Trastuzumab in the treatment of advanced breast cancer: single-center experience.

A significant number of women with advanced breast cancer fail to respond to standard-dose chemotherapy. From the beginning of 1999, 17 women with HER2 positive advanced breast cancer received Herceptin as monotherapy or in combination with paclitaxel or other non-anthracyclines. Eight (47%) women previously received high-dose chemotherapy followed by haematopoiesis stem cell rescue. Three women received Herceptin alone, eleven Herceptin plus paclitaxel and three Herceptin and some of the other non-anthracyclines (CCNU, cisplatin and gemcitabine). In the group of patients who received Herceptin monotherapy, one has partial response (PR), one stable disease (SD) and in the third patient the disease progressed. Out of three patients who received Herceptin in combination with other non-anthracyclines, two have SD and one progressed. In the group of 11 women who received Herceptin + Taxol, 7 (64%) patients achieved PR, 2 (18%) SD, and 2 (18%) had disease progression. Grade 3-4 neutropenia has been observed in four (23%) women. Febrile neutropenia was observed in two cases and resolved completely when antibiotics were introduced. Other grade 3 toxicity that has been noted is peripheral neuropathy in three (18%) patients, diarrhoea in four (23%) and onycholysis in one (6%). Serial heart ultrasound showed no significant decline in left ventricular ejection fraction. According to our preliminary experience, Herceptin therapy showed promising results in women with metastatic breast cancer.

Mobilisation of cadmium by meso- and racemic-2,3-dimercaptosuccinic acid (DMSA) in rats.

A higher efficiency of cadmium binding with racemic than with meso-2,3-dimercaptosuccinic acid (rac-DMSA; meso-DMSA) was found in an in vitro speciation model by Fang et al. (1996). This finding has not yet been tested in vivo. This paper presents results on mobilisation of cadmium by meso- and rac-DMSA in rats. Cadmium chloride was administered as the radioactive isotope 109Cd intraperitoneally to all animals. One group was an untreated control and two groups were treated with meso- and rac-DMSA, respectively. Treatment with chelators was applied twice, immediately after 109Cd and 24 hr afterwards intraperitoneally at the dose of 1 mmol/kg, each. Six days later radioactivity was measured in the liver and kidneys. Whole-body counting was carried out on days 1, 2, 3 and 6 of the experiment. At the end of the experiment, both treatments caused a decrease in 109Cd whole-body retention with rac-DMSA being more efficient (decrease from 83% in control to 74% and 64% in groups treated with meso- and rac-DMSA, respectively). The same reduction of 109Cd was obtained by both chelators in the liver (from 57% to about 47%). In the kidney only rac-DMSA produced significant reduction of 109Cd (from 5.3% to 3.5%). In conclusion, these results show modest reduction of cadmium in the body by two isoforms of DMSA with rac-DMSA being slightly more efficient than meso-DMSA.

Combined chelation therapy in reducing tissue lead concentrations in suckling rats.

The very young are more prone to lead poisoning than adults, and the treatment with chelating agents, either as monotherapy or combined treatment, is still a matter of dispute. The purpose of this work was to evaluate the efficiency of three chelating agents administered either as monotherapies or as combined treatments in sucklings. Lead acetate (5 mg Pb kg(-1) i.p.) was administered to the 7-day-old rat pups in eight litters on experimental day 1 and chelating agents on experimental days 2 and 3. Pups were divided into six groups: (1) untreated control; (2) EDTA (calcium disodium ethylendiaminetetraacetate, 0.3 mmol kg(-1) i.p. at 4 p.m.); (3) meso-DMSA (meso-2,3-dimeracaptosuccinic acid, 0.5 mmol kg(-1) p.o. at 10 a.m.); (4) rac-DMSA (racemic-2,3-dimeracaptosuccinic acid, 0.5 mmol kg(-1) p.o. at 10 a.m.); (5) EDTA+meso-DMSA; and (6) EDTA+rac-DMSA. Rats were killed on experimental day 5. Tissue element concentrations were analyzed by atomic absorption spectrometry. Treatment with EDTA did not affect tissue Pb, but it reduced Zn in the carcass and liver. Meso-DMSA reduced Pb in the kidneys and brain, and it did not affect organ essential elements. Rac-DMSA most efficiently reduced Pb concentrations in the carcass, kidneys and brain, but it also reduced Zn and Cu in the liver and Zn in the kidneys. Combined treatments with EDTA never improved the efficiency of either DMSA isoform in decreasing tissue Pb but they did reduce tissue Zn concentrations. All treatments caused the same decrease in the carcass Ca concentrations. The results do not support combined treatment in this age group, which is especially sensitive to trace element deficiencies, and suggest that meso-DMSA might be the treatment of choice in acute lead poisoning in infants.

Meso-2,3-dimercaptosuccinic acid in the treatment of occupationally exposed lead workers.

The aim of this study was to evaluate the efficacy of meso-2,3-dimercaptosuccinic acid (DMSA) treatment in workers with increased lead absorption and no overt symptoms of lead poisoning. Seven occupationally lead exposed male workers with blood lead concentrations (PbB) exceeding 50 micrograms/100 ml and a positive calcium disodium ethylenediaminetetraacetate (EDTA) lead mobilization test were treated with DMSA for 19 days. Individual doses were 700 mg DMSA, three times a day from day one to five, and twice a day from day six to 19. The treatment intensified urinary lead excretion, most rapidly during the first five days. The increased elimination was followed by a decline of mean PbB to 15% of the pretreatment values. However, 15 days after the treatment, the PbB concentrations rebounded, yet kept below the baseline values and did not exceed 40 micrograms/100 ml. After repeated EDTA lead mobilization test, urine lead was 23-68% of that before DMSA treatment. It can be concluded that DMSA can effectively reduce chelatable lead in occupationally exposed workers.

Combined oral treatment with racemic and meso-2,3-dimercaptosuccinic acid for removal of mercury in rats.

Racemic dimercaptosuccinic acid (DMSA) was found more efficient than the meso-isoform in enhancing the removal of mercury in rats. However, racemic-DMSA has recently been found more toxic. The efficiency of combined oral treatment with the two isoforms of DMSA for removal of mercury has now been evaluated. Female albino rats were treated orally for four days with meso- (M) and/or racemic- (R) DMSA (1 mmol/kg each), five days after a single intraperitoneal administration of 203Hg with 0.5 mg HgCl2/kg. The animals were divided into six groups according to the number of treatments with each isomer: control (untreated), 4M, 1R + 3M, 2R + 2M, 3R + 1M, and 4R. Whole body, kidney, liver and brain mercury contents were measured nine days after 203Hg administration. In all treated groups retention in the whole body and kidneys was greatly reduced. The groups treated with racemic-DMSA, regardless of the number of doses, showed a greater removal of mercury than the group treated with meso-DMSA alone (4M). All treatments were less efficient in reducing liver retention, and the brain retention was not affected. It was concluded that even a single application of the more toxic racemic-DMSA during a four-day oral treatment regimen is sufficient to improve the removal by meso-DMSA of mercury from rats.

Individual variation in response to lead exposure: a dilemma for the occupational health physician.

Subclinical lead poisoning with no clinical symptoms is a dilemma for the occupational health physician. He is supposed to assess when and how to treat workers at risk mainly by the results of biological monitoring. The aim of this study was to demonstrate different responses of biological indices in 50 lead-exposed workers who have been working in the same plant of lead pigment production factory. Twenty-one had normal, that is, permissible blood lead concentrations (PbB), erythrocyte protoporphyrin (EP), and aminolevulinic acid activity (ALAD) measured during regular periodic examinations (group 1). No differences between two measurements were found, although they were continuously working with lead. In 18 of the 50 workers (group 2), PbB and EP concentrations increased, whereas ALAD activity decreased: those parameters improved after a 3- to 6-month cessation of lead exposure. Seven of the 50 workers also had altered values of biological indices, but their condition improved spontaneously without cessation of lead exposure (group 3), while in the remaining four workers, elevated concentrations of biological indices did not change during the observation period. The reasons for such discrepancies and indications for chelation therapy are discussed.

Racemic-2,3-dimercaptosuccinic acid for inorganic mercury mobilization in rats.

The efficiency of racemic-2,3-dimercaptosuccinic acid (rac-DMSA) compared with meso-2,3-dimercaptosuccinic acid (meso-DMSA) in mobilizing inorganic mercury was evaluated in female rats. Chelators were administered orally at a dose of 0.5, 1.0 or 2.0 mmol kg-1 on four consecutive days, 5 days after a single intraperitoneal 203Hg injection (with 0.5 mg HgCl2 kg-1). Both chelators reduced 203Hg retention in whole body and kidney and at higher doses also in the liver. Racemic-DMSA was more efficient at lower dose levels and equal to meso-DMSA at the highest dose level. Kidney retention decreased after rac-DMSA to 27, 10 and 10% of controls and after meso-DMSA to 68, 39 and 10% of control values at the 0.5, 1.0 and 2.0 mmol kg-1 dose level, respectively. Since meso-DMSA is already approved for human use, its stereoisomeric form, rac-DMSA, deserves further attention for treatment of mercury poisoning.

Contribution of lead poisoning to renal impairment.

The late effects of lead on kidney function and blood pressure were studied in 38 persons occupationally poisoned in the past and in 23 workers exposed to lead. Parameters evaluated in all subjects were: creatinine clearance, hippuran renal flow, blood lead, erythrocyte protoporphyrin, aminolevulinic acid dehydratase, and blood pressure. Out of 11 combined variables, four significant factors were identified by factor analysis. The results showed the presence of the delayed adverse effect of previous occupational lead poisoning on kidney function and blood pressure. This phenomenon is a complex interplay of lead poisoning in the past, overall duration of lead exposure, and age as a major confounding variable related to aging process of the kidneys.

Meso-2,3-dimercaptosuccinic acid mono-N-alkylamides: syntheses and biological activity as novel in vivo cadmium mobilizing agents.

Three meso-2,3-dimercaptosuccinic acid mono-N-alkylamides (meso-RNHCOCH(SH)CH(SH)-COOH, where R = CHMe2, Mi-PDMA; CH2CHMe2, Mi-BDMA; and CH2CH2CHMe2, Mi-ADMA), were prepared via a synthetic route using the sulfhydryl-protected anhydride. 2,2-Dimethyl-1,3-dithiolane-4,5-cis-dicarboxylic acid anhydride was opened up with 1 mol of corresponding amine to give the SH-protected monoamide. Subsequent deblocking of the vicinal dithiol functionality was accomplished by conversion of the dithiolane into the mercury complex followed by reaction with H2S to give the target molecule. The potential utility of these compounds in chronic cadmium intoxication was examined by evaluation of their cadmium mobilizing efficacy in vivo in cadmium-loaded female albino rats using sodium N-benzyl-D-glucamine-N-carbodithioate (BGDTC) as the standard drug. Compared to BGDTC, the new compounds were, except at the highest dosage studied, equally or more effective in decreasing retention of hepatic cadmium, while mostly less effective in decreasing renal cadmium. The greatest reductions were obtained with Mi-BDMS at 4 x 1.5 mmol/kg, where liver and kidney cadmium levels were reduced to 12% and 59% of control levels, while at the same dosage BGDTC induced a reduction to 50% and 13% of control levels. The order of the efficacy of the monoamides as hepatic cadmium mobilizing agents was found to be Mi-PDMA > Mi-BDMA > Mi-ADMA. However, the isopropyl analog, though very effective at reducing hepatic cadmium at a low dosage, was found to be more toxic than the isobutyl and isoamyl monoamides. While the new compounds were shown to be effective cadmium mobilizing agents, the specific compounds examined did not possess optimized structures in terms of the balance between effectiveness and toxicity.

Chronic lead poisoning, renal function and immune response.

The aim of this study was to investigate possible correlations between chronic, recurrent lead poisoning, renal function and immune response. The study involved 74 patients with a history of at least one lead poisoning. Fifty-three patients were occupationally poisoned, and 21 were poisoned accidentally after consumption of alcohol beverages or food from lead glazed pottery. In all patients glomerular filtration rate (GFR) was determined by measuring creatinine and DTPA clearances, and T- and B-lymphocytes were assessed as indicators of cellular and humoral immunity. A significant negative correlation was found between the number of past lead poisonings indicating increased lead body burden, and both creatinine and DTPA clearances. There was a significant positive correlation between the number of poisonings and the percentage of B-lymphocytes (r = 0.31; P < 0.05), and no correlation at all with the T-lymphocyte count. Our results show that chronic, recurrent lead poisoning with a consequently increasing lead body burden can cause an impairment in renal function and a concomitant stimulation of humoral immunity.

Lead poisoning associated with the use of Ayurvedic metal-mineral tonics.

OBJECTIVE: The aim of this study was to confirm the connection between lead poisoning and the use of traditional Ayurvedic metal mineral tonics. METHODS: The study group comprised 29 subjects (26 adults and three children) who had previously taken Ayurvedic metal mineral tonics. All subjects were tested for lead absorption by blood lead, erythrocyte delta-aminolevulinic acid dehydratase activity and erythrocyte protoporphyrin. RESULTS: Eighteen samples of Ayurvedic preparations were obtained from 15 subjects and analyzed for lead content. Five adult subjects with established lead poisoning received chelation therapy. In Ayurvedic preparations a wide range of lead content was found (0.9-72,990 micrograms Pb/g; 0.35-29,900 micrograms Pb/capsule or tablet). The blood lead, erythrocyte delta-aminolevulinic acid dehydratase and erythrocyte protoporphyrin of the subjects, grouped according to the remedies used, correlated with the lead content in the preparations (p < 0.001). Chelation therapy was successful in normalization of laboratory findings and clinical recovery. CONCLUSION: Ayurvedic metal-mineral tonics are again identified as a potential source of high lead. The import of such tonics should be strictly controlled.

Delayed effects of lead on the kidney--factor analysis.

A late, i.e. delayed, effect of lead on kidney function and blood pressure was studied in 23 workers with a history of occupational lead poisoning. Twenty lead exposed workers with no known history of lead poisoning were a positive control. Four important factors out of 11 combined variables derived from 22 single variables were identified by factor analysis. The first factor comprised the variables kidney function, blood pressure, age, duration of lead exposure and the number of previous lead poisonings. The second factor comprised the variables duration of lead exposure and biological indicators of lead exposure. The third factor correlated the frequency of previous lead poisonings with the renal blood flow, erythrocytic protoporphyrin and age. The fourth factor comprised the variables length of work service, creatinine clearance and erythrocytic protoporphyrin. The results confirm the presence of the adverse late effect of previous occupational lead poisoning on kidney function regardless of treatment. The phenomenon is not a single event but a complex interplay of past lead poisoning, duration of exposure to lead, "normal" age effect on an increase in systolic and diastolic blood pressure and blood creatinine and a decrease in renal function as revealed by decreased creatinine clearance and a slow down in renal flow time. The complexity of dealing with the confounding variable of age and lack of appropriate classification of renal function impairment may account for the conflicting results of chronic lead effect upon kidney function in the past. The kidney appears to be a critical target organ, reflecting the total lead body burden in chronic lead exposure and poisoning. Therefore monitoring of kidney function in lead exposed workers needs to be mandatory.

[Late changes in renal function after lead poisoning and chelation therapy]. / Odgodene promjene funkcije bubrega nakon otrovanja olovom i lijecenja kelatima.

Glomerular filtration rate was examined by determination of creatinine clearance in 22 adult males with a past history of lead poisoning. Eighteen subjects had been poisoned after many years of occupational exposure to lead and four had been poisoned by ingestion of alcohol beverage kept in lead-glazed pots. Seventeen subjects were treated with the chelating agent calcium-disodium-edetate (CaNa2EDTA), the remaining five received no treatment. The aim of the study was to examine the delayed effects of lead poisoning on kidney function and the possible difference in functional impairment between the treated and the non-treated subjects. The results obtained demonstrated a significantly reduced glomerular filtration rate, adjusted for age, in subjects poisoned by lead in the past who failed to receive specific treatment (P < 0.01). This indicates the possibility of marked, delayed adverse effect of lead on the kidneys in cases when lead body burden has not been reduced by treatment.