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PubMed1985

The theoretical aspects of the time dependent Z equation as a means of postmortem interval estimation using body temperature data only.

It has been clearly demonstrated that the rectal cooling curve does not obey Newton's Law, which is exponential. The first success in modelling rectal cooling mathematically was achieved by Marshall and Hoare [1]. An amendment was made to the simple exponential curve which led to a good mathematical model, exhibiting the three main sections of rectal cooling, i.e. lag, linear and quasi-exponential. The resultant method of postmortem interval estimation required a knowledge of the body mass and height. The present study has led to a totally different amendment to Newton's Law, which provides a means of postmortem interval estimation from body temperature data only. The derivation of the method, with a background on Newton's Law follows.

Body Temperature↗
PubMed2004

Symphoria: the success of modeling the active site function of oxo-molybdoenzymes.

The success of modeling the active site function of oxomolybdoenzymes have been claimed generally on the basis of reactivity of the synthetic analogues towards PPh(3) or DMSO (dimethyl sulfoxide). Here it has been shown that the success of modeling the active site function of these enzymes may not be determined by the ability of a model to undergo oxotransfer with PPh(3) or DMSO (except for the modeling of DMSO reductase) and one should adhere to the criteria accepted by the bioinorganic community. A critical evaluation of two of those criteria which requires a synthetic analogue (a) should react with the enzyme substrate (b) should follow the same rate law as does the enzyme, has been presented in this paper. We have shown that the fulfillment of criterion (b) and the inhibition phenomena to that effect both are dictated by symphoria (from sympherin in Greek: the bringing together of reactants into the proper spatial relationship) on the basis of kinetic studies of the reactivity of enzyme substrate the HSO(3)(-) and its analogues (anions of oxyacids of phosphorous) towards a functional model sulfite oxidase [Bu(4)N](2)[Mo(VI)O(2)(mnt)(2)] (mnt(2-)=1,2-dicyanoethylenedithiolate) but with the caveat that the mechanistic inference drawn from such studies may not be the same as in the case of native enzyme. In view of this ambiguity it has been pointed out that the fulfillment of this criterion is not a definitive conclusion towards our understanding of the structure-function relationship of an enzyme and, therefore, the criterion of a 'structural analogue' and 'functional analogue' have been revised subject to an amendment of criterion (a) to include substrate analogues. It has also been shown for the first time on the basis of kinetic studies that the effect of medium can lead to substrate - inhibitor type dualism and hence the effect of medium is also a factor that can play a key role for the success of modeling the active site function of an enzyme. Here we also provide the details of the inhibition mechanisms proposed in our earlier report with an indirect proof to that effect.

Binding Sites↗
PubMed1999

Remacemide hydrochloride: a double-blind, placebo-controlled, safety and tolerability study in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Remacemide hydrochloride and its principal active desglycinyl metabolite are low-affinity noncompetitive N-methyl-D-aspartate (NMDA)-receptor channel blockers. Remacemide hydrochloride has demonstrated neuroprotection in animal models of hypoxia and ischemic stroke. This study assessed the safety, tolerability, and pharmacokinetics of ascending doses of remacemide hydrochloride in patients with recent onset (within 12 hours) ischemic stroke. METHODS: This was a placebo-controlled, dose escalating, parallel group study. Groups of 8 patients (6 active, 2 placebo) were planned to receive twice-daily treatment, with l00 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg remacemide hydrochloride given as 2 intravenous infusions followed by 6 days' oral treatment. Patients who were unable to swallow discontinued study medication but continued to be monitored for safety; these patients were replaced. A CT or MRI scan was performed within 48 hours of admission to establish the cause of focal neurological deficit. Patients with ischemic stroke continued in the study. Patients with other causes of focal neurological deficit were withdrawn and replaced. Because the frequency of dysphagia after stroke in the first dose group (100 mg BID) was higher than had been anticipated, the protocol was amended so that subsequent dose groups received 6 intravenous infusions (2 doses per day for 3 days). Neurological and functional outcome data were collected, but the study was not powered to demonstrate drug efficacy. Patient safety was assessed by clinical observation, laboratory tests, and ECGs, while tolerability was assessed by recording adverse events. Blood sampling was included to determine plasma concentrations of remacemide and the desglycinyl metabolite at fixed points during the dosing period. RESULTS: The most common adverse events considered by the investigator to be possibly treatment related were related to the central nervous system (CNS), and these events appeared to increase with dose. Four patients were withdrawn from the study because of CNS-related events: 1 in the placebo group, 1 in the 500 mg BID group, and 2 in the 600 mg BID group. Infusion site reactions and gastrointestinal upset were also reported and considered to be treatment related. One patient in the placebo group and 4 patients in the 600 mg BID dose group experienced vomiting, whereas this event was not reported by patients in the other dose groups. CONCLUSIONS: On the evidence of this study, the maximum well-tolerated dose for remacemide hydrochloride in acute stroke is 400 mg BID. Doses of 200 mg BID or higher attained the putative neuroprotective plasma concentrations of remacemide predicted from animal models (250 to 600 ng/mL). The expected gradual accumulation of active metabolite might suggest that optimal neuroprotective concentrations are unlikely to be achieved within the early hours of treatment at this dose. However, plasma concentrations do not directly reflect brain concentrations, because studies in rats show that remacemide and the desglycinyl metabolite rapidly reach comparable brain concentrations within 1 hour, despite a lower plasma concentration of the metabolite.

Acetamides↗
PubMedDate not supplied

[Use of topical antifungal agents].

Topical antifungal agents are not absorbed when given orally. They act by direct contact on the fungus, this type of action requires the simultaneous presence of antifungal and fungus for a minimum of time. There are a large number of compounds belonging to different families of antifungals: polyens, azoles, allylamine and morpholine and antiseptic substances. The treatment of oropharyngeal candidiasis is based on topical antifungal agents: amphotericin B or nystatin, imidazoles such as clotrimazole or miconazole. Systemic antifungal agents are indicated in case or poor compliance to topical agents, in prophylaxis of highly relapsing disease, in oesophageal candidiasis and in Candida onychomycosis. A topical antifungal agent is the first choice to treat Candida intertrigo. In any case predisposing factors should be eradicated or amended. Infection to Malassezia spp. are treated topically with azoles or selenium sulphur. Oral ketoconazole is an alternative in severe cases. Dermatophytosis requires a systemic antifungal treatment such as terbinafine in chronic, dry, moccassin type palmoplantar infection and for onychomycosis. Intertrigo and tinea corporis are treated with topical agents such as azoles, terbinafine or tolnaftate. Tinea capitis responds to oral griseofulvine, however a topical antifungal must be added to eradicate contagious conidia. Whatever the localisation is, an other superficial site of infection must be looked for and a source of infection should be investigated and eradicated.

Animals↗
PubMed1991

Medicare Program; OBRA '87 conforming amendments; correction--HCFA. Final rule; correction.

Federal Register document No. 91-4415, beginning on page 8832 of the issue of Friday March 1, 1991, conformed numerous sections of the HCFA regulations with self-executing provisions of the Omnibus Budget Reconciliation Act of 1987. A one-page revision, dealing with the application of the Medicare blood deductible, was unintentionally omitted from column 2 of page 8852, where only the heading "P. Part 489" appears. Also omitted was a conforming change needed in section 482.12(c)(1)(iv) to reflect the amendment made by section 9336(a) of the Omnibus Budget Reconciliation Act of 1986 (Pub. L. 99-509). Section 9336(a) removed the provision that limited Medicare coverage of optometrist services to aphakia. This means that any optometrist services permitted by State medical practice laws are now covered. This notice corrects the omissions by publishing the amendment to part 489, which was discussed in section "D" of the preamble in the first column of page 8834, and including the revision of section 482.12(e)(1)(iv). The notice also makes numerous other minor corrections.

Aged↗
PubMed1992

Medicare and state health care programs: fraud and abuse; safe harbors for protecting health plans--HHS. Interim final rule with request for comment.

In accordance with section 14 of the Medicare and Medicaid Patient and Program Protection Act of 1987, this interim final rule establishes two new safe harbors and amends one existing safe harbor to provide protection for certain health care plans, such as health maintenance organizations and preferred provider organizations. The first new provision protects certain incentives to enrollees (including waiver of coinsurance and deductible amounts) paid by health care plans. The second new provision protects certain negotiated price reduction agreements between health care plans and contract health care providers. Finally, an existing safe harbor has been amended to protect certain agreements entered into between hospitals and Medicare SELECT insurers. These safe harbors specifically set forth various standards and guidelines that, if met, will result in the particular arrangement being protected from criminal prosecution or civil sanctions under the anti-kickback provisions of the statute.

Centers for Medicare and Medicaid Services, U.S.↗
PubMed2005

[Ethics as a scientific basis for animal protection - on the advancement and amendment of the Codex Veterinarius].

Seven years ago, the veterinary association for animal protection (Tieraerztliche Vereinigung fuer Tierschutz e.V., TVT) in Germany first published an orientation guide on the ethics of animal protection aimed at the entire veterinary profession: the "Codex Veterinarius - ethical guiding principles on veterinary action for the good and the protection of animals". The dilemmas of the veterinary profession have not changed since then, but as the principle that "nothing can be so good that it cannot be improved" also applies to the Codex, the two authors have attempted to optimise the few weak spots of the Codex. Joerg Luy sees the task of the Codex in surpassing the animal protection law in two respects: on the one hand regarding moral aspects that cannot be regulated (e.g. respect for the "intrinsic value" of the animal, which is greater than its "utilitarian value") and on the other hand in cases where the law does not live up to its own goals (e.g. regarding the inconsistent regulation on causing "longer term or repeated grave pain or suffering").

Animal Rights↗
PubMed2005

Consensus conference on cancer registration of brain and central nervous system tumors.

The passage of Public Law 107-260, the Benign Brain Tumor Cancer Registries Amendment Act, in October 2002 has made the collection of all primary brain tumors a reality. However, at the first Consensus Conference on Brain Tumor Definition for Registration in 2002, and during the development of training materials for benign brain tumor collection, several issues were identified that were tabled for future discussion. These and other issues were addressed at the subsequent 2003 Consensus Conference on Cancer Registration of Brain and Central Nervous System Tumors, at which the Central Brain Tumor Registry of the United States facilitated a discussion among epidemiologists, neurosurgeons, and neuropathologists. Multidisciplinary consensus was reached on four points, for which the following recommendations were made: (1) amend the histology coding scheme for cysts and tumor-like lesions that currently have a code in the third edition of the International Classification of Disease for Oncology (ICDO), (2) collect data on all instances of specific cysts and tumor-like lesions that are located in brain and other CNS sites but currently lack ICDO codes, (3) establish a new ICDO topography site for skull base tumors for the brain and CNS, and (4) collect data on genetic syndromes in patients diagnosed with brain or CNS tumors. We view this conference as part of a continuing process. Because classification of primary intracranial and other CNS tumors is dynamic, and the registration and coding of these tumors will need to be periodically reviewed.

Central Nervous System Neoplasms↗
PubMed2006

Estimating the unknown components of nutrient mass balances for forestry plantations in mine rehabilitation, upper Hunter Valley, New South Wales, Australia.

Commercial forestry plantations as a postmining land use in the Upper Hunter Valley of New South Wales, Australia are restricted by both the poor nutrient availability of mining substrates and low regional rainfall. An experiment was conducted to investigate whether municipal waste products and saline groundwater from coal mining operations could improve early tree growth without impacting on the environment through salt accumulation and/or nutrient enrichment and changes in groundwater quality. Potential impacts were investigated by quantifying the nutrient cycling dynamics within the plantation using an input-output mass balance approach for exchangeable calcium (Ca(2+)), exchangeable magnesium (Mg(2+)), exchangeable potassium (K(+)), exchangeable sodium (Na(+)), nitrogen (N), and phosphorus (P). Measured inputs to and outputs from the available nutrient pool in the 0-30 cm of the overburden subsystem were used to estimate the net effect of unmeasured inputs and outputs (termed "residuals"). Residual values in the mass balance of the irrigated treatments demonstrated large leaching losses of exchangeable Ca, Mg, K, and Na. Between 96% and 103% of Na applied in saline mine-water irrigation was leached below the 0-30-cm soil profile zone. The fate of these salts beyond 30 cm is unknown, but results suggest that irrigation with saline mine water had minimal impact on the substrate to 30 cm over the first 2 years since plantation establishment. Accumulations of N and P were detected for the substrate amendments, suggesting that organic amendments (particularly compost) retained the applied nutrients with very little associated losses, particularly through leaching.

Calcium↗
PubMed2002

A micro case study of the legal and administrative arrangements for river health in the Kangaroo River (NSW).

Kangaroo Valley is a drinking water supply catchment for Kangaroo Valley village, parts of the Southern Highlands and Sydney. It is also a popular recreation area both for swimming and canoeing. Land use has traditionally been dominated by dairy farming but there has been significant and continuing development of land for hobby farms and rural residential subdivision. Dairy industry restructuring has affected the viability of some farms in the Valley and created additional pressure for subdivision. River health is a function of flows, water quality, riparian vegetation, geomorphology and aquatic habitat and riverine biota. River flows in the Kangaroo River are affected by water extraction and storage for urban water supply and extraction by commercial irrigators and riparian land holders which have a significant impact at low flows. Current water quality often does not meet ANZECC Guidelines for primary contact and recreation and the river is a poor source of raw drinking water. Key sources of contaminants are wastewater runoff from agriculture, and poorly performing on-site sewage management systems. Riparian vegetation, which is critical to the maintenance of in-stream ecosystems suffers from uncontrolled stock access and weed infestation. The management of land use and resulting diffuse pollution sources is critical to the long term health of the river. The Healthy Rivers Commission of New South Wales Independent Inquiry into the Shoalhaven River System Final Report July, 1999 found that the longer term protection of the health of the Kangaroo River is contingent upon achievement of patterns of land use that have regard to land capability and also to the capability of the river to withstand the impacts of inappropriate or poorly managed land uses. This micro case study of Kangaroo Valley examines the complex legal and administrative arrangements with particular reference to the management of diffuse pollution for river health. In the past, diffuse pollution has fallen through the gaps in legislation and its administration. Although water pollution legislation is broad enough to embrace diffuse pollution, in practice the Environment Protection Authority has focused on regulating point sources. Water legislation has traditionally been concerned with issues of water quantity rather than water quality. Legislation which allows agency intervention in relation to land degradation has grown from soil conservation roots, neglecting the flow-on effects upon water quality. Under the land use planning system existing land uses are protected from new regulatory requirements. A number of recent developments in NSW law and its administration have set the scene for addressing this past neglect. Water planning provisions in the Water Management Act 2000 have the potential to enable community based Water Management Committees to move away from a narrow focus on water quantity to the broader issues of river health, including water quality. Improved management of on-site sewage management systems is expected as a result of the Local Government (Approvals) Amendment (Sewage Management Regulation) 1998. A draft Regional Environmental Plan prepared for the Sydney Catchment Authority aims to improve the assessment of new development in terms of its impact on drinking water quality. It also moves away from an exclusive concern with controlling new development towards grappling with existing uses. Proposed amendments to the Environmental Planning and Assessment Act, 1979 as detailed in the White Paper, Plan First (2001) include the integration of imperatives derived from catchment strategies and water management plans into local land use plans.

Animals↗
PubMed2003

Regulating (for the benefit of) future persons: a different perspective on the FDA's jurisdiction to regulate human reproductive cloning.

The Food and Drug Administration (FDA) has taken the position that human reproductive cloning falls within its regulatory jurisdiction. This position has been subject to criticism on both procedural and substantive grounds. Some have contended that the FDA has failed to follow administrative law principles in asserting its jurisdiction, while others claim the FDA is ill suited to the task of addressing the ethical and social implications of human cloning. This Article argues, that, notwithstanding these criticisms, the FDA could plausibly assert jurisdiction over human cloning as a form of human gene therapy, an area in which the FDA is already regarded as having primary regulatory authority. Such an assertion would require that the FDA's jurisdiction extend to products affecting future persons, i.e., those not yet born. This Article demonstrates, for the first time, that such jurisdiction was implicit in the enactment of the 1962 Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act and that the FDA has historically relied on such authority in promulgating regulations for drugs and devices.

Cloning, Organism↗
PubMed2003

A comparison of DNA profiling techniques for monitoring nutrient impact on microbial community composition during bioremediation of petroleum-contaminated soils.

Amplicon length heterogeneity PCR (LH-PCR) and terminal restriction fragment length polymorphisms (TRFLP) were used to monitor the impact that nutrient amendments had on microbial community dynamics and structural diversity during bioremediation of petroleum-contaminated soils. Slurried soils contaminated with petroleum hydrocarbons were treated in airlift bench-scale bioreactors and were either amended with optimal inorganic nutrients or left unamended. Direct DNA extraction and PCR amplification of whole eubacterial community DNA were performed with universal primers that bracketed the first two or three hypervariable regions of the 16S rDNA gene sequences. The LH-PCR method profiled a more diverse microbial community than did the TRFLP method. The LH-PCR method also tracked differences between the communities due to nutrient amendments. An in silico database search for bacterial genera with amplicon lengths represented in the community fingerprints was performed. It was possible to qualitatively identify different groups in the microbial community based on the amplicon length variations. A similar "virtual" search was performed for the TRFLP fragments using the web-based TAP-TRFLP program. Cloning and sequencing of the PCR products confirmed the in silico database matches. The application of the LH-PCR method as a monitoring tool for bioremediation could greatly enhance and extend the current understanding of the microbial community dynamics during the biodegradation of environmental contaminants.

Bacteria↗
PubMedDate not supplied

Environmental risks of applying sewage sludge compost to vineyards: carbon, heavy metals, nitrogen, and phosphorus accumulation.

Biosolids are applied to vineyards to supply organic matter. However, there is concern that this practice can increase the concentration of macronutrients and heavy metals in the soil, some of which can leach. We evaluated the environmental hazard of sewage sludge compost applied in March 1999 at 10, 30, and 90 Mg ha-1 fresh weight in a vineyard in southeastern France. Soil organic matter increased in all plots by 3 g kg-1 18 mo after the amendment. Neither total nor available heavy metal concentrations increased in the soil. Mineral nitrogen (N) in the topsoil of amended plots of 10, 30, and 90 Mg ha-1 increased by 5, 14, and 26 kg (NO3(-)-N + NH4(+)-N) ha-1, respectively, the first summer and by 2, 5, and 10 kg (NO3(-)-N + NH4(+)-N) ha-1, respectively, the second summer compared with controls. At the recommended rate, risks of N leaching is very low, but phosphorus (P) appeared to be the limiting factor. Phosphorus significantly increased only in plots amended with the highest rate in the topsoil and subsoil. At lower rates, although no significant differences were observed, P added was greater than the quantities absorbed by vines. In the long run, P will accumulate in the soil and may reach concentrations that will pose a risk to surface waters and ground water. Therefore, although the current recommended rate (10 Mg ha-1) increased soil organic matter without the risk of N leaching, total sewage sludge loading rates on vineyards should be based on P concentrations.

Agriculture↗
PubMed2003

Application of ultrafiltration and stable isotopic amendments to field studies of mercury partitioning to filterable carbon in lake water and overland runoff.

Results from pilot studies on colloidal phase transport of newly deposited mercury in lake water and overland runoff demonstrate that the combination of ultrafiltration, and stable isotope amendment techniques is a viable tool for the study of mercury partitioning to filterable carbon. Ultrafiltration mass balance calculations were generally excellent, averaging 97.3, 96.1 and 99.8% for dissolved organic carbon (DOC), total mercury (Hg(T)), and methylmercury (MeHg), respectively. Sub nanogram per liter quantities of isotope were measurable, and the observed phase distribution from replicate ultrafiltration separations on lake water agreed within 20%. We believe the data presented here are the first published colloidal phase mercury data on lake water and overland runoff from uncontaminated sites. Initial results from pilot-scale lake amendment experiments indicate that the choice of matrix used to dissolve the isotope did not affect the initial phase distribution of the added mercury in the lake. In addition there was anecdotal evidence that native MeHg was either recently produced in the system, or at a minimum, that this 'old' MeHg partitions to the same subset of DOC that binds the amended mercury. Initial results from pilot-scale overland runoff experiments indicate that less than 20% of newly deposited mercury was transported in the filterable fraction (<0.7 microm). There is some indication of colloidal phase enrichment of mercury in runoff compared to the phase distribution of organic carbon, but the mechanism of this enrichment is unclear. The phase distribution of newly deposited mercury can differ from that of organic carbon and native mercury, suggesting that the quality of the carbon (available ligands), not the quantity of carbon, regulates partitioning. Further characterization of DOC is needed to clarify the underlying mechanisms.

Biological Availability↗
PubMed2005

The broad spectrum of quality in deceased donor kidneys.

The quality of the deceased donor organ clearly is one of the most crucial factors in determining graft survival and function in recipients of a kidney transplant. There has been considerable effort made towards evaluating these organs culminating in an amendment to allocation policy with the introduction of the expanded criteria donor (ECD) policy. Our study, from first solitary adult deceased donor transplant recipients from 1996 to 2002 in the National Scientific Transplant Registry database, presents a donor kidney risk grade based on significant donor characteristics, donor-recipient matches and cold ischemia time, generated directly from their risk for graft loss. We investigated the impact of our donor risk grade in a naive cohort on short- and long-term graft survival, as well as in subgroups of the population. The projected half-lives for overall graft survival in recipients by donor risk grade were I (10.7 years), II (10.0 years), III (7.9 years), IV (5.7 years) and V (4.5 years). This study indicates that there is great variability in the quality of deceased donor kidneys and that the assessment of risk might be enhanced by this scoring system as compared to the simple two-tiered system of the current ECD classification.

Adolescent↗
PubMed2005

Dehalogenation of the herbicides bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) and ioxynil (3,5-diiodino-4-hydroxybenzonitrile) by Desulfitobacterium chlororespirans.

Desulfitobacterium chlororespirans has been shown to grow by coupling the oxidation of lactate to the metabolic reductive dehalogenation of ortho chlorines on polysubstituted phenols. Here, we examine the ability of D. chlororespirans to debrominate and deiodinate the polysubstituted herbicides bromoxynil (3,5-dibromo-4-hydroxybenzonitrile), ioxynil (3,5-diiodo-4-hydroxybenzonitrile), and the bromoxynil metabolite 3,5-dibromo-4-hydroxybenzoate (DBHB). Stoichiometric debromination of bromoxynil to 4-cyanophenol and DBHB to 4-hydroxybenzoate occurred. Further, bromoxynil (35 to 75 microM) and DBHB (250 to 260 microM) were used as electron acceptors for growth. Doubling times for growth (means +/- standard deviations for triplicate cultures) on bromoxynil (18.4 +/- 5.2 h) and DBHB (11.9 +/- 1.4 h), determined by rate of [14C]lactate uptake into biomass, were similar to those previously reported for this microorganism during growth on pyruvate (15.4 h). In contrast, ioxynil was not deiodinated when added alone or when added with bromoxynil; however, ioxynil dehalogenation, with stoichiometric conversion to 4-cyanophenol, was observed when the culture was amended with 3-chloro-4-hydroxybenzoate (a previously reported electron acceptor). To our knowledge, this is the first direct report of deiodination by a bacterium in the Desulfitobacterium genus and the first report of an anaerobic pure culture with the ability to transform bromoxynil or ioxynil. This research provides valuable insights into the substrate range of D. chlororespirans.

Anaerobiosis↗
PubMed1984

European Ethical Review Committee: the experience of an international ethics committee reviewing protocols for drug trials.

An international ethics review committee, founded seven years ago, has several unusual features: it selects its own members, who are independent of the drug industry; it includes members with no medical or paramedical background, such as lay people and lawyers; and it reviews protocols together with the study's sponsor. Membership of 31 from nine European countries enables frequent meetings and there is a full meeting of the committee every year to review progress and consider policy. Of the first 294 protocols for phase I, II, or III trials reviewed, 37 were admitted outright, 243 were amended (usually during the discussion of the protocol), and 14 were rejected. It is suggested that, to overcome the problem of ethics review in smaller institutions, regional health authorities in Britain might consider establishing similar committees.

Clinical Trials as Topic↗
PubMed1996

Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer.

PURPOSE: To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS: Patients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response. RESULTS: One complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case. CONCLUSION: Irinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.

Adenocarcinoma↗