Determination of plasma levels of the active thiol form of the direct-acting PrC-210 ROS-scavenger using a fluorescence-based assay.

PrC-210 is a direct-acting ROS-scavenger. It's active when administered orally, IV, or topically; it has none of the nausea/emesis nor hypotension side effects that have precluded human amifostine use. PrC-210 confers 100% survival to mice and rats that received an otherwise 100% lethal radiation dose and 36% reduction of ischemia-reperfusion-induced mouse myocardial infarct damage, and thus is a viable candidate to prevent human ROS-induced ischemia-reperfusion and ionizing radiation toxicities. We report the first assay for the pharmacologically active PrC-210 thiol in blood. PrC-210 has no double-bonds nor light absorption, so derivatizing the thiol with a UV-absorbing fluorochrome enables quantification. This assay: i) is done on the benchtop; it's read with a fluorescence plate reader, ii) provides linear product formation through 60 min, iii) quantifies µM to low mM rodent blood levels of PrC-210 that confer complete radioprotection, iv) accurately reflects PrC-210 thiol formation of mixed disulfides with other thiols in blood, and v) shows excellent between-day assay outcome with very low standard deviation and coefficient of variation. A fluorescence assay quantifying formation of a PrC-210 thiol-bimane adduct enables measurement of blood PrC-210 thiol. A blood assay will help in the development of PrC-210 for use in the human clinical setting.

Impact of the PrC-210 Radioprotector Molecule on Cancer Deaths in p53-Deficient Mice.

Radiation-induced cancer is an ongoing and significant problem, with sources that include clinics worldwide in which 3.1 billion radiology exams are performed each year, as well as a variety of other scenarios such as space travel and nuclear cleanup. These radiation exposures are typically anticipated, and the exposure is typically well below 1 Gy. When radiation-induced (actually ROS-induced) DNA mutation is prevented, then so too are downstream radiation-induced cancers. Currently, there is no protection available against the effects of such <1 Gy radiation exposures. In this study, we address whether the new PrC-210 ROS-scavenger is effective in protecting p53-deficient (p53-/-) mice against X-ray-induced accelerated tumor mortality; this is the most sensitive radiation tumorigenesis model currently known. Six-day-old p53-/- pups received a single intraperitoneal PrC-210 dose [0.5 maximum tolerated dose (MTD)] or vehicle, and 25 min later, pups received 4.0 Gy X-ray irradiation. At 5 min postirradiation, blood was collected to quantify white blood cell c-H2AX foci. Over the next 250 days, tumor-associated deaths were recorded. Findings revealed that when administered 25 min before 4 Gy X-ray irradiation, PrC-210 reduced DNA damage (c-H2AX foci) by 40%, and in a notable coincidence, caused a 40% shift in tumor latency/incidence, and the 0.5 MTD PrC210 dose had no discernible toxicities in these p53-/- mice. Essentially, the moles of PrC-210 thiol within a single 0.5 MTD PrC-210 dose suppressed the moles of ROS generated by 40% of the 4 Gy X-ray dose administered to p53-/- pups, and in doing so, eliminated the lifetime leukemia/lymphoma risk normally residing "downstream" of that 40% of the 4 Gy dose. In conclusion: 1. PrC-210 is readily tolerated by the 6-day-old p53-/- mice, with no discernible lifetime toxicities; 2. PrC-210 does not cause the nausea, emesis or hypotension that preclude clinical use of earlier aminothiols; and 3. PrC-210 significantly increased survival after 4 Gy irradiation in the p53-/- mouse model.

Gender-Related Differences on Polyamine Metabolome in Liquid Biopsies by a Simple and Sensitive Two-Step Liquid-Liquid Extraction and LC-MS/MS.

Polyamines are involved in the regulation of many cellular functions and are promising biomarkers of numerous physiological conditions. Since the concentrations of these compounds in biological fluids are low, sample extraction is one of the most critical steps of their analysis. Here, we developed a comprehensive, sensitive, robust, and high-throughput LC-MS/MS stable-isotope dilution method for the simultaneous determination of 19 metabolites related to polyamine metabolism, including polyamines, acetylated and diacetylated polyamines, precursors, and catabolites from liquid biopsies. The sample extraction was optimized to remove interfering compounds and to reduce matrix effects, thus being useful for large clinical studies. The method consists of two-step liquid-liquid extraction with a Folch extraction and ethyl acetate partitioning combined with dansyl chloride derivatization. The developed method was applied to a small gender-related trial concerning human serum and urine samples from 40 obese subjects. Sex differences were found for cadaverine, putrescine, 1,3-diaminopropane, γ-aminobutyric acid, N8-acetylspermidine, and N-acetylcadaverine in urine; N1-acetylspermine in serum; and spermine in both serum and urine. The results demonstrate that the developed method can be used to analyze biological samples for the study of polyamine metabolism and its association with human diseases.

Validated HPLC method for simultaneous quantification of mutant IDH1/2 inhibitors (enasidenib, ivosidenib and vorasidenib) in mouse plasma: Application to a pharmacokinetic study.

Isocitrate dehydrogenase (IDH) inhibitors comprise a novel class of anticancer drugs, which are approved to treat acute myeloid leukemia patients having mutations on IDH1/2. We report the development and validation of a high-performance liquid chromatography (HPLC) method for the simultaneous quantitation of IDH inhibitors, namely enasidenib (EDB), ivosidenib (IDB) and vorasidenib (VDB), in mouse plasma as per the US Food and Drug Administration regulatory guidelines. The method involves extraction of EDB, IDB and VDB along with internal standard (IS; phenacetin) from mouse plasma (100 µl) using a simple protein precipitation process. The chromatographic analysis was performed on an HPLC system using a gradient mobile phase (comprising 10 mm ammonium acetate and acetonitrile in a flow-gradient) and an X-Terra Phenyl column. The UV detection wave length was set at λmax 265 nm. EDB, IDB, VDB and the IS eluted at 7.36, 8.60, 9.50 and 5.12 min, respectively, with a total run time of 10 min. The calibration curve was linear over a concentration range of 0.20-12.5 µg/ml for EDB and 0.50-12.5 µg/ml for IDB and VDB (r2  = ≥0.998 for all of the analytes). Validation results met the acceptance criteria. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.

Quantitative plasma biomarker analysis in HDI exposure assessment.

Quantification of amines in biological samples is important for evaluating occupational exposure to diisocyanates. In this study, we describe the quantification of 1,6-hexamethylene diamine (HDA) levels in hydrolyzed plasma of 46 spray painters applying 1,6-hexamethylene diisocyanate (HDI)-containing paint in vehicle repair shops collected during repeated visits to their workplace and their relationship with dermal and inhalation exposure to HDI monomer. HDA was detected in 76% of plasma samples, as heptafluorobutyryl derivatives, and the range of HDA concentrations was < or =0.02-0.92 microg l(-1). After log-transformation of the data, the correlation between plasma HDA levels and HDI inhalation exposure measured on the same workday was low (N = 108, r = 0.22, P = 0.026) compared with the correlation between plasma HDA levels and inhalation exposure occurring approximately 20 to 60 days before blood collection (N = 29, r = 0.57, P = 0.0014). The correlation between plasma HDA levels and HDI dermal exposure measured on the same workday, although statistically significant, was low (N = 108, r = 0.22, P = 0.040) while the correlation between HDA and dermal exposure occurring approximately 20 to 60 days before blood collection was slightly improved (N = 29, r = 0.36, P = 0.053). We evaluated various workplace factors and controls (i.e. location, personal protective equipment use and paint booth type) as modifiers of plasma HDA levels. Workers using a downdraft-ventilated booth had significantly lower plasma HDA levels relative to semi-downdraft and crossdraft booth types (P = 0.0108); this trend was comparable to HDI inhalation and dermal exposure levels stratified by booth type. These findings indicate that HDA concentration in hydrolyzed plasma may be used as a biomarker of cumulative inhalation and dermal exposure to HDI and for investigating the effectiveness of exposure controls in the workplace.

An intranasal irritation assessment of antibacterial ointment alone or in combination with mupirocin versus Bactroban Nasal in rabbits.

The purpose of this study was to evaluate the potential irritating effects and the systemic exposure level of an antibacterial ointment containing REP8839 as a single agent or in combination with mupirocin versus Bactroban Nasal in rabbits. Additionally, the reversibility of REP8839 effects during a 14-day recovery period was assessed. Five treatment groups of six male and six female New Zealand White rabbits received dose levels of 1%, 2%, and 4% REP8839, 2% Bactroban Nasal, or 2% REP8839/2% mupirocin combination. One additional group of six animals/sex served as the control and received the vehicle, Petrolatum/Softisan 649. The test article or vehicle was administered to all groups via topical administration to the external nares, twice a day (approx. 8h intervals between the doses) for 21 consecutive days, at a dose volume of 100 microL per nare/dose for a total of 400 microL per day (200 microL per nare). Two animals/sex/group were maintained for a 14-day recovery period. The external nares were reflected back and the mucosal lining was evaluated and scored for erythema and edema within 30-60 min following the first dose each day. Blood samples were collected from all animals at designated time points on Day 21 of the study to assess systemic exposure levels. Cross-sectioning of the nasal tract was conducted in all the groups for microscopic evaluation. Mucosal scoring of the nares did not reveal any edema or erythema in any of the dose groups with the antibacterial alone, with the combination product, or with Bactroban Nasal. Mean body weights and food consumption were not adversely impacted by the test articles. Minimal plasma exposure was observed in the rabbits (<5 ng/mL). The REP8839 groups did appear to have dose-responsive exposure (from below the limit of quantitation to 5 ng/mL with 1%, 2%, and 4% REP8839, respectively). Microscopic changes on the nasal sectioning noted in these animals were infrequent and considered incidental findings unrelated to administration of the test articles. In conclusion doses of up to 4% of REP8839 ointment as a single agent or 2% in the combination product, as well as 2% Bactroban Nasal, were not found to induce mucosal irritation when applied topically to the external nares twice a day for 21 consecutive days. Additionally, no delayed effects were observed in the recovery animals.

Antibacterial activity in serum of the 3,5-diamino-piperidine translation inhibitors.

Translation inhibitors of the 3,5-diamino-piperidine series act as aminoglycoside mimetics that inhibit bacterial growth. Here we show antibacterial SAR in the presence and absence of serum with a particular focus toward Pseudomonas aeruginosa.

Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug.

SQ109 is a novel [1,2]-diamine-based ethambutol (EMB) analog developed from high-throughput combinatorial screening. The present study aimed at characterizing its pharmacodynamics and pharmacokinetics. The antimicrobial activity of SQ109 was confirmed in vitro (Mycobacterium tuberculosis-infected murine macrophages) and in vivo (M. tuberculosis-infected C57BL/6 mice) and compared to isoniazid (INH) and EMB. SQ109 showed potency and efficacy in inhibiting intracellular M. tuberculosis that was similar to INH, but superior to EMB. In vivo oral administration of SQ109 (0.1-25 mg kg(-1) day(-1)) to the mice for 28 days resulted in dose-dependent reductions of mycobacterial load in both spleen and lung comparable to that of EMB administered at 100 mg kg(-1) day(-1), but was less potent than INH at 25 mg kg(-1) day(-1). Monitoring of SQ109 levels in mouse tissues on days 1, 14 and 28 following 28-day oral administration (10 mg kg(-1) day(-1)) revealed that lungs and spleen contained the highest concentration of SQ109, at least 10 times above its MIC. Pharmacokinetic profiles of SQ109 in mice following a single administration showed its C(max) as 1038 (intravenous (i.v.)) and 135 ng ml(-1) (p.o.), with an oral T(max) of 0.31 h. The elimination t(1/2) of SQ109 was 3.5 (i.v.) and 5.2 h (p.o.). The oral bioavailability was 4%. However, SQ109 displayed a large volume of distribution into various tissues. The highest concentration of SQ109 was present in lung (>MIC), which was at least 120-fold (p.o.) and 180-fold (i.v.) higher than that in plasma. The next ranked tissues were spleen and kidney. SQ109 levels in most tissues after a single administration were significantly higher than that in blood. High tissue concentrations of SQ109 persisted for the observation period (10 h). This study demonstrated that SQ109 displays promising in vitro and in vivo antitubercular activity with favorable targeted tissue distribution properties.

Quantification of antimalarial bisthiazolium compounds and their neutral bioprecursors in plasma by liquid chromatography-electrospray mass spectrometry.

BACKGROUND: A new class of antimalarial drugs targeting membrane biogenesis during intraerythrocytic Plasmodium falciparum development has been identified. The bisthiazolium salts T3 and T4 have superior in vitro and in vivo parasite-killing properties and need to be monitored. METHODS: We used a liquid chromatography-electrospray ionization mass spectrometry method (positive mode) to quantify two bisthiazolium compounds (T3 and T4) and a related prodrug (TE4c) in human and rat plasma. Verapamil was used as internal standard. Verapamil and the TE4c compound were characterized by protonated molecules at m/z 455.7 and m/z 725.7, respectively. T3 and T4 were detected through two ions [(M2+)/2] at m/z 227.7 and m/z 241.8 and by their adducts with trifluoroacetic acid [M+TFA]+ at m/z 568 and m/z 596, respectively. The sample clean-up procedure involved solid-phase extraction. HPLC separation was performed on a reversed-phase column, using a water-acetonitrile gradient, with both solvents containing TFA. Stability under various conditions was also investigated. RESULTS: The peak-area ratios (drugs/internal standard) were linked to concentrations (6.4-1282 microg/L for T3; 6.5-1309.8 microg/L for T4; 20-2000 microg/L for TE4c) according to a quadratic equation. The accuracy ranged from 85% to 113.1%, and the imprecision from 2.2% to 15%. The mean extraction recoveries were 87%, 98%, and 80% for T3, T4, and TE4c, respectively. The lower limit of quantification was 6.4 mug/L for the two bisthiazolium compounds, whereas it was 20 mug/L for TE4c, the related lipophilic prodrug. CONCLUSION: This highly specific and sensitive method is suitable for analyzing samples collected during preclinical pharmacokinetic studies in rats and to determine the percentage binding of T3 and T4 to human plasma proteins.

Development, validation and characterization of an analytical method for the quantification of hydrolysable urinary metabolites and plasma protein adducts of 2,4- and 2,6-toluene diisocyanate, 1,5-naphthalene diisocyanate and 4,4'-methylenediphenyl diisocyanate.

Occupational exposure to diisocyanates within the plastic industry causes irritation and disorders in the airway. The aim of this study was to develop, validate and characterize a method for the determination of 2,4-toluenediamine (2,4-TDA), 2,6-toluenediamine (2,6-TDA), 1,5-diaminonaphthalene (1,5-NDA) and 4,4'-methylenedianiline (4,4'-MDA) in hydrolysed urine and plasma, and to study the correlation between the plasma and urinary levels of these potential biomarkers of 2,4-toluene diisocyanate (2,4-TDI), 2,6-toluene diisocyanate (2,6-TDI), 1,5-naphthalene diisocyanate (1,5-NDI) and 4,4'-methylenediphenyl diisocyanate (4,4'-MDI), respectively. Samples were hydrolysed with 0.3 M NaOH at 100 degrees C for 24 h. The diamines were extracted, derivatized with pentafluoropropionic acid anhydride, and quantified by selected ion monitoring on gas chromatography-mass spectrometry. The repeatability and reproducibility of the method were 7-18% and 7-19%, respectively. Dialysis experiments showed that the metabolites of 2,4-TDI, 2,6-TDI, 1,5-NDI and 4,4'-MDI in plasma were exclusively protein adducts. No free diamines were found in urine, indicating that all diisocyanate-related metabolites were in a conjugated form. For each diisocyanate-related biomarker, there were strongly significant correlations (p<0.001) between individual levels of metabolites in plasma and urine, with Spearman's rank correlation coefficient (rs) values of 0.74-0.90. The methods presented here will be valuable for the development of biological monitoring methods for diisocyanates.

[Changes in tissue and blood polyamine levels following chemotherapy in rats with urinary bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl) nitosamine in rats].

BACKGROUND: Polyamines are recognized as cell growth factors. We attempted to determine whether alterations in the levels of tissue and blood polyamines were useful biochemical makers for monitoring the efficacy of the chemotherapy for bladder tumors. METHODS: The concentrations of three polyamines of diamine, spermidine and spermine in urinary bladder and blood were determined in male F344 rats with urinary bladder carcinoma induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), following chemotherapy with cisplatin, methotrexate and pirarubicin. RESULTS: Bladder carcinoma was observed in 5 of 20 rats of the chemotherapeutic group, and 16 of 20 rats of the control group given saline alone. The levels of spermidine, spermine and total polyamine in both bladder and blood of the treated rats were significantly lower than those of the control rats. CONCLUSION: The study suggested that the levels of tissue and blood polyamines could be used as biochemical markers for monitoring the efficacy of the chemotherapy for bladder tumors.

Test chamber exposure of humans to 1,6-hexamethylene diisocyanate and isophorone diisocyanate.

An isocyanate generation apparatus was developed and stable isocyanate atmospheres were obtained. At a concentration of 5 micrograms 1,6-hexamethylene diisocyanate (HDI) per m3 the precision was found to be 7% (n = 5). Three volunteers were each exposed to three different concentrations of HDI (11.9, 20.5, and 22.1 micrograms/m3) and three concentrations of isophorone diisocyanate (IPDI) (12.1, 17.7, and 50.7 micrograms/m3), in an exposure chamber. The duration of the exposure was 2 h. Urine and blood samples were collected, and hydrolysed under alkaline conditions to the HDI and IPDI corresponding amines, 1,6-hexamethylene diamine (HDA) and isophorone diamine (IPDA), determined as their pentafluoropropionic anhydride amides (HDA-PFPA and IPDA-PFPA). The HDA- and IPDA-PFPA derivatives were analysed using liquid chromatography mass spectrometry with thermospray monitoring negative ions. When working up samples from the exposed persons without hydrolysis, no HDA or IPDA was seen. The average urinary excretion of the corresponding amine was 39% for HDI and 27% for IPDI. An association between the estimated inhaled dose and the total excreted amount was seen. The average urinary elimination half-time for HDA was 2.5 h and for IPDA, 2.8 h. The hydrolysis condition giving the highest yield of HDA and IPDA in urine was found to be hydrolysis with 3 M sodium hydroxide during 4 h. No HDA or IPDA could be found in hydrolysed plasma (< ca 0.1 micrograms/l).

Inhalation toxicity of 1,6-hexanediamine dihydrochloride in F344/N rats and B6C3F1 mice.

1,6-Hexanediamine (HDA) is a high production volume chemical which is used as an intermediate in the synthesis of paints, resins, inks, and textiles and as a corrosion inhibitor in lubricants. Two- and 13-week studies of the toxicity of the dihydrochloride salt of HDA (HDDC) were conducted in male and female Fischer 344/N rats and B6C3F1 mice using whole-body inhalation exposure. Both species were evaluated for histopathologic and reproductive effects, and rats were examined for clinical chemistry and hematologic changes. In the 2-week inhalation studies, animals were exposed to 10-800 mg HDDC/m3, 6 hr per day. All rats, all female mice, and two of five male mice in the high-exposure group died before the end of the study. Surviving mice in this group had a dose-dependent depression in body weight gain. Clinical signs were primarily related to upper respiratory tract irritation and included dyspnea and nasal discharge in both species. Treatment-related histopathologic lesions included inflammation and necrosis of the laryngeal epithelium of both species and the tracheal epithelium of mice, as well as focal inflammation and ulceration of the respiratory and olfactory nasal mucosa. In the 13-week inhalation studies, animals were exposed to HDDC at concentrations of 1.6-160 mg/m3 for 6 hr per day, 5 days per week. In addition to the base study groups, a supplemental group of rats at each exposure level was included to assess the effect of HDDC on reproduction. No treatment-related changes in organ weights or organ-to-body-weight ratios occurred in rats, and no treatment-related clinical signs or gross lesions were seen in either species. Chemical-related microscopic lesions were limited to the upper respiratory tract (larynx and nasal passages) in the two highest exposure groups and were similar in both species. These lesions included minimal to mild focal erosion, ulceration, inflammation, and hyperplasia of the laryngeal epithelium, in addition to degeneration of the olfactory and respiratory nasal epithelium. HDDC caused no significant changes in sperm morphology or vaginal cytology and no significant adverse effects on reproduction in rats or mice. Hematologic and clinical chemistry changes in rats were minor and sporadic and were not accompanied by related histologic findings. HDDC did not increase the frequency of micronucleated erythrocytes in mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological monitoring of isocyanates and related amines. II. Test chamber exposure of humans to 1,6-hexamethylene diisocyanate (HDI).

Five male subjects were exposed to 1,6-hexamethylene diisocyanate (HDI) atmospheres for 7.5 h. The exposures were performed in an 8 m3 stainless steel test chamber, and the HDI atmospheres were generated by a gas-phase permeation method. HDI in air was determined by an HPLC method utilizing the 9-(N-methylaminomethyl)-anthracene reagent, and by a continuous monitoring device (MDA 7100). The average air concentration was ca 25 micrograms/m3, and the inhaled dose of HDI for the different subjects was estimated at ca 100 micrograms. The related amine 1,6-hexamethylene diamine (HDA) was after acid hydrolysis of urine and plasma, determined as a heptafluorobutyric derivative, by glass capillary gas-chromatography and selected ion monitoring (SIM), in a chemical ionization mode using ammonia as reagent gas. The cumulated urinary excretion of HDA during 28 h was 8.0 to 14 micrograms, which corresponds to ca 11 to 21% of the inhaled dose of HDI. The urinary level of HDA, in samples collected immediately after the end of the exposures, was on average 0.02 mmol/mol creatinine (range 0.01-0.03 mmol/mol creatinine). The urinary elimination was rapid, and half-time (t 1/2), for the concentration of HDA in urine, showed an average of 1.2 h (range 1.1-1.4 h). No specific IgE and IgG antibodies to HDI were detected before and after provocation; nor were spirometry or bronchial reactivity changed immediately and 15 h after provocation. Analysis of HDA in hydrolysed urine, as a marker of short-time exposure to HDI, is proposed.

[Detection of polyamines by a new enzymatic differential assay. (4). Fundamental study on a new enzymatic differential assay of blood].

The enzymatic method for isolation and determination of urinary polyamines was modified to measure the polyamines in the blood. High recovery rates of polyamine in blood by enzymatic hydrolyzation were obtained, namely, 101.9 +/- 4.4% for diamine, 96.0 +/- 5.4% for spermidine and 104.1 +/- 3.3% for spermine. Furthermore excellent linearity was demonstrated. Within-run precision of polyamine in blood was excellent, namely, in C.V., 1.15% for Reaction 1, 2.11% for Reaction 2 and 2.79% for Reaction 3. This method was compared with high pressure liquid chromatography (HPLC), and a close correlation was demonstrated for all the fractions: diamine r = 0.8824, y = 1.367x+0.0417 (n = 15); spermidine r = 0.9878, y = 0.806x+5.218 (n = 15); spermine r = 0.9764, y = 1.068x-0.9195 (n = 15).

[Detection of polyamines by a new enzymatic differential assay. (5). Studies on polyamine in the blood of patients with malignant genitourinary diseases].

Using the new enzymatic assay for isolation and determination of polyamine in blood presented in Report 4, the polyamines in the blood were isolated and determined in 84 patients with genitourinary cancer. In the early diagnosis, the positive rates of each fraction were not so high, but, relatively high positive rates were demonstrated, when any one of the polyamines were found positive: namely, 85.7% in renal cell cancer, 66.7% in renal pelvic and ureteral cancer, 44.0% in bladder cancers. These results seem to support the usefulness of the new method, and encourage further investigation of polyamines in the blood as tumor markers.

Serum levels of polyamines in patients with chronic renal failure.

Serum levels of total putrescine, cadaverine, spermidine and spermine were measured in 10 normal subjects, 11 nondialyzed patients with chronic renal failure, and 25 patients undergoing maintenance hemodialysis. The measurement of the serum levels of four polyamines was done with high-performance cation-exchange chromatographic separation and fluorometric detection using o-phtalaldehyde. In normal subjects, the serum levels of putrescine and spermine were 0.24 +/- 0.09 and 0.20 +/- 0.05 nmoles/ml. In patients with chronic renal failure, the levels of polyamines were obtained in the order of putrescine, cadaverine, spermidine, and spermine: 0.51 +/- 0.15; 0.05 +/- 0.01; 0.34 +/- 0.08; and 0.05 +/- 0.04 nmoles/ml. In dialyzed patients, predialysis values of polyamines in the same order as above were: 0.88 +/- 0.31; 0.12 +/- 0.10; 0.67 +/- 0.31; and 0.09 +/- 0.08 nmoles/ml. The results show that, compared to normal subjects, the serum levels of all four polyamines are significantly elevated either in nondialyzed patients with chronic renal failure or in dialyzed patients. In dialyzed patients, the postdialysis putrescine and spermidine levels are significantly low. Serum levels of putrescine and spermidine are both significantly correlated with serum urea nitrogen and serum creatinine in a combined group of normal subjects and patients with chronic renal failure. In dialyzed patients, none of the four polyamine serum levels show correlations either with serum urea nitrogen or serum creatinine; with hematocrit, only spermine exhibits a correlationship, whereas other polyamines do not.

Monoacylcadaverines in schizophrenia.

Monoacetylcadaverine and monopropionylcadaverine were found in the blood of schizophrenic patients in higher concentrations than in the blood of nonschizophrenic subjects. The blood levels of both monoacylcadaverines in schizophrenics were relatively higher during exacerbation of the illness and were relatively lower during improvement.

Pharmacokinetics of guanazole in patients with acute myelocytic leukemia.

Levels of guanazole (GZ) in plasma and packed cells were determined after a single tracer dose of 14C-guanazole or during a 5-day continuous intravenous therapeutic infusion of unlabeled drug to 5 patients with acute myelocytic leukemia (AML). The levels of unlabeled drug were determined colorimetrically. GZ infected as a tracer dose was rapidly distributed in an apparent volume of 0.61 l/kg, which is somewhat less than that of total body water, and the drug appeared to be eliminated essentially unchanged by glomerular filtration. The mean apparent volume of distribution increased by about 15% during infusion. An increase of 60% was also noted in the half-life (t1/2) values, with a concimitant decrease in the mean value of renal clearance rate by 40%, except in 1 case. The study demonstrates that monitoring levels of guanazole is possible during infusion therapy and indicates that the data could be used to evaluate pharmacokinetic parameters predicting the time-course of such levels in patients.