Search PubMed⌕ Search

Biomedical subjects

T Ahmed

Publications and source records attributed to T Ahmed.

At least 199 records · Page 11Linked to original sources
PubMed1989

Microenvironmental toxicity of azidothymidine: partial sparing with hemin.

Azidothymidine (AZT) is a useful drug in management of AIDS. Nevertheless, its hematologic toxicity such as anemia and neutropenia present further complications to an already compromised hematopoietic state in patients. We studied the effects of AZT on human and murine bone marrow (BM) colony growth as determined by assays of CFU-E, BFU-E, CFU-GM, and fibroblastoid stromal (CFU-Fb) colonies. Cultures were grown in methylcellulose with growth factors and scored after three- to 14-day incubation. In general, murine marrow cultures were more sensitive to AZT as compared with human marrow. Furthermore, interindividual variation in toxicity to AZT was observed between marrow samples; 1 mumol/L AZT inhibited murine CFU-E, BFU-E, and CFU-GM by 98% to 100%, whereas human marrow was inhibited by 52%, 87%, and 65%, respectively. Lower concentrations of AZT (0.1 mumol/L) inhibited murine erythroid colony growth by 85% to 90%, whereas human growth was inhibited by only 39% to 52%. Myeloid colony inhibition was similar for human and murine systems. CFU-Fb growth was markedly suppressed (75%) by 1 mumol/L AZT. Hemin, at a concentration of 10 mumol/L, overcame some of the inhibitory effects of 1 to 0.1 mumol/L AZT without hindering antiviral activity. Inhibition of human CFU-E growth was completely overcome with hemin, whereas CFU-GM growth was recovered to 66% to 74% of control. A similar but less pronounced effect was observed for BFU-E. Furthermore, hemin does not decrease AZT's effects of HIV antigen content in vitro. We conclude that anemia and neutropenia, occurring as a result of AZT, may not be as pronounced in the presence of hemin. Furthermore, CFU-Fb was significantly reduced in the presence of low concentrations of AZT. This may indicate a major target site for BM toxicity since the stromal microenvironment may be responsible for maintaining short- and long-term hematopoiesis.

Animals↗
PubMed1989

Erythropoietin controls heme metabolic enzymes in normal human bone marrow culture.

Erythropoietin (Epo) was found to act as a concentration-dependent inducer of aminolevulinic acid (ALA) synthase and porphobilinogen (PBG) deaminase in normal human bone marrow in culture. Epo increased enzymatic activities in individual plated nucleated cells. At a low concentration of Epo, heme oxygenase activity did not change in human bone marrow erythroid progenitor cells. However, Epo at a concentration of 2 U/ml increased heme oxygenase as demonstrated by an increase in both the enzyme protein and its mRNA. In experiments with an inhibitor of heme synthesis, succinylacetone (SA), Epo failed to stimulate erythroid colony-forming unit (CFU-E) growth, but this CFU-E inhibition by SA was completely overcome by the addition of hemin. Epo nevertheless potentiated induction of ALA synthase in the presence of SA. Hemin exerted its regulatory role by negative feedback on ALA synthase in the presence of SA and Epo. Heme potentiated Epo action and resulted in the increase of human marrow erythroid progenitor cell proliferation and differentiation and a concomitant stimulation of ALA synthase and PBG deaminase. The potentiating effects of hemin on CFU-E growth were observed in human bone marrow cells cultured in media supplemented with fetal calf serum or serum-free media with interleukin 3 (IL-3). These results indicate that Epo is a potent inducer of ALA synthase and PBG deaminase in normal human bone marrow. In addition, our results may explain the mechanisms by which heme potentiates Epo or IL-3 enhancement of erythropoiesis. 1) Heme may stimulate the translation of several globin and nonglobin mRNAs, including those of ALA synthase and PBG deaminase; 2) as endogenous cellular heme synthesis reaches optimal levels, heme exerts its regulatory role on ALA synthase by negative feedback inhibition. Additionally, an increase in cellular heme may lead to an increase in its own degradation by induction of heme oxygenase.

5-Aminolevulinate Synthetase↗
PubMed1989

Treatment of patients with advanced cancer using multiple long-term cultured lymphokine-activated killer (LAK) cell infusions and recombinant human interleukin-2.

Escalating doses of recombinant human interleukin-2 (rIL-2) were combined with long-term cultured rIL-2 activated killer cells to treat patients with disseminated melanoma, renal cell cancer, and colon cancer. Twenty-four patients were entered, 12 with renal cell cancer, 8 with colon cancer, and 4 with melanoma; 23 were evaluable for efficacy and toxicity. The (dose-related) toxicities were moderate to severe and consisted of fever, chills, rigors, weight gain, hypotension, mild confusion, elevation of liver enzymes and serum creatinine, thrombocytopenia, and eosinophilia. No cardiac events (arrhythmias or myocardial infarction) were recorded. None of the patients were admitted to the intensive care unit, and no deaths occurred. Two partial responses were observed, one at relatively low doses of rIL-2 in a patient with renal cell carcinoma and one at the highest dose level in a patient with malignant melanoma. The maximally tolerated dose level of rIL-2 for this study was 6 X 10(6) U/m2 i.v./day. The recommended dose for further studies is 3 X 10(6) U/m2 i.v./day in three divided doses.

Adult↗
PubMed1988

Phase II trial of fludarabine phosphate (F-Ara-AMP) in patients with advanced breast cancer.

Eighteen patients with advanced breast cancer were entered into a phase II study of fludarabine phosphate. Fludarabine phosphate was given by continuous infusion for 5 days, at a starting dose of 20 mg/m2 per day for patients previously treated with two or more regimens and 25 mg/m2 per day for minimally treated patients with less than two prior regimens; therapy was repeated every 3-4 weeks. Of the 18 patients, 11 had undergone more than two prior regimens and 7 patients had undergone one prior regimen. One patient achieved a partial response (PR) for 22 months. Myelosuppression was the most common toxicity observed. Four patients developed mild nausea and vomiting and two developed a nonspecific dermatitis that resolved spontaneously. No renal, hepato-, or neurotoxicity was observed. Our study demonstrates that in heavily pretreated patients, fludarabine phosphate given on this schedule has minimal efficacy in treating advanced breast cancer. This drug might possibly have shown more activity in a previously nontreated patient population. However, patients with advanced breast cancer, who have not undergone previous treatment are not often encountered.

Adult↗
PubMed1988

The role of calcium antagonists in bronchial reactivity.

Calcium (Ca) ions play an important pathophysiologic role in allergic reactions. Thus, mediator release from mast cells, synthesis of some newly formed chemical mediators, airway smooth muscle contraction, and nerve-impulse conduction are all dependent on the availability and flux of Ca ions. It is likely, therefore, that Ca antagonists would modify allergic bronchoconstriction. In vitro, Ca antagonists have been demonstrated to inhibit mediator release (histamine, slow-reacting substance of anaphylaxis, and platelet-activating factor) from mast cells, passively sensitized human lung fragments, and leukocytes. Ca antagonists have also been found to inhibit synthesis of leukotrienes in rat lungs and cyclooxygenase products in sheep, possibly by inactivating phospholipase A2 and/or 5-lipoxygenase. In addition, nifedipine, verapamil, and gallopamil have demonstrated inhibition of airway smooth muscle contractions to histamine, carbachol, and antigen in various species. In vivo effects of Ca antagonists are variable, depending on the species, experimental design, the stimulus or the agonist, and the Ca antagonist used. Animal studies have demonstrated the inhibition of histamine, methacholine, citric acid, and prostaglandin F2 alpha-induced bronchoconstriction in guinea pigs and dogs by intravenous nifedipine. In contrast, verapamil inhibited antigen-induced bronchoconstriction in allergic sheep without any effect on histamine- and carbachol-induced responses. Ca antagonists (nifedipine and verapamil) have been of limited value in human subjects and generally have no significant bronchodilating activity. Both nifedipine and verapamil prevent the exercise-induced asthma and partly attenuate the histamine and methacholine-induced bronchoconstriction. Oral nifedipine is generally more effective than oral verapamil against acute antigen-induced bronchoconstriction; however, this efficacy may be limited by systemic side effects. Inhaled Ca antagonists may be more effective and free of systemic side effects, as demonstrated by greater efficacy of inhaled verapamil. A new Ca antagonist, gallopamil (a methoxy derivative of verapamil), is being investigated as an aerosol, and preliminary studies in animals and humans have found it fourfold to seventeenfold more potent than verapamil. In sheep, gallopamil has been found to attenuate histamine, carbachol, and platelet-activating factor-induced bronchoconstriction, as well as to inhibit early and late-phase allergic airway responses. Studies in human subjects have also demonstrated the inhibition of antigen-induced bronchoconstriction by inhaled gallopamil, with efficacy comparable or better than cromolyn sodium.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Inhibition of antigen-induced bronchoconstriction by a new calcium antagonist, gallopamil: comparison with cromolyn sodium.

We have previously demonstrated partial attenuation of antigen-induced bronchoconstriction by aerosolized verapamil (Chest 1985;88:176-80). In the present investigation, we studied the effect of a new calcium antagonist, gallopamil, on allergic bronchial reactivity and compared it to that of cromolyn sodium. Nine asymptomatic subjects with ragweed hypersensitivity and a history of bronchial asthma were studied on 4 different days, without and after pretreatments with aerosolized placebo, gallopamil (10 mg), or cromolyn sodium (20 mg) solution, in a single-blind, randomized, crossover design. Bronchial reactivity was measured as the cumulative provocative dose of ragweed antigen in breath units (PD35) that caused a 35% decrease in specific airway conductance (SGaw). Baseline SGaw was comparable on control, placebo-, gallopamil- and cromolyn sodium-treatment days. The airway deposition dose of gallopamil and cromolyn sodium was calculated at 1.05 mg and 2.1 mg, respectively. Neither cromolyn sodium nor gallopamil had a significant effect on mean SGaw. Mean +/- PD35 on control and placebo-treatment days was 0.54 +/- 0.95 and 0.23 +/- 0.17 breath units, respectively. Aerosolized gallopamil and cromolyn sodium increased the mean PD35 to 56 +/- 41 and 24 +/- 35 breath units, respectively (p less than 0.05). Gallopamil completely inhibited the antigen-induced bronchoconstriction in six (67%) subjects, whereas cromolyn sodium was totally effective in two of the nine (22%) subjects. These results demonstrate that aerosolized gallopamil inhibits allergic bronchial reactivity with efficacy comparable or better than cromolyn sodium.

Adult↗
PubMed1988

Effect of gallopamil, a calcium channel blocker, on carbachol- and histamine-induced bronchoconstriction in sheep.

We compared the in vivo effectiveness of the calcium channel blockers, gallopamil and verapamil, in inhibiting carbachol- and histamine-induced bronchoconstriction in conscious sheep. In 13 sheep, specific lung resistance (SRL) was measured before and after aerosol challenge with histamine (50 breaths; 5% solution) and carbachol (10 breaths; 2.5% solution), without and with pretreatment with intravenous and aerosolized gallopamil and verapamil. Histamine increased mean SRL by 213%. Intravenous (20 micrograms/kg) and aerosolized (5 mg) gallopamil markedly inhibited the histamine-induced bronchoconstriction. Mean SRL increased by 19% and 23%, respectively, whereas 2.5 mg of aerosolized gallopamil partly inhibited the histamine-induced response with SRL increasing by 115% (p less than 0.05). Carbachol increased mean SRL by 380%. Pretreatment with 2.5 mg of aerosolized gallopamil had no effect on carbachol-induced bronchoconstriction, whereas intravenous and 5 mg of aerosolized gallopamil partly attenuated the carbachol response; mean SRL increased by 204% and 177%, respectively (p less than 0.05). Intravenous (150 micrograms/kg) and aerosolized (10 mg and 20 mg) verapamil did not prevent either histamine- or carbachol-induced bronchoconstriction. These results indicate that gallopamil (parenteral and aerosol) attenuates carbachol- and histamine-induced bronchoconstriction, is more potent than verapamil, and may be of therapeutic potential.

Aerosols↗
PubMed1988

Effect of verapamil on pulmonary and eicosanoid responses to endotoxin in awake sheep.

Leukotrienes have been suggested to play a role in the endotoxin-induced changes of the pulmonary hemodynamics and airway mechanics. Since Ca2+ is necessary for contraction of airway and vascular smooth muscle as well as for activation of phospholipase A2 and 5-lipoxygenase enzymes, we wondered whether the calcium antagonist verapamil would modify the endotoxin-mediated pulmonary effects as well as the generation of circulating eicosanoids. In twelve conscious sheep, measurements of pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), lung resistance (RL), arterial PO2 (PaO2), leukocyte (WBC) count, arterial thromboxane B2 (TxB2), prostaglandin (PG) F2 alpha, and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) concentrations were obtained before and at predetermined intervals after a 10-min infusion of Escherichia coli endotoxin (0.3 microgram/kg). On separate occasions, the sheep received a bolus injection of verapamil (150 micrograms/kg) before endotoxin, followed by a continuous infusion of verapamil [10 micrograms.kg-1.min-1 (n = 5) or 20 micrograms.kg-1.min-1 (n = 7)] for up to 4 h post-endotoxin. Endotoxin caused a biphasic response with an increase in mean PVR and RL to 326 and 276% of base line during phase I (0-1 h) and lesser increases to 177 and 157% of base line during phase II (1.5-4 h), respectively (P less than 0.05). SVR also showed biphasic increases of 44 and 42% during phase I and II, respectively. Mean PaO2 decreased by 16 Torr and WBC count decreased from 6.4 +/- 1.5 to 3.3 +/- 1.1 thousand/mm3, associated with marked increases in plasma TxB2, PGF2 alpha, and 6-keto-PGF1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Hypoxia-induced enhancement of nonspecific bronchial reactivity: role of leukotrienes.

Because alveolar hypoxia has been shown to cause an increase of leukotrienes in lung lavage fluid, we tested the hypothesis that enhancement of nonspecific bronchial reactivity during alveolar hypoxia may be mediated by leukotrienes. In nine conscious sheep we determined specific lung resistance (sRL) before and after exposure to either air or a hypoxic gas mixture (13% O2) for 30 min. The sheep then inhaled 50 breaths of aerosolized 5% histamine solution (n = 6) or 10 breaths of 2.5% carbachol solution (n = 6) on different days, and the measurements of sRL were repeated. On subsequent days the above protocols were repeated after pretreatment with aerosolized FPL 57231 (3 ml, 1% solution), a leukotriene receptor antagonist. Inhalation of histamine and carbachol after exposure to air caused an increase in mean sRL to 337 and 342% of base line, respectively (P less than 0.05). Exposure to the hypoxic gas mixture had no effect on sRL but enhanced the histamine- and carbachol-induced increases in mean sRL to 621 and 646% of base line, respectively (P less than 0.05); these increases were significantly higher than those observed after air exposure (P less than 0.05). FPL 57231 prevented the hypoxia-induced enhancement of bronchial reactivity to histamine and carbachol without affecting the airway responsiveness to these agents after air. In another group of eight sheep, aerosolized leukotriene C4, at a dose (50 micrograms) that per se had no affect on sRL, enhanced the bronchial reactivity to carbachol. These data suggest that in sheep during alveolar hypoxia airway hyperresponsiveness may be due to the priming of airway smooth muscle by leukotrienes.

Airway Resistance↗
PubMed1988

Effect of cold air exposure and exercise on nonspecific bronchial reactivity.

Exercise and eucapnic hyperventilation with cold air can produce bronchoconstriction in asthmatic subjects, but their enhancement of nonspecific bronchial reactivity remains unclear. We studied the effect of submaximal exercise and cold air exposure on bronchial reactivity to methacholine in a normal control group (n = 10) and in subjects with bronchial asthma (n = 17). Bronchial provocation testing was performed to determine the provoking dose (PD35) of methacholine that caused a 35 percent decrease in specific airway conductance (Gaw/VL) in the two groups. Each subject was studied on three different occasions to determine the PD35 to methacholine on a control day, after ten minutes of submaximal exercise, and after a 30-minute exposure to cold air. Methacholine challenge was performed after the Gaw/VL had returned to the baseline values. In the normal group, neither cold air exposure nor exercise challenge had any significant effect on baseline Gaw/VL, whereas in the asthmatic group, both stimuli caused 20 percent and 15 percent decreases in Gaw/VL, respectively (p less than .05). Mean +/- SD control PD35 was 6.1 +/- 11.6 breath units in the asthmatic group, which decreased to 2.2 +/- 2.8 after exercise and 3.0 +/- 5.0 breath units after cold air exposure (p less than .05). In the normal group, control PD35 was 73 +/- 32 breath units, which was not different from PD35 values of 64 +/- 75 and 52 +/- 64 breath units after exercise and cold air exposure, respectively (p = NS). These data suggest that submaximal exercise and cold air exposure enhance nonspecific bronchial reactivity in asthmatic but not in normal subjects.

Adult↗
PubMed1988

Amsacrine with high-dose cytarabine is highly effective therapy for refractory and relapsed acute lymphoblastic leukemia in adults.

Thirty-six patients with relapsed acute lymphoblastic leukemia (ALL) and four with primary refractory ALL were treated with a regimen that included amsacrine, 200 mg/m2, intravenously daily for three days with cytarabine, 3 gm/m2, by infusion over three hours daily for five days. There were 27 remissions in the 36 relapsed patients and two in the four patients with primary refractory disease. Seventeen of the 23 patients with common ALL, four of the six with T-cell ALL, one of the three with B-cell ALL, and seven of eight whose cells were not characterized responded. Toxicity of this regimen was comparable to other reinduction regimens for ALL, but the side effects characteristic of high-dose cytarabine therapy were absent. Since these results compare favorably with conventional induction regimens, its use in the primary treatment of adults and children with high-risk ALL is proposed.

Adolescent↗
PubMed1988

Prevention and reversal of endotoxin-induced pulmonary hypertension by a leukotriene antagonist.

We investigated the role of leukotrienes in endotoxin-induced changes in pulmonary circulation. In six conscious sheep, haemodynamic measurements were obtained for the calculation of pulmonary vascular resistance (PVR), along with measurements of arterial oxygen tension (PaO2), leucocyte count (WBC), thromboxane B2 (TxB2), 6-Keto-PgF1 alpha and PgF2 alpha, before and at predetermined intervals after a 10-min infusion of E. coli endotoxin (0.3 microgram/kg), with and without treatment with the leukotriene receptor antagonist, FPL-57231. Endotoxin caused a biphasic response (i.e., phase I = 0-1 h, phase II = 1.5-4 h), with a mean +/- SE increase in PVR to 415 +/- 112% of baseline during phase I and a lesser increase of 175% (range = 153-199%) of baseline during phase II. Mean +/- SE PaO2 decreased from 86 +/- 4 to 67 +/- 6 mmHg and WBC count decreased from 8.6 +/- 0.6 to 2.8 +/- 0.7 thousand/mm3 during phase I, whereas TxB2 increased from 145 +/- 28 to 3164 +/- 1082 pg/ml, 6-Keto-PgF1 alpha from 129 +/- 14 to 438 +/- 114 pg/ml and PgF2 alpha from 122 +/- 7 to 242 +/- 43 pg/ml. One hour infusion of FPL-57231 (1 mg/kg/min) administered prior to and throughout phase I attenuated the phase I increases in PVR without preventing the increases in TxB2; however, it partly attenuated 6-Keto-PgF1 alpha and enhanced generation of PgF2 alpha during phase I. Discontinuation of FPL-57231 was followed by an exaggerated response of PVR during phase II to an average of 209% of baseline (range = 186-235%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Malignant lymphomas in a population at risk for acquired immune deficiency syndrome.

Certain neoplasia are closely associated with acquired immune deficiency syndrome (AIDS). To evaluate this relationship the authors reviewed the occurrence of lymphomas in populations at high risk for AIDS; the study population included prisoners from New York State and nonprisoner intravenous drug abusers (IVDA). Non-Hodgkin's lymphoma was diagnosed in 16 prisoners, all of whom were IVDA, and four nonprisoner IVDA. The observed number of prisoners with non-Hodgkin's lymphoma (11) diagnosed between January 1, 1981 and December 12, 1984, significantly greater than the expected number (2.28) based on age adjusted incidence rates for the US population (P less than 0.001). The calculated average incidence rate for non-Hodgkin's lymphoma among New York State prisoners aged 20 to 49 years was 21.5/10(5) to 67.2/10(5), which was nearly sixfold to 18-fold higher than the general population. For prisoner IVDA, specifically, this incidence may be as high as 164/10(5), which represents a 40-fold increase in the relative risk compared with the general population. It is concluded that, non-Hodgkin's lymphoma is frequently a manifestation of AIDS among IVDA, and is the most common malignancy seen in IVDA with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1987

A new regimen of amsacrine with high-dose cytarabine is safe and effective therapy for acute leukemia.

Amsacrine and high-dose cytarabine (HiDAc), when administered as single agents, are effective treatment of acute leukemia. When used in combination, a high remission rate is also possible. We treated 47 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and blastic phase of chronic myelogenous leukemia (CML) with a combination of amsacrine and HiDAc. The patients received amsacrine 200 mg/m2 daily for three days and, concurrently, HiDAc 3 g/m2 over three hours once daily for five days. Of 20 evaluable patients with AML in relapse, there were 12 remissions; of seven additional patients with primary refractory AML, there were two remissions, and of 12 patients with ALL in relapse, there were eight remissions. The three patients with blastic phase CML and the three patients with biphenotypic leukemia did not respond. Nausea, vomiting, stomatitis, hepatic dysfunction, and diarrhea were common, but cutaneous, conjunctival, and significant cerebellar and cerebral side effects were absent. We conclude that this regimen is highly effective therapy for AML and ALL and is also safe, eliminating the major toxicities encountered with HiDAc.

Acute Disease↗
PubMed1987

Preparation for blood group-incompatible bone marrow transplantation: comparison of two techniques.

Two similar techniques of red cell depletion of blood group-incompatible marrow prior to bone marrow transplantation were compared in 8 patients. The first method involved a single sedimentation step and removed a mean of 91% of marrow red cells and 33% of marrow nucleated cells. The second method involved multiple sedimentation steps and removed a mean of 96% of red cells and 29% of nucleated cells. Both methods can be recommended to a transfusion service newly involved in a bone marrow transplantation program.

Blood Group Incompatibility↗
PubMed1987

Prostatic and bladder cancer in the elderly.

Prostate and bladder cancer are the second and fifth leading cancers, respectively, in men over the age of 75 years. Urinary tract cancer represents 4 per cent of all malignancies in women. With careful patient selection, aggressive therapy may be employed with successful outcome.

Aged↗