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Biomedical subjects

N Alcock

Publications and source records attributed to N Alcock.

17 recordsLinked to original sources
PubMed1998

Population monitoring: experience with residents exposed to uranium mining/milling waste.

More emphasis should be placed upon using biomarkers to address potential health risk among populations exposed to high concentrations of environmental toxicants. Among these studies, those which integrate exposure measurements with analyses of validated biomarkers may provide more reliable information for risk assessment and disease prevention. We have used a multidisciplinary approach to elucidate potential health hazards in a population living around uranium mining/milling facilities. The study included 24 target and 24 control residents who were matched for age and gender and selected based on time of residence in the study areas and proximity to mining/milling sites. Environmental samples were analyzed for uranium-238 (238U) concentrations and lead isotope ratios using inductively coupled plasma-mass spectrometry (ICP-MS) procedures, and blood samples were collected for cytogenetic analysis. We found that the 238U concentrations in soil samples were significantly higher than those in the control areas. In addition, the concentrations in the surface soil were significantly higher than in the subsurface soil (p<0.05) from target areas indicating environmental contamination by the mining/milling activities. Lead isotope data from soil samples taken near a railroad transfer location was significantly different from those of other sites, indicating contamination by non-native ore transported from sources outside of the region to local milling facilities for processing. Therefore, local residents have been exposed to low levels of radioactive contamination from the mining/milling activities on a daily basis for many years. From our cytogenetic analysis, the target population had more chromosome aberrations than the controls, although the differences were not significant (p<0.05). However, using our challenge assay, cells from the target population had a significantly abnormal DNA repair response, compared to cells from the same control population. In conclusion, the observed environmental contamination by uranium is consistent with the observed genotoxic effects in the target residents. Therefore, the residents have increased health risk and some of the health problems will most likely be related to exposure to the radioactive contaminants. Since the chromosome aberration frequency revealed increased, but not significant differences between the exposed and the control populations, we conclude that the health risk among the exposed residents is similar to those among nuclear workers.

Anencephaly↗
PubMed1991

Ba2+ release from soda glass modifies single maxi K+ channel activity in patch clamp experiments.

Glasses used to fabricate patch pipettes may release components which affect ion channels (Cota, G., and C.M. Armstrong. 1988. Biophys. J. 53:107-109; Furman, R.E., and J.C. Tanaka. 1988. Biophys. J. 53:287-292; Rojas, L., and C. Zuazaga. 1988. Neurosci. Lett. 88:39-44). The gating properties of maxi K+ channels from Necturus gallbladder epithelium depend on whether borosilicate glass (BG) or blue tip hematocrit glass (SG) is used to construct the patch pipettes. The data are consistent with solubilization from SG of a component which exerts voltage-dependent, cytosolic-side specific block, closely resembling "slow block" by Ba2+ ions. Ringer's solution preincubated with SG, but not with BG, blocked inside-out maxi K+ channels when used as bathing solution. Mass spectrometry revealed that Ba2+ is released by the glass from fast and slow-release compartments (SG contains 3% wt/wt BaO), and is the only ion found in the solution at concentrations consistent with the observed channel block. Additionally, SG released O2-, Na+, Ca2+, and Mg2+, all to micromolar concentrations. These elements do not interfere with maxi K+ channels but they could in principle alter the properties of other ion channels. Thus, screening for channel-modifying substances released by the glass may be necessary for the adequate interpretation of patch-clamp results.

Animals↗
PubMed1990

Skeletal effects of sodium fluoride during hypokinesia.

This study tested the capacity of fluoride (F) to prevent the disuse-associated reduction in bone formation/growth. Suspending young male Wistar rats by the tail for 2-2.5 weeks reduced femoral cortical (P less than 0.05) and trabecular (P less than 0.01) bone areas. Tetracycline labelling showed that the decrement in cortical area was largely due to a reduction in the percent periosteal mineralizing surface (PsMS). Periosteal mineral apposition rate (PsMAR) was not affected. Endosteal mineralizing surface (EsMS) and mineral apposition rate (EsMAR) were significantly stimulated spontaneously during the second week of suspension. F treatment (5 mg/kg/day i.p.) prevented the loss in bone area, and established a trend toward increased PsMS without affecting EsMS and EsMAR. None of these changes are associated with alterations in serum Ca, P or osteocalcin. F treatment in hypokinetic animals caused a decrease in serum PTH (-21% compared to control; P = 0.001). We conclude that F prevents the development of hypokinetic osteopenia in rats.

Animals↗
PubMed1988

Hormonal and metabolic response to recombinant human tumor necrosis factor in rat: in vitro and in vivo.

Tumor necrosis factor (TNF; cachectin) has been implicated as a mediator of the toxic manifestations of overwhelming bacterial infection as well as the chronic catabolic state of cancer cachexia. We have examined the acute metabolic and hormonal response after administration of recombinant human TNF in the rat. TNF given by intraperitoneal injection produced dose- and time-related increases in hepatic amino acid uptake, decreases in serum trace metal concentrations, and a pattern of endocrine hormone alterations characteristic of the acute phase response to tissue injury. In vitro zinc transport studies by rat hepatocytes cultured in the presence of TNF alone, or in combination with recombinant human interleukin 1, another mediator of the acute phase response, demonstrated that neither monokine was capable of directly stimulating zinc transport into cells. These findings suggest that TNF may function as an endogenous mediator of the early metabolic response to sepsis and that the trace metal changes induced by TNF in vivo may occur through a secondary mechanism.

Amino Acids↗
PubMed1987

Gallium nitrate in prostatic cancer: evaluation of antitumor activity and effects on bone turnover.

Gallium nitrate, an agent known to inhibit bone resorption, was evaluated in patients with bidimensionally measurable hormone-refractory prostatic cancer. The starting dose was 200 mg/m2 iv by continuous infusion over 7 days. Two patients (10%; 95% confidence limits, 0%-22%) achieved short partial remissions of 1 and 6+ months, while seven of 23 (30%; 95% confidence limits, 14%-52%) showed a diminution of bone pain. Serial indices of bone turnover including serum calcium, phosphorus, and urinary hydroxyproline excretion showed a significant decrease at the completion of the infusion which returned to baseline prior to the next cycle. The data suggest the effect on bone was too short to produce consistent improvement. Reasons for the dissociation of pain relief and antitumor activity are discussed.

Adenocarcinoma↗
PubMed1987

[13N]cisplatin PET to assess pharmacokinetics of intra-arterial versus intravenous chemotherapy for malignant brain tumors.

The biodistribution, blood clearance, and in vivo transformation of cisplatin (cisdiaminedichloroplatinum, DDP) were studied in rats using 13N-labeled and unlabeled DDP. Following the i.v. injection of [13N]DDP, virtually no 13N activity was detected in brain tissue, and no measurable amount of the 13N label was displaced from [13N]DDP. Based on these results, [13N]DDP/positron emission tomographic (PET) scans were performed in two glioblastoma patients undergoing Phase II intra-arterial (i.a.) DDP chemotherapy: [13N]DDP was infused i.v. over 13-15 min, during which time serial PET scans were obtained. One hour later, [13N]DDP mixed with cold DDP (100 mg/m2 therapeutic dose) was infused at the same rate i.a., and a second sequence of PET scans was acquired. The pharmacologic advantage of i.a. administration was calculated as the ratio of integrated tumor/brain count ratios for the i.a. and i.v. studies. Our preliminary results demonstrate the feasibility of quantifying the pharmacologic advantage of i.a. DDP chemotherapy in individual brain tumor patients using [13N]DDP and PET.

Animals↗
PubMed1986

Bone disease in prolonged parenteral nutrition: osteopenia without mineralization defect.

A metabolic bone disease characterized by a mineralization defect, low plasma 1,25(OH)2D, and hypercalciuria has been described in patients receiving prolonged total parenteral nutrition (TPN). Because the practice of TPN differs from center to center, we investigated 13 home TPN patients to determine whether they had similar or different bone abnormalities. They had received TPN for a mean period of 51 +/- 38 mo. Bone pain occurred in six patients and two had multiple vertebral and rib fractures (with trauma in one patient). Bone pain was mild to moderate and not incapacitating. Bone histomorphometry showed reduced bone volume, reduced osteoid with normal resorption and calcification rates. These abnormalities were associated with hypercalciuria, but the plasma levels of 1,25(OH)2D were normal. Abnormalities in bone metabolism in this group of patients suggest a fundamental decrease in bone matrix-formation rather than a mineralization defect as the underlying mechanism.

Adult↗
PubMed1985

Malabsorption and mucosal abnormalities of the small intestine in the acquired immunodeficiency syndrome.

Diarrhea and weight loss may accompany the acquired immunodeficiency syndrome. We studied 30 patients with the syndrome, 20 of whom had diarrhea and weight loss and 10 of whom did not. Patients with identifiable enteric infections or small intestinal Kaposi's sarcoma were excluded. Malabsorption was common in the patients with diarrhea and weight loss, as shown by abnormal D-xylose and 14C-glycerol-tripalmitin absorption tests. In these patients, duodenal biopsy specimens showed a histiocytic infiltrate containing numerous acid-fast organisms in 5 and a mild-moderate chronic inflammation in 13. In asymptomatic patients, duodenal biopsy specimens were normal in 6 and showed chronic inflammation in 4. These results suggest that malabsorption is common in patients with the acquired immunodeficiency syndrome with chronic diarrhea and may contribute to their weight loss.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Cisplatin nephrotoxicity. Correlation with plasma platinum concentrations.

Plasma platinum concentrations were measured in 45 patients receiving 46 courses of cisplatin (DDP) 100-120 mg/m2 and in 21 patients receiving 35-60 mg/m2. Samples were drawn 5 minutes, 24, and 48 hours following completion of the DDP infusion. Nephrotoxicity was defined as a greater than 50% increase in serum creatinine measured at 24 and/or 48 hours when compared to the baseline pretreatment value. In patients receiving DDP 100-120 mg/m2, 5/20 with 5-minute plasma platinum concentrations greater than 6 micrograms/ml developed nephrotoxicity; 0/26 with concentrations less than 6 micrograms/ml became nephrotoxic (p less than 0.05). Concentrations at 24 and 48 hours in toxic and nontoxic patients were similar. Five-minute plasma platinum concentrations in excess of 6 micrograms/ml did not occur in the 21 patients receiving DDP 35-60 mg/m2. Only one of these 21 patients became nephrotoxic. The data suggest that an increased incidence of acute nephrotoxicity is related to high peak plasma platinum concentrations.

Cisplatin↗
PubMed1983

Tissue concentrations and proliferative effects of massive doses of ascorbic acid in the mouse.

The effect of ascorbic acid supplementation on CF1 mice fed ascorbic acid for approximately six months at dose levels of 1%, 5%, and 10% of diet was investigated by analysis of tissue ascorbic acid concentration in the liver, kidney, stomach, small intestine, and large bowel. The effect on epithelial cell proliferation was also examined in the small and large bowel but only at the 5% level. In the control animals, ascorbic acid concentration was lowest in the liver (0.406 +/- 0.07 mg/g) and highest in the small bowel (0.754 +/- 0.16 mg/g). Dietary intake of 5% and 10% ascorbic acid significantly elevated levels in the liver (0.741 +/- 0.13; p less than 0.05), and all doses of ascorbic acid significantly raised tissue concentrations in the kidney and colon. No difference was observed in the percentage of DNA-synthesizing cells in the jejunum of controls or animals fed 5% ascorbic acid at 1 or 24 hours after 3HTdR injection. However, at 1 hour a significantly decreased level of proliferation was observed in the distal colon of ascorbic-acid-treated mice compared with controls (labeling index [L.I.] = 7.3 +/- 0.28 vs. 10.1 +/- 1.15; p less than 0.05), and an even greater suppression of DNA synthesis was achieved by 24 hours (L.I. = 11.4 +/- 1.06 vs. 18.6 +/- 1.61; p less than 0.01). None of the doses of ascorbic acid employed was toxic to the experimental mice.

Animals↗
PubMed1983

Intravenously administered amino acids with either dextrose or lipid as nutritional support in surgical patients.

The relative efficacy of exogenous fat or glucose in preserving lean body mass in surgical patients is controversial. In this study, peripheral intravenously administered amino acids with either lipid or dextrose were given to well nourished patients undergoing elective total cystectomy and ileal diversion. Patients were well matched for age, sex, nutritional status and degree of operative stress. Twenty-eight patients received 1.2 grams per kilogram per day of amino acids plus either dextrose (440 kilocalories per day) (17 patients) or 10 per cent fat emulsion (550 kilocalories per day) (11 patients) for three days preoperatively and seven days postoperatively. No significant differences between the groups were noted in mean nitrogen balances during the preoperative and postoperative periods or in the mean cumulative adjusted (for change in blood urea nitrogen and body weight) nitrogen balances for the total study time. Mean nitrogen excretion per 100 nonprotein calories infused was also similar. Changes in mean body weight, blood urea nitrogen, serum glucose and serum albumin were similar in the two groups. No deaths or major infectious complications occurred in either group. In well nourished patients matched for age, sex, nutritional status and degree of operative stress, the addition of either hypocaloric fat or dextrose to intravenously infused amino acid solutions resulted in an equivalent metabolic and clinical outcome.

Aged↗
PubMed1982

Pharmacokinetics of cisplatin regional hepatic infusions.

Cisplatin (DDP), a potent antineoplastic agent, is usually administered via a peripheral vein. Recently, there has been considerable interest in intraarterial regional infusions of DDP. The pharmacokinetics of DDP when administered by this technique have not been explored in detail. We studied DDP pharmacokinetics in dogs given DDP by infusion and bolus injection in the hepatic artery (H.A.), portal vein (portal V), and peripheral vein (P.V.). Blood and biliary platinum concentrations ([Pt]) were assayed by flameless atomic absorption spectrophotometry. During an infusion into the H.S., peak [Pt] in the vessel were markedly higher (mean value 19 micrograms/ml) than those found, simultaneously, in the portal V or superior vena cava. Following a bolus injection of DDP into the H.A., higher H.A. [Pt] were also seen, but [Pt] rapidly (within 5-10 minutes) equilibrated in all sites sampled. During the H.A. infusion, most [Pt] was in its free (active) form. Bile and hepatic tissue were also sampled. Hepatic artery infusions of DDP give high drug concentrations in the perfusing blood, while systemic [Pt] are much lower. During the infusion, the majority of DDP is in its active (unbound) state.

Animals↗
PubMed1982

Phase I clinical trial and pharmacokinetics of 4'-carboxyphthalato(1,2-diaminocyclohexane)platinum(II).

4'-Carboxyphthalato(1,2-diaminocyclohexane)platinum(II) is a new, second generation platinum analog which had demonstrated in vitro activity in L1210 cell lines resistant to cisplatin and had less nephrotoxicity than did cisplatin in preclinical animal testing. A Phase I trial with this agent has been performed in 45 patients with advanced refractory cancers. Nine dosage levels, ranging from 40 to 800 mg/sq m, were studied. Major toxicities seen were myelosuppression, nephrotoxicity (which was generally mild), nausea and vomiting (which was quantitatively less than that seen with cis-platin), allergic reactions, and a peripheral neuropathy. The dose-limiting toxicity was thrombocytopenia. Pharmacokinetics performed at three dosage levels indicates that 4'-carboxyphthalato-(1,2-diaminocyclohexane)platinum(II) has a long t1/2 of 20 to 30 hr (total platinum) and is only partially excreted in the urine and that a high proportion of the drug is nonfilterable within 30 to 60 min of administration. Therapeutic responses were seen in nasopharyngeal carcinoma, adenocarcinoma of the cervix, and lung and gastric cancer. As a starting dose for Phase II studies, which are planned for patients with ovarian, testicular, lung, gastric, and esophageal cancers, 640 mg/sq m given every 3 to 4 weeks is recommended.

Creatinine↗
PubMed1981

Pharmacokinetics of Malonato (1,2 diaminocyclohexane) platinum.

Malonato-(1,2 diaminocyclohexane) platinum (MP) is a new platinum analog currently undergoing phase I clinical trials. Using flameless atomic absorption spectrophotometry, the pharmacokinetics of MP were studied at five dosage levels. The drug was given as a prolonged intravenous infusion, lasting from 6 to 24 hours. Peak plasma platinum concentrations (Pt) were seen at the end of the infusion, and ranged from 1.1 microgram/ml when 3 mg/kg was given to 14-20.5 micrograms/ml at the 24-mg/kg level. Following completion of the infusion, a prolonged T1/2 beta (mean 63.5 hours) was noted. The percentage of free:total platinum was high (90-95%) at the beginning of the infusion but fell rapidly, to only 15-21% at the end of the 24-hour infusions. Urinary excretion accounted for 16-37.5% of the total administered dose. MP appears to have several pharmacokinetic features in common with cisplatin: rapid binding to protein, a prolonged terminal phase half-life involving primarily bound platinum, and incomplete excretion by the kidney.

Dose-Response Relationship, Drug↗
PubMed1980

Pharmacokinetics of gallium nitrate in man.

Gallium nitrate is a new antineoplastic agent that has shown activity in a number of in vitro tumor systems. During a Phase I clinical trial, the pharmacokinetics of two methods of administration of gallium nitrate were studied: a seven-day continuous intravenous infusion, and a weekly rapid intravenous infusion. During the continuous infusion of 200 mg/M2 of gallium nitrate, plasma gallium concentrations of 0.9 +/- 0.2 microgram/ml in one patient, and 1.9 +/- 0.4 microgram/ml in a second were noted. Urine excretion of gallium approximated the daily administered dose by day 2-3. Overall, 68-107% of the total administered dose was recovered in the urine. Following a rapid intravenous infusion, a biphasic curve was generated. The T1/2 alpha ranged from 8.3-26 minutes; the T1/2 beta from 6.3-196 hours. From 69-91% of the administered dose was recovered in the urine. The effects of gallium nitrate on tissue localization and body retention of 67Ga are also presented.

Adolescent↗
PubMed1980

Preclinical and phase I studies of malonatoplatinum.

After preclinical toxicologic study in baboons, we are conducting a phase I trial of malonatoplatinum, starting with 3 mg/kg and now reaching 1 mg/kg. Toxicity, mainly hematologic, was mild and our study was mainly limited by poor solubility. Regressions, which have been rare in the advanced-tumor patients, have been observed in three patients considered as clinically resistant to cisdichlorodiammino-platinum (DDP). Malonatoplatinum pharmacokinetics appeared similar to those of DDP as far as total platinum is concerned.

Adolescent↗