Clinical practice guidelines on the screening and treatment of precancerous lesions for cervical cancer prevention in Saudi Arabia

BACKGROUND: Cervical cancer is the third most common gynecological malignancy in Saudi women with an estimated incidence rate of 1.9 cases per 100 000 women-years. More than 40% of cervical cancer cases are diagnosed at advanced stages due to lack of a routine screening program in Saudi Arabia. Thus, national guidelines for routine screening and treatment of precancerous cervical lesions are needed. METHODS: The Saudi Centre for Evidence-Based Healthcare invited a panel of local experts and partnered them with a team from McMaster University in Canada for methodological support, to develop national clinical practice guidelines on the screening and treatment of precancerous lesions for cervical cancer. After the panel identified key clinical questions, the McMaster University working group updated existing systematic reviews that had been used for the 2013 WHO Guidelines for screening and treatment of precancerous lesions for cervical cancer prevention. Recommendations were based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. Those recommendations took into account the available evidence, patient values and preferences, and resource use in the Saudi context. The panel provided recommendations on two major issues: screening for precancerous lesions (cervical intraepithelial neoplasia 2 & 3) and treatment of those lesions to prevent cervical cancer in women who tested positive after screening. CONCLUSIONS: The Saudi expert panel recommends using the HPV DNA test followed by colposcopy or cytology (Pap test) followed by colposcopy to screen for CIN2+ in women at risk of cervical cancer. The panel recommends cryotherapy or loop excision electrosurgery procedure (LEEP) over cold knife cone biopsy to treat women at risk of cervical cancer that tests positive for CIN2+. Universal screening for precancerous cervical dysplasia in women in Saudi Arabia is recommended using HPV testing and or cytology. Either cryotherapy or LEEP are preferred for treatment. CONCLUSIONS: National studies on cervical cancer screening modalities and treatment of precancerous cervical lesions, including HPV prevalence and its association with cervical cancer, are scarce.

The in vitro antitumor assay of 5-(Z)-arylidene-4-imidazolidinones in screens of AIDS-related leukemia and lymphomas.

Thirty-one different 5-(Z)-arylidene-4-imidazolidinones were tested on six AIDS-related lymphoma (ARL) tumor cell lines, one leukemia CCRF-CEM cell culture and five different lymphoma cell lines: RL, KD-488, AS283, PA682 and SU-DHL-7. The investigated compounds showed remarkable activity against ARL, compounds 3d and 5c proved to inhibit AS283 and SU-DHL-7 cell lines, respectively, both at a GI50 value of 0.03 microM. The 2-(2-carboxyphenylamino) series proved to be the most active members in this investigation. Compounds 6b and 6d showed GI50 (MGMID) values of 6.1 and 8.7 microM, respectively, against the studied six ARL.

Effects of two newly synthesized analogues of lidocaine on rat arterial blood pressure and heart rate.

Two new analogues of lidocaine were synthesized at the College of Pharmacy, King Saud University: compound I (Methyl-2-[2-(N,N-diethylamino) acetamido]-3-cyano-4,5-dimethylbenzoate) and compound II (Methyl-2-[2-(piperidino) acetamido]-3-cyano-4,5-dimethylbenzoate). Their influence on the arterial blood pressure and the heart rate of urethane-anaesthetized rats was studied and compared with the actions of lidocaine. Compounds I, II and lidocaine induced significant dose-dependent decreases in the arterial blood pressure and heart rate, which usually returned to basal values within 3-5 min. There were significant differences in the potency of the three compounds in producing their effects on blood pressure and heart rate (P< 0.0001, ANOVA). Compound II was 14 and 6 times more potent in reducing blood pressure and 8 and 2 times more capable of reducing the heart rate than lidocaine and compound I, respectively. The results of this study also indicated the ineffectiveness of antagonists of autonomic, histaminergic and 5-HT receptor, and various vasodilators in blocking the actions of the three compounds on blood pressure and heart rate. Pretreatment with CaCl(2)significantly reduced the hypotension and bradycardia induced by the three compounds, suggesting the involvement of calcium channels, probably of the L type. Several possible mechanisms are postulated. In conclusion, the results direct attention to the capability of the two new compounds to decrease blood pressure and heart rate; affects that may have clinical potential.

Synthesis and biological evaluation of certain alpha,beta-unsaturated ketones and their corresponding fused pyridines as antiviral and cytotoxic agents.

A new series of 3,5-bis(arylidene)-4-piperidones, as chalcone analogues carrying variety of aryl and heteroaryl groups, pyrazolo[4,3-c]pyridines, pyridolo[4,3-c]pyrimidines, and pyrido[4,3-c]-pyridines, carrying an arylidene moiety, and a series of pyrano[3,2-c]pyridines, as flavone and coumarin isosteres, were synthesized and screened for their in vitro antiviral and antitumor activities at the National Cancer Institute (NCI). Compounds 9 and 18 proved to be active against herpes simplex virus-1 (HSV-1), while compound 13 showed moderate activity against human immunodeficiency virus-1 (HIV-1). Compounds 14, 26, 28, 33, and 35 exhibited a broad spectrum antitumor activity. In addition, compounds 26, 33, and 35 proved to be of moderate selectivity toward leukemia cell lines. The pyrano[3,2-c]pyridines heterocyclic system proved to be the most active antitumors among the investigated heterocycles.

The voltammetric study and determination of ramipril in dosage forms and biological fluids.

The voltammetric behavior of ramipril was studied using cyclic voltammetry, direct current polarography (DCt), differential pulse polarography (DPP) and alternating current polarography (ACt). Ramipril developed well-defined cathodic waves in Britton-Robinson buffers over the pH range 6-12. The waves were characterized as being diffusion-controlled, irreversible and partially affected by adsorption phenomenon. The diffusion-current constant (Id) was 1.24 +/- 0.02. The current-concentration plots were rectilinear over the range 10-50, 4-40 and 0.16-12 micrograms/ml in the DCt, DPP and ACt modes, respectively, with a minimum detectability (S/N = 2) of 0.02 microgram/ml (4.8 x 10(-8) M) using the latter mode. The proposed method was successfully applied to the determination of ramipril in commercial tablets. Hydrochlorothiazide, which is frequently co-formulated with ramipril, did not interfere with the assay. Furthermore, the proposed method was applied to the determination of ramipril in urine and plasma adopting the ACt technique. The percentage recoveries were 97.12 +/- 0.56 and 94.97 +/- 0.62%, respectively. A pathway for the electrode reaction was proposed.

The voltammetric behavior of nizatidine and its determination in biological fluids.

The voltammetric behavior of nizatidine (a newly introduced antiulcer drug) was studied using direct current (DCt), alternating current and differential pulse polarography (DPP). Well-defined cathodic waves were obtained over the whole pH range in Britton-Robinson buffers, in addition to 0.1 and 1 M HCl media. The main reduction wave was characterized as being irreversible and diffusion-controlled, although adsorption phenomena played a limited role in the electrode process. The current-concentration relationship was found to be rectilinear over the range 1x10(-5)-6x10(-4) and 2x10-6) -2x10(-4) M using DCt and DPP modes respectively, with a minimum detectability (S/N = 2) of 2x10(-7) M using the latter technique. The number of electrons involved in the reduction process was established, and the mechanism of electrode reaction was verified. The proposed method was successfully applied to determination of nizatidine in spiked human plasma and urine and the percentage recoveries were 96.12+/-0.40 and 97.12+/-0.17, respectively.

Methods of analysis of 4-quinolone antibacterials.

A comprehensive review with 270 references for the analysis of the members of an important class of drugs, 4-quinolone antibacterials, is presented. The review covers most of the methods described for the analysis of these drugs either per se, in dosage forms or in biological fluids.

Determination of (S)(-)-cathinone by spectrophotometric detection.

Previous studies on the Khat plant (Catha edulis, Celastraceae) illustrated the importance of using freshly harvested young shoots and leaves such that cathinone, the principle active component and Schedule I controlled drug contained within the plant, could be suitably isolated and identified. The purpose of this work was to develop a quantitative analytical technique for the determination of cathinone. The proposed method is based on treating the reductant cathinone with copper(II)-neocuproine reagent in sodium acetate-buffered medium followed by measuring the absorbance of the copper(I)-neocuproine complex at 455 nm. The calibration plot is linear in the range 0.08-25 micrograms ml-1 with a detection limit of 0.08 microgram ml-1. The precision of the method, expressed as the relative standard deviation, is 1.35% for 10 micrograms ml-1 cathinone. Good recoveries have been obtained in applying the method to the analysis of cathinone in Khat leaves.

Limitations of clinical CT in assessing cortical thickness and density.

The peak CT number (CT) and full width at half maximum (FWHM) were obtained from the image profiles of aluminium of thickness ranging from 0.1-9.5 mm. The scans were performed at different fields of view (FOVs) and with different reconstruction algorithms ('bone' and 'standard'). Above 3 mm, CT and FWHM provide measures of the density and thickness which are largely independent of FOV (i.e. pixel size) and algorithm. Below 3 mm, CT falls progressively whilst FWHM remains relatively constant. At these small thicknesses the effect of FOV on CT is more pronounced when the bone algorithm is used, whilst FWHM remains relatively constant and independent of both FOV and algorithm. The results are discussed in terms of thickness relative to pixel size and spatial resolution as characterized by the point spread function. A linear relationship was found between the product CT x FWHM and thickness that is independent of both FOV and algorithm. This product may be useful in studies of cortical bone and changes due to osteoporosis.

Synthesis and biological evaluation of new cyclopenteno[b]thiophene derivatives as local anesthetic and antiarrhythmic agents.

A series of ethyl 2-substituted amino-cyclopenteno[b]thiophen-3-carboxylates was synthesized as a carticaine analogues and evaluated for their local anesthetic and antiarrhythmic activity. Compounds ethyl 2-[1-oxo-2-(ethylamino)ethylamino]-(4a), ethyl 2-[1-oxo-2-(n-propylamino)-ethylamino]-(4c), ethyl 2-[1-oxo-2-(4-methylpiperazino)ethylamino]-(4e), ethyl 2-[1-oxo-2-(ethylamino)propylamino]-(5a) and ethyl 2-[1-oxo-2-(n-propylamino)propylamino]cyclopenteno[b]thiophen++ +-3-carboxylate (5c) proved to possess local anesthetic and antiarrhythmic activity comparable to carticaine and lidocaine. The active compounds exert their antiarrhythmic potency via blocking Na+ channels as in case of 5c or blocking Ca+2 channels as in case of 4a, 4c and 5c. Compound 4e exhibited a dual mechanism by blocking both Na+ and Ca+2 channels.

Spectrophotometric determination of methoxamine using cerium(IV) in presence of sodium lauryl sulphate and rhodamine-B.

A sensitive spectrophotometric assay has been developed for the determination of methoxamine in pure dosage form and in its pharmaceutical preparations. The method is based on the acidic oxidation of methoxamine with cerium(IV) in the micellar medium of sodium lauryl sulphate at 96 degrees C. The reaction yields a water-soluble purple product which can be quantified spectrophotometrically at 505 nm. The calibration curve was linear between 1.0 and 20 micrograms ml-1 with a limit of detection 0.5 microgram ml-1. The molar absorptivity at 505 nm is 8.3 X 10(3) iota mol-1 cm-1. The method is simple and rapid since the product is measured directly in solution without extraction.

5-substituted-2-thiohydantoin analogs as a novel class of antitumor agents.

Certain series of 2-thiohydantoin derivatives, carrying various substituents at position 5 such as 5-bromo-2-thienylmethylene, 5-(2-carboxyphenylthio)-2-thienylmethylene and 2-methylene-4H-thieno[2,3-b][1]benzothiopyran-4-one, were evaluated for their antitumor activity. Compound 5-(5-bromo-2-thienylmethylene)-3-morpholinomethyl-2-(2,3,4,6 -tetra-O-acetyl -beta-D-glucopyranosylthio)hydantoin proved to possess a broad spectrum antitumor activity against a wide range of different human cell lines of nine tumor subpanels causing both cytostatic and cytotoxic effects, resulting in full panel median growth inhibition (GI50) and total growth inhibition (TGI), with a median lethal concentration (LC50) at 15.1, 41.7 and 83.2 microM, respectively. On the other hand, compound 5-(5-bromo-2-thienylmethylene)-2-thiohydantoin and compound 5-(5-bromo-2-thienylmethylene)-3-phenyl-2- (2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl-thio)hydantoin showed potential selectivity against leukemia cell lines. Further derivatization of these compounds, deduced from the obtained tentative structure-activity relationships, may lead to more potent agents.

Synthesis, local anaesthetic and antiarrhythmic activity of methyl N-(2-substituted aminopropanoyl)-3-cyanoanthranilates.

A series of methyl N-(2-substituted aminopropanoyl)-3-cyanoanthranilates (4a-i), that are structurally-related to tocainide and lidocaine, was synthesized and was found to be active when evaluated for local anaesthetic activity using the frog-foot withdrawal reflex, the guinea pig wheal derm and the rabbit corneal reflex tests. A selected numbers of the series were preliminarily evaluated for antiarrhythmic activity using CaCl2-induced arrhythmia test. Compounds 4a, 4c and 4f at lower doses completely protected the animals against the induced arrhythmias.

Colorimetric determination of astemizole in bulk and in its pharmaceutical dosage forms using flow injection.

A continuous flow spectrophotometric method for determining 0.5-100 micrograms ml-1 of astemizole in pure and in dosage forms is suggested. It depends on forming a pinkish orange product which can be quantified spectrophotometrically at 495 nm. The coloured product was due to the action of N-bromosuccinimide on astemizole in alkaline medium and in the presence of a cetyltrimethylammonium bromide micellar medium. The procedure is automated and solutions can be analysed at a rate of 167 h-1 with a relative error of about 1.25%. The limit of detection is 0.5 microgram ml-1 (approximately 1.09 x 10(-6) M). The method is evaluated by a recovery study and by the analysis of commercial formulations.

Synthesis of 2-[[1-oxo-2-(substituted amino)propyl]amino]-4,5,6,7-tetrahydrobenzo[b]thiophen-3-carboxylic acid ethyl esters as potential local anesthetic agents.

The synthesis of a series of 10 compounds related to 2-[[1-oxo-2-substituted amino)propyl]amino]-4,5,6,7-tetrahydrobenzo[b]thiophen-3-carboxyli c acid ethyl esters (III-XII) that are structurally-related to carticaine and the results of a study of their biological activity are reported. Most of the these compounds showed significant activity at lower concentrations when evaluated for local anesthetic activity using the frog-foot withdrawal reflex, the guinea pig wheal derm and the rabbit corneal reflex tests. Compounds III, V, VII and X displayed the shortest onset times and the longest duration of activity, compared to the model drug lidocaine.

Differential pulse polarographic assay of tolmetin sodium capsules.

Differential pulse polarography (DPP) is proposed as a direct method for the quantitation of tolmetin sodium in a capsule formulation (Tolectin--200 mg as the sodium dihydrate salt). Classical direct-current (DC) polarography has been employed to investigate the nature of the reduction occurring at the surface of the dropping mercury electrode (DME) using acetate buffer of pH 5.0 as the supporting electrolyte. The mean value of the results obtained by DPP expressed as a percentage of the stated amount, and the standard deviation, were found to be 99.87 +/- 0.43. The standard addition procedure used to assess the accuracy of the proposed method gave a mean percentage recovery of the total drug of 100.15 +/- 0.75%.

Coupling of TLC and UV-measurement for quantification of naproxen and its main metabolite in urine.

A simple sensitive method of high specificity and selectivity for quantitative determination of the non-steroidal anti-inflammatory drug naproxen and its main metabolite, 6-demethylated derivative, in biological specimens is described. Like naproxen, its metabolite absorbs maximally at 232 nm; this makes their simultaneous quantification, via direct UV-measurements at lambda max, in biological fluids quite impossible. Simple TLC-separation on silica gel F254 using chloroform + methanol (85:15, v/v) achieved the best fractionation of the unchanged drug and its metabolite from the matrix-contents of urine. UV-quantification of fractionated components could reach concentration levels of 0.2-3.0 micrograms ml-1 (ppm) in worked up urine samples. Varying levels of unchanged antiinflammatory drug and the phenolic metabolite could be accurately traced in urine samples following a 2.9 mg/kg oral dose after different time-intervals. Synthetic preparation of the metabolite by demethylation of naproxen is briefly mentioned.