Early Stage Of Administration Research Articles

Safety assessment of anti-B cell maturation antigen chimeric antigen receptor T cell therapy: a real-world study based on the FDA adverse event reporting system database.

On April 18, 2024, the U.S. Food and Drug Administration officially required updating of the "boxed warning" for T cell malignancies for all chimeric antigen receptor T cell (CAR-T) therapies. Given the clinical significance of these therapies, a rigorous safety assessment is paramount. However, comprehensive real-world safety studies have been lacking for the newly marketed CAR-T products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which target B cell maturation antigen, especially regarding the risk of secondary malignancies. Therefore, we aimed to thoroughly analyze the adverse events (AEs) information in the FDA Adverse Event Reporting System (FAERS) database to comprehensively understand the safety risks of ide-cel and cilta-cel. We extracted AE reports related to ide-cel and cilta-cel from the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.) from January 1, 2019 to December 31, 2023. Disproportionality analysis and Bayesian analysis were used to identify risk signals across subgroups and specific cases (including for death and secondary malignancies). Weibull distribution analysis was employed to determine the time to AE onset. A total of 695 AE reports for ide-cel and 848 for cilta-cel were included in the FAERS database. This analysis identified 81 positive signals for ide-cel and 74 for cilta-cel. Notably, comparisons with the drug labels revealed "unexpected signals," including febrile bone marrow aplasia (reporting odds ratio=69.10; confidence interval 39.12-122.03) and plasma cell myeloma (12.45; 8.18-18.95) for ide-cel, and increased serum ferritin (24.98; 8.0-77.58) and large intestine perforation (18.57; 5.98-57.69) for cilta-cel. Both drugs showed a higher AE incidence among male recipients and patients aged ≥65 years, although female recipients faced a greater risk. Most AEs occurred at the early stage of administration. However, secondary malignancies were detected for both drugs, primarily occurring one-year post-administration. This study provides a foundation for understanding the safety profile of CAR-T cell therapy, particularly in relation to the emergence of secondary malignancies. Such insights are helpful for clinical decision-making and the safe and effective utilization of these therapeutic agents.

Association between tenofovir plasma trough concentrations in the early stage of administration and discontinuation of up to five years tenofovir disoproxil fumarate due to renal function-related adverse events in Japanese HIV-1 infected patients

BackgroundThe relationship between plasma tenofovir (TFV) concentration at the beginning of tenofovir disoproxil fumarate (TDF) administration and the development of renal dysfunction during long-term administration of TDF has not been demonstrated yet. The objective of the present study was to determine whether plasma TFV trough concentrations during early TDF administration could serve as an indicator of renal dysfunction when TDF is administered for long periods.MethodsWe included 149 HIV-1 infected Japanese patients who were prescribed TDF. We investigated the relationship between plasma TFV trough concentrations and the rate of discontinuation due to the development of renal dysfunction for up to five years after the start of TDF administration. We also examined how the decrease in renal function over time due to TDF administration was related to factors associated with high TFV levels and plasma TFV trough concentrations.ResultsThe median TFV trough concentration in the TDF discontinuation group was 88 ng/mL, which was significantly higher (p = 0.0041), than that in the continuation group (72 ng/mL). Further, using an ROC curve, the cut-off value for TFV trough concentration at which TDF discontinuation was significantly high was found to be 98 ng/mL. Logistic multivariate analysis of factors associated with discontinuation of TDF due to renal function-related adverse events showed that being ≥ 50 years old (OR = 2.96; 95% CI, 1.01–8.64), having eGFR < 80 mL/min/1.73m2 at the start of TDF administration (OR = 5.51; 95% CI, 1.83–17.5), and TFV trough concentration ≥ 98 ng/mL (OR = 2.96; 95% CI, 1.16–7.60) were independent factors.ConclusionsThe results suggested that the importance of measuring TFV concentrations to evaluate the risk of developing renal function-related adverse events during long-term TDF administration.

Effect of sodium-glucose cotransporter 2 inhibitors on the rate of decline in kidney function: A systematic review and meta-analysis.

To investigate the influence of sodium/glucose cotransporter-2 inhibitors (SGLT-2i) on renal function during the course of its administration, particularly in the initial weeks. Randomized controlled trials (RCTs) related to SGLT-2i were searched in databases (MEDLINE, EMBASE, and Cochrane Central Register) from the database's inception to August 31, 2021. All RCTs reported the kidney outcomes of SGLT2i versus active or placebo control were included, regardless of the presence of diabetes in the patients and the baseline estimated glomerular filtration rate (eGFR). The Cochrane Collaboration risk of bias tool was used to assess the quality of the included studies. All outcome comparisons were performed using the RevMan 5.4 software. Eleven RCTs with 58 534 participants reporting prespecified renal outcomes were identified. There was no heterogeneity in the baseline eGFR and urine albumin-to-creatinine ratio in the included studies. In the initial 2-4 weeks, there was an acute decline of eGFR in the SGLT-2i group compared with placebo group (weighted mean difference [WMD] -3.35 ml/min/1.73 m2 ; 95% CI, -3.81 to -2.90; I2 = 35%, p=.15); When compared to baseline eGFR in the SGLT-2i group, the WMD was -4.02 ml/min/1.73 m2 (95% confidence interval [CI], -3.61 to -4.44; I2 = 0%, p=.45). The renoprotective effect gradually appeared, and the decline rate of eGFR in the SGLT-2i group was sustained slower than placebo. However, the statistically significant benefit of SGLT-2i did not appear until the 104th week (the second year) (WMD 0.35 ml/min/1.73 m2 , 95% CI, 0.04 to 0.66; I2 = 45%, p=.08). Subgroup analysis showed SGLT-2i had a similar benefit on renal function regardless of baseline eGFR values. SGLT-2i consistently slowed the deterioration of eGFR since the early stage of administration, even in patients with chronic kidney disease. However, there was an acute decline in eGFR in the initial 2-4 weeks; afterwards the renoprotective effect of SGLT-2i gradually appeared and remained stable in the next few years.

Mathematical Analysis for the Effects of Medicine Supplies to a Solid Tumor

Objective: 1. Interpretation of the variations of solute medicine amount in blood vessels and TAF concentration with respect to the flow rates of injected drugs into liver and heart. 2. Description of the alteration of tumor cell density versus the time and radius variations. Methodology: Step 1. Compartmental analysis is adopted for the concentration of chemotaxis caused by injected substances L and H based on the assumption: two different medicines I1 and I2 are injected into heart and liver to recover the functions of each organ, respectively, without any side effects. Step 2. A partial differential equation is derived for the growth of TAF considering the diffusion of TAF and the rate of decay of TAF according to the disturbance of medicine M in blood vessels. Step 3. A partial differential equation is derived for the motion of tumor cells in the lights of random motility and chemotaxis in response to TAF gradients. Step 4. Exact solutions are obtained for the concentration of chemotaxis caused by injected substances L and H under the assumption that the loss of mass is proportional to mass itself. Step 5. Exact solution is obtained for the partial differential equation describing the growth of TAF using the separation of variables. Step 6. A finite volume approach is executed to search approximated solutions due to the complexity of the partial differential equation describing the motion of tumor cells. Results: 1. The concentration of medicine (M) decreases as the ratio of flow rate from heart into vessel to flow rate from liver into heart (k1k2) increases. 2. TAF concentration increases with the growth of the value of ratio k1k2 and TAF shows the smallest concentration when the flow rate of each injected medicine is similar. 3. Tumor cells react highly sensitive as soon as medicine supplies and tumor cell’s density is decreased drastically at the moment of medicine injection. 4. Tumor cell density decreases exponentially at an early stage and the density decrease is developed in a fluctuating manner along the radius. Conclusions: 1. The presented mathematical approach has the potential for the profound analysis of the variations of solute medicine amount in blood vessels, TAF concentration, and the alteration of tumor cell density according to the functional recoveries of liver and heart. 2. The mathematical approach may be applicable in the investigation of tumor cell’s behavior on the basis of complex interaction among five represented organs: kidney, liver, heart, spleen, and lung. A mathematical approach is developed to describe the variation of a solid tumor cell density in response to drug supply. The investigation is progressed based on the assumption that two different medicines, I1 and I2, are injected into heart and liver with flow rates k1 and k2 to recover the functions of each organ, respectively. A medicine function system for the reactions of tumor angiogenic factors (TAF) to medicine injection is obtained using a compartmental analysis. The mathematical governing equations for tumor cells motion are derived taking into account random motility and chemotaxis in response to TAF gradients and a finite volume method with time-changing is adopted to obtain numerical solutions due to the complexity of the governing equations. The variation of the flow rates k1 and k2 exerts profound influences on the concentration of medicine, and similar flow rate of k1 and k2 produces the greatest amount of medicine in blood vessels and suppresses strong inhibition in TAF movement. Tumor cells react very sensitively to drug injection and the tumor cell density decreases to less than 20% at an early stage of administration. However, the density of tumor cell diminishes slowly after the early stage of sudden change and the duration for complete therapy of tumor cells requires a long time.

Superior antibacterial activity of sulfur-doped g-C3N4 nanosheets dispersed by Tetrastigma hemsleyanum Diels & Gilg's polysaccharides-3 solution

Bacterial resistance has become a serious global health issue over the past decades due to the misuse and abuse of antibiotics. The development of effective antibacterial drugs with a new antibacterial mechanism is thus very critical. At present, there are many reports on the antibacterial properties and mechanisms of two-dimensional materials. Currently, the modification of g-C3N4 materials, as widely used two-dimensional materials, has become a key step in extending their potential applications in the field of antimicrobial therapy. In the present work, we prepared sulfur-doped g-C3N4 nanosheets (SCNNSs), which have good water dispersibility and sharp tips. The electrostatic interaction of SCNNSs with Tetrastigma hemsleyanum Diels & Gilg's polysaccharide-3 (THDG-3) provides a new strategy that can improve the killing efficiency of SCNNSs. In addition, THDG-3 can rapidly inhibit bacterial proliferation in the early stage of administration. Combined with the antibacterial activity of the SCNNSs, TPS/SCNNSs can inhibit bacteria for a long time. Scanning electron microscopy (SEM) observation of Escherichia coli (E. coli) after administration of the materials revealed that the bacterial cells were ruptured and their intracellular contents were completely separated from the cell membrane. Therefore, we speculate that the bactericidal mechanism of the TPS/SCNNSs probably involves cell membrane damage. In summary, TPS/SCNNSs achieve fast, long-term, dual-function bacteriostatic properties.

Antitumour Activity of Muricatacin Isomers and its Derivatives in Human Colorectal Carcinoma Cell HCT116.

Colorectal cancer is one of the leading causes of cancer-related death in elderly people. The natural product muricatacin is an important member of the γ-lactone family, and it has exhibited antitumour activity in multiple cancer cell lines; however, the antitumour activities of muricatacin stereoisomers and their derivatives in colorectal cancer cells have not yet been systematically explored. The colorectal carcinoma cell line HCT116 was investigated in this study. Cell proliferation was assessed by MTT assay or crystal violet staining. Cell cycle arrest and cell apoptosis were evaluated by flow cytometry assay. The expression levels of p53, p21, cyclin E, cyclin D1, caspase-3, cleaved caspase-3, caspase-9, cleaved caspase-9 and LC3B were measured using western blot analysis. Autophagy induced by M2 was monitored by immunofluorescence assay with an antibody against LC3B. Cell proliferation assays showed that both naturally occurring muricatacin (M4) and its synthetic stereoisomer (M2) are potent cell growth inhibitors in HCT116 cells, with IC50 values of 79.43 and 83.17μM, respectively; these values are much lower than those of the other two isomers, M1 and M3, and those of the sixmembered lactone analogues. The flow cytometry analysis revealed that M2 and M4 induced significant cell cycle arrest during G0/G1 phase and caused relatively low apoptosis rates in HCT116 cells. Further analysis indicated that M2 caused p53-independent p21 induction and cyclin E/cyclin D1 downregulation. In addition, M2 also markedly induced autophagy in the early stage of administration. Our results suggested that muricatacins possess potent antitumour activity against the colorectal carcinoma cell line HCT116 through inducing G0/G1 phase cell cycle arrest and autophagy in the early stage of administration.

Penicillamine Increases Free Copper and Enhances Oxidative Stress in the Brain of Toxic Milk Mice

Wilson disease (WD) is characterized by the accumulation of copper arising from a mutation in the ATP7B gene. Penicillamine (PA) makes 10–50% of the patients with neurologic symptoms neurologically worse at the early stage of administration. The aim of this study was to determine how the copper metabolism changes and whether the change impairs the brain of toxic milk (tx) mice, an animal model of WD, during the PA administration. The free copper and protein-bound copper concentrations in the serum, cortex and basal ganglia of tx mice with PA administration for 3 days, 10 days and 14 days, respectively, were investigated. The expression of copper transporters, ATP7A and CTR1,was analyzed by real-time quantitative PCR, immunofluorescence and Western blot. Then SOD, MDA and GSH/GSSG were detected to determine whether the oxidative stress changed correspondingly. The results revealed the elevated free copper concentrations in the serum and brain, and declined protein-bound copper concentrations in the brain of tx mice during PA administration. Meanwhile, transiently increased expression of ATP7A and CTR1 was observed generally in the brain parenchyma by immunofluorescence, real-time quantitative PCR and Western blot. Additionally, ATP7A and CTR1 were observed to locate mainly at Golgi apparatus and cellular membrane respectively. Intense staining of ATP7A in the choroid plexus was found in tx mice on the 3rd and 10th day of PA treatment, but rare staining of ATP7A and CTR1 in the blood-brain barrier (BBB). Decreased GSH/GSSG and increased MDA concentrations were also viewed in the cortex and basal ganglia. Our results suggested the elevated free copper concentrations in the brain might lead to the enhanced oxidative stress during PA administration. The increased free copper in the brain might come from the copper mobilized from brain parenchyma cells but not from the serum according to the ATP7A and CTR1 expression analysis.

Preventive effect of Kaempferia parviflora ethyl acetate extract and its major components polymethoxyflavonoid on metabolic diseases

Previously, we reported that rhizome powder of Kaempferia parviflora Wall. Ex. Baker prevented obesity and a range of metabolic diseases. In this study, to clarify which molecular mechanisms and active ingredients of K. parviflora have an anti-obesity effect, we investigated the effect of ethyl acetate extract of K. parviflora (KPE) on TSOD mice, a spontaneously obese Type II diabetes model, and on pancreatic lipase. In the TSOD groups, KPE showed a suppressive effect on body weight increase and visceral fat accumulation and also showed preventive effects on symptoms related to insulin resistance, hypertension and fatty liver. In addition, KPE also suppressed body weight increase and food intake in TSNO mice groups, which served as reference animals, at an early stage of administration. Searching for the ingredients in KPE revealed that KPE contains at least 12 kinds of polymethoxyflavonoid (PMF). Furthermore, KPE and its component PMFs showed an inhibitory effect on pancreatic lipase. The above results suggest that KPE has a preventive effect on obesity and various metabolic diseases. The mechanisms of action probably involve inhibition of pancreatic lipase by the PMFs in KPE.

IL-18 accelerates the cell apoptosis by up-regulating Cysteinyl Leukotriene 2 Receptor Expression in Human Umbilical Vein Endothelial Cells at the early stage of administration

The purpose of the present study is to identify whether interleukin (IL)-18 can modulate cysteinyl leukotriene 2 receptor (CysLT 2R) expression in Human Umbilical Vein Endothelial Cells (HUVECs) and how it influences the cell death. According to the results from real-time reverse transcription PCR, confocal laser scanning microscopy, and western blotting, a dose-dependent augmentation of CysLT 2R protein expression in HUVECs was triggered by IL-18 for the first 2 h followed by down-regulation within the next 22 h after IL-18 administration. The flow cytometry showed that non-selective CysLT 1R and CysLT 2R antagonist BAY-u9773 could attenuate the early stage apoptosis mediated by IL-18 whereas CysLT 1R antagonist Montelukast couldn't. Also, pretreatment with BAY-u9773 suppressed calcium influx of HUVECs induced by IL-18 whereas Montelukast didn't work. The observation that progression of cell death aggravated by IL-18 could be attenuated by BAY-u9773 may offer a chance to develop a novel way to treat arteriosclerosis.

Effects of Dietary Administration of Plant-Derived Anthocyanin-Rich Colors to Spontaneously Hypertensive Rats

Anthocyanins have beneficial effects such as free radical scavenging activity. We investigated the effects of continuous administration of colors from purple corn (PCC), purple sweet potato (PSC) and red radish (RRC) to spontaneously hypertensive rats (SHR). These are rich in anthocyanins. Animals were fed with diets containing PCC, PSC or RRC (1 mass% of diets) for 15 wk. While the body weight and the daily food intake of administered rats were not different from those of the non-administered control rats through the experimental period, the blood pressure and the heart rate of SHR administered each color decreased as compared to the control group from the early stage of administration. These results suggest that plant-derived colors containing anthocyanins have anti-hypertensive effects on hypertensive animals.

CARCINOGENICITY TEST OF POLYOXYETHYLENE(10)NONYLPHENYL ETHER (NP-10) IN FEMALE B6C3F&lt;SUB&gt;1&lt;/SUB&gt; MICE

A carcinogenicity study of polyoxyethylene(10)nonylphenyl ether (NP-10) to B6C3F1 mouse was performed using 50 females per group of 4 study groups, or 200 mice in total. Diets containing NP-10 at 0, 500, 1500 and 4500 ppm were prepared and orally administered to the animals repeatedly for 104 weeks, and observation of general conditions, body weight analysis, food consumption analysis, hematologic examination, organ weight analysis and pathological examination were performed. The results are summarized as follows. The mean intake of the test substance in the 500, 1500 and 4500 ppm groups for 104 weeks was 81.5, 254 and 873 mg/kg/day, respectively. There were no differences observed in mortality among the groups and the mortality did not exceed the background data in any groups. There were no signs attributable to the administration of the test substance, and various signs which increased in occurrence with aging were observed in all groups at a similar frequency. Body weight gain was suppressed only in the 4500 ppm group throughout the entire administration period. Food consumption was increased in all treated groups around the early stage of administration and, thereafter, in the 1500 and 4500 ppm groups until the mid-stage of administration. Decreased food efficiency was observed in the 4500 ppm group alone. As a result of the hematologic examination, no changes attributable to the administration of the test substance were observed in any groups. As a result of the organ weight analysis, lower absolute weights of the liver and kidney and higher relative weights of the brain, liver and kidney, which were considered to be changes accompanying the suppressed body weight gain, were observed in the 4500 ppm group. The pathological examination revealed no marked changes in the gross findings in the treated groups. As a result of the histological examination, there were no neoplastic or non-neoplastic lesions in the treated groups which were unequivocally observed to have increased in occurrence. As the above findings show, NP-10 did not cause any increase in the incidence of neoplastic lesions in the mouse by oral administration for 2 years at 873 mg/kg/day (4500 ppm) and was determined to have no carcinogenicity.

Reproduction study of propiverine hydrochloride (2)--teratological study in rats by oral administration

A teratogenicity study was performed in Sprague-Dawley rats by oral administration of propiverine hydrochloride (P-4) at dose levels of 0 (control), 2, 10 and 50 mg/kg/day to dams from day 7 to day 17 of pregnancy. Twenty two or twenty three female rats in each group were sacrificed on day 21 of pregnancy for examination of their fetuses, and thirteen female rats were allowed to deliver for the postnatal examination of their offspring. In dams, the dose of 50 mg/kg caused toxic signs consisting of mydriasis, salivation and rale, body weight loss in the early stage of administration, and reduced food intake and increased water intake. The dose of 10 mg/kg caused rale, very slight suppression of body weight gain and slight reduction of food intake. Body weight of the fetuses was decreased very slightly in the 50 mg/kg group. However, embryonal or fetal mortality and incidences of external, visceral or skeletal anomalies were not increased. In offspring, P-4 had no adverse effect on the postnatal development such as viability, growth, differentiation, emotionality, learning ability or reproductive performance. The results suggest that the non-effective dose level of P-4 is 2 mg/kg/day in maternal animals, 10 mg/kg/day in fetuses and 50 mg/kg/day in offspring.

Sequential changes of nuclear DNA content caused by chemotherapy in experimental canine gastric cancer.

It is well known that the nuclear DNA content closely correlates with the histologic grade of malignancy. In this study, eight beagle dogs with gastric cancer induced by N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) received weekly administration of 7-N-(p-hydroxyphenyl)-mitomycin C (M-83), a variant of mitomycin C. Endoscopic observations were carried out biweekly, and a biopsy specimen was taken from the same tumor site on each occasion. The nuclear DNA content of these biopsy specimens was measured by Feulgen-DNA-cytofluorometry and was sequentially observed in comparison with histologic findings. In conclusion, 1) the appearance rate of cells over 4C decreased from 25.6% to 14.7% on an average (p less than 0.02); 2) the maximum value of distribution decreased from 9.55C to 7.64C on an average (p less than 0.001); 3) the stem line reduced from 2.63C to 2.20C on an average (p less than 0.05) at the early stage of administration of the oncostatic agent prior to the appearance of histologic changes; 4) in the chemotherapy-effective group, the histogram approached a normal pattern; 5) this procedure will be useful for objective evaluation of oncostatic effects at the cytomorphologic level.

Evolution of activation-detoxification enzyme patterns during precarcinogenesis in synergism: 3-methylcholanthrene and dimethylnitrosamine.

The effects of 3-methylcholanthrene (3MC) and dimethylnitrosamine (DMN), administered singly or in combination at chronic carcinogenic doses, on the evolution of activity patterns of enzymes involved in the metabolism of DMN and polycyclic hydrocarbons were studied in the liver and lung of Sprague-Dawley rats and Swiss mice. In the pulmonary tissues of rats, during the early stage of administration (7 weeks), there was substantial increase of epoxide hydrase and glutathione S-epoxide transferase activity; from then on these detoxifying enzyme activities rapidly decreased toward 25 weeks, and this decreasing trend coincided with a substantial surge of aryl hydrocarbon hydroxylase (AHH) activity at 15 weeks; 65%, 95%, and 50% increase with 3MC, DMN, and DMN+3MC, respectively. The activity of DMN-demethylase was slightly increased following treatment with DMN or DMN+3MC for 15 weeks. On the other hand, decrease of DMN-demethylase activity in the liver of rats throughout most of the experimental period was apparent and, after an initial small increase at 7 weeks, there was a trend of decreasing AHH activity from 7 toward 25 weeks with DMN+3MC; the 7-week increase in AHH was moreover compensated by the large increases in the activity of the three detoxifying enzymes, epoxide hydrase, glutathione S-epoxide transferase, and UDP-glucuronyl transferase at the same period. The data suggest that the previously observed pulmonary syncarcinogenesis between 3MC and DMN in rats (Hoch-Ligeti et al. 1968) is probably due to increase of reactive metabolites of both 3MC and DMN. In the mouse liver, a combination of initial increase of epoxide hydrase and UDP-glucuronyl transferase activity at 5 weeks, together with decrease of AHH activity at 10 weeks, suggests a decrease of activated hydrocarbon metabolites available for binding to macromolecules. While AHH activity showed a strongly decreasing trend in the mouse lung, increases of 21%, 30%, and 113% in DMN-demethylase activity were observed after the mice were given 3MC, DMN, or DMN+3MC, respectively, for 10 weeks. The pulmonary syncarcinogenic effect of 3MC and DMN in mice (Cardesa et al. 1973; Argus et al. 1982) appears to be due primarily to increase of reactive metabolite(s) of DMN. The data are consistent with previous observations (Arcos et al. 1978) that activated metabolites originating from liver are unlikely to be contributors in DMN+3MC pulmonary syncarcinogenesis.

CLINICO-CHEMICAL STUDIES ON SUBACUTE CADMIUM POISONING IN RABBITS

GOT, GPT, LDH, total Ac-P, prostatic Ac-P, Al-P, cholesterol, free fatty acid, Ca, and P in plasma were measured once a week on rabbits injected subcutaneously with 0.5 and 1.0 mg Cd/kg daily for 11 weeks respectively, and Cd, Cu, Mn, and Zn contents in organs were determined at the termination of the experiment.Prostatic Ac-P activity, cholesterol, and free fatty acid levels in plasma rose in the early stage of administration, and GOT, GPT, LDH, and Al-P activities rose in the latter stage of administration. Ca and P levels in plasma did not change in all periods of the experiment. From these results, it could be concluded that a measurement of prostatic Ac-P, cholesterol, and free fatty acid is available for knowing an excess intake of Cd.Cd contents in heart, lungs, spleen, and testes of rabbits injected with 1.0 mg Cd/kg increased significantly compared with those with 0.5 mg Cd/kg, but a difference between the two groups in Cd contents in liver, kidneys and submandibular glands which contained high concentration of Cd was not recognized. Zn contents in organs of rabbits injected with Cd increased remarkably, while Cu contents decreased generally. This phenomenon was especially remarkable in liver and kidneys.