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A Ahsan

Publications and source records attributed to A Ahsan.

At least 19 recordsLinked to original sources
PubMed2001

Synthetic heparin pentasaccharide depolymerization by heparinase I: molecular and biological implications.

A synthetic pentasaccharide (SR90107/ ORG31540) representing the antithrombin III (ATIII) binding sequence in heparin is under clinical development for the prophylaxis and management of venous thromboembolism. This pentasaccharide exhibits potent anti-factor Xa (AXa) effects (>750 IU/mg) and does not exhibit any anti-factor IIa (AIIa) activity. Previous reports have suggested that synthetic heparin pentasaccharides are resistant to the digestive effects of heparinase I. To investigate the effect of heparinase I on the AXa activity of pentasaccharide SR90107/ORG31540, graded concentrations (1.25-100 microg/ml) were incubated with a fixed amount of heparinase I (0.1 U/ml). Heparinase I produced a strong neutralizing effect on this pentasaccharide, as measured by AXa activity. This observation led to further studies where high performance liquid chromatography (HPLC) analysis was employed to determine the potential breakdown products of the pentasaccharide. The experiment with the pentasaccharide included incubation (37 degrees C) at 1 mg/ml and exposure to graded concentrations of heparinase I (0.125-1 U/ml). After 30 min of incubation, the enzymatic activity was stopped by heat treatment and the mixture was analyzed using high performance size exclusion chromatography (HPSEC). Heparinase I concentration-dependent cleavage of the pentasaccharide was evident. The breakdown products exhibited a mass of 1,034 d and 743 d, respectively, suggesting the generation of a trisaccharide and a disaccharide moiety. The extinction of a disaccharide moiety in the UV region was high, indicating the presence of a double bond in this molecule. These data clearly suggest that pentasaccharide SR90107/ORG31540 is digestible by heparinase I into its two components. Furthermore, these data support the hypothesis that heparinase I can be used as a neutralizing agent for pentasaccharide overdose. Additionally, a highly methylated analog of the previously mentioned synthetic pentasaccharide. SanOrg34006, which has also been subjected to similar experiments, has shown complete resistance to the depolymerizing function of heparinase I; therefore, its use may be appropriate in chronic situations as a long-acting form of the pentasaccharide.

Antithrombin III↗
PubMed2001

A case notes analysis of hysterectomy performed for non-neoplastic indications at Liaquat National Hospital, Karachi.

OBJECTIVE: To determine the indications, associated morbidity, mortality and histopathological findings in women who underwent hysterectomy for non-neoplastic indications at Liaquat National Hospital Karachi. MATERIAL AND METHODS: This is a five year retrospective case note study of 143 women who underwent hysterectomy, excluding all those performed for benign or malignant pelvic neoplasms (excluding fibroids) and hysterectomy following childbirth for postpartum haemorrhage. RESULTS: Menorrhagia was the commonest indication for performing hysterectomy. The majority of the patients were in their forties; the commonest post operative complications were pyrexia, urinary tract and wound infections in 16% of the patients. There was no mortality associated with the procedure. The histopathology of the specimens revealed adenomyosis followed by leiomyoma to be the commonest pathology. CONCLUSION: It appears that adenomyosis is a common pathology in women from various ethnic and social backgrounds in Karachi, who are suffering from menorrhagia. Early diagnosis with high-resolution ultrasound is possible and hysterectomy may be offered earlier to these women, as they do not usually respond to medical treatment.

Adult↗
PubMed2000

Isoamyl nitrite depolymerized heparin as a universal calibrator for heparins and low molecular weight heparins.

Because the subcutaneous absorption of heparin depends on its molecular weight, high performance size exclusion chromatography methods, among others, have been developed for its determination. Because heparin consists of polymer chains of varying lengths, a large number of calibrators, 19 in our work, are required for these molecular weight analyses. Because the preparation of that many calibrants is both time-consuming and expensive, other methods requiring fewer calibrants are being sought. In pursuit of these aims, a heparinase-degraded heparin has been accepted as the first international reference preparation low molecular weight heparin for molecular weight calibration. We have previously proposed another calibrant, the Heparin Mass Calibrator. In this article, we introduce another calibrant, called the Heparin Molecular Mass Calibrant. It offers the advantage of a much wider availability because it is a commercial product. In addition to having a superior refractive index chromatography run profile, when used in combination with two Narrow Range Calibrators with molecular weights of 34.4 and 18.4 kDa, this new calibrant covers both the higher and the lower molecular weight ranges. Besides, ultraviolet detection is not needed for molecular weight calculations. Therefore, it is proposed that its feasibility as a universal reference calibrator for both heparins and low molecular weight heparins be considered.

Amyl Nitrite↗
PubMed2000

Pathologic evaluation of sentinel lymph nodes in colorectal carcinoma.

BACKGROUND: The identification of lymph node metastases in colorectal resection specimens is necessary for accurate tumor staging. However, routine lymph node dissection by the pathologist yields only a subset of nodes removed surgically and may not include those nodes most directly in the path of lymphatic drainage from the tumor. Intraoperative mapping of such sentinel lymph nodes (SLNs) has been reported in cases of melanoma and breast cancer. We applied a similar method to cases of colorectal carcinoma, with emphasis on the pathology of the SLNs. METHODS: Eighty-three consecutive patients with colorectal carcinoma were evaluated after intraoperative injection of 1 to 2 mL of 1% isosulfan blue dye (Lymphazurin) into the peritumoral subserosa. Blue-stained lymph nodes were suture-tagged by the surgeon within minutes of the injection for identification by the pathologist, and a standard resection was performed. Designated SLNs were sectioned at 10 levels through the block; a cytokeratin immunostain (AE1) was also obtained. To evaluate the possibility that increased detection of metastases in the SLN might be solely due to increased histologic sampling, all initially negative non-SLNs in the first 25 cases were sectioned also at 10 levels. RESULTS: Sentinel lymph nodes were identified intraoperatively in 82 (99%) of 83 patients and accounted for 152 (11.9%) of 1275 lymph nodes recovered, with an average of 1.9 SLNs per patient. A total of 99 positive lymph nodes (38 positive SLNs and 61 positive non-SLNs) were identified in 34 node-positive patients. The SLNs were the only site of metastasis in 17 patients (50%), while 14 patients (41%) had both positive SLNs and non-SLNs. Three patients (9%) had positive non-SLNs with negative SLNs, representing skip metastases. In patients with positive SLNs, 91 (19%) of 474 total lymph nodes and 53 (12%) of 436 non-SLNs were positive for metastasis. In patients with negative SLNs, 8 (1%) of 801 total lymph nodes and 8 (1.2%) of 687 non-SLNs were positive for metastasis. Multilevel sections of 330 initially negative non-SLNs in the first 25 patients yielded only 2 additional positive nodes (0. 6%). All patients with positive SLNs were correctly staged by a combination of 4 representative levels through the SLN(s) together with a single cytokeratin immunostain. CONCLUSIONS: Intraoperative mapping of SLNs in colorectal carcinoma identifies lymph nodes likely to contain metastases. Focused pathologic evaluation of the 1 to 4 SLNs so identified can improve the accuracy of pathologic staging.

Adult↗
PubMed2000

Pharmacokinetics of argatroban in primates: evidence on endogenous uptake.

BACKGROUND: Antithrombin agent, argatroban, is currently undergoing several clinical trials for cardiovascular indications. Because of its solubility, this drug is usually administered via an intravenous bolus followed by infusion. The purpose of this study was to determine the pharmacokinetics of argatroban after intravenous bolus injection in primates. METHODS: Parallel in vitro studies in primate whole blood were carried out to simulate a one-compartment system. Argatroban (range 1.0-7.5 mg/kg) was administered to four groups of primates and blood samples were drawn at various time periods. Argatroban measurements were made in plasma using functional (aPTT, Heptest, TT) and HPLC methods. RESULTS: In vitro, argatroban primarily distributed in the plasma in proportionate amounts. Relative uptake of argatroban to the blood cells (leukocytes and erythrocytes) was minimum. However, in vivo, argatroban followed a complex pharmacokinetics. Within 5 min after the bolus administration, only <20% of argatroban was recovered. The recovered amount was proportionate to the dosage and followed the expected kinetics with a half-life of <20 min. Simultaneous quantitation of M1-metabolite of argatroban revealed only a fraction of recovered argatroban (approximately 25%) converted into M1 in these experimental settings. Results obtained from the functional and absolute methods correlated well. HPLC profile did not reveal the presence of any other metabolite(s). CONCLUSIONS: These observations suggest that argatroban may be endogenously taken up by the vascular or other sites and may exhibit a complex kinetics. In acute settings, the metabolic transformation of argatroban to M1 is relatively low. To further clarify the pharmacokinetics/pharmacodynamics of this drug, additional studies are warranted.

Animals↗
PubMed1999

Simultaneous monitoring of argatroban and its major metabolite using an HPLC method: potential clinical applications.

Argatroban is a peptidomimetic inhibitor of thrombin that is currently undergoing extensive clinical trials as a heparin substitute for thrombotic complications. Argatroban is readily metabolized into a major derivative, M1, that has pharmacological characteristics distinct from its parent compound. The currently available clot-based assays measure the cumulative anticoagulant effect of argatroban and its metabolite(s). Available HPLC methods do not differentiate between argatroban and M1-metabolite. A modified method was developed to simultaneouly quantitate M1-metabolite and argatroban in biological fluids. Initial validation studies for the method included clinical trials of argatroban in patients with heparin-induced thrombocytopenia, (ARG 911 Study) and coronary interventional procedures (ARG 310 Study). Plasma samples were extracted with acetonitrile and reconstituted in a mobile phase. Calibration curves were prepared by running known standards of argatroban and M1-metabolite in normal human plasma. Ultraviolet detection was made at 320 nm. The retention times for argatroban and M1-metabolite peaks were found to be 10.5 +/- 0.3 minutes and 3.9 +/- 0.1 minutes, respectively. The extraction efficiency was > 95% (r2 = 0.99). In heparin-induced thrombocytopenia patients with major bleeding complications (n = 30), the relative increase in M1-metabolite compared to argatroban varied widely (two- to eight-fold). The mean concentration of argatroban during the steady infusion period was found to be 0.7 +/- 0.35 microgram/mL, and for M1-metabolite, it was 5.5 +/- 2.8 micrograms/mL. Proportionate results were not seen when higher dosages of argatroban were administered (coronary angioplasty studies). Argatroban and M1-metabolite levels also compared well with the results in global clotting assays. Owing to the simultaneous quantitation of argatroban and M1-metabolite, this method provides a rapid assessment of the pharmacokinetics and pharmacodynamics of argatroban. The differential quantitation may be useful in the assessment of relative metabolic turnover of argatroban that can be related to the hepatic and renal functions in a given patient.

Anticoagulants↗
PubMed1999

Apert syndrome: a case report with discussion of craniofacial features.

Apert syndrome is a rare congenital anomaly characterized by acrocephaly, syndactyly, and abnormalities of other organs. It has characteristic features in the orofacial region, affecting the eyes, palate, middle third of face, and uvula. In this case report, the features of Apert syndrome, particularly in relation to the orofacial region, are discussed.

Acrocephalosyndactylia↗
PubMed1999

Clinical laboratory monitoring of a synthetic antithrombin agent, argatroban, using high performance liquid chromatography and functional methods.

BACKGROUND: Argatroban is a peptidomimetic inhibitor of thrombin which is in clinical trials for thrombotic complications. Clot-based assays measure the cumulative anticoagulant effect of argatroban and its metabolites(s). To monitor the absolute concentrations of argatroban, a specific HPLC method was developed. METHODS: Validation studies included normal volunteers administered with escalating doses of argatroban (ARG 102 Study), patients undergoing coronary interventional procedures (ARG 310), and patients receiving argatroban in conjuction with streptokinase for acute myocardial infarction (ARG 230). Plasma samples were extracted with acetonitrile and reconstituted in a mobile phase. UV detection was made at 333 nm. Calibratrion curves were prepared with known standards of argatroban in normal human plasma. RESULTS: The retention time for argaeroban was 6.0+/-0.5 min and the extraction efficiency was >98% (r2=0.99). In the ARG102 Study, argatroban levels were: 0.84+/-0.23 (day 1), 1.55+/-0.34 (day 2), 2.92+/-0.15 (day 3), and 3.04+/-0.49 (day 4). In the ARG310 trial, the mean argatroban levels were: 0.23+0.09 microg/ml (preinfusion), 5.77+/-0.92 microg/ml (postinfusion/intraprocedure), and 2.23+/-0.29 microg/ml (postprocedure). In the ARG 230 Study, the mean argatroban levels at 2-8 hrs were between 1.5-2.0 microg/ml. Upon completion of the infusion, a time-dependent clearance of argatroban was noted. CONCLUSIONS: Since heparinization, hemodilution and hypofibrinogenemia due to thrombolysis influence the clotting tests, absolute quantitation of argatroban by HPLC in these patients provides a more reliable means of monitoring this anticoagulant and helps in the dosage-optimization of this agent. The current HPLC method is of value in the monitoring of patients who are simultaneously administered with thrombolytic drugs.

Anticoagulants↗
PubMed1998

Elasticity theory of the B-DNA to S-DNA transition.

We propose in this note a simple model--the two-state Worm Like Chain--to describe the elasticity of the recently discovered stress-induced transformation from B-DNA to S-DNA. The model reduces for low tractions to the well-known Worm Like chain theory, which is used to describe the elastic properties of B-DNA, while in the limit of high chain-bending moduli it reduces to the two-state Ising model proposed by Cluzel et al. for the B-S transition [Cluzel, P., A. Lebrun, C. Heller, R. Lavery, J-L. Viovy, D. Chatenay, and F. Caron. 1996. DNA: an extensible molecule. Science. 271:792-794]. Our model can be treated analytically to produce an explicit form of the force-extension relationship which agrees reasonably with the observations. We use the model to show that conformational fluctuations of the chain play a role also for the B to S transformation.

DNA↗
PubMed1997

Biochemical and pharmacologic characteristics of Reviparin, a low-molecular-mass heparin.

The introduction of low-molecular-mass heparins (LMMHs) has added a new dimension to the prophylactic and therapeutic management of thromboembolic disorders. These agents are now globally accepted as drugs of choice for postsurgical prophylaxis of deep vein thrombosis (DVT). Currently, the LMMHs are being developed for various therapeutic and cardiovascular indications. Reviparin is an optimized LMMH prepared by controlled nitrous acid digestion of porcine mucosal heparin. This drug has been developed utilizing validated procedures and exhibits a relatively narrow molecular mass distribution in contrast to most other commercially available LMMHs. The specific activity in the anticoagulant assays is approximately 40 U/mg whereas the specific activity in amidolytic anti-Xa assays is approximately 100 anti-Xa U/mg. Reviparin is capable of producing dose- and time-dependent antithrombotic effects in animal models of thrombosis. Although ex vivo anticoagulant effects are initially observed at dosages that are antithrombotic, this agent has been found to produce sustained antithrombotic effects when ex vivo anticoagulant actions are not measurable. Repeated administration of this LMMH induces progressively stronger antithrombotic effects. This drug has also been found to release tissue factor pathway inhibitor (TFPI) following both intravenous (IV) and subcutaneous (SC) administration. The studies included in this article are designed to provide additional data on the molecular profile using new calibration methods and additional results on pharmacologic studies. In particular, the release of TFPI following IV and SC administration to nonhuman primates is described. The effect of repeated administration of Reviparin mimicking the postsurgical prophylaxis of DVT is also reported in terms of any augmentation of the antithrombotic or hemorrhagic effects of this agent.

Animals↗
PubMed1996

Preclinical studies on a low molecular weight heparin.

Some major developments in the area of antithrombotic therapy have occurred during the past decade. Of these, the concept of fractionation of heparin has resulted in the development of several products from this agent. The introduction of low molecular weight heparins (LMWHs) has added a new chapter to the prophylactic and therapeutic management of thromboembolic disorders. These agents are now globally accepted as drugs of choice for post-surgical prophylaxis of deep vein thrombosis (DVT). Currently, the LMWHs are being developed for various therapeutic and cardiovascular indications. Reviparin is an optimized LMWH prepared by controlled nitrous acid digestion of porcine mucosal heparin. This drug has been developed using validated procedures and exhibits a relatively narrow molecular weight distribution in contrast to most other commercially available LMWHs. The specific activity in anticoagulant assays is approximately 32 U/mg whereas the specific activity in terms of anti-Xa units is 120 anti-Xa U/mg. Reviparin is capable of producing a dose- and time-dependent antithrombotic effect in animal models of thrombosis. While the ex vivo effects initially occur at dosages that are antithrombotic, this agent has been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. This agent has also been found to release tissue factor pathway inhibitor (TFPI) after both intravenous and subcutaneous administration. Repeated administration of reviparin produces progressively stronger antithrombotic effects. The current studies are designed to provide additional data on its molecular profile using new calibration methods and additional results on the pharmacological studies in a dose-dependent manner. In particular, the release of TFPI following i.v. and s.c. administration in a primate model is described. The effect of repeated administration mimicking the post-surgical prophylaxis of DVT is also reported in terms of any increase in the antithrombotic or haemorrhagic effects of this agent. Comparative antithrombotic and pharmacological studies are also reported to compare the pharmacological profiles of reviparin, nadroparin and enoxaparin.

Animals↗
PubMed1996

Catheter ablation for successful management of left posterior fascicular tachycardia: an approach guided by recording of fascicular potentials.

OBJECTIVE: To assess whether catheter ablation of fascicular tachycardia can be facilitated by the recording of sharp deflections arising from the mid-septum---inferior apical septum of the left ventricle. PATIENTS AND METHODS: Seven consecutive patients (mean age 29 (range 16-43) years) with ventricular tachycardia originating from the left posterior fascicle underwent electrophysiology study and detailed mapping of endocardial activation. Selection of ablation sites in the last five patients was based on the recording, during left posterior fascicular tachycardia and sinus rhythm, of a discrete potential preceding the earliest ventricular electrogram, which was thought to represent conduction through the posterior fascicle. RESULTS: Patients were treated with low energy direct current or radiofrequency current ablation. The median fluoroscopy and procedure times were 23 (range 6-42) min and 110 (range 50-176) min, respectively. In a follow up period of 4 to 16 months, six patients were asymptomatic and one had minor symptoms. No patient had any change in intraventricular conduction. Similar potentials were also recorded from the left posterobasal septum in three of eight patients who underwent catheter ablation of left free wall accessory pathways. CONCLUSION: Fascicular potentials can be reproducibly recorded in left posterior fascicular tachycardia and may serve as a reliable marker for successful ablation procedures. The relation of these potentials with the substrate of the tachycardia, however, remains obscure.

Adult↗
PubMed1995

Molecular profiling and weight determination of heparins and depolymerized heparins.

The recently proposed calibrant LHN-1 (lot F537; henceforth designated F537), for the molecular weight (MW) determination by high-performance size-exclusion chromatography of heparins, is shown here to have a range too narrow to allow for the accurate MW determination of all low molecular weight heparins (LMWHs). We have recently demonstrated, by this same methodology, that a chemically degraded benzyl ester of unfractionated heparin, heparin mass calibrator (HMC), is a better calibrant. Weight-average MW, number-average MW, peak MW, and dispersity values were calculated with F537, HMC, and by a reference narrow-range-calibration method for various LMWHs and unfractionated heparins. Values for these parameters determined with HMC were not significantly different from those determined by the reference method until the MW of the substance exceeded 15.0 kDa. In contrast, the MW profile obtained with F537 was appreciably different from that obtained by the reference method for samples with MWs > 7.5 kDa. The range exhibited by HMC should allow this calibrant to be used for both LMWHs and unfractionated heparins.

Heparin↗
PubMed1995

Pharmacologic validation of the clinical effects of an optimized low-molecular-weight heparin-reviparin.

Reviparin is a low-molecular-weight heparin (LMWH) prepared by controlled nitrous acid digestion of porcine mucosal heparin. The trade name designation for this agent is Clivarin. This agent has been released in Germany and France for the prophylaxis of deep venous thrombosis (DVT) in surgical patients. This agent is developed utilizing optimized procedures and exhibits a uniform, narrow-molecular-weight distribution in comparison to the other commercially available LMWHs. The specific activity in the anticoagulant assays is approximated to be 32 U/mg whereas the specific activity in terms of anti-Xa units is designated 120 aXa U/mg. Reviparin is capable of producing a dose- and time-dependent antithrombotic effect in animal models of thrombosis. While the ex vivo effects are initially presented at antithrombotically active dosages, this agent has been found to produce antithrombotic effects without any detectable ex vivo actions. This agent is also known to release tissue factor pathway inhibitor (TFPI) after both intravenous (IV) and subcutaneous (SC) administration. Repeated administration of Reviparin produces progressively stronger antithrombotic effects. Similarly, the bleeding as measured by rabbit ear blood loss is also progressively increased. However, the ratio between the dosage producing these effects is quite large. The current studies are designed to provide additional data on the molecular profile using new calibration methods and additional results on the pharmacologic studies in a dose-dependent manner. In particular, the release of TFPI following IV and SC administration in a primate model is described. The effect of repeated administration mimicking the post-surgical prophylaxis of DVT is also reported in terms of any augmentation of the antithrombotic or hemorrhagic effects of these agents.

Animals↗
PubMed1994

Feasibility study of heparin mass calibrator as a GPC calibrator for heparins and low molecular weight heparins.

The proposed European Pharmacopoeial (EP) method for molecular weight determination of low molecular weight heparins (LMWHs) has been shown to have a range which is too narrow to allow for the accurate molecular weight determinations of all LMWHs. We have recently shown that a chemically degraded benzyl ester of unfractionated heparin, ITH-3, is a better calibrator using this methodology. Data is presented here which indicates that this calibrator cannot only be used to determine the molecular weights of LMWHs but also of unfractionated heparins. Therefore, it is now renamed heparin mass calibrator or HMC because of this extension of range. Weight average molecular weight, number average molecular weight, peak molecular weight, and dispersity values were calculated using the HMC calibration and a reference narrow-range 19-calibrator method for various LMWHs and unfractionated heparins. Values for the parameters calculated using the HMC calibration were found not to be significantly different from those of the reference method until the molecular weight exceeded 15.0 kDa. In contrast, the molecular weight profile obtained with the proposed EP method was significantly different from the reference method for samples > 8.0 kDa. The range exhibited by the HMC calibrator should allow it to be used for both LMWHs and unfractionated heparins.

Chromatography, High Pressure Liquid↗
PubMed1994

Use of therapeutic ultrasound in percutaneous coronary angioplasty. Experimental in vitro studies and initial clinical experience.

BACKGROUND: Previous studies have shown the feasibility of peripheral arterial ultrasound angioplasty. METHODS AND RESULTS: In this report, we describe the use of percutaneous therapeutic ultrasound for coronary angioplasty. In vitro, 11 postmortem, atherosclerotically occluded coronary arteries were obtained to assess catheter-delivered ultrasound for arterial recanalization as well as for assessment of the size of particulate debris. Clinically, coronary ultrasound angioplasty was performed in 19 patients (mean age, 56 years) to assess safety and feasibility for the treatment of obstructive coronary atherosclerosis. Three patients with unstable angina and 16 with exercise-induced myocardial ischemia were treated with a prototype 4.6F coronary catheter ultrasound ablation device with a 1.7-mm diameter ball tip. The ultrasound coronary catheter delivered ultrasound energy at 19.5 kHz, with a power output of 16 to 20 W at the transducer. Energy is delivered in a pulsed mode with a 50% duty cycle of 30 milliseconds. Patients were treated for a mean of 493 seconds (range, 130 to 890) with intracoronary ultrasound ablation. All lesions were treated with adjunctive balloon angioplasty. All 11 postmortem coronary occlusions were recanalized, and 99% of the particulates generated were < 10 microns in diameter. We found that after ultrasound, mean (+/- SD) coronary arterial stenosis fell from 80 +/- 12% to 60 +/- 18% (P < .001) and to 26 +/- 11% (P < .001) after adjunctive balloon angioplasty. Mean pressures required to achieve full balloon inflation were 2.7 atm (range, 1 to 5.5) with a median of 3.0-mm balloon size (2.5 to 3.5). No ultrasound-related complications were identified. CONCLUSIONS: Intracoronary ultrasound plaque ablation appears to be safe. Our findings suggest that catheter-delivered high-intensity, low-frequency ultrasound may be useful for lesion debulking and enhancing arterial distensibility, allowing balloon dilation at relatively low pressures.

Angioplasty, Balloon, Coronary↗