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Biomedical subjects

S A Saeed

Publications and source records attributed to S A Saeed.

At least 19 recordsLinked to original sources
PubMed2001

Molecular mechanisms involved in human platelet aggregation by synergistic interaction of platelet-activating factor and 5-hydroxytryptamine.

Our recent studies have shown that co-activation of Gq and Gi proteins by 5-hydroxytryptamine (5-HT) and adrenaline show synergism in human platelet aggregation. This study was conducted to examine the mechanism(s) of synergistic interaction of 5-HT and platelet activating factor (PAF) in human platelets. We show that PAF, but not 5-HT, increased platelet aggregation in a concentration-dependent manner. However, low concentrations of 5-HT (2 microM) potentiated platelet aggregation induced by subthreshold concentration of PAF (40 nM) indicating a synergistic interaction between the two agonists and this synergism was blocked by receptor antagonists to either 5-HT or PAF. 5-HT also potentiated the effect of PAF on thromboxane A2 (TXA2) formation and phosphorylation of extracellularly regulated mitogen-activated protein kinases (ERK1/2). The synergism of 5-HT and PAF in platelet aggregation was inhibited by calcium (Ca2+) channel blockers, verapamil and diltiazem, phospholipase C (PLC) inhibitor, U73122, cyclooxygenase (COX) inhibitor, indomethacin, and MEK inhibitor, PD98059. These data suggest that synergistic effect of 5-HT and PAF on human platelet aggregation involves activation of PLC/Ca2+, COX and MAP kinase pathways.

Diltiazem↗
PubMed2001

Second messengers in platelet aggregation evoked by serotonin and A23187, a calcium ionophore.

We investigated the combined effect of 5-hydroxytryptamine (5-HT, serotonin) and calcium ionophore (A23187) on human platelet aggregation. Aggregation, monitored at 37 degrees C using a Dual-channel Lumi-aggregometer, was recorded for 5 min after challenge by a change in light transmission as a function of time. 5-HT (2-200 microM) alone did not cause platelet aggregation, but markedly potentiated A23187 (low dose) induced aggregation. Inhibitory concentration (IC50) values for a number of compounds were calculated as means +/- SEM from dose-response determinations. Synergism between 5-HT (2-5 microM) and A23187 (0.5-2 microM) was inhibited by 5-HT receptor blockers, methysergide (IC50 = 18 microM) and cyproheptadine (IC50 = 20 microM), and calcium channel blockers (verapamil and diltiazem, IC50 = 20 microM and 40 microM respectively). Interpretation of the effects of these blockers is complicated by their lack of specificity. Similarly, U73122, an inhibitor of phospholipase C (PLC), blocked the synergistic effect at an IC50 value of 9.2 microM. Wortmannin, a phosphatidylinositide 3-kinase (PI 3-K) inhibitor, also blocked the response (IC50 = 2.6 microM). However, neither genistein, a tyrosine-specific protein kinase inhibitor, nor chelerythrine, a protein kinase C inhibitor, affected aggregation at concentrations up to 10 microM. We conclude that the synergistic interaction between 5-HT and ionophore may be mediated by activation of PLC/Ca2+ and PI 3-kinase signalling pathways, but definitive proof will require other enzyme inhibitors with greater specificity.

Adult↗
PubMed2001

Acute diquat poisoning with intracerebral bleeding.

A case of severe diquat poisoning complicated by the development of aggressive behaviour, oliguric renal failure, and intracerebral bleeding is described. The patient was successfully managed and made a complete recovery. In this paper special attention has been given to the major clinical differences between diquat and paraquat intoxication.

Acute Kidney Injury↗
PubMed2001

Wortmannin inhibits platelet aggregation produced by interaction of gamma-aminobutyric acid and the calcium tonophore, A23187.

Platelet aggregation by gamma-aminobutyric acid (GABA) agonists combined with a calcium ionophore was studied. GABA, baclofen and mucimol markedly amplified aggregatory responses to a subthreshold concentration of the ionophore, A23187. This effect was inhibited by wortmannin, a blocker of phosphoinositide 3-kinase. However, several antagonists of GABA receptors had no effect on the response, and benzodiazepines inhibited aggregation. These results suggest that the GABA effect is not mediated by traditional neuronal GABA receptors. We propose that wortmannin inhibits aggregation at a nexus downstream from membrane mechanisms triggered by the GABA-A23187 interaction.

Androstadienes↗
PubMed2000

Paan without tobacco: an independent risk factor for oral cancer.

Oral cancer is the second most common cancer in women and the third most common in men in Pakistan. Tobacco is smoked and chewed extensively in Pakistan. Paan is a quid of piper betel leaf that contains areca nut, lime, condiment, sweeteners, and sometimes tobacco, which is also used extensively. We did this study to clarify the independent association of paan and oral cancer. Between July 1996 and March 1998, we recruited biopsy-proven, primary cases of oral squamous-cell carcinoma, from 3 tertiary teaching centers in Karachi, Pakistan, and controls pair-matched for age, gender, hospital and time of occurrence, excluding persons with a past or present history of any malignancy. There were 79 cases and 149 controls. Approximately 68% of the cases were men, 49 years old on average, the youngest being 22 years old and the eldest 80. People with oral submucous fibrosis were 19.1 times more likely to develop oral cancer than those without it, after adjusting for other risk factors. People using paan without tobacco were 9.9 times, those using paan with tobacco 8.4 times, more likely to develop oral cancer as compared with non-users, after adjustment for other covariates. This study identifies an independent effect of paan without tobacco in the causation of oral cancer. Its findings may be of significance in South Asian communities where paan is used, and among health-care providers who treat persons from South Asia.

Adolescent↗
PubMed2000

Hypotensive action of coumarin glycosides from Daucus carota.

Daucus carota (carrot) has been used in traditional medicine to treat hypertension. Activity-directed fractionation of aerial parts of D. carota resulted in the isolation of two cumarin glycosides coded as DC-2 and DC-3. Intravenous administration of these compounds caused a dose-dependent (1-10 mg/kg) fall in arterial blood pressure in normotensive anaesthetised rats. In the in vitro studies, both compounds caused a dose-dependent (10-200 microg/ml) inhibitory effect on spontaneously beating guinea pig atria as well as on the K+ -induced contractions of rabbit aorta at similar concentrations. These results indicate that DC-2 and DC-3 may be acting through blockade of calcium channels and this effect may be responsible for the blood pressure lowering effect of the compounds observed in the in vivo studies.

Animals↗
PubMed2000

Cefuroxime induced lymphomatoid hypersensitivity reaction.

An 84 year old woman developed erythematous blotchy erythema and purpuric rashes over the lower limbs three days after being started on intravenous cefuroxime for acute diverticulitis. A skin biopsy specimen showed a mixed infiltrate of lymphoid cells and eosinophils; many of the lymphocytes were large, pleomorphic, and showed a raised mitotic rate. Immunohistochemistry showed the infiltrate to be T cell rich, with all the large cells being CD30 positive. Typical mycosis fungoides cells, marked epidermotropism, and Pautrier's abscesses were not seen. The rash disappeared 10 days after cessation of cefuroxime and the patient remained asymptomatic 15 months later. This apparent cutaneous T cell lymphoma-like reaction is best described as lymphomatoid vascular reaction. The drug induced immune response with an atypical cutaneous lymphoid infiltrate mimics a cutaneous pseudolymphoma.

Aged↗
PubMed1999

Social anxiety disorder: a common, underrecognized mental disorder.

Social phobia is a highly prevalent yet often overlooked psychiatric disorder that can cause severe disability but fortunately has shown responsiveness to specific pharmacotherapy and psychotherapy. Recognition of its essential clinical features and the use of brief, targeted screening questions can improve detection within family practice settings. Cognitive behavioral therapy, with or without specific antidepressant therapy, is the evidence-based treatment of choice for most patients. Adjunctive use of benzodiazepines can facilitate the treatment response of patients who need initial symptom relief. The use of beta blockers as needed has been found to be helpful in the treatment of circumscribed social and performance phobias. Treatment planning should consider the patient's preference, the severity of presenting symptoms, the degree of functional impairment, psychiatric and substance-related comorbidity, and long-term treatment goals.

Adrenergic beta-Antagonists↗
PubMed1999

Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling.

Curcumin, a dietary spice from turmeric, is known to be anti-inflammatory, anticarcinogenic, and antithrombotic. Here, we studied the mechanism of the antiplatelet action of curcumin. We show that curcumin inhibited platelet aggregation mediated by the platelet agonists epinephrine (200 microM), ADP (4 microM), platelet-activating factor (PAF; 800 nM), collagen (20 microg/mL), and arachidonic acid (AA: 0.75 mM). Curcumin preferentially inhibited PAF- and AA-induced aggregation (IC50; 25-20 microM), whereas much higher concentrations of curcumin were required to inhibit aggregation induced by other platelet agonists. Pretreatment of platelets with curcumin resulted in inhibition of platelet aggregation induced by calcium ionophore A-23187 (IC50; 100 microM), but curcumin up to 250 microM had no inhibitory effect on aggregation induced by the protein kinase C (PKC) activator phorbol myrsitate acetate (1 microM). Curcumin (100 microM) inhibited the A-23187-induced mobilization of intracellular Ca2+ as determined by using fura-2 acetoxymethyl ester. Curcumin also inhibited the formation of thromboxane A2 (TXA2) by platelets (IC50; 70 microM). These results suggest that the curcumin-mediated preferential inhibition of PAF- and AA-induced platelet aggregation involves inhibitory effects on TXA2 synthesis and Ca2+ signaling, but without the involvement of PKC.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Co-activation of Gi and Gq proteins exerts synergistic effect on human platelet aggregation through activation of phospholipase C and Ca2+ signalling pathways.

Our previous studies have shown that subthreshold concentrations of two platelet agonists exert synergistic effects on platelet aggregation. Here we studied the mechanism of synergistic interaction of 5-hydroxytryptamine (5-HT) and epinephrine mediated platelet aggregation. We show that 5-HT had no or little effect on aggregation but it did potentiate the aggregation response of epinephrine. The synergistic interaction of 5-HT (1-5 microM) and epinephrine (0.5-2 microM) was inhibited by alpha2-adrenoceptor blocker (yohimbine; IC50= 0.4 microM), calcium channel blockers (verapamil and diltiazem with IC50 of 10 and 48 mM, respectively), PLC inhibitor (U73122; IC50=6 microM) and nitric oxide (NO) donor, SNAP (IC50=1.6 microM)). The data suggest that synergistic effects of platelet agonists are receptor-mediated and occur through multiple signalling pathways including the activation PLC/Ca2+ signalling cascades.

Blotting, Western↗
PubMed1999

Additive effect of indomethacin and methotrexate on suppression of growth in rats.

The purpose of this study was to investigate the medium-term effects of methotrexate (MTX) and indomethacin on the growth of young rats. Four equal groups of Sprague-Dawley male rats (four animals in each group; mean+/-S.D. body weight, 183+/-13 g, in their rapid growth phase) were subjected to the following drug treatment: one group was given MTX (0.2 mg kg(-1) body weight) subcutaneously on every fourth day, another received indomethacin (2.5 mg kg(-1) body weight) subcutaneously daily and the third group was given both of these drugs (MTX on every fourth day and indomethacin daily). The fourth group was injected subcutaneously with physiological saline every day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 10 weeks. After this period, liver, spleen and kidneys were excised, weighed and analysed for MTX and dihydrofolate reductase activity. Compared with the groups, which received MTX alone, indomethacin alone, or physiological saline, mean increase (17+/-11 g) in body weight of rats was minimal in the group receiving both MTX and indomethacin. The difference was statistically significant (p=0.001) when the values of mean increase in body weight of rats in different treatment groups after a 10-week treatment were compared. The mean weights of liver and spleen in this group receiving both MTX and indomethacin were also found to be significantly less than the weights of these organs in the control group (p<0.01). There also appears to be a decline in food consumption in this group (p<0.05). This negative effect on growth of animals in this group appears to be not only due to decreased food consumption but also due to increased inhibition of de novo pathway of DNA synthesis. This is supported by increased accumulation of MTX and decreased dihydrofolate reductase activity in this group receiving both MTX and indomethacin, as compared with the group receiving MTX alone. The data indicate an additive effect of MTX and indomethacin on the suppression of growth in young rats, alluding to the notion that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving these two drugs concomitantly over a long period of time might be at a risk of experiencing short-term suppression of growth.

Animals↗
PubMed1998

The inhibitory effect of cinchonine on human platelet aggregation due to blockade of calcium influx.

The Cinchona bark contains alkaloids like quinine, quinidine, cinchonine and cinchonidine. These agents are effective antimalarial drugs and have been used clinically in malaria caused by Plasmodium falciparum. Previous studies show that quinine and quinidine exert effects on cardiovascular system. This study was conducted to examine the effect of cinchonine on human platelet aggregation. The results show that cinchonine inhibited platelet aggregation mediated by platelet agonists, epinephrine (200 microM), ADP (4.3 microM), platelet activating factor (PAF; 800 nM) and collagen (638 nM) but had no effect on arachidonic acid (AA; 0.75 mM). Cinchonine was most effective in inhibiting aggregation induced by platelet activating factor and epinephrine with IC50 values of 125 and 180 microM respectively, however, higher concentrations of cinchonine were required to inhibit aggregation mediated by ADP or collagen (IC50; 300 microM). Pretreatment of platelets with cinchonine inhibited aggregation caused by Ca2+ ionophore, A-23187 (6 microM), in a dose-dependent manner (IC50; 300 microM) indicating an inhibitory effect on Ca2+-signaling cascade. This was supported by measuring [Ca2+]i in platelets loaded with Fura-2AM where cinchonine inhibited the rise in cytosolic Ca2+ mediated by A-23187 (6 microM) or collagen (638 nM). Results show that cinchonine (20 microM) also inhibited aggregation when platelets were pretreated with protein kinase C (PKC) activator, phorbol myristate acetate (PMA; 0.1 microM) in combination with low doses of platelet activating factor (80 nM). Cinchonine, however, had no effect on AA-induced platelet aggregation and thromboxane A2 (TXA2) synthesis in platelets. These results suggest that antiplatelet effects of cinchonine are mediated mainly through inhibition of Ca2+-influx and protein kinase C pathways in platelets.

Adenosine Diphosphate↗
PubMed1998

Panic disorder: effective treatment options.

Panic disorder is a distressing and debilitating condition with a familial tendency; it may be associated with situational (agoraphobic) avoidance. The diagnosis of panic disorder requires recurrent, unexpected panic attacks and at least one of the following characteristics: persistent concern about having an additional attack (anticipatory anxiety); worry about the implications of an attack or its consequences (e.g., a catastrophic medical or mental consequence) and making a significant change in behavior as a consequence of the attacks. A variety of pharmacologic interventions is available, as are non-pharmacologic cognitive or cognitive-behavioral therapies that have demonstrated safety and efficacy in the treatment of panic disorder. Early detection and thoughtful selection of appropriate first-line interventions can help these patients, who often have been impaired for years, regain their confidence and ability to function in society.

Humans↗