Forest restoration treatments increased growth and did not change survival of ponderosa pines in severe drought, Arizona.

We report on survival and growth of ponderosa pines (Pinus ponderosa Douglas ex P. Lawson & C. Lawson) 2 decades after forest restoration treatments in the G. A. Pearson Natural Area, northern Arizona. Despite protection from harvest that conserved old trees, a dense forest susceptible to uncharacteristically severe disturbance had developed during more than a century of exclusion of the previous frequent surface-fire regime that ceased upon Euro-American settlement in approximately 1876. Trees were thinned in 1993 to emulate prefire-exclusion forest conditions, accumulated forest floor was removed, and surface fire was re-introduced at 4-years intervals (full restoration). There was also a partial restoration treatment consisting of thinning alone. Compared with untreated controls, mortality of old trees (mean age 243 years, maximum 462 years) differed by <1 tree ha-1 and old-tree survival was statistically indistinguishable between treatments (90.5% control, 92.3% full, 82.6% partial). Post-treatment growth as measured by basal area increment of both old (pre-1876) and young (post-1876) pines was significantly higher in both treatments than counterpart control trees for more than 2 decades following thinning. Drought meeting the definition of megadrought affected the region almost all the time since the onset of the experiment, including 3 years that were severely dry. Growth of all trees declined in the driest 3 years, but old and young treated trees had significantly less decline. Association of tree growth with temperature (negative correlation) and precipitation (positive correlation) was much weaker in treated trees, indicating that they may experience less growth decline from warmer, drier conditions predicted in future decades. Overall, tree responses after the first 2 decades following treatment suggest that forest restoration treatments have led to substantial, sustained improvement in the growth of old and young ponderosa pines without affecting old-tree survival, thereby improving resilience to a warming climate.

The Fire and Tree Mortality Database, for empirical modeling of individual tree mortality after fire.

Wildland fires have a multitude of ecological effects in forests, woodlands, and savannas across the globe. A major focus of past research has been on tree mortality from fire, as trees provide a vast range of biological services. We assembled a database of individual-tree records from prescribed fires and wildfires in the United States. The Fire and Tree Mortality (FTM) database includes records from 164,293 individual trees with records of fire injury (crown scorch, bole char, etc.), tree diameter, and either mortality or top-kill up to ten years post-fire. Data span 142 species and 62 genera, from 409 fires occurring from 1981-2016. Additional variables such as insect attack are included when available. The FTM database can be used to evaluate individual fire-caused mortality models for pre-fire planning and post-fire decision support, to develop improved models, and to explore general patterns of individual fire-induced tree death. The database can also be used to identify knowledge gaps that could be addressed in future research.

Slow carbon and nutrient accumulation in trees established following fire exclusion in the southwestern United States.

Increasing tree density that followed fire exclusion after the 1880s in the southwestern United States may have also altered nutrient cycles and led to a carbon (C) sink that constitutes a significant component of the U.S. C budget. Yet, empirical data quantifying century-scale changes in C or nutrients due to fire exclusion are rare. We used tree-ring reconstructions of stand structure from five ponderosa pine-dominated sites from across northern Arizona to compare live tree C, nitrogen (N), and phosphorus (P) storage between the 1880s and 1990s. Live tree biomass in the 1990s contained up to three times more C, N, and P than in 1880s. However, the increase in C storage was smaller than values used in recent U.S. C budgets. Furthermore, trees that had established prior to the 1880s accounted for a large fraction (28-66%) of the C, N, and P stored in contemporary stands. Overall, our century-scale analysis revealed that forests of the 1880s were on a trajectory to accumulate C and nutrients in trees even in the absence of fire exclusion, either because growing conditions became more favorable after the 1880s or because forests in the 1880s included age or size cohorts poised for accelerated growth. These results may lead to a reduction in the C sink attributed to fire exclusion, and they refine our understanding of reference conditions for restoration management of fire-prone forests.

Community occupancy responses of small mammals to restoration treatments in ponderosa pine forests, northern Arizona, USA.

In western North American conifer forests, wildfires are increasing in frequency and severity due to heavy fuel loads that have accumulated after a century of fire suppression. Forest restoration treatments (e.g., thinning and/or burning) are being designed and implemented at large spatial and temporal scales in an effort to reduce fire risk and restore forest structure and function. In ponderosa pine (Pinus ponderosa) forests, predominantly open forest structure and a frequent, low-severity fire regime constituted the evolutionary environment for wildlife that persisted for thousands of years. Small mammals are important in forest ecosystems as prey and in affecting primary production and decomposition. During 2006-2009, we trapped eight species of small mammals at 294 sites in northern Arizona and used occupancy modeling to determine community responses to thinning and habitat features. The most important covariates in predicting small mammal occupancy were understory vegetation cover, large snags, and treatment. Our analysis identified two generalist species found at relatively high occupancy rates across all sites, four open-forest species that responded positively to treatment, and two dense-forest species that responded negatively to treatment unless specific habitat features were retained. Our results indicate that all eight small mammal species can benefit from restoration treatments, particularly if aspects of their evolutionary environment (e.g., large trees, snags, woody debris) are restored. The occupancy modeling approach we used resulted in precise species-level estimates of occupancy in response to habitat attributes for a greater number of small mammal species than in other comparable studies. We recommend our approach for other studies faced with high variability and broad spatial and temporal scales in assessing impacts of treatments or habitat alteration on wildlife species. Moreover, since forest planning efforts are increasingly focusing on progressively larger treatment implementation, better and more efficiently obtained ecological information is needed to inform these efforts.

Posttreatment tree mortality after forest ecological restoration, Arizona, United States.

Pine-oak forests are of high ecological importance worldwide, but many are threatened by uncharacteristically severe wildfire. Forest restoration treatments, including the reintroduction of a surface fire regime, are intended to decrease fire hazard and emulate historic ecosystem structure and function. Restoration has recently received much management attention and short-term study, but little is known about longer-term ecosystem responses. We remeasured a replicated experimental restoration site in the southwestern United States 5 years after treatments. Basal area, tree density, and canopy cover decreased in the treated units at a faster rate than in controls. Delayed mortality, not evident right after treatment, decreased density modestly (13% in treated units and 10% in controls) but disproportionately affected large trees ("large" ponderosa pines were those with diameter at breast height [dbh] > or =37.5 cm; other species dbh > or =20 cm). In treated units, 10.9 large trees ha(-1) died, whereas 6.2 trees ha(-1) died in control units. Compared with reference conditions, the experimental blocks remained higher in pine density and, in three of the four blocks, in basal area. Pine trees grew significantly faster in treated units than in controls, enough to reach the reference level of basal area in 6 years. Although mortality of large trees is a concern, the treated units have vigorous growth and low density, indicating that they will be relatively resistant to future drought and fire events. Similar treatments may be beneficial in many areas of the United States and in related pine-oak ecosystems elsewhere.

Oral uracil and Ftorafur plus leucovorin: pharmacokinetics and toxicity in patients with metastatic cancer.

PURPOSE: To assess the pharmacokinetics of Ftorafur (tegafur, FT), 5-fluorouracil (5-FU), and uracil in 31 cancer patients who were enrolled in phase I studies of oral uracil and FT (UFT). The correlation between pharmacokinetic parameters and toxic effects of UFT was evaluated. METHODS: Uracil and FT were orally administered in a 4:1 molar ratio at FT doses of 200-400 mg/m2 per day. Patients also received leucovorin at 150 mg/day. Daily doses were divided into three doses and administered at 8-h intervals for 28 consecutive days. Plasma FT concentrations were measured by high-performance liquid chromatography, and plasma 5-FU and uracil concentrations were determined using gas chromatography-mass spectrometry. National Institutes of Health Common Toxicity Criteria were used for assessment of toxicity. RESULTS: The concentrations of FT, 5-FU, and uracil showed wide interpatient variations. Maximum plasma concentrations (Cp(max)) of all three compounds were achieved in 0.3 to 4.0 h. At the various study doses, the terminal half-life (t 1/2beta) of FT ranged from 3.9 to 5.9 h, the area under the concentration-versus-time curve (AUC0-6h) ranged from 16,220 to 52,446 (ng/ml)h, the total clearance (ClT) ranged from 100 to 175 ml/min, and the steady-state volume of distribution (Vd(ss)) ranged from 18.3 to 28.7 l. The 5-FU generated from FT had an apparent distribution half-life (t 1/2alpha) and an apparent elimination half-life (t 1/2beta) of 0.3-1.3 h and 4.9-7.0 h, respectively. The AUC0-6h of 5-FU ranged from 120 to 325 (ng/ml)h. Uracil had a t 1/2alpha of 0.2-0.5 h and the level quickly returned to the endogenous level. The AUC0-6h for uracil ranged from 605 to 3764 (ng/ml)h, the ClT ranged from 3225 to 7748 ml/min, and the Vd(ss) ranged from 341 to 1354 l. The Cp(max) and AUC0-6h of both FT and uracil were significantly correlated with FT doses (P-values of 0.0244 and 0.0112) and with uracil doses (P-values of 0.0346 and 0.0083), respectively. In addition to interpatient variations, intrapatient variations were also observed in six patients who had pharmacology studies done on days 1 and 26+/-2 at the same study dose. We found that the repeated treatment with UFT caused cumulative increases in the values of Cp(max), Ctrough, and AUC0-6h of FT and 5-FU. The major toxic effects observed were diarrhea and nausea and vomiting. The occurrence of these toxic effects correlated significantly with the Cp(max) and AUC0-6h of 5-FU. CONCLUSIONS: The pharmacology studies showed that FT and uracil were readily absorbed orally and that FT was rapidly converted to 5-FU. The preliminary findings suggest that determination of plasma levels of 5-FU after oral administration of UFT may help predict subsequent toxic effects.

Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2'-tetrahydrofuryl)-5-fluorouracil.

Plasma 5-fluorouracil (5-FU) levels were compared in the same patients after approximately equimolar doses (1.9 mmol/ m2/day) of 5-day continuous i.v. infusion of 5-FU (CIFU) and oral administration of a formulation of two combined pharmacological agents, uracil (U) plus N1-(2'-tetrahydrofuryl)-5-fluorouracil (ftorafur or FT), a prodrug of 5-FU. Ten patients received CIFU for 5 days, then, after a week wash-out period, began the 28-day oral UFT regimen, which was given in three daily divided doses. Following 1 h of CIFU, the plasma 5-FU levels reached a steady state of 0.6+/-0.2 microM (mean+/-SD; day 1), which was maintained for the entire 5-day infusion period (0.6+/-0.1 microM). In contrast, the maximum 5-FU concentrations (Cpmax) generated from oral UFT at 1 h after dose administration on days 1 and 5 were 2.1+/-1.5 microM and 2.3+/-1.9 microM, respectively, which were higher than the steady-state levels during CIFU. These high 5-FU levels disappeared with an apparent elimination half-life (tl/2,beta) of 5.2+/-2.4 h (day 1) and 7.2+/-3.9 h (day 5). On day 1 of both regimens, CIFU patients had significantly larger 5-FU area under the concentration versus time curve (AUC0-8h) values (4.4+/-1.3 microM.h) than the AUC value when they received the UFT regimen (2.6+/-1.7 microM.h; P = 0.02). However, by day 5, there were no significant differences between AUC0-8 h values in patients receiving CIFU and UFT, respectively (4.8+/-1.5 microM.h versus 3.8+/-2.2 microM.h; P = 0.30)]. On day 5, the average concentration of the metabolite 5-FU at steady-state (Css,aver) within dose interval of 8 h (0.48+/-0.28 microM) for the oral UFT treatment is comparable with the Cpss values of 5-FU from CIFU-treated patients. The post-UFT generated 5-FU pharmacokinetic parameters (higher Cp(mx, comparable Css,aver, equal AUC values, and longer apparent t1/2,beta of 5-FU) may make oral UFT a preferred method of delivering this fluoropyrimidine over CIFU. In addition, oral UFT would eliminate the incidence of venous thrombosis and catheter-related infections sometimes seen in patients treated with CIFU. Furthermore, the convenience and decreased cost of oral administration may be preferable for many patients, particularly those receiving 5-FU for palliation.

Clinical pharmacology of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo (7.4.1.0(2,7).0(10,12) tetradeca-2,4,6-trien-6,9-diyl diacetate (FK 973).

FK 973, a novel substituted dihydrobenzoxazine structurally similar to mitomycin C, is a derivative of the product isolated from Streptomyces sandaensis. In vitro and in rodents, it is a potent antitumor agent. During Phase I clinical trials, we evaluated the pharmacologic properties of FK 973 in eight adenocarcinoma patients after a 30-min i.v. infusion of doses ranging from 7 to 45mg/m2. An established enzyme immunoassay that measures the stable deacetylated active metabolite FR66980 showed that the plasma drug levels declined biphasically with a terminal half life (t1/2 beta) of 4.7 +/- 1.6hr (mean +/- S.D.) The total clearance rate was 438 +/- 113ml/(min/m2). Both the maximum plasma drug concentrations (Cmax) and the area under the concentration-versus-time curve (AUC) were dose related. In addition to nausea and vomiting, alopecia, and myelosuppression, three patients experienced a delayed vascular-leak syndrome. The 3 patients had received doses among the highest studied, and the toxicity appeared to be dose related and cumulative. The evidence suggests that higher doses generated higher Cmax and AUC values, which may be correlated with toxic effects.

Depletion of patients' plasma tryptophan using tryptophan side-chain oxidase columns.

The use of the enzyme tryptophan side-chain oxidase, isolated from Pseudomonas XA, was explored in 3 patients with refractory acute lymphocytic leukemia. Patients were given either a low-tryptophan diet or tryptophan-free hyperalimentation, prior to and during therapy. Their plasma, separated by pheresis, was continuously passed through a tryptophan depletion column containing the immobilized tryptophan side-chain oxidase. Up to 4 plasma volumes were passed through the column daily, 5 days per week for 2-3 weeks, and plasma tryptophan levels, both free and total, were measured by high-performance liquid chromatography. Pre- and postcolumn plasma samples were collected throughout the pheresis procedure. All postcolumn plasma samples had unmeasurable tryptophan levels throughout the treatment period, whereas precolumn samples were always measurable. Generally, tryptophan levels of plasma isolated from peripheral blood decreased after therapy, but rebounded by the next day. The enzyme depletion column reduces circulating plasma tryptophan levels, and its use is well tolerated by patients. However, further development of this method will require study of the effects of diet and of the duration, interval, and frequency of use of this column on therapeutic efficacy. Problems include difficulties with extended diet compliance and apparently intensive mobilization of tryptophan from body stores, which may preclude the clinical application of this enzyme depletion column.

Clinical pharmacology of combined oral uracil and ftorafur.

Phase I clinical trials of the combination of oral uracil with ftorafur (Ft) were conducted in patients with solid tumors over either a 5-day (345 mg/m2/day) or a 28-day (160 mg/m2/day) period. The uracil dose, which was four times the Ft dose (molar basis), was previously shown to be optimal at inhibiting the degradation of 5-fluorouracil (5-FU). Pharmacology was performed on the first dose of the first day of therapy. Ft was measured by HPLC, whereas uracil and 5-FU were measured using GC/MS. Plasma levels were highest for Ft, followed by uracil and 5-FU at all time points. Peak and trough levels after selected subsequent doses were also measured; these varied in the individual from day to day. Maximum plasma levels (Cpmax) for Ft, uracil, and 5-FU except in one patient were achieved at 0.6-2.1 hr, 0.6-4.1 hr, and 0.7-2.0 hr, respectively. Generally, lower doses yielded more rapid decay of 5-FU and uracil levels than did higher doses. No correlation was observed between myelotoxicities (granulocytopenia and leukopenia) and the Cpmax and AUC0-6hr of Ft (p > 0.2). However, after the highest uracil and Ft dose (approximately 300 mg/m2/Ft study dose), the Cpmax and AUC0-6hr values of 5-FU revealed significant differences (p < 0.05) in three patients each with and without myelotoxicity. These associations were similarly observed with uracil. Our findings thus indicate that measuring plasma uracil and more importantly, the 5-FU levels, may predict hematological toxicity and enable subsequent dose adjustments.

Determination of plicamycin in plasma by radioimmunoassay.

This article describes a method for the determination of plicamycin in plasma by radioimmunoassay. The anti-plicamycin antibody was produced against a plicamycin-bovine serum albumin conjugate prepared by using diazotized p-aminobenzoic acid as a cross-linker. The radiolabeled ligand, 125I-plicamycin, was prepared by the chloramine-T method. The linear plicamycin concentration range was 7-400 ng/ml. The coefficients of variation for intra- and interday variabilities were 7.5 and 15%, respectively. No interference was observed from either the structurally related chromomycin A or concomitantly used drugs hydroxyurea or allopurinol. With this method of testing, plicamycin levels in plasma could be determined in patients receiving small (0.85-1.0 mg/m2) therapeutic plicamycin doses. Preliminary pharmacokinetic data in humans indicate that the plasma drug disappearance curve was biphasic with a mean elimination half-life of 10.6 +/- 1.7 h, total clearance rate of 11.1 +/- 0.4 ml/min/m2, and area under the plasma drug concentration-time curve of 1,289-1,546 ng-h/ml. This assay method is clinically useful for pharmacokinetic studies of plicamycin and may be helpful in the design of rational therapeutic drug trials.

Clinical pharmacology of 1-beta-D-arabinofuranosyl-5-azacytosine (fazarabine) following 72-hour infusion.

The clinical pharmacology of fazarabine (1-beta-D-arabinofuranosyl-5-azacytosine), a structural analogue of 1-beta-D-arabinofuranosylcytosine (ara-C) and 5-azacytidine, was assessed in 14 patients with various malignancies during a phase I trial. Since the starting dose for the protocol was low (0.2 mg/m2/hr over a 72-hr continuous iv infusion), a radioimmunoassay (RIA) using commercially available ara-C antibody and [3H]ara-C was developed to measure the anticipated low plasma drug levels. The assay could be used to measure fazarabine accurately in plasma and urine with a sensitivity of 0.08 ng/ml. The RIA does not require extraction of samples. Using both RIA and HPLC, similar results were obtained in plasma samples from a patient receiving a high dose (180 mg/m2/hr) of fazarabine. The assay is simple, sensitive, reproducible, and specific. Following the infusion, plasma levels declined triphasically with a terminal half-life of 5.7 +/- 2.0 hr. The AUC was linearly related to dose. When the various doses were normalized to 1.75 mg/m2/hr (the maximum tolerated dose as determined from the phase I trial) the mean AUC value was 4232 +/- 987 (ng/ml)hr. Plasma steady-state drug levels (CPss) were achieved in 2-4 hr and were linearly dependent to dose. Also, when normalized, the mean CPss was 58 +/- 13 ng/ml, which is within the reported concentration range necessary for inhibiting malignant cell growth. Total clearance was rapid, 528 +/- 138 ml/(m2.min), and not dose-related.

Metabolism and disposition of (R)-4-[3-(2-hydroxy-2-phenyl)ethylamino-3-methylbutyl]benzamide Hcl (LY 195448) in rodents.

The disposition and metabolism of (R)-4-[3-(2-hydroxy-2-phenyl)ethylamino-3-methylbutyl]benzamide HCl, or LY 195448 (LY), were studied in rodents 1 hr following a single iv injection of 14C-LY at 30 mg/m2 (10 mg/kg mice and 5 mg/kg rats), In all tissues and carcases, recovery of 14C was nearly complete. The majority of radioactivity was recovered from intestine (40%) whereas liver and urine accounted for 10% each, kidney for 3-5%, and plasma for 1-3% of total administered radioactivity. Analyzing by HPLC and TLC, para-hydroxy-LY (para-OH-LY) in addition to unchanged drug, was found in all tissues. Meta-OH-LY was detected only in urine, intestine and kidney. These metabolites were found to be conjugated with either glucuronide or sulfate moieties. Peaks coeluting with authentic para-OH-meta-methoxy-LY and di-OH-LY were also observed.

Clinical pharmacology of trimetrexate.

The clinical pharmacokinetics of trimetrexate were determined in 11 patients during the phase I trial. The plasma drug disappearance curve was triphasic, with a t1/2 alpha of 8 +/- 5 minutes, t1/2 beta of 102 +/- 48 minutes, and t1/2 gamma of 15.2 +/- 5.7 hours. The AUC was 373 +/- 336 (micrograms/ml) hr (normalized to a dose of 200 mg/m2), volume of distribution by the area method (Varea) was 25.2 +/- 16.1 L/m2, total clearance (CL) was 14 +/- 8 ml/min/m2, and renal clearance (CLR) was 8 +/- 6 ml/min/m2. Four patients who received 190 to 200 mg/m2 did not develop severe toxicity. However, three patients who received 120 to 210 mg/m2 developed severe myelosuppression, skin rash, and stomatitis. This latter group had significantly longer terminal half-lives, greater AUCs, smaller Vareas, and lower rates of CL and CLR. One of these patients received an unusually large total amount of trimetrexate (470 mg) because of his obesity. The remaining two patients had renal problems. One developed toxicity despite having received a reduced dose (120 mg/m2) because of impaired renal function. The other patient, with normal renal function, had ascites and had undergone a unilateral nephrectomy for renal carcinoma. These data suggest that prolonged exposure to high trimetrexate levels may lead to increased toxicity. Dosage adjustment may have to be considered for patients who have renal dysfunction.