Risk Factors for Thrombocytopenia Induced by Capecitabine Plus Oxaliplatin Therapy in Patients With Colorectal Cancer.

BACKGROUND/AIM: Capecitabine plus oxaliplatin (CapeOX) therapy is used as an adjuvant chemotherapy regimen for patients with colorectal cancer (CRC). Although oxaliplatin induces thrombocytopenia, the risk factors for thrombocytopenia in oxaliplatin-treated patients with CRC are not well established. We aimed to investigate the risk factors for thrombocytopenia in CapeOX-treated patients with CRC. In addition, we evaluated platelet counts and non-invasive liver fibrosis indices, specifically the aspartate aminotransferase-to-platelet ratio index (APRI) and the fibrosis-4 index (FIB-4), during CapeOX therapy in these patients. PATIENTS AND METHODS: Between July 2017 and June 2020, we enrolled CapeOX-treated patients with high-risk stage II or stage III CRC at seven hospitals collaborating with the Division of Oncology, Aichi Prefectural Society of Hospital Pharmacists (Aichi prefecture, Japan). In this retrospective study, we investigated patients' backgrounds, laboratory data, concomitant medications, number of cycles of CapeOX and oxaliplatin, cumulative dose of oxaliplatin, and administration period. The cut-off values were calculated using receiver operating characteristic analysis of platelet counts and APRI and FIB-4 scores. RESULTS: Fifty-five patients without thrombocytopenia and 44 patients with thrombocytopenia were enrolled. During CapeOX therapy, the thrombocytopenia group showed a significant decrease in platelet count and a significant increase in APRI and FIB-4 scores compared to the non-thrombocytopenia group. Baseline albumin level ≤3.5 g/dl and platelet count ≤238×103/µl were independently associated with ≥grade 2 thrombocytopenia in CapeOX-treated patients. CONCLUSION: Baseline albumin level and platelet count may be useful for predicting thrombocytopenia in CapeOX-treated patients with high-risk stage II or stage III CRC.

Social communication impairments and restricted, repetitive patterns (Kodawari) considered from the Comprehension section of the WISC-IV in autism spectrum disorder

Abstract Background Many studies have used the Wechsler Intelligence Scale (WISC) to examine the characteristics of autism spectrum disorder (ASD). However, most studies have been based on profile analysis, not on content analysis. Objective The objective of the present study was to apply the WISC-IV to clinical assessment of ASD and clarify how the characteristics of the disorder were reflected in specific items. Methods The study participants were 20 patients aged 5-16 years diagnosed with ASD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We recruited 20 patients with attention-deficit/hyperactivity disorder (ADHD) and 20 patients with other disorders (neurotic disorders) as controls. We then compared the scores of the ninth item of the WISC-IV ("Comprehension") among the three groups. Results The differences observed between the ASD vs. the other disorders group were not significant by the standard scoring method. Thus, a two-level scoring method of 0 and ≥1 point was adopted. As a result, significantly more participants in the ASD group scored 0 points compared with the ADHD and other disorders groups. Discussion The results of the present study revealed that a characteristic of ASD appeared in the ninth item of "Comprehension" on the WISC-IV.

Dietary Adherence, Self-Efficacy, and Health Behavior Change of WASHOKU-Modified DASH Diet: A Sub-analysis of the DASH-JUMP Study.

BACKGROUND: We previously reported the nutritional characteristics and effects of the DASH-JUMP diet, which is a WASHOKU-modified DASH diet, in Japanese participants with untreated high-normal blood pressure or stage 1 hypertension. The dietary adherence of the DASH diet in Japanese participants has never been evaluated before. OBJECTIVE: We aimed to assess the relationships between dietary adherence, self-efficacy, and health behavior change among study participants who received the DASH-JUMP diet by home delivery. METHODS: Participants were treated with the DASH-JUMP diet for 2 months and consumed their usual diets for the next 4 months. We conducted surveys using the stage of behavior change model questionnaire and the modified perceived health competence scale Japanese version questionnaire at baseline and 1, 2, 3, and 6 months to assess dietary adherence. RESULTS: Forty-three participants (25 men, 18 women; mean age 53.6 ± 8.2 years) returned completed questionnaires, which we analyzed. Health behavior change was motivated by previous behavioral changes and improved biomarkers. The improvement and maintenance of self-efficacy were deeply related to health behavior change and previous self-efficacy. The experience of the DASH-JUMP study for participants included three processes to improve lifestyle habits: Phase 1, reflecting on previous lifestyle habits; Phase 2, learning through new experiences and the acquisition of knowledge; and Phase 3, desiring to maintain their own health. CONCLUSION: It indicated that the DASH-JUMP diet significantly increased self-efficacy and promoted health behavior change.

The Nutritional Characteristics of the Hypotensive WASHOKU-modified DASH Diet: A Sub-analysis of the DASH-JUMP Study.

BACKGROUND: We developed a WASHOKU-modified DASH diet named DASH-JUMP. We previously reported the hypotensive effect of the DASH-JUMP diet in Japanese participants with untreated high-normal Blood Pressure (BP) or stage 1 hypertension. OBJECTIVE: We aim to introduce the DASH-JUMP diet worldwide as a new lifestyle medicine. Accordingly, we prospectively assessed the nutritional characteristics of the DASH-JUMP diet. METHODS: Participants were treated with the DASH-JUMP diet for 2 months. Then, for 4 months after the intervention, they consumed their usual diets. We conducted a nutritional survey using the FFQg nutrient questionnaire at baseline and after 1, 2, 3, and 6 months. We received completed questionnaires from 55 participants (28 men and 27 women; mean age 54.2 ± 8.0 years) and analyzed them. RESULTS: The DASH-JUMP diet is rich in green-yellow vegetables, seaweed, milk, and mushrooms, while it has low contents of meat, eggs, confectionery, oils and fats, pickles, shellfish boiled in sweetened soy sauce, and fruits. Nutrients significantly associated with the observed change in systolic BP were niacin (P = 0.005) and carbohydrate (P = 0.033). The results of the FFQg questionnaire revealed that participants who had an increased BP at 1 month after ceasing the intervention had eating habits that broadly imitated the DASH-JUMP diet at 4 months after ceasing the intervention. Therefore, the systolic and diastolic BP values at 4 months after ceasing the intervention decreased significantly compared to those at baseline. CONCLUSION: The DASH-JUMP diet may represent a new lifestyle medicine for reducing hypertension.

Development and Evaluation of an Enzyme-Linked Immunosorbent Assay Using a Nonpoisonous Extraction System for the Determination of Crustacean Protein in Processed Foods.

Crustacean proteins are food allergens that cause severe allergic reactions in patients with food allergies; therefore, the identification of crustaceans such as shrimp, crab, and lobster as ingredients in processed food products is mandatory in Japan. We previously developed and validated an ELISA method coupled with an extraction process using the surfactant sodium dodecyl sulfate and the reductant 2-mercaptoethanol (2-ME) to quantify crustacean protein. However, 2-ME was designated as poisonous in Japan in 2008. Therefore, in this study, we developed and evaluated an ELISA method for detecting and quantifying crustacean protein that uses sodium sulfite (Na2SO3) in place of 2-ME for extraction. The proposed ELISA method showed high sensitivity, with an LOQ of 0.66 µg protein/g food sample. Furthermore, the proposed method showed high specificity for the Decapoda order within the subphylum Crustacea, with recoveries ranging from 83.8 to 100.8% for model processed foods, as well as high reproducibility (intra- and interassay CVs of ≤8.2%) and high correlation with our previously validated ELISA method for processed foods (correlation coefficient of 0.996). The proposed ELISA method does not require the use of poisonous reagents, provides acceptable accuracy, and is useful for the routine monitoring of food products.

Effects of the DASH-JUMP dietary intervention in Japanese participants with high-normal blood pressure and stage 1 hypertension: an open-label single-arm trial.

The Dietary Approaches to Stop Hypertension (DASH) diet is recommended by the American Heart Association to lower blood pressure (BP); however, its effects in Japanese participants have not been rigorously studied. We assessed the effects of the DASH-Japan Ube Modified diet Program (DASH-JUMP), a modified DASH diet, on cardiometabolic and inflammatory biomarkers in Japanese participants with untreated high-normal BP or stage 1 hypertension. Fifty-eight participants (30 men and 28 women; mean age 54.1±8.1 years) with untreated high-normal BP or stage 1 hypertension followed the DASH-JUMP (salt 8.0 g per day) for 2 months. After the intervention period, they resumed their usual diets for 4 months. The DASH-JUMP significantly decreased the participants' body mass index values (24.6±3.5 kg m-2 at baseline23.2±3.3 kg m-2 at 2 months, P=0.000), BP (153±14/91±11 mm Hg at baseline130±16/80±9 mm Hg at 2 months, P=0.000 and 139±16/85±10 mm Hg at 6 months, P=0.000), fasting serum glucose level (100±26 mg dl-194±15 mg dl-1 at 2 months, P=0.003) and fasting insulin level (6.9±5.9 µIU ml-14.4±2.7 µIU ml-1 at 2 months, P=0.000). The mean compliance of the participants for the DASH-JUMP diet was 88.5%. The DASH-JUMP diet reduced cardiovascular risk factors and may be an effective nutritional strategy for preventing cardiovascular events.

Development of an enzyme-linked immunosorbent assay system for detecting ß'-component (Onk k 5), a major IgE-binding protein in salmon roe.

A novel enzyme-linked immunosorbent assay (ELISA) system has been established for selective detection of chum salmon (Oncorhynchus keta) yolk protein (SYP). Rabbit and rat polyclonal Immunoglobulin G antibodies to ß'-component (the major allergic protein in fish roe; anti-ß) were applied for designing the ELISA system. The sandwich ELISA using rabbit anti-ß for the capture antibody and horseradish peroxidase-labeled F(ab')2 fragment of rat anti-ß for the detection antibody obtained high sensitivity and narrow specificity for SYP. Protein extraction using sodium dodecyl sulfate and 2-mercaptoethanol ensured strict specificity of the ELISA, and components of three popular processed foods had no effect on the ELISA response. The limits of determination and quantification of SYP were estimated to be 0.78 µg/g and 2.60 µg/g of food sample, respectively. In conclusion, the developed ELISA system has a probability to be applied for the detection of contaminated chum salmon roe in processed food.

Development and validation of a lateral flow assay for the detection of crustacean protein in processed foods.

We developed and validated a novel lateral flow assay for the detection of crustacean protein in processed foods. This assay had high sensitivity; the visual detection limit for shrimp protein extract was 25µg/L, equivalent to 1µg/g protein in a food sample, and results could be obtained within 20min without sophisticated procedures or expensive equipment. Concordance between our assay and another validated quantitative enzyme-linked immunosorbent assay was 97% for commercially processed foods. This assay is rapid, simple, reliable, and highly correlated with validated enzyme-linked immunosorbent assays and is thus suitable for monitoring of food products, especially in food-processing facilities.

Production of ethanol from mannitol by the yeast strain Saccharomyces paradoxus NBRC 0259.

Mannitol is a promising marine macroalgal carbon source. However, organisms that produce ethanol from mannitol are limited; to date, only the yeast Pichia angophorae and the bacterium Escherichia coli KO11 have been reported to possess this capacity. In this study, we searched a yeast strain with a high capacity to produce ethanol from mannitol and selected Saccharomyces paradoxus NBRC 0259 for its ability to produce ethanol from mannitol. This ability was enhanced after a 3-day cultivation of this strain in medium containing mannitol; the enhanced strain was renamed S. paradoxus NBRC 0259-3. We compared the ability of strain NBRC 0259-3 to produce ethanol from mannitol and glucose, under several conditions, with those of P. angophorae and E. coli KO11. As a result, we concluded that S. paradoxus NBRC 0259-3 strain is the most suitable yeast strain for the production of ethanol from mannitol.

Lanthanum carbonate for hyperphosphatemia in patients on peritoneal dialysis.

BACKGROUND: The efficacy of the phosphate binder lanthanum carbonate has been demonstrated for hemodialysis patients, but no studies have focused on patients undergoing continuous ambulatory peritoneal dialysis (CAPD). We evaluated whether lanthanum carbonate could control phosphate levels in patients on CAPD. ♢ METHODS: In this 48-week open-label prospective study, 28 patients on CAPD with a phosphate level of 6 mg/dL or greater were given lanthanum carbonate titrated from 750 mg to 2250 mg daily to achieve a target serum phosphate level of less than 6 mg/dL. The primary efficacy endpoint was reduction of serum phosphate to less than 6 mg/dL. Serum levels of calcium and parathyroid hormone were also evaluated, as were the Ca×P product and adverse effects. ♢ RESULTS: From week 4 to the end of the study at week 48, we observed a significant reduction of serum phosphate to 5.25 ± 0.97 mg/dL from 6.88 ± 1.06 mg/dL at study start (p < 0.01). At the end of the study, 78.6% of participants had achieved the target of less than 6 mg/dL. Because no change of serum calcium occurred, the Ca×P product declined significantly during the study. Intact parathyroid hormone declined gradually over the study period, but the change had not reached significance at the end of the study (p = 0.11). The mean final dose of lanthanum carbonate was 946 mg daily. The only adverse effect reported was mild nausea in 1 patient. ♢ CONCLUSIONS: Lanthanum carbonate is an effective phosphate binder that can control serum phosphate and Ca×P product in CAPD patients with hyperphosphatemia. Lanthanum carbonate was well tolerated in our population.

Unique heparan sulfate from shrimp heads exhibits a strong inhibitory effect on infections by dengue virus and Japanese encephalitis virus.

The structure and biological activities of a highly sulfated heparan sulfate (HS) extracted from shrimp (Penaeus brasiliensis) heads were characterized. Structurally the shrimp HS was more heterogenous than heparin, although it is still highly sulfated. The molecular mass of the shrimp HS preparation was determined to be 32.3 kDa by gel filtration HPLC. Analysis by surface plasmon resonance demonstrated that various growth/differentiation factors specifically bound to the shrimp HS with comparable affinity. Notably, the shrimp HS had a greater inhibitory effect against infections by dengue virus type 2 as well as Japanese encephalitis virus than heparin. Experiments on anticoagulant activity indicated that the shrimp HS exhibited significant anti-thrombin activity, but less than the commercial heparin. Hence, the HS preparation from shrimp heads, an industrial waste, is a prospective agent for a variety of clinical applications.

Lipocalin-type prostaglandin D synthase is associated with coronary vasospasm and vasomotor reactivity in response to acetylcholine.

BACKGROUND: Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the biosynthesis of PGD(2), which acts as an anticoagulant, vasodilator, and inflammatory mediator. We examined the serum L-PGDS level, coronary macro- and microvasomotor functions, and their relationship in patients with chest pain and angiographically normal coronary arteries. METHODS AND RESULTS: The study included 96 patients who underwent diagnostic coronary angiography and had angiographically normal coronary arteries. Blood flow of the left anterior descending coronary artery (LAD) was analyzed by Doppler guidewire examination. Serum L-PGDS level was determined by ELISA. Infusion of acetylcholine (ACh) induced vasospasm of the LAD in all patients with vasospastic angina (VSA) (n=45), but in none of the patients without VSA (n=51). There were no significant differences in the baseline clinical characteristics of the nonVSA and VSA groups, except for the frequency of smoking. Serum L-PGDS level in the VSA group was significantly higher than that in the nonVSA group (77.1±4.4 vs. 63.9±2.5 µg/dl, P<0.01). Significant negative correlations were observed between the degree of LAD vasomotion in response to ACh and serum L-PGDS level (3 µg/min: r=-0.33; 10 µg/min: r=-0.35; 30 µg/min: r=-0.33, P<0.01). CONCLUSIONS: The L-PGDS level was elevated in patients with VSA and was associated with epicardial coronary vasomotion in response to ACh.

Environmental mutagens may be implicated in the emergence of drug-resistant microorganisms.

The emergence of drug-resistant microorganisms is an important medical and social problem. Drug-resistant microorganisms are thought to grow selectively in the presence of antibiotics. Most clinically isolated drug-resistant microorganisms have mutations in the target genes for the drugs. While any of the many mutagens in the environment may cause such genetic mutations, no reports have yet described whether these mutagens can confer drug resistance to clinically important microorganisms. We investigated how environmental mutagens might be implicated in acquired resistance to antibiotics in clinically important microorganisms, which causes human diseases. We selected mutagens found in the environment, in cigarette smoke, or in drugs, and then exposed Pseudomonas aeruginosa to them. After exposure, the incidence of rifampicin- and ciprofloxacin-resistant P. aeruginosa strains markedly increased, and we found mutations in genes for the antibiotic-target molecule. These mutations were similar to those found in drug-resistant microorganisms isolated from clinical samples. Our findings show that environmental mutagens, and an anticancer drug, are capable of inducing drug-resistant P. aeruginosa similar to strains found in clinical settings.

[Study of preparation of the calibration standard for the crustacean protein detection method].

We examined the preparation method of the calibration standard for an ELISA kit for measuring crustacean protein in food products. The initial extract of the calibration standard was stabilized by addition of protease inhibitor to the extracting solution and heating at 100 degrees C for 10 min. In accordance with the preparation procedure for calibrators, we prepared 3 lots of initial extract of calibration standard and analyzed the protein concentration and SDS-electrophoretic pattern. Single bands at 160, 41, 37 kDa and 4 bands in the range of 16-20 kDa were observed on SDS-PAGE. The range of protein concentration of the initial extract of the calibration standard was 2.74-4.10 mg/mL.

Effects of application method on skin penetration of carboxyfluorescein incorporated in liposomes.

We investigated the skin penetration of liposomes under two different application conditions; occluded and large application amount (1 ml/cm(2)), and open and small application amount (10 mul/cm(2)). Liposomes containing fluorescence-labeled phospholipids or carboxyfluorescein (CF) were used. In application under occluded conditions, phospholipids showed no penetration, even in the stratum corneum (SC). CF penetration in the skin after application of liposome was no different that after application of CF solution. In contrast, phospholipids penetrated the skin, particularly the SC and hair follicles, under open conditions. CF in liposome showed enhanced penetration in the SC and epidermis, but not in the dermis. On observation of the drying process, CF recrystallized from solution, but this did not occur with CF incorporated into liposome. It is possible that crystallization of CF is prevented by encapsulation in liposome, or that penetration occurs more readily with liposome.

De novo synthesis, uptake and proteolytic processing of lipocalin-type prostaglandin D synthase, beta-trace, in the kidneys.

Lipocalin-type prostaglandin D synthase (L-PGDS) is a multifunctional protein that produces prostaglandin D(2) and binds and transports various lipophilic substances after secretion into various body fluids as beta-trace. L-PGDS has been proposed to be a useful diagnostic marker for renal injury associated with diabetes or hypertension, because the urinary and plasma concentrations are increased in patients with these diseases. However, it remains unclear whether urinary L-PGDS is synthesized de novo in the kidney or taken up from the blood circulation. In crude extracts of monkey kidney and human urine, we found L-PGDS with its original N-terminal sequence starting from Ala23 after the signal sequence, and also its N-terminal-truncated products starting from Gln31 and Phe34. In situ hybridization and immunohistochemical staining with monoclonal antibody 5C11, which recognized the amino-terminal Ala23-Val28 loop of L-PGDS, revealed that both the mRNA and the intact form of L-PGDS were localized in the cells of Henle's loop and the glomeruli of the kidney, indicating that L-PGDS is synthesized de novo in these tissues. However, truncated forms of L-PGDS were found in the lysosomes of tubular cells, as visualized by immunostaining with 10A5, another monoclonal antibody, which recognized the three-turn alpha-helix between Arg156 and Thr173. These results suggest that L-PGDS is taken up by tubular cells and actively degraded within their lysosomes to produce the N-terminal-truncated form.

Highly efficient antiviral CD8+ T-cell induction by peptides coupled to the surfaces of liposomes.

In previous studies, we have demonstrated that liposomes with differential lipid components display differential adjuvant effects when antigens (Ags) are chemically coupled to their surfaces. When ovalbumin was coupled to liposomes made by using unsaturated fatty acids, it was found to be presented not only to CD4(+) T cells but also to CD8(+) T cells and induced cytotoxic T lymphocytes (CTLs) which effectively eradicated the tumor from mice. In this study, we coupled liposomes to immunodominant CTL epitope peptides derived from lymphocytic choriomeningitis virus (LCMV) and evaluated its potency as an antiviral vaccine. The intramuscular immunization of mice with the peptide-liposome conjugates along with CpG resulted in the efficient induction of antiviral CD8(+) T-cell responses which conferred complete protection against not only LCMV Armstrong but also a highly virulent mutant strain, clone 13, that establishes persistent infections in immunocompetent mice. The intranasal vaccination induced mucosal immunity effective enough to protect mice from the virus challenge via the same route. Complete protection was achieved in mice even when the Ag dose was reduced to as low as 280 ng of liposomal peptide. This form of vaccination with a single CTL epitope induced Ag-specific memory CD8(+) T cells in the absence of CD4(+) T-cell help, which could be shown by the complete protection of CD4-knockout mice in 10 weeks as well as by the analysis of recall responses. Thus, surface-linked liposomal peptide might have a potential advantage for the induction of antiviral immunity.

Synthetic peptides coupled to the surface of liposomes effectively induce SARS coronavirus-specific cytotoxic T lymphocytes and viral clearance in HLA-A*0201 transgenic mice.

We investigated whether the surface-linked liposomal peptide was applicable to a vaccine based on cytotoxic T lymphocytes (CTLs) against severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV). We first identified four HLA-A*0201-restricted CTL epitopes derived from SARS-CoV using HLA-A*0201 transgenic mice and recombinant adenovirus expressing predicted epitopes. These peptides were coupled to the surface of liposomes, and inoculated into mice. Two of the liposomal peptides were effective for peptide-specific CTL induction, and one of them was efficient for the clearance of vaccinia virus expressing epitopes of SARS-CoV, suggesting that the surface-linked liposomal peptide might offer an effective CTL-based vaccine against SARS.

Association of serum lipocalin-type prostaglandin D synthase levels with subclinical atherosclerosis in untreated asymptomatic subjects.

Recent studies suggest that lipocalin-type prostaglandin (PG) D synthase (L-PGDS), which converts PGH2 to PGD2, is implicated in the pathogenesis of atherosclerosis. However, clinical evidence for the association between serum L-PGDS levels and atherosclerosis has not been reported. In this study, we measured the serum L-PGDS concentration using sandwich enzyme-linked immunosorbent assay (ELISA) and investigated the association with traditional cardiovascular risk factors and surrogate atherosclerotic indices, such as the maximum score of the intima-media complex thickness of the carotid artery (C-IMT(max)) and the brachial-ankle pulse wave velocity (ba-PWV), in 500 non-treated asymptomatic subjects. The serum concentration of L-PGDS was 0.56+/-0.01 (mean+/-SEM, range 0.25-1.27, median 0.54) mg/L. Serum L-PGDS levels increased with age and were higher in men than in women. Serum L-PGDS was higher in subjects with hypertension and increased with increasing numbers of the traditional atherosclerotic risk factors. When the subjects were divided into four groups according to the levels of serum L-PGDS, the age-adjusted values of C-IMT(max) and ba-PWV were significantly increased in subjects with higher serum L-PGDS levels (quartile 3 and quartile 4) compared to those in the lowest quartile (quartile 1), for both genders. Multiple regression analysis including risk factors revealed that serum L-PGDS was an independent determinant for ba-PWV (beta=0.130, p<0.001). Serum L-PGDS tended to associate with C-IMT(max) but was not statistically significant (beta=0.084, p=0.075). In conclusion, our results suggest that an increase in serum L-PGDS concentration is associated with the progression of atherosclerosis.

Pharmacokinetics of recombinant human lipocalin-type prostaglandin D synthase/beta-trace in canine.

Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is identical to beta-trace, a major protein in human cerebrospinal fluid (CSF), and acts as both a PGD(2)-producing enzyme and as an extracellular transporter for lipophilic ligands. In this study, we investigated the pharmacokinetics of recombinant human L-PGDS (rh-L-PGDS) in canines. After an intravenous bolus injection of rh-L-PGDS, the serum concentration decreased bi-exponentially with a half-life of the terminal line phase of 0.77h, which was markedly shorter than that of other proteins with the same molecular weight as that of rh-L-PGDS. The distribution volume was 55.4ml/kg, which was close to the volume of canine circulation plasma, indicating that the administrated rh-L-PGDS was distributed mainly in the blood. Only 10.3% of the administered rh-L-PGDS was excreted to the urine, suggesting that rh-L-PGDS was actively degraded within the body. After an intrathecal injection, the peak serum concentration of rh-L-PGDS was observed at 4-5h. The area under the plasma concentration-time curve obtained for 12h after the intrathecal injection was one third of the value for 3h after the intravenous injection, suggesting that at least one third of the intrathecally injected rh-L-PGDS shifted to the blood.