el- and Cyp2c-type enzymes, respectively (11% and 25% inhibition in induced microsomes). SR 4233 itself inhibited benzphetamine N-demethylase, which is catalysed by Cyp2b-type enzymes but not erythromycin N-demethylase which is catalysed by Cyp3a-type isoforms. Immunoinhibition studies with epitope specific monoclonal antibodies were consistent with the major involvement of phenobarbitone- and steroid-inducible products of the Cyp2b and Cyp2c subfamilies. These forms contributed at least 53% and 26%, respectively, of the cytochrome P450-associated SR 4233 reductase activity in the induced microsomes. The findings support our earlier conclusion that cytochrome P450 is the major SR 4233 reductase in mouse liver and provides leads as to the possible involvement of specific isoforms in human tumours and normal tissues.

Animals↗
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

Unintentional suffocation by rebreathing: a death scene and physiologic investigation of a possible cause of sudden infant death.

As part of a 1-year study of sudden unexpected infant deaths in St. Louis, we performed both a specialized death scene investigation and, in selected cases, a physiologic reconstruction of the death scene with a rabbit model. Those cases in which the infant was found face down with nose and mouth covered by bedding were chosen for the physiologic testing; our goal was to assess the potential for lethal rebreathing of expired air. The physiologic studies reconstructed the infants' premortem ventilatory environment by using the head from an infant mannequin positioned on the actual bedding on which an infant had died and a rabbit breathing through the mannequin's nares. The specialized scene investigation was carried out in 31 of 32 deaths from sudden infant death syndrome, diagnosed by the usual methods. Of 31 infants, eight died with their faces downward and covered by bedding, and the bedding was obtained for further study in seven of eight cases. The bedding had low resistance to airflow (6.25 to 22.6 cm H2O/L per second), and caused considerable rebreathing that was lethal to the rabbits in five of seven cases. We conclude that items of bedding in common use are capable of causing lethal rebreathing by prone-sleeping infants whose nose and mouth become covered; suffocation by rebreathing was the probable mechanism of death in a substantial number of these deaths that had been attributed to sudden infant death syndrome.

Animals↗