Biomedical subjects
Publications and source records attributed to S Lichtman.
Post-transplant complications are common among patients receiving immunosuppressive medications, including pain syndromes. Recently, a pain syndrome, calcineurin-inhibitor induced pain syndrome (CIPS) has been described. To our knowledge, this article is the second report of tacrolimus-associated CIPS, and the first report in the pediatric setting.
The liver is a major source of circulating insulin-like growth factor I (IGF-I), and it also synthesizes several classes of IGF binding proteins (IGFBPs). Synthesis of IGF-I and IGFBPs is regulated by hormones, growth factors, and cytokines. They are nutritionally regulated and expressed in developmentally specific patterns. To gain insight into cellular regulatory mechanisms that determine hepatic synthesis of IGF-I and IGFBPs and to identify potential target cells for IGF-I within the liver, we studied the cellular sites of synthesis of IGF-I, IGF receptor, growth hormone (GH) receptor, and IGFBPs in freshly isolated rat hepatocytes, endothelial cells, and Kupffer cells. We also localized cellular sites of IGFBP synthesis by in situ hybridization histochemistry. Western ligand and immunoblot analyses were used to determine IGFBP secretion by isolated cells. Two IGF-I mRNA subtypes with different 5' ends (class 1 and class 2) were detected in all isolated liver cell preparations. Type 1 IGF receptor mRNA was detected in endothelial cells, indicating that these cells are a local target for IGF actions in liver. GH receptor was expressed in all cell preparations, consistent with GH regulation of IGF-I and IGFBP synthesis in multiple liver cell types. The IGFBPs expressed striking cell-specific expression. IGFBP-1 was synthesized only in hepatocytes, and IGFBP-3 was expressed in Kupffer and endothelial cells. IGFBP-4 was expressed at high levels in hepatocytes and at low levels in Kupffer and endothelial cells. Cell-specific expression of distinct IGFBPs in the liver provides the potential for cell-specific regulation of hepatic and endocrine actions of IGF-I.
A chart review of dextroamphetamine treatment in 27 traumatic brain injury patients during rehabilitation therapy suggests that amphetamine treatment enhanced the recovery and functional status of 15 patients.
Zeniplatin, a more water-soluble organoplatinum than cisplatin, was evaluated for clinical pharmacology in the context of a phase II trial in previously treated patients with ovarian carcinoma. A total of 12 patients were given zeniplatin at 120 mg/m2 by rapid intravenous infusion over 90 min, with both blood and urine being sampled. All platinum moieties were analyzed in whole blood, plasma, plasma ultrafiltrate, and urine by atomic absorption, and free zeniplatin was analyzed in plasma ultrafiltrate by specific high-performance liquid chromatography (HPLC). In a comparison of the platinum-time concentration curve, AUC (area under the curve) values indicated that approximately 90% of platinum moieties were bound to circulating plasma proteins. There was no evidence of drug accumulation after repetitive dosing. The terminal half-life (t1/2) of this drug in plasma ultrafiltrate (3.7-7.2 h.) as measured by HPLC was slightly longer than that of carboplatin, whereas total platinum moieties in plasma displayed a long t1/2 (124-154 h). Approximately 60% of platinum moieties could be recovered in the urine within 24 h. These findings suggest that zeniplatin has a pharmacokinetic profile similar to that of carboplatin.
Etiocholanedione (ED), a natural metabolite of dehydroepiandrosterone, has antiobesity effects in animals when given orally and is nontoxic. We carried out a trial of oral ED in obese humans. In a 20-week randomized double-blind crossover study, 14 subjects lost significantly more weight and body fat during treatment with oral ED, 4 gm daily, than during placebo administration. Mean weight loss during ED administration was 2.8 +/- 5.5 kilograms, which was equivalent to 0.53 +/- 0.91 kilograms per week per 100 kilograms of body fat; mean weight change during placebo administration was essentially zero: +0.21 +/- 4.2 kg, or +0.04 +/- 0.74 kg/wk/100 kg body fat. The difference between the weight changes in the two periods was significant: for delta kg, P < 0.05; for delta kg/wk/100 kg body fat, P < 0.03. Densitometric measurement of body fat content showed that the mean weight loss coincided almost exactly with the mean decrease in fat content; thus, over the 10-week period of ED administration, the mean fat loss was about 5% of the initial body fat content. Three of the obese subjects had strikingly greater fat loss, about 18%, 19%, and 25% of the initial body fat content. There were no significant subjective or objective side effects of ED administration.
PURPOSE: To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. PATIENTS AND METHODS: Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count > or = 4,000/microL, and platelet count > or = 100,000/microL, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m2/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m2/d. RESULTS: Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m2, with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m2/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, but two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peak plasma concentrations at 5 minutes, with a terminal half-life (t1/2) of 7 minutes. Etoposide reached peak concentrations at 7 to 8 minutes, with a t1/2 of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (Cmax) and area under the curve (AUC). CONCLUSION: Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m2 on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens.
Seven severely obese, outpatient dieters lost weight (mean +/- SEM, 14 +/- 1 kg), and the composition of weight lost was determined by six different models. Total body water (TBW), total body potassium (TBK), and body density, bone mineral content, and fat as determined by dual photon absorptiometry (DPA) were measured while subjects were weight-stable, before and after weight loss. Fat loss was calculated by three two-compartment models (2C-TBW, 2C-TBK, and hydrodensitometry [2C-HD]), one three-compartment model (HD with correction for water content of fat-free mass [FFM], 3C), and one four-compartment model (HD with correction for water and mineral content of FFM, 4C), and was measured directly by DPA. Mean composition of weight loss was similar for all models (mean weight lost as fat: 89% for DPA, 91.5% for 4C, 89% for 3C, 88.6% for 2C-HD, and 87% for 2C-TBW) except 2C-TBK (weight lost as fat, 66%). There was a much wider range of individual values for the 2C-TBW and 2C-TBK models (17% to 138% and 18% to 93%, respectively) than for the multicompartment models (63% to 112%) and DPA (76% to 107%). Almost opposite results were obtained for the same individual when using the 2C-TBK and 2C-TBW models. The discrepancy between these models was due to the inverse relationship between changes in TBW and TBK in the group as a whole (r = -.34, NS). In addition, TBK loss was found to be dependent on the initial level of hyperinsulinemia, calculated as the area under the 2-hour oral glucose tolerance curve.(ABSTRACT TRUNCATED AT 250 WORDS)
This study tested the hypothesis that black females have an increase in skeletal muscle and bone mineral mass compared with white females matched for age (+/- 5 y), weight (+/- 2 kg), height (+/- 3 cm), and menstrual status. Conventional [underwater weighing, whole body 40K counting (WBC), 3H2O dilution] and newly developed (dual-photon absorptiometry) techniques were used to provide ethnicity-independent estimates of body composition in 28 pairs of matched subjects. Black females had greater appendicular skeletal muscle (P less than 0.001), bone mineral (P less than 0.001), and total body potassium (TBK) (P = 0.05) compared with white females. Two classic coefficients used in body composition research [density of fat-free mass (FFM) for underwater weighing and TBK/FFM for WBC] differed significantly (P less than 0.05) between black and white females; currently applied coefficients underestimated fat in black females. This study confirms that black and white females differ in body composition and that errors in fat estimates occur when ethnicity is not accounted for in body composition models.
Interleukin-2 (IL-2) and interferon-beta (IFN-beta) have demonstrated activity against lymphoid malignancies, presumably mediated by the augmentation of lymphokine-activated killer (LAK) cell and natural killer (NK) cell activity. There is in vitro and in vivo evidence to suggest that the combination of IL-2 and IFN-beta is synergistic. The Cancer and Leukemia Group B (CALGB) conducted a randomized phase II trial of IL-2 with or without IFN-beta in 49 patients with relapsed or refractory non-Hodgkin's lymphoma (NHL). Overall toxicity was severe, with 17 patients experiencing life-threatening toxicity. Three patients had treatment-related deaths. Responses were noted in seven patients (17%). There were no meaningful differences between treatment arms in toxicity profile, response rate, or modulation of in vivo NK and LAK activity. We conclude that IL-2 with or without IFN-beta is not effective therapy for NHL in the doses and schedule used in this study.
Many studies have suggested that the positive effect of running on bone mass does not fully compensate for the negative effects of athletic amenorrhea. These studies have made this conclusion based on measurements of bone at a limited number of sites. This study used dual-photon absorptiometry to measure bone mineral content and bone mineral density in the total body as well as in several regions in amenorrheic runners (N = 13), eumenorrheic runners (N = 13), and sedentary controls (N = 12). The subjects were 21-35 years old. Runners had run at least 40 km/week for at least the past 3 years. Controls had body mass indices similar to those of the runners. The amenorrheic women had significantly lower values for total bone mineral content (P = .01), total bone mineral density (P = .04), and total bone mineral content as a percent of normal values (P = .04) than eumenorrheic women, but they were not significantly different from the controls. When total bone mineral content and total bone mineral density were adjusted for body weight, there were no significant differences among the groups. The eumenorrheic subjects had significantly greater bone mineral density in the trunk than the amenorrheic women; eumenorrheics and controls had significantly greater bone mineral density in the spine compared with amenorrheics. Lumbar spine bone mineral density showed a trend toward greatest values for controls and lowest for amenorrheic women (P = .069), although this measurement is relatively imprecise. Arms and legs showed no significant differences among the groups.(ABSTRACT TRUNCATED AT 250 WORDS)
The purposes of this study were to determine whether there are significant differences between two- and four-compartment model estimates of body composition, whether these differences are associated with aqueous and mineral fractions of the fat-free mass (FFM); and whether the differences are retained in equations for predicting body composition from anthropometry and bioelectric resistance. Body composition was estimated in 98 men and women aged 65-94 y by using a four-compartment model based on hydrodensitometry, 3H2O dilution, and dual-photon absorptiometry. These estimates were significantly different from those obtained by using Siri's two-compartment model. The differences were associated significantly (P less than 0.0001) with variation in the aqueous fraction of FFM. Equations for predicting body composition from anthropometry and resistance, when calibrated against two-compartment model estimates, retained these systematic errors. Equations predicting body composition in elderly people should be calibrated against estimates from multicompartment models that consider variability in FFM composition.
Cystic fibrosis (CF) patients frequently malabsorb nutrients because of pancreatic failure. Standard therapy entails oral administration of porcine pancreatic enzymes, with meals. Porcine enzymes contain in excess of 25 potentially antigenic proteins. To evaluate antigenicity of one of these (porcine trypsin), we developed ELISA techniques capable of measuring total immunoglobulin G (IgG) and IgG directed against porcine trypsin in patient sera. Cross-sectional evaluation of sera from 12 controls and 41 CF patients showed that IgG directed against porcine trypsin was detectable in 12/17 CF patients receiving porcine enzymes (50.6 +/- 56.0 ng/ml; range 0-154.0 ng/ml), while none was detected in controls or the 26 CF subjects not receiving enzymes. In the 17 CF patients receiving enzymes, porcine trypsin binding IgG contributed 0.85 +/- 0.83% of the total IgG pool. Levels of porcine trypsin binding did not correlate with total IgG. Longitudinal evaluation was then performed in 26 CF patients, before and after commencement of enzyme therapy. Prior to commencing therapy, porcine trypsin binding IgG was undetectable in sera from 24/26 patients. Within 4.2 years of commencing therapy, 25/26 patients (96%) developed porcine trypsin binding IgG. Thus, serum IgG responses to porcine trypsin appear to be common in CF patients receiving porcine enzymes and contribute considerably to total IgG levels. Other individual enzymes in porcine extracts are likely to elicit similar antigenic response.
Six chemical compartments [water, protein, mineral (osseus and cellular), glycogen, and fat] consisting of 11 elements (N, C, Ca, Na, Cl, K, H, P, O, S, and Mg) comprise greater than or equal to 99% of body weight in living humans. The combination of three neutron-activation systems, whole body 40K counting, and 3H2O dilution at Brookhaven National Laboratory now potentially makes it possible to quantify greater than or equal to 96% of the chemical and elemental determinants of body weight in vivo. The aims of the present study were 1) to develop 6- and 11-compartment chemical and elemental models, respectively, and 2) to evaluate these models in a group of 20 healthy adults. Results demonstrated that body weight estimated from either chemical or elemental components was highly correlated with (both r = 0.97, P less than 0.001) and on average differed by less than 4% from actual body weight. The compartmental results obtained using the chemical model were also evaluated by comparing calculated and actual body density (Db) estimated by underwater weighing. Calculated Db [1.041 +/- 0.017 (SD) g/ml] agreed closely and was highly correlated with actual Db (1.039 +/- 0.018 g/ml; r = 0.82; P less than 0.001). Hence a near-complete chemical and elemental analysis of living human subjects is now possible and, with potential future refinements, represents an important opportunity to quantify the effects of gender, aging, and ethnic status on body composition.
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Thirty two patients with refractory or recurrent acute leukemia or blast crisis of chronic myelocytic leukemia were treated with 1-beta-D-arabinofuranosylcytosine (Ara-C), 100 mg/m2 [group I (n = 15)] or 200 mg/m2 [group II (n = 18)], and tetrahydrouridine (THU) 350 mg/m2, given concurrently as a 3 h continuous intravenous infusion at 12 h interval for eight doses. Two of 13 (15.3%) evaluable patients in group I achieved a complete response, both of whom had acute myelocytic leukemia. In group II, seven of 14 evaluable patients (50%) obtained objective responses--six with complete responses (42.8%) and one with partial response (7%). Myelosuppression was seen in all patients with a median duration of 32.5 days (group I) and 36.3 days (group II), respectively. Non-hematologic toxicity consisted of nausea, vomiting, diarrhea, conjunctivitis, skin rash, hepatocellular toxicity, hemorrhage, and renal toxicity. Pharmacokinetic studies revealed, for group I, mean peak plasma Ara-C levels at 3 h (Cp3h) of 1254 ng/ml, area under the curve (AUC) 4651 ng x h/ml, total body clearance (TBC) 32.65 l/h/m2, renal clearance (RC) 7.04 l/h/m2 with a mean of 12.36% of the injected amount of Ara-C excreted unchanged in urine over the first 24 h. The corresponding mean values for group II are Cp3h 3305 ng/ml, AUC 15080 ng x h/ml, TBC 20.48 l/h/m2, RC 7.02 l/h/m2 and 26.23%. Ara-C 200 mg/m2 combined with THU gave serum Ara-C levels and response rates comparable to those achieved with high dose Ara-C (HiDAC) (greater than or equal to 1 g/m2). Central nervous system toxicity associated with HiDAC was not seen. Pharmacokinetics for uracil arabinoside (Ara-U) in patients treated with Ara-C 200 mg/m2 plus THU, were comparable to values seen with Ara-C for Cp3h, AUC and 24 h urine, amounting to 3160 ng/ml, 21717 ng x h/ml and 23.62% whereas TBC was significantly lower (p less than 0.001) for Ara-U than for Ara-C (3.02 versus 20.48 l/h/m2).
We report a case of extranodal T-cell lymphoma with fever, hepatosplenomegaly, pancytopenia, and diffuse sinusoidal infiltration of the spleen, liver, and bone marrow by the tumor cells, mimicking malignant histiocytosis. This is the second case of T-gamma (T-cell suppressor) lymphoma resembling the case reported by Kadin et al. [N Engl J Med 304:648, 1981]. The lack of lymph node involvement in this case supports the theory that this type of lymphoma arises in the spleen. This paper draws attention to the extranodal T-cell lymphoma groups that mimic malignant histiocytosis and the need of immunophenotyping for a correct diagnosis. The causes for the absence of T-cell receptor gene rearrangement in T-cell tumors are discussed.
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Vinzolidine (VZL) is a semisynthetic vinca alkaloid with broad antitumor activity in animal models of malignancy but had unpredictable toxic effects when given orally to humans. To minimize the toxic effects due to potential erratic gastrointestinal absorption, this drug was restudied in man as an intravenous preparation given as a rapid injection every two weeks. The maximum tolerated dose (MTD) on this schedule was 9.0 mg/m2 with unpredictable leukopenia (usually occurring 5-14 days post treatment but appearing erratically), constipation, paralytic ileus, and inappropriate ADH syndrome as major toxicities. Nonhematologic toxicities were dose-limiting. Repetitive dosing at two week intervals was associated with leukopenia at D 14-15 in some but not all patients treated above 5.0 mg/m2 precluding further treatment on schedule. In contrast, the oral MTD of this agent in our prior studies was 45 mg/m2 with no evidence of delayed leukopenia. Intrapatient variability of toxicity was small; interpatient variability of toxicity was substantial and did not correlate with prior therapy. Because of the presence of delayed hematologic toxicity on repetitive dosing schedules, intravenous VZL should be given on a dosing schedule longer than 14 days. No antitumor activity was seen in this study.