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Biomedical subjects

S Nash

Publications and source records attributed to S Nash.

At least 37 records · Page 2Linked to original sources
PubMed1995

Crescentic glomerulonephritis and eosinophilic interstitial infiltrates in a patient with hypereosinophilic syndrome.

Crescentic glomerulonephritis with immune complex deposition and acute eosinophilic interstitial nephritis developed in a patient with the hypereosinophilic syndrome. Acute renal failure ensued but was rapidly reversed by high-dose oral prednisone. Confounding factors and unusual findings are described with a review of recent literature. This mode of presentation has not previously been reported.

Acute Disease↗
PubMed1994

Phase I and pharmacokinetic study of ormaplatin (tetraplatin, NSC 363812) administered on a day 1 and day 8 schedule.

Ormaplatin (tetraplatin, NSC 363812) is a platinum(IV) analogue that is active against cisplatin-resistant cell lines in preclinical models. A schedule previously shown to be active and well tolerated for cisplatin was evaluated in 26 patients. Ormaplatin was administered over a dose range of 4.4-60.8 mg/m2 i.v. given over 30 min on a day 1 and day 8 schedule every 28 days. Twenty-three patients had received prior chemotherapy, and the median performance status was 1. Nausea/vomiting (> or = grade 2) occurred in 40% of patients but was well controlled with standard antiemetic therapy. One patient had grade 2 renal toxicity and 1 patient had grade 3 hepatotoxicity (grade 2 pretreatment). No toxicity limited the dose given during the first course. With repeated drug administration delayed severe neurotoxicity developed in 4 patients, manifested as a sensory polyneuropathy in 3 patients and a possible autonomic neuropathy in one. Prospective nerve conduction studies did not detect subclinical neuropathy prior to the onset of symptoms. Patients who received cumulative doses above 200 mg/m2 were at increased risk for developing neurotoxicity. Plasma elimination of ultrafilterable platinum (measured by atomic absorption spectrometry) was biphasic with a harmonic mean terminal half-life of 15.8 h. The mean total body clearance and renal clearance of ultrafilterable platinum were 173 and 29.8 ml/min/m2, respectively. Thus, renal clearance accounted for 16% of total clearance suggesting that extensive protein/tissue binding was responsible for the majority of platinum clearance. Approximately 60% of the platinum is protein bound (one-half irreversibly) at the end of the infusion. Pharmacokinetic parameters were not dose dependent. No pharmacokinetic parameters were more predictive of neurotoxicity than the cumulative ormaplatin dose. A phase II dose cannot be recommended on this schedule because severe and unpredictable neurotoxicity precludes the administration of more than three cycles at the three highest doses levels tested.

Adult↗
PubMed1994

Preservative efficacy in cefuroxime and ceftazidime eye drop formulations.

The efficacy of various common antimicrobial preservatives was tested in eye drop formulations containing the cephalosporin antibiotics cefuroxime and ceftazidime. The British Pharmacopoeia test for the efficacy of antimicrobial preservatives was used and the formulations were challenged with Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. The survival of organisms was monitored over 14 days. Cefuroxime sodium, 50 mg/ml, was studied in simple aqueous solution, and dissolved in an artificial tear formulation, Sno Tears (Smith and Nephew Pharmaceuticals), which contains benzalkonium chloride 0.004% w/v. Ceftazidime (50 mg/ml) was also studied in these two vehicles and, in addition, in a phenylmercuric acetate solution (0.002% w/v) and chlorhexidine acetate (0.02% w/v). Cefuroxime and ceftazidime contributed little, in the short-term, towards a microbicidal preservative effect in the unpreserved aqueous formulations, even against organisms for which they were active. Cefuroxime was adequately preserved in a vehicle of Sno Tears, which contains benzalkonium chloride as the antimicrobial preservative. Ceftazidime was less well preserved in this vehicle, but it was superior to phenylmercuric acetate (0.002% w/v) or chlorhexidine acetate (0.02% w/v).

Ceftazidime↗
PubMed1994

Stability of bendrofluazide in a low-dose extemporaneously prepared capsule.

The stability of bendrofluazide 1.25 mg in capsules was studied. The formulation is intended to provide a unit dose powder for administration by dispersing the contents in liquid. The capsules were prepared from ground bendrofluazide tablets 5 mg from two different manufacturers, diluted with lactose and packed manually by weight into hard gelatin capsule shells. The capsules were stored at ambient temperature exposed to light or 75% relative humidity, and at 45 or 60 degrees C. The ambient temperature and 60 degrees C conditions were studied for up to 1 year. Bendrofluazide was determined by a stability-indicating HPLC method. The capsule contents remained easy to disperse in liquid by the end of the study. The weight of contents which could be extracted from the capsules also remained satisfactory. A 7-month storage life at ambient temperature would be feasible, based on the lower 95% confidence limits of the time to 5% degradation.

Bendroflumethiazide↗
PubMed1993

Report of phase II trial of concurrent chemoradiotherapy with radical thoracic irradiation (60 Gy), infusional fluorouracil, bolus cisplatin and etoposide for clinical stage IIIB and bulky IIIA non-small cell lung cancer.

PURPOSE: To assess the response rate, median and long-term survival of patients (pts) with locally advanced, initially inoperable non-small cell lung cancer (NSCLC) treated on a phase II study of radical thoracic radiotherapy (TRT) and concurrent radiosensitizing chemotherapy. METHODS AND MATERIALS: From 3/87 to 7/90, 41 previously untreated patients at Fox Chase Cancer Center with locally advanced non-small cell lung cancer, 24 with bulky clinical Stage IIIA, and 17 with IIIB disease, received concurrent thoracic radiotherapy (60 Gy/2.0 Gy/d in 6 weeks) and 2 cycles of infusional 5FU (640-800 mg/m2/24 hrs x 5 d); cisplatin (20 mg/m2 qd x 5); and etoposide (50 mg/m2 d 1, 2, 5) administered days 1 and 28 of TRT. RESULTS: Forty of 41 were evaluable. Response rate was 90%, with radiographic CR in 20%. Thirteen pts (33%) underwent thoracotomy and complete resection with clinical downstaging in 10, including three pathologic CR's. Overall median survival was 14 months and 2-year survival was 38% with no difference between CS IIIA and IIIB pts (p = 0.2224). At median potential follow-up of 42 months, 8/40 pts. (20%) are alive and progression-free, including 4 of 13 resected pts. The chief toxicity was esophagitis, occurring in 32 pts. (80%), Grade 3-4 in 21 (52%), with 13 (33%) requiring hospitalization and 7 (18%) needing TPN. Grade 3-4 granulocytopenia was noted in 20 pts. (50%) with ten episodes of fever mandating intravenous antibiotics. Cardiac ischemia was documented in 2 (5%). Of 13 thoracotomy pts, six underwent lobectomy without perioperative mortality; 3 of 7 pneumonectomy pts died post-operatively, two from broncopleural fistula, and one from ARDS. CONCLUSION: This aggressive regimen produced a 2-year survival (38%) comparable to the best arm of cancer and leukemia groups B study 8433, which administered radical thoracic radiotherapy after protoadjuvant vinblastine and cisplatin in similar and earlier stage non-small cell lung cancer patients. Toxicity, particularly esophagitis, was severe, but of short duration. An unacceptably high complication rate was seen following pneumonectomy, but not lobectomy.

Adult↗
PubMed1993

Intraperitoneal cisplatin and etoposide in peritoneal mesothelioma: favorable outcome with a multimodality approach.

Ten patients with histologically documented peritoneal mesothelioma were treated with intraperitoneal cisplatin 200 mg/m2, sodium thiosulfate rescue and etoposide 65-290 mg/m2 every 4 weeks for a maximum of six cycles. All had epithelial or mixed epithelial-fibrous histology. Toxicity was tolerable, with 50% sustaining grade 3 or 4 granulocytopenia. There was one episode of neutropenic fever. Grade 2 peripheral neuropathy occurred in one patient, grade 1 in five patients. Complete remission occurred in one of five patients with measurable disease. Median survival for patients whose tumors were surgically debulked to < 2 cm residua prior to treatment was 22 months, while it was 5 months for those with measurable, surgically inaccessible disease (P = 0.0731 by Cox regression proportional hazard model). These data suggest that patients who present with resectable disease may benefit from an aggressive adjuvant approach. This possibility warrants prospective testing in a randomized clinical trial.

Adult↗
PubMed1992

Cl- secretion in a model intestinal epithelium induced by a neutrophil-derived secretagogue.

A secreted product of activated neutrophils, NDS (neutrophil-derived secretagogue), elicits a short circuit current (Isc) in epithelial monolayers derived from the human intestinal cell line T84 (J. Clin. Invest. 1991. 87:1474-1477). Here, we identify and characterize the source of this Isc and examine associated signaling pathways. 125I efflux studies suggested that NDS activates an anion conductive channel. Bidirectional 22Na 36Cl flux studies showed that electrogenic Cl- secretion fully accounts for the NDS-induced Isc response. NDS behaved in many respects as a cAMP-mediated secretagogue: NDS did not further increase maximal cAMP-induced Cl- secretion; NDS potentiated Ca(2+)-mediated Cl secretion; and NDS elicited measurable 125I but not 86Rb effluxes. However, NDS did not elicit a detectable rise in intracellular cAMP. Such data suggest that NDS may elicit Cl- secretion by effecting distal events in the cAMP-mediated pathway. Data derived from cell volume assays of isolated guinea pig intestinal crypt cells indicated that NDS also directly elicits Cl- secretion from natural intestinal epithelia. Additionally, since NDS activity is released from PMN by stimuli normally present in the colonic lumen, since NDS is active when applied apically to this model intestinal epithelium, and since the NDS-elicited Isc response is indicative of electrogenic chloride secretion, we speculate NDS may contribute to the secretory diarrhea encountered in many patients with inflammatory intestinal disease.

Adult↗
PubMed1992

Phase I trial of thiotepa in combination with recombinant human granulocyte-macrophage colony-stimulating factor.

PURPOSE: The ability of growth factors to stimulate marrow recovery suggests their potential for use in dose intensification of cytotoxic drugs. We performed a phase I study of the alkylating agent thiotepa in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), with the goal of dose-escalation of thiotepa. Thiotepa was selected based on its capacity for dose escalation to more than 1 g/m2 in the marrow transplantation setting. PATIENTS AND METHODS: The starting dose of thiotepa (75 mg/m2) was the highest dose evaluated in our previous phase I trial. Thirteen patients received 22 courses of thiotepa and GM-CSF. The dose of GM-CSF was 10 micrograms/kg subcutaneously daily in six patients and 5 micrograms/kg in seven patients. RESULTS: Three patients (23%) developed grade 3 to 4 neutropenia on the first course, with a recovery to more than 1000/mm3 in 4.7 days (mean). Recovery was as rapid with the 5 micrograms/kg as it was with the 10 micrograms/kg GM-CSF dose. Thrombocytopenia grade 3 to 4 affected seven of 13 (54%) patients in the first course; counts recovered to more than 50,000/mm3 in a median of 15 days. GM-CSF at either dose did not influence markedly the severity or duration of thrombocytopenia, and did not permit dose escalation of thiotepa. Among the seven patients who received a second cycle of treatment, six of seven experienced grade 3 or 4 thrombocytopenia that lasted a median of 15.5 days. Five had thrombocytopenia that lasted more than 35 days after one to three cycles of treatment. Plasma concentrations of thiotepa and tepa were measured by gas chromatography in eight patients. The plasma elimination of thiotepa fit a two-compartment open model with a harmonic mean terminal half-life of 2.44 hours. The mean total body clearance was 217.9 mL/min/m2, and the mean steady-state volume of distribution (Vdss) was 36.8 L/m2. The half-life of tepa was 7.98 hours, and the ratio of the area under the plasma concentration versus time curve (AUC) of tepa to that of thiotepa was 0.79. CONCLUSIONS: These data were consistent with our previous observations at this dose, and indicated that the severity of toxicity in these patients was not explained by aberrant pharmacokinetic indices. We conclude that, independent of effects on neutropenia, severe and cumulative platelet toxicity precludes further escalation of thiotepa dose despite the use of GM-CSF.

Aged↗
PubMed1991

Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid.

The glutathione transferases comprise a family of isoenzymes, one or more of which are involved in the conjugation of alkylating agents to glutathione (GSH). Increased GSH transferase activity has been shown to underlie acquired resistance to several alkylating agents. Ethacrynic acid inhibits the isoenzymes of GSH transferase with 50% inhibitory concentration values ranging from 0.3 to 6.0 microM and has been shown to restore sensitivity to alkylating agents in drug-resistant animal tumor models. We entered 27 previously treated patients with advanced cancer on a study of ethacrynic acid (25 to 75 mg/m2 p.o. every 6 h for 3 doses) and thiotepa (30 to 55 mg/m2 i.v. 1 h after the second dose of ethacrynic acid). The major toxicity of ethacrynic acid was diuresis, which was observed at every dose level; in addition, severe metabolic abnormalities occurred at 75 mg/m2. At 50 mg/m2, the diuretic effects were manageable. Myelosuppression was the most important effect of the combination. Two of seven courses of ethacrynic acid, 50 mg/m2, and thiotepa, 55 mg/m2, were associated with grade 3 or 4 neutropenia and/or thrombocytopenia. Nausea/vomiting greater than or equal to grade 2 was observed in 16% of courses. GSH transferase activity was assayed spectrophotometrically in the peripheral mononuclear cells of all patients. At each dose level, activity decreased following ethacrynic acid administration, with recovery by 6 h. Administration of ethacrynic acid, 50 mg/m2, resulted in a mean nadir of transferase activity of 37% of control. The pharmacokinetics of thiotepa and its principal metabolite TEPA were studied in 23 patients. The plasma disappearance of thiotepa fit a two-compartment open model with a terminal half-life of approximately 2 h. Plasma TEPA levels peaked at a mean of 2.16 h following thiotepa administration. The harmonic mean terminal half-life of TEPA was 10.4 h, and the TEPA area under the curve (AUC) did not increase with increasing thiotepa dose. The AUC of thiotepa was approximately twice, and the clearance about one-half, of the values obtained in a previous study of single agent thiotepa. The AUC of TEPA was lower than that previously observed. The data suggest that ethacrynic acid inhibits enzymes involved in the metabolic disposition of thiotepa, including its oxidative desulfuration to TEPA. The severity of the platelet toxicity was correlated with the AUC of thiotepa, but not with that of TEPA. This combination of thiotepa and ethacrynic acid will be tested further in Phase II trials.

Adult↗
PubMed1991

Neutrophil-epithelial cell interactions in the intestine.

PMN transmigration across intestinal epithelia and into crypt lumens is a hallmark of active intestinal disease. Models of the transmigratory event indicate that movement of PMN across intercellular tight junctions transiently increases junctional permeability, thus decreasing epithelial barrier function. Once accumulated in the lumen, activated PMN may release unidentified mediators which activate the epithelial transport mechanisms responsible for secretory diarrhea. Further characterization of such epithelial-PMN interactions may allow identification of rational treatment strategies aimed at intervening in the epithelial dysfunction characterizing this type of cell-cell interaction.

Cell Communication↗
PubMed1991

Phase II trial of thio-TEPA in relapsed and refractory ovarian carcinoma.

On the basis of a Phase I reevaluation of thio-TEPA in which 3 of 9 patients with ovarian carcinoma responded, we instituted a Phase II study at high doses. Fourteen patients with a histologic diagnosis of epithelial carcinoma of the ovary, who had received at least one prior cisplatin-based regimen, were entered. Thio-TEPA was initially administered intravenously at a dose of 65 mg/m2 every 4 weeks, but was reduced to 50 mg/m2 after severe myelotoxicity developed in the first 5 patients. In 4 patients stable disease lasted 3, 4, 5, and 9 months; 10 patients progressed. There were no objective responses. At this dose and schedule, thio-TEPA has a response rate less than 20% in ovarian cancer patients previously treated with cisplatin.

Adenocarcinoma↗
PubMed1991

Learning to discriminate the sex of conspecifics in male Japanese quail (Coturnix coturnix japonica): tests of "biological constraints".

Male Japanese quail learn to approach and remain near female, but not male, quail if they are allowed to copulate with female quail and receive noncopulatory exposures to males. The generality of the mechanisms involved in this type of discrimination learning was investigated in the present study. In Experiment 1, Ss learned to spend more time near initially unfamiliar blonde quail than familiar brown female or male quail as a result of being allowed to copulate with the blonde, but not the brown, quail. In Experiment 2, Ss learned to respond more to nonreproductive male as compared with female quail as a result of being allowed to copulate with the males, but not with the females. The experiments provided some evidence of a bias favoring responding to females independent of copulatory reinforcement contingencies. However, the results also indicated remarkable plasticity of discrimination learning about species-specific sexual stimuli.

Animals↗
PubMed1991

Stability of steroid ointments diluted with Compound Zinc Paste B.P.

The chemical stability of a range of corticosteroid ointments diluted with Compound Zinc Paste B.P. was studied by high-performance liquid chromatography (HPLC). Betamethasone dipropionate degraded by first-order kinetics at both 25 degrees C and 32 degrees C. At 25 degrees C the mean first-order reaction rate constant was 9.58 x 10(-3)/day, with a t90 (time to reach 90% of the original concentration) of 11.0 days. At 32 degrees C the mean first-order reaction rate constant was 2.42 x 10(-2)/day, with a t90 of 4.4 days. Of the other steroids studied, Fluocinolone acetonide was the least stable, with 33.8% remaining after a 7-day storage period at 25 degrees C. Betamethasone-17-valerate and fluocinonide were of intermediate stability between betamethasone dipropionate and fluocinolone acetonide. None of the steroid ointments studied had adequate stability in Compound Zinc Paste B.P. to allow extemporaneous dilution with this base.

Adrenal Cortex Hormones↗
PubMed1991

In vitro model of intestinal crypt abscess. A novel neutrophil-derived secretagogue activity.

In order to model crypt abscesses, a histological finding which correlates with disease activity in intestinal inflammation, human polymorphonuclear leukocytes (PMN) were layered onto monolayers of the human intestinal epithelial cell line T84, a crypt-like epithelium which is capable of Cl- secretion. Such PMN-epithelial interaction had no substantial effect on monolayer integrity or function. However, when PMN were stimulated by conditions including those present naturally in the human colonic lumen, monolayers responded with a bumetanide-sensitive short circuit current (Isc) indicative of Cl- secretion, the basis of secretory diarrhea. This Isc response was induced by a neutrophil-derived secretagogue (NDS), which was only active when applied to the luminal surface of monolayers and did not require PMN-epithelial contact. NDS activity is resistant to boiling, acid, and trypsin and passes a 500 nominal mol wt cutoff filter. NDS activity is not secondary to the respiratory burst products O2- or H2O2 and does not appear to be a myeloperoxidase product. We speculate NDS elicited Cl- secretion may contribute to the secretory diarrhea seen in patients with intestinal inflammation and crypt abscesses.

Abscess↗
PubMed1991

Is essential tremor benign?

We analyzed the results of the Sickness Impact Profile, a self-reporting measure of sickness-related dysfunction in 753 essential tremor (ET) patients, 87 controls from the general population, and 145 patients with Parkinson's disease (PD). Compared with the general population, ET patients had significantly greater dysfunction in all but one category. Communication, Work, Emotional Behavior, Home Management, and Recreation and Pastimes were particularly impaired in ET. The PD patients had significantly higher dysfunction in all categories as compared with ET patients. We conclude that significant disability can occur in ET and, compared with PD, ET tends to be less severe but causes relatively greater psychosocial dysfunction.

Aged↗
PubMed1990

Generalized lentigines in a silver cat.

Lentigines were seen on the head and trunk of a 4-year-old 4-kg domestic silver shorthair cat. Excisional biopsy specimens were obtained to confirm lentigo simplex. The lentigo lesions were similar to those described in orange, cream, red, and tri-colored cats; however, the coloring of this cat and diffuse distribution of lesions were unusual.

Animals↗
PubMed1990

Benign lesions of the gastrointestinal tract that may be misdiagnosed as malignant tumors.

Benign lesions of the gastrointestinal tract (GIT) that may be misdiagnosed as malignant tumors are described and illustrated in this review. The clinicopathologic features that are important for the accurate diagnosis of each lesion are presented in detail. The entities chosen for discussion include inflammatory pseudotumors (IPT), pseudosarcomatous granulation tissue in GI polyps, pseudocarcinomatous invasion in GI polyps, and GI ulcers induced by radiation and chemotherapy.

Diagnosis, Differential↗