B. Angar. Saint Cloud State University.

Original license in Form 11/11-A to make the debit for the quantity imported under respective bill of entry 100mg suhagra. If goods are not directly supplied from the manufacturer then the port officer may verify the authenticity of goods at manufacturer‘s end through e-mail/fax or his authorized registered agent in India suhagra 100 mg. After scrutiny of the aforesaid documents and making the necessary entry in the records/computer 100 mg suhagra, the technical staff to put up the Bill of entry (B/E) to the port officer suhagra 100mg. The Port officer should examine B/E and should decide at this stage whether:- a) Labelling & marking need to be checked by the port officers and samples may be drawn (If the drug imported is in small container of 5 kg or less than the original container may be called for to check the markings/label) b) When required Samples to be sent for testing / analysis to the Government / Approved testing lab . However , the port officer may draw more samples depending on the previous test reports , number of consignments and the reputation of the manufacturer/ importer . There are no proper labels/markings or no markings on the containers or the markings are illegible . Drugs imported from a supplier/manufacturer have been reported to be not of standard quality/spurious etc at this port or any other port in India . The price of the drug imported is abnormally low as compared with the previous imports. Pending testing report, to avoid demurrage if the importer gives an undertaking (Rule 40 (1)) in writing not to dispose of the drugs without the consent of Customs commissioner etc. Drugs requiring cold storage such as sera, vaccines, may be released forthwith conditionally on L/G for test etc. If there are any labelling defects and importer desire to rectify the defects at their place, they may be allowed to be clear the consignment on L/G for rectification of labelling and/or test. Samples are drawn as far as possible under the direct supervision of a technical representative of the port office. Also, sampling should invariably be carried out in the presence of the importer‘s representative. In case of drugs requiring special precautions due to their hygroscopic, thermo labile nature etc. If the drug is sterile, the importers should be asked to make arrangement for drawing of samples under sterile conditions. Usually √n+1 number of 417 samples may be drawn, where n is number of containers / batches as per requirements. No samples should be drawn from the consignments imported for the purpose of registration only. It is responsibility of the Port Officer to ensure that all samples intended for test, are sent to laboratory as early as possible. The first part of the sample (original) is for test, the second part (Duplicate) is to be retained in the Port Office. Samples drawn from bulk containers to be sent to the laboratories with a code number in order to maintain secrecy. Port officer should ensure that the seal of the samples should remain intact at required temperature / cold chain shall be maintained during the transportation. If the goods on test by the laboratory are found to be of standard quality and are labelled as prescribed, they may be released. If the goods, on test, are declared to be not of standard quality, the Customs Commissioner is informed about this along with 2 copies of the test Report. The proforma of the Communication for action under Rule 41(1) used is given in Annexure: P-7, intimation about such imports are made to the Deputy Drugs Controller (India) with copies to the other Port Offices, the proforma used for such communication is given in Annexure: P-8. On the basis of the advice of the Port Officers the Customs will issue a show Cause memo to the firm concerned. On the basis of the party‘s reply the case will be finally adjudicated after ascertaining views of the Port Officers. In case the importers appeal for a retest by submitting sufficient evidence like manufacturer‘s protocols of test on the items in question, the case should be referred to the Deputy Drugs Controller (India) for orders along with comments of the Port Officer. If the Deputy Drugs Controller (India) so directs, a fresh sample shall be drawn, should be sent for retest to the laboratory. The orders passed by the Deputy 419 Drugs Controller (India) on the basis of such retest are final. Where the defect is such, that the importers undertake to recondition the goods up to the required standard, they must submit along with their appeal - a) The method that will be adopted for re-processing of Bulk Drugs. In case of grossly substandard / spurious / adulterated drugs, Commissioner of customs is to be informed stating that the import of these goods constitutes an offence u/s. In case of not of standard quality, other than those mentioned in point 6 above, the importers may be given the option to reship the goods to the country of origin if they so desire or forfeit them to the Central Government for destruction. For the import of non-notified diagnostic kits/reagents, only import license in Form-10 is required. The product label should comply with Rule 96 of Drugs and Cosmetics Rules including name and address of the manufacturer as stated in the Form-10, import license number. There are substances which are covered under the definition of the drug but are not used for medicinal purpose and are used in other industries like textile industries, chemical industries and food industries etc. After release of the goods, the same to be informed to the concerned State Drug Controller and the Zonal officer for post import check. The procedure to be followed in case of imports for personal use is detailed under Rule 36 of Drugs & Cosmetics Rule 1945. Other documents may be asked by the port officer to ensure the authenticity and quality of the cosmetics 4. Sample to be drawn at random and sent for test to Government appoved Testing Laboratories only. As regard to testing and follow up action is provided under Rule 131, the guidelines 424 and protocols to be followed is very much similar to the Drugs, only sections and rules to be changed. Simultaneously, the matter to be informed to the concerned State Drug Controller / Zonal Officer for the re- import check. Export permissions issued by the Deputy Drugs Controller for / fixed dose combinations / medicines beyond Schedule V limits / unapproved/approved new drugs/banned drugs under 26-A / without labels etc. Rule 94 violations – In case of export by loan licensee, the name and any address of manufacturer mentioned on the license may be acceptable. In case of neutral code, the consignment may be allowed as long as the identity of the manufacturer is ascertained with licence / code number available on the label. Aurvedic Drugs In case of export of ayurvedic drugs following documents are to be examined before release i) shipping bill, ii) Invoice, iii) packing list , iv) Mfg‘s test report of ayurvedic items for presence of heavy metals, Pb As, Sb, Hg within permissible limits (as per ayush guidline),specimen label/specimen sample, valid mfg. Licence with list of approved items labelling provision of ayurvedic drugs for export should comply with Rule 161A of D&C Rule. Subsequent to the above Notification, representations have been received from various Drug Manufacturers Associations requesting for exemption from registration requirements of the Drugs & Cosmetics Act for imports under the Advance Licensing Scheme. The requests have been considered and It has been decided that import of approved & unapproved drugs under the Advance Licensing Scheme will not be subjected to the Registration procedure and the imports will be permitted subject to the following conditions: i. Import license will only be given against an existing valid export order and to the extent raw material is required as per that order. A copy of the license would be endorsed to the Drug Controller and the concerned State Drug Controller. Any violation is punishable under the Foreign Trade Development and Regulation Act and the Customs Act. The Drug Controller could also make provisions for penalizing the Drug Manufacturing Units in terms of suspension or cancelling of his license. Export obligation will be fulfilled within a period of six months from the date of issuance of the license. However, if they make supplies to the domestic market, they will have to follow the formalities of registration as under the Drugs & Cosmetics Act. Representations have also been received regarding issuance of Form-10 under the Drugs & Cosmetics Act for manufacturers. It is clarified that Form -9 issued by the registered manufacturers should also be accepted for the purpose of issuing Form-10 license under the Drugs & Cosmetics Act. In addition as far as imports of drugs/raw materials for purposes of (i) clinical trials & (ii) for formulation development is concerned, it is clarified that exemption in such cases will be permitted on case to case basis. The exemption from registration procedure of the Drugs & Cosmetics Act will not only cover those drugs listed in Notification No. The Licensing Authority will make an endorsement on the licence that the exemption has been granted in terms of Policy Circular No. All importers making imports against advance licences, which have not been issued in terms of Policy Circular No. The export obligation period for the advance licences issued as per Policy Circular No. I) shall however be applicable for advance licences issued under Policy Circular 9 dated 30. Na M E Lan sh Shel Shel Batc i t N me din elf f f h t a o & ( g Lif Life Life wise l. That we shall arrange for inspection of the goods as soon as they arrive in the go-down and follow the instructions of representative of the O/o. Assistant Drugs Controller (I), with regard to drawing of samples for test, rectification of labelling defects etc. That we shall not dispose of the said goods without the consent of the Collector of Customs or any Officer on his behalf in writing. That we shall return the said goods in whole or in part as the Collector of Customs or any officer on his behalf may direct within ten days of receipt of a notice from the Collector of Customs or any officer on his behalf to return the goods. That we shall reship or surrender the said goods within two months of the receipt of any order to that effect from the Collector of Customs or any officer in his behalf. Any amount due under this bond may be recovered in the manner laid down in the subsection of the Section 142 of the Customs Act, 1962 without prejudice to any other mode or recovery. The undertakings referred to above is given in view of rule 40 of the drugs and Cosmetics Rules 1945. We hereby undertake: 1) That we shall arrange for inspection of the goods as soon as they arrive in our go-down by a representative of Asst. Drugs Controller (India) and obey his instructions as regards drawing samples under proper conditions and rectification of labelling defects if any etc 2) That we shall not dispose of the said goods without the consent of the Collector of Customs or any officer on his behalf in writing. Any amount due under this bond may be recovered in the, manner laid down in subsection of the Section 142 of the Customs Act, 1962 without prejudice to any other mode of recovery. The undertakings referred to above is given in view of Rule 40 of the Drugs and Cosmetics Rules, 1945. That we shall label the goods mentioned above as required under the above rules within a month or such extended period as the Collector of Customs or any officer on his behalf may allow. That we shall not dispose of the said goods without the consent of the Collector of Customs or any officer on his behalf in writing. That we shall return the said goods in whole or in part us the Collector of Customs or any officer on his behalf nay direct within ten days of receipt of a notice from the Collector of Customs or any officer on his behalf to return the goods. That we shall reship or surrender the said goods within two months of the receipt of any order to that effect from the Collector of Customs or any Officer on his behalf. Any amount due under this bond may be recovered in the, manner laid down in subsection of the Section 142 of the Customs Act, 1962 without prejudice to any other mode of recovery. The undertakings referred to above is given in view of Rule 40 & 96 of the Drugs and Cosmetics Rules, 1945. Office of the Assistant Drugs Controller (India) Mumbai / Kolkata / Chennai / Delhi Ahmadabad / Hyderabad/Cochin Date: 1. The importers, may however please be given the option to have the goods wither reshipped to the country of origin or have them destroyed in the presence of Assistant Drugs Controller (India) or a Custom Officer, provided under Rule 41 ( 1) of the Drugs and Cosmetics Rules. The goods are lying in the docks /air-shed/ were cleared on a Letter of Undertaking for test pending the receipt of the test report. Office of the Assistant Drugs Controller (India) Mumbai / Kolkata / Chennai / Delhi Ahmadabad / Hyderabad/Cochin Dt. A sample of the subject drug sent for test under Rule 40 of the Drugs and cosmetics Rule from a consignment imported by M/s……………………………………………………… (Name and full address of the importers), has since been reported by the Director, C. Value ……………………………………………………………………………………………… The Customs authorities have been advised to take necessary action under Rule 41(1) of the Drugs and Cosmetics Rules in respect of the above goods which are lying in the Docks / were cleared on Letter of undertaking for test. The import of these goods are prohibited under Section 10(a) of the Drugs and Cosmetics act read with Section 11 of the same act and liable to absolute confiscation under Section 111 (d) of the Customs act, 1962. You are hereby required to show cause why action should not be taken to confiscate the goods under Section…………………………………of the Customs Act. You are required to indicate whether you would like to re-export the goods to the country of origin as per option given in rule 41 (1) of the Drugs and Cosmetics Rules, 1945. You are further required to show cause why a personal penalty should not be imposed on you under the aforesaid section. Your written explanation should be presented within …………………day hereof to the undersigned along with all the documentary evidence. You should also indicate in the written explanation whether you wish to be heard in person before the case is adjudicated. If you fail to submit the written explanation in time or do not appear before the adjudicating authority when the case is posted for hearing, the case will be adjudicated on the basis of the evidence on record without any further reference to you. Office of the Assistant Drugs Controller (India) Mumbai / Kolkata / Chennai / Delhi Ahmadabad / Hyderabad/Cochin Dt. Date The import of these goods are prohibited under Section 10 (bb) --- of the Drugs & Cosmetics Act, read with Section 11 of the same Act and the goods are liable to absolute confiscation u/s. Wherever required the officials of the Drugs Control Department posted at the port offices shall retain a sample of the subject consignment for the purpose of reference and tracking of the manufacturer / exporter of the subject product. Gujral) Director General of Foreign Trade & Ex-Officio Additional Secretary to the Govt. Selection of studies Inspection can be carried out as a routine surveillance or for any specific cause(s). The inspector should provide verbal summary of methods and procedures to be followed during the inspection.

Te use of pioglitazone and the liver cancer and colorectal cancer in type 2 diabetes risk of bladder cancer in people with type 2 diabetes: mellitus suhagra 100 mg. Single- Bosetti C 100 mg suhagra, Rosato V suhagra 100mg, Buniato D 100mg suhagra, Zambon A , La Vecchia and multiple-dose pharmacokinetics of pioglitazone C , Corrao G (2013) . J Clin Pharmacol , thiazolidinediones for type 2 diabetes: a meta-anal- 45(10):1137–44 . Important safety information on the Pharmacokinetics of oral rosiglitazone in Taiwanese use of medicinal products containing pioglita- and post hoc comparisons with Caucasian , Japanese, zone. Absorption, disposition, vitro characterization of rosiglitazone metabolites and and metabolism of rosiglitazone, a potent thiazoli- determination of the kinetic parameters employing dinedione insulin sensitizer, in humans. Review and evaluation of pharmacology macroVascular Events): a randomised controlled and toxicology data: Rosiglitazone. Avandia the dorsal and ventral urinary bladder and kidney (Rosiglitazone Maleate) Tablets, Application No. Cohort study of Medicines Agency recommends suspension of pioglitazone and cancer incidence in patients with Avandia, Avandamet and Avaglim. Assessment report Pioglitazone bladder cancer: a meta-analysis of controlled studies. Association of diabetes duration and tract of mice exposed to cigarette smoke and treated with diabetes treatment with the risk of hepatocellular carci- chemopreventive agents. Lancet, Lefebvre A-M, Chen I, Desreumaux P, Najib J, Fruchart 378(9802):1543–4, author reply 1544–5. Report estimation of metformin hydrochloride, pioglitazone with Data from 1 January 1997 to 31 December 2010. Diabetologia, thiazolidinediones and fractures in type 2 diabetes: 51(11):2108–16. High-performance liquid chromatography synthetic hypoglycemic drugs added illegally to ‘natural’ quadrupole time-of-fight mass spectrometry method anti-diabetic herbal products. Chromatographia, for the analysis of antidiabetic drugs in aqueous envi- 70:1353–1359. Rosiglitazone and risk of cancer: a meta-anal- Piccinni C, Motola D, Marchesini G, Poluzzi E (2011). Hazardous Substances Data Bank: National Radhakrishna T, Sreenivas Rao D, Om Reddy G (2002a). Biochem Biophys Res method for the simultaneous analysis of diltiazem, Commun, 278(3):704–11. Co-solvent solubilization urine by liquid chromatography/tandem mass spec- of some poorly-soluble antidiabetic drugs. Selective and validated spectro- cancer: a population-based cohort study in Taiwan. Int J human studies: is it diabetes itself, diabetes drugs, Clin Pract Suppl, (121):13–8. Determination of piogli- a population-based cohort study using the National tazone in dog serum using solid-phase extraction and Health Insurance in Taiwan. Diabetes Res Clin Simultaneous estimation of six anti-diabetic drugs– Pract, 98(1):159–63. Multi-component plasma quantitation of anti-hyperglycemic pharmaceutical compounds using liquid chromatography-tandem mass spectrometry. Quantitative determination of pioglita- zone in human serum by direct-injection high-perfor- mance liquid chromatography mass spectrometry and its application to a bioequivalence study. High-performance liquid chromatographic determination of pioglitazone and its metabolites in human serum and urine. Exposure Data Te Working Group noted that most of what has been used under the term “digitalis” in North America and Europe has been digoxin; Digoxin is a cardiac glycoside isolated from however, there may be parts of the world where plants of the genus Digitalis. William Withering published his monograph “An account of the foxglove and some of its medical uses” (Withering, 1785; Albrecht & Geiss, 2000). Furthermore, 3-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl- the term “digitalis use” found in many reports -(1→4)-O-2,6-dideoxy-β-D-ribo-hexo- probably refers not to the use of plant mate- pyranosyl-(1→4)-2,6-dideoxy-β-D-ribo- rial, which is not commercially available as a hexopyranosyl)oxy]-12,14-dihydroxy-, medicinal product, but to the use of the isolated (3β,5β,12β)- (SciFinder, 2013) compounds. Te Working Group 4,5-dihydroxy-6-methyloxan-2-yl] estimated that digoxin represents at least 90% of oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4- the world market for digitalis glycosides. Tus, studies reporting thren-17-yl]-2H-furan-5-one (PubChem, use of “digitalis” should be carefully scrutinized 2013) since the agent to which people were actually Synonyms: 12β-hydroxydigitoxin exposed could have been any one of the four digitalis glycosides. Te purity of digoxin is pressure, 760 Torr) (SciFinder, 2013) 382 Digoxin typically at least 95% (see Section 1. Name: 3β-[(O-2,6-dide- glucosidase enzymes at 30–37 °C until glucose oxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6- is completely removed. Extraction procedures, dideoxy-β-D-ribo-hexopyranosyl-(1→4)- usually followed by precipitation of tannic 2,6-dideoxy-β-D-ribo-hexopyranosyl) acid and related phenolic products with lead oxy]-14-hydroxy-4β,14β-card-20(22)-enolide. Compendial methods to determine digoxin and digitoxin in pharmaceutical preparations 1. For detection in (a) Indications human plasma or urine, liquid chromatography Digoxin and digitoxin are therapeutically the with mass spectrometric detection is required to most widely used digitalis glycosides. Te lists the most commonly reported clinical indica- analytical methods are summarized in Table 1. Digoxin is generally maintenance therapy because its long half-life less efective than other drugs in producing (5 – 9 days) provides a sustained therapeutic efect consistent reduction of heart rate, particularly even if a dose is missed. For congestive heart failure, use of digoxin (b) Dosage fails to improve survival (Digitalis Investigation Group, 1997) when compared with placebo, Administration is typically oral, although unlike other leading therapies. It does, however, preparations for intravenous administration provide symptomatic benefts in some cases exist. Typically, digoxin is used orally for months and is associated with reduced risk of hospital- to years, while intravenous use requires careful ization. Te absorption ratio was found to be angiotensin-converting-enzyme inhibitors and 70%, the decay ratio is 20%, the efective dose β-blockers) fail to produce adequate symptom level is 2 mg, and the maintenance dose is 0. Most generic tablet preparations of digoxin Globally, there are 160 licensed products average 70–80% oral bioavailability, with containing digoxin, while there are only seven 90–100% oral bioavailability for digoxin elixir licensed products containing digitoxin in and the encapsulated gel preparation. Parenteral Germany, Austria, Hungary, and Norway (Index digoxin is available for intravenous administra- Nominum, 2013). Caution to avoid over- strategies, cardiac glycosides are still widely used, dosing is necessary in elderly patients or those and digoxin belongs to the 10 most frequently with renal impairment (Li-Saw-Hee & Lip, 1998). Other nations tions may be correlated to the range of available reporting appreciable use of digoxin included tablet strengths. Afer leaf-tissue damage or for cancer of the breast (Stenkvist, 1999; Haux, plant harvest, the primary glycoside lanatoside C 1999); however, because so little information is converted to the secondary glycoside digoxin was provided and larger studies with stronger by the endogenous enzyme, digilanidase, present designs were available, these early studies were in the leaves, and by subsequent deacetylation. Environmental factors that infuence the digoxin Varied designs were used in these studies. Te Digoxin is specifed in several ofcial phar- studies describing “digitalis” use are therefore macopoeias (Table 1. Data on before diagnosis was compared in 109 hyper- risk factors were limited to information available tensive women with cancer of the breast and in physician interviews by mail or telephone, and in 109 matched hypertensive women without clinical record reviews. However, the Working were collected in diferent ways and the Working Group noted that some important risk factors Group questioned the quality of the data obtained of cancer of the breast, notably parity, obesity, from medical records and physician interviews. Many variables were eval- Using data from persons enrolled in the uated using self-administered questionnaires, Kaiser Permanente Medical Care Programme, including use of prescribed drugs. Among all Friedman & Ury (1980) linked prescription-drug drugs assessed, digoxin stood out most strongly, use for 95 drugs and drug classes between 1969 with odds ratios for digoxin of 1. Te drugs evaluated included “digi- body mass index determined from self-estimated talis” as a group. A more detailed presentation weight and height 10 years before diagnosis, the of digitalis-related associations used cancer-out- association between cancer of the breast and come data for 143 594 subjects updated to 1980 digoxin use was still 1. Use of digoxin was limited and there was some concern about the ascertained by county-level prescription registry large number of comparisons. Adjustments and men in Trondheim, Norway, who were included age, past use of hormone replacement undergoing their frst treatment with digitoxin therapy, nonsteroidal anti-infammatory drugs between 1986 and 1996. An analysis of the relationship between the efect of menopausal status; however, most risk of cancer and serum concentration of digi- women included were postmenopausal (median toxin did not show a coherent relationship for age, 79 years). While there are many risk factors that the national population used as comparison for cancer of the breast, the inability to control group was external to the study population and for alcohol drinking and obesity was likely to be may difer in its underlying disease risk or in the of greatest concern. Tumours in requiring digitoxin, rather than the use of digi- users were signifcantly more likely (P = 0. In addition, estimates of digitoxin be estrogen receptor-positive (85%) than estrogen dose were based on a single measurement at the receptor-negative (79%), and to have low versus start of treatment and there was no information high histological grades, features suggesting about ongoing exposure. Risks associated with current and Cohort study former use, and duration of current use among See Table 2. Patterns of risk with dura- high-quality study with robust fndings adjusted tion of digoxin use were not consistent by cancer for an extensive array of covariates. An increased risk of cancer of the prostate was also reported in the Norwegian cohort study by 2. Data on use of digoxin Case–control study were obtained by self-administered question- naire at baseline and at 2-year intervals during See Table 2. Te inverse association was seen Among 49 medications evaluated (along with regardless of indication for digoxin use (heart many other health conditions and immuniza- failure or arrhythmia), present when digoxin tions), the odds ratios for use of digitalis were was the only cardiac medication used (other 1. Te adjusted risk ratio for cancer of the with duration of use was found in women, but prostate decreased with duration of use from not in men. Te could be due to an association between smoking onset of pharmacological action, afer intrave- and cardiovascular disease for which digitalis nous administration, is detected within 15–30 was prescribed. Equilibrium between compartments is achieved afer a minimum of 6 hours, distribution half-life is 35 minutes, onset of action (oral) approximately 30–120 minutes, and time to peak action (oral) is 6–8 hours (Currie et al. Tis may refect the importance Oral bioavailability (F) of digoxin varies of genotype in determining absorption afer oral with formulation, and between individuals. No infu- membranes of enterocytes of the small intestine, ence on digoxin parameters was detected for by active extrusion of digoxin, back into the other single-nucleotide polymorphisms (Johne lumen of gastrointestinal tract. It is likely that passive difusion (G e r l o f Tis metabolic route comprised initial et al. In addi- with steroid-ring hydroxylation, producing two tion, genetic variation in regulatory proteins, isomers. In individuals demonstrating extensive for example, the pregnane X receptor, involved metabolism, the lactone ring may be opened in regulation of P-glycoprotein, may also afect (possibly by a lactonase), forming a highly polar digoxin disposition (Birkenfeld et al. Te metabolite, or reduced, forming dihydro-metab- absorption of digoxin may also be infuenced by olites (Gault et al. Similar results were obtained metabolic sequence of digoxin hydrolysis, oxida- over a 24-hour exposure time in cultured human tion, and conjugation, leading to polar end-me- hepatocytes, and also in human liver microsomal tabolites. Of these patients, 13 were sively metabolized by human cultured hepato- receiving maintenance therapy with digoxin and cytes to a single, more polar metabolite, which were at steady state. Te extent and time course of was subsequently completely hydrolysed by metabolism of digoxin varied between subjects, β-D-glucuronidase, and thus identifed as the but variation was not signifcant between the two glucuronide of digoxigenin mono-digitoxoside. For all 15 Te extent of glucuronidation analysed in human patients, at 6 hours afer drug administration, liver microsomal fractions prepared from 13 26% (range, 7–76%) of the radiolabel was in the diferent subjects was shown to vary among indi- form of polar metabolites (quantitatively the viduals by a factor of 3 (Lacarelle et al. Te strated a non-renal mechanism of elimination of intracellular concentration of 3-epi-digoxigenin digoxin, entailing direct secretion into the small decreased, due to conversion to polar compounds, intestine from the systemic circulation, which which efuxed from the cells as formed. In had greater importance than elimination via bile human liver microsomes, no metabolites were (Drescher et al. Digoxin is a substrate digoxigenin in vitro is the formation of 3-epi-di- for a sodium-dependent transporter, shown to goxigenin, which is conjugated to a glucuronide be endogenously expressed in a human kidney (Lacarelle et al. Recovery of digoxin in the urine was reported (d) Interactions as 70–85% (Currie et al. Drug recovery in the faeces was, on Te bioavailability of digoxin is afected by average, 14. Bile-duct A proposed metabolic pathway for digoxin is ligation produced comparable pharmacokinetic shown in Fig. In ureter ligation, the plasma half-life of digoxin contrast, the rat metabolizes approximately 60% was increased to 4 hours (Harrison & Gibaldi, of an intraperitoneal dose, and approximately 1976). Tese oxidation reactions plasma-protein binding or the blood-to-plasma were unafected by chemical or immunological partition coefcient. Indeed, the capacity that metabolizes digoxigenin mono-digitoxoside for renal excretion remained substantial, and remains to be identifed (Salphati & Benet, 1999). Tus, intestinal P-glycoprotein acts Digoxin is eliminated primarily via the by directly excreting digoxin into the intestinal kidney through glomerular fltration and tubular lumen, and also limiting the rate of its re-up- secretion. P-glycoprotein has a role in the elimi- take from the intestine by biliary excretion, thus nation of digoxin. Tis causes an increase in intracel- considered due to biotransformation of digoxin. A main excretory route for digoxigenin bis-dig- Digoxin shares some structural homology with itoxoside was shown to be biliary as indicated steroid hormones, suggesting functional similar- by high levels of this metabolite in plasma and ities (Schussheim & Schussheim, 1998; Newman urine of rats with ligated bile ducts (Harrison & et al. It was mechanism of inhibition of these toxins was concluded that increases in digoxin clearance competitive, while the inhibition shown by 10% rates afer weaning may be attributed, at least uraemic serum was non-competitive. However, mechanistic evidence was limited to a demonstration that digitoxin inhib- Studies in humans have assessed the risk of ited the binding of estradiol to specifc, saturable cancer in patients who may have used digoxin, binding sites in the rat uterine cytosol. Te prin- epithelial cells contain several estrogen-binding cipal cancer of interest is cancer of the breast. Summary of Data Reported Nordic countries, France, and Switzerland, and a nationwide cohort study of women in Denmark, 5. Statistically signifcant increases in the occur- Digoxin is a glycoside isolated from Digitalis rence of cancer of the breast in users of digoxin lanata and is used in the treatment of chronic were seen in three case–control studies; in one heart failure and irregular heart rhythm. Other countries with an increased risk for current users (hazard ratio, appreciable use included Japan, Canada, and the 1. In a case–case comparison Statistically signifcant associations of cancer among a subset of the same population, tumours of the breast with use of digoxin were observed occurring in digitalis users were reported to have consistently in women and men, across diferent more favourable prognostic features (estrogen geographical regions, and with diferent study receptor-positive) than in non-users. Cancer of the breast is rare in men and the association of cancer of the breast with use strengthens the validity of association observed of digitoxin were available from one cohort study for cancer of the breast in women. Te record- in women in Denmark, which reported a positive linkage studies that provided key evidence were association (relative risk, 1. Tese studies had not able to adjust for many of the recognized risk limited ability to account for other risk factors factors for cancer of the breast, notably obesity for cancer of the breast, with obesity and alcohol and alcohol drinking, although there was no drinking being of greatest concern.

suhagra 100mg

Several routes 100 mg suhagra, including intramuscular 100mg suhagra, subcutaneous suhagra 100mg, intravenous suhagra 100 mg, intradermal , nasal , and oral administration , have been investigated for the administration of genetic vaccines . Of these routes , intramuscular injection of genetic vaccines generated the best response . Mature myotube has been shown to be the target for the uptake of plasmid after intramuscular administration. Plasmid can enter the bloodstream and lymphatic system after intramuscular administration and traffic to the spleen, liver, kidney, lymph nodes and bone marrow. It is not clear whether the production of antigens in muscle has unique properties with respect to the elicitation of a prolonged immune response or whether expression in any tissue in the periphery is sufficient for the induction of an antigen-specific immune response. Single injection provides for a full humoral and T cell response for 60–70 weeks, with the antibody titer being higher than that achieved by intramuscular injection. Skin is rich in dendritic cells, which are potent initiators of immune responses and possess the co- stimulatory and adhesion molecules required for T cell activation. Thus, transfection of plasmids into these cells is likely to elicit both cellular and humoral responses. Specific targeting of dendritic cells residing in the lymph nodes will likely represent an attractive strategy for providing a robust immune response with nucleic acid vaccines. Plasmid-based (or non-viral) gene therapy has generated considerable research interest because of many inherent advantages over the viral vectors in terms of safety, immunogenicity and ease of manufacture. Gene therapy offers unique opportunities in the development of novel products that produce intracellular proteins. Several plasmid-based approaches are already in clinical trials and offer the potential of safe and effective gene therapy. To enhance the therapeutic efficacy of 356 proteins using plasmid-based expression systems, many fundamental questions related to their pharmaceutical formulation, biodistribution and intracellular trafficking still need to be addressed. Describe the pharmacodynamic and pharmacokinetic barriers to effective plasmid-based gene delivery. Outline the various approaches to cancer gene therapy presently being investigated. Traditionally new chemical entities have been identified by the screening of natural products and chemical libraries to identify potential lead compounds. These lead compounds have then been optimized through an iterative lead-optimization process involving the synthesis of analogs, the development of quantitative-structure-activity relationships and the use of molecular modeling to obtain new chemical entities with high specificity and affinity for the therapeutic target for pharmaceutical development. The development of combinatorial chemistry has led to the ability to produce vast libraries of compounds for initial screening. The evaluation of combinatorial libraries using high-throughput screening technologies allows the rapid screening of potential lead compounds with a wider molecular diversity against a broad range of therapeutic targets. Until recently, therapeutic targets were identified through the application of basic pharmacology and biochemistry with both receptor and enzyme targets being identified and isolated from specific tissues. The identification of potential therapeutic targets has been further enhanced through the recent development of genomics and proteomics. These techniques provide mechanisms to identify upregulated gene and protein expression in diseased tissue providing pointers towards potential means of therapeutic intervention. The advances in molecular biology have also led to the ability to clone receptors into various cell types to facilitate screening of potential ligands against such targets. The parallel development of cell biology has led to the ability to utilize cell-based assays rather than tissue-based assays for drug screening and the advances in robotics have led to the development of high-throughput screening technologies. The development of genomics, proteomics, high-throughput screening and combinatorial chemistry has led to an information explosion within pharmaceutical companies requiring better mechanisms for the storage and manipulation of biological and chemical data. This has driven the development of the field of bioinformatics which serves to provide searchable databases allowing comparison of molecular and biological information to potentially identify other therapeutic targets and lead compounds. This chapter aims to provide a brief overview of these different technologies to provide a basis for the reader to develop their understanding of this field in order to appreciate how these technologies will underpin the future of drug delivery and targeting. The majority of combinatorial approaches utilize polymeric solid supports as a base onto which the compounds are synthesized. However, there are also approaches which utilize solution- based chemistries to generate combinatorial libraries. Such supports are traditionally composed of polymeric resin beads on to which the synthesis of a peptide is undertaken in a stepwise fashion with each amino acid being added sequentially to the peptide chain (Figure 15. After coupling the amino acid to the peptide chain, the protecting group is removed from the terminal amino acid exposing a reactive site to which another amino acid may subsequently be coupled. This technique relies on the clean coupling of amino acids in peptide synthesis, the ability to easily remove reactants and solvents and wash the products between each stage of the synthesis and the ability to protect and deprotect reactive groups on the solid support as necessary. An example of a 3×3×3 combinatorial split and mix combinatorial synthesis is shown in Figure 15. The technique involves three initial batches of resin beads to which are initially coupled, for example, a different amino acid. These batches are then combined, mixed and split again into three batches; each batch now containing a mixture of beads containing different amino acids. A different amino acid is then coupled to each of these batches of beads, the beads mixed, split and the process repeated a third time. This simple 360 3×3×3 combinatorial split and mix approach generates a library of beads containing 27 different compounds in only 6 coupling reactions. A10×10×10×10×10 split and mix reaction scheme will produce 10,000 compounds in only 50 reactions. It is therefore clear that these strategies can produce large libraries of compounds of wide molecular diversity. As each resin bead contains only a single molecule the beads can be screened individually for bioactivity by either screening for activity of bound peptide in the biological assay or by cleaving the resultant peptide from the bead before undertaking the bioanalysis. The identity of any active compounds can then be determined by using mass spectrometry to sequence the active peptide. These involve the synthesis of a large number of combinatorial libraries making it possible to identify the sequence of the active agent from the identification of the libraries containing the active agent. For example, if we were interested in a 5 amino acid peptide we could use an indexed library approach. This approach involves the initial synthesis of 20 combinatorial libraries using 20 different amino acids as the first amino acid. By screening these libraries we would be able to identify a library containing the most active peptide against a therapeutic target—this library would indicate which amino acid is required in the first position of the peptide. If we then, keeping the first amino acid constant, synthesize a further 20 libraries using 20 different amino acids in the second position we will be able to identify the second amino acid required for optimal activity. Such a process allows the most active agent to be identified from a potential pool of 3. Parallel array libraries use a similar strategy but the libraries are all synthesized in parallel. For example, if we were looking for a small molecule drug which could be synthesized from three basic building blocks A, B and C each of which had 12 different possible variants (e. The first set of libraries would each contain a known variant of A, the second set of libraries a known variant of B and the third set of libraries a known variant of C. By screening all the libraries and identifying the most active library from each set it is immediately possible to identify the structure of the most active compound, as only one compound will be common to the libraries (e. All these approaches assume that the only a single compound will be synthesized on each bead at each coupling stage, that there are no side-reactions and that other members of the libraries do not interfere with the binding of the most active compound to the ligand of interest during screening. Although these limitations may seem highly significant, these techniques have been successfully validated using combinatorial techniques to identify known endogenous receptor ligands. These techniques provide a wide range of molecularly diverse molecules with potential therapeutic applications. In addition, the field of combinatorial chemistry has led to the development of (i) a vast range of clean chemical reactions which give rise to a single products, (ii) novel linker technologies allowing molecules to be readily linked to solid supports and subsequently cleaved on completion of the coupling reactions, (iii) novel protecting strategies and (iv) novel chemistries which allow the synthesis of a diverse range of molecules including benzodiazepines, saccharides and lactams, in addition to the more traditional peptides and oligonucleotides on solid supports. The recent developments in molecular biology and robotics have provided the impetus for such technology. However, more recently the industry has been considering 384 and even 1,536 microwell plates. The advances in robotics allow assays to be fully automated and run continually day and night with minimal operator intervention. Molecular biology has provided the means to clone human receptors in a variety of cells and express different enzymes in model systems. Other detection systems use radioactive ligands, bioactivated fluorescent markers or fluorescent quenching approaches in which the interaction with the test compound causes a reduction in the fluorescence of a plate bound enzyme/receptor-conjugate. Novel, rapid methods of detecting both drug- ligand interations and receptor/enzyme activation are continually being developed in order to provide more rapid and sensitive detection systems. These lead compounds are then isolated and characterized, if necessary, before production and optimization on a larger scale. With the developments in high-throughput screening the issues of bioavailability and drug metabolism can be addressed at the earlier stages in the drug discovery/development program ultimately allowing the pharmaceutical industry to select compounds for development with acceptable bioavailability and metabolic profile, and reducing the development costs associated with developing a suitable means of delivering such agents. Nowhere is the impact of this new science more dramatic than in medicine and pharmaceutical drug discovery. Previously “invisible” traditional drug targets are today being examined in detail at the molecular level through the systematic analysis of the genes and proteins which encode them. Coupled with powerful approaches to determining protein structure, such as X-ray crystallography and Fourier-transform two- dimensional electron microscopy, their detailed molecular architecture and the molecular mechanisms by which they work are also being revealed. This molecular information, when coupled with a detailed knowledge of the pharmacological behavior of the same receptors in specific tisssues, gives pharmacologists and medicinal chemists new starting points for drug discovery and optimization, leading to more selective and potentially safer medicines. Currently, very few examples of the successful ab initio design of effective drugs exist, let alone their specific optimization for delivery. However, with the definition of robust molecular approaches for building specific delivery and activation characteristics into broad classes of drug, there is an increasing opportunity for converting already known drugs with limited selectivity into highly targeted agents. As the search for safer, more effective medicines continues, the availability of routine methods for optimizing delivery is one stage of the development process which offers considerable commercial potential. It has been a stimulating period for molecular biology, with a raft of innovative technologies providing the basis for profound advances in our appreciation of the inner workings of cells, tissues and, increasingly, whole organisms. A heady mixture of scientific opportunism and commercial exploitation has led us to the point where virtually all the genes in the human genome are now known. However, as unfair as it may seem, this genetic heritage is not yet available to all scientists. A small number of companies still hold the keys to the majority of these genes, 364 and, with recent developments, it looks as though the same may prove true for the framework sequence of the entire genome. Potentially more frustrating for the academic scientist, the patenting of such information may lock away the fruit of genomics for decades to come. From this it has proved possible to survey the majority of the genes expressed in a particular cell or tissue. The broad applicability of such techniques not only to tissues but also to established cell lines and model cell systems is illustrated in Figure 15. The latter effort is still under way in companies as well as in public institutions. The economies of scale provided by industrial-scale sequencing have hastened progress to the point where at least two companies now have the majority of expressed human genes in their freezers. This has certainly had the effect of restricting access to key therapeutic genes, but on the other hand subscribers to these proprietary databases have early access to information which would not otherwise be available. At the moment, the main beneficiaries of this commercial effort are pharmaceutical and biotech companies who see such access as conferring a significant competitive advantage on their research and development activities. Although there are as yet no methodologies for real-time gene expression observations, the attempt by companies such as Incyte and Affymetrix to place whole genomes on silicon chips, together with the advent of continuous flow hybridization approaches, promises a much greater depth to temporal analysis of complex biological processes than hitherto possible, bringing with it new opportunities for defining appropriate therapeutic intervention points in complex biological cascades. This information can now be complemented by hybridization array approaches, in which the expression of defined subsets of genes (or indeed the expression of entire genomes) can be carefully monitored at high volume across specific time courses and dose regimens, providing a degree of accuracy and reproducibility in determining the level of gene expression which sequencing alone cannot achieve. Together, sequencing and arraying techniques can be used to provide information on both the biology of disease and the behavior of compounds as they impact a biological system. The scientific basis of hybridization arraying as a technique for the determination of gene expression levels is shown in Figures 15. A full description of these hybridization arraying approaches has been published and is also available on the Web (see Table 15. Access to comprehensive sequence databases and the bioinformatics tools to analyze them plays a central role in these gene expression monitoring approaches, illustrating their “reach-through” impact in genomics in general. A further technique which holds considerable promise for evaluating individual gene expression at the histological or cellular level is in situ hybridization. This provides a cellular level of resolution to gene expression analysis which complements that of microarray analyses. All the above techniques have major potential applications in drug delivery, from defining new members of key transporter and receptor gene families and their expression, to providing experimental systems for evaluating the efficacy of new delivery systems. Similar databases will undoubtedly emerge from mammalian systems as mammalian cell genome closure and proteomics advance. Systematic approaches to biological function are encompassed within the broad area of “functional genomics”. For most of this century, our knowledge of cell biology has been primarily descriptive, reproducible in vitro work dating only from the 1960s. From the ability to induce neuronal cell differentiation to the observation of cellular apoptosis, cell culture is now offering radically new insights into the way in which genetic programs are executed at a functional level. The advent of genomic biology places cell structure and structural biology in a new context. Processes fundamental to cell biology, such as protein translocation and apoptosis, can now be seen as variations on an evolutionarily conserved theme. For drug discovery and delivery, this growing knowledge of cell biology is extremely useful. Not only has an intimate appreciation of cellular processes behind disease revealed new therapeutic targets, the inner workings of the cell have now become accessible to exploitation. The development of cell-based screening technologies, ranging from yeast-based screening to reporter gene assays, underlies the increasing trend towards directly harnessing cell biology to drug discovery.

Placing together of these two electrodes in a solution obviously gives rise to an electrochemical cell ; and consequently the voltage thus generated across the electrodes may be determined by connecting it either to a potentiometer or a millivoltmeter that has a sensitivity to measure ± 0 suhagra 100mg. Under these experimental parameters when an extremely feeble current suhagra 100 mg, of the order of less than 5 pA 100mg suhagra, is drawn from the electrodes 100 mg suhagra, the e . In usual practice , the loss of electrons or reduction occurs from the prevailing chemical system at the cathode ; whereas the gain of electrons or oxidation takes place at the anode . Direct Potentiometry : The procedure adopted of employing a single measurement of electrode potential to determine the concentration of an ionic species in a solution is usually termed as direct potentiometry . Disadvantages : Direct potentiometry has the following two serious disadvantages namely : (a) From the Nernst Eq . Therefore , for an ion M+ (monovalent) a ten-time change in the electrode potential E by approximately 60 millivolts (mV) ; whereas for an ion M2+ (bivalent) a change in identical magnitude of activity shall bring forth alternation of E by about 30 mV. Hence, it is evident that to attain a desired accuracy and precision to the extent of 1% in the estimated value for the direct concentration using the technique of direct potentiometry, for M+ ion—the E should be measurable correctly within 0. Remedial Measures : There are two ways to eliminate the above anomaly, namely : (i) to replace the reference electrode with a concentration-cell i. As the name suggests, it is indeed a titrimetric method whereby a series of potentiometric measurements are recorded so as to locate the end-point as correctly as possible. In this procedure, it is particularly of more interest to know the exact changes in the observed electrode potential after each addition of the titrant, rather than a precise and accurate electrode potential often brought about by a given solution. Thus, in a way the impact due to liquid-junction-potential (E ) has been eliminated completely. It is pertinentj to mention here that in a potentiometric titration procedure the apparent change in cell e. The general principles which govern the above different types of reactions will be discussed briefly in the sections that follow : 16. Neutralization Reactions The accuracy and precision with which the end-point can be determined potentiometrically solely depends upon the quantum of change in the observed e. In this case, the first-break in the titration curve signifies that the stronger of the two acids i. In order to get fruitful and reproducible results it is quite necessary that the strengths between either the two acids or bases in question must vary by at least 105 to 1. Demerits of the Method : The neutralization reactions often found to be giving unsatisfactory results in the following two instances. They are : (a) when both the acid and the base are appreciably weak, and (b) when either the acid or the base is very weak (i. Choice of Electrodes : Indicator Electrodes : Hydrogen, Glass or Antimony electrodes ; Reference Electrode : Calomel electrode. Redox Reactions In this particular case the ratio of the concentrations of the oxidized and reduced forms of ionic species establishes the determining factor. In other words, the potential of the immersed indicator electrode is solely controlled and monitored by the ratio of the ionic concentrations in Eq. Furthermore, in the course of either reduction of an oxidizing agent or vice-versa i. Precipitation Reactions In this the determining factor mainly rests on the solubility product of the resulting nearly insoluble material generated in the course of a precipitation reaction and its ionic concentration at the equivalence point. It is, however, pertinent to mention here that the indicator electrode must readily come into equilib- rium with one of the ions. Salt-Bridge : For the determination of a halide the salt-bridge should be a saturated solution of potassium nitrate. Choice of Electrodes : Indicator Electrode : Silver electrode ; Reference Electrodes : Colomel electrode ; Mercury-mercury (I) sulphate electrode. Potentiometric Titration in Non-Aqueous Solvents The potentiometric technique has proved to be of great significance and utility for determining end- points of titrations in a non-aqueous media. The mV scale rather than the pH scale of the potentiometer must be used for obvious reasons, namely : (i) pH scale based upon buffers has no logical significance in a non-aqueous media, and (ii) the potentials in non-aqueous media may exceed the pH scale. The resulting titration curves are more or less emperical and afford a reasonably dependable and reproducible means of end-point detection. These may be illustrated exclusively by employing the titration data provided in Table 16. Ultimately, the end-point is determined from the point of maximum slope of the curve i. However, the degree of accuracy and precision with which this point of inflexion can be located from the plotted graph largely depends on the individual number of data points observed in the close proximities of the end-point. The central portion of the sigmoid curve, in fact is the critical zone where the point of inflexion resides and this may be located by adopting any one of the follow- ing three procedures, namely : (i) Method of parallel tangents, (ii) Method of bisection, and (iii) Method of circle fitting. Thus, the second derivative becomes zero at the point of inflexion and hence, affords a more exact measurement of the equiva- lence point. Invariably, in most of the reactions employed in potentiometric analysis, the titration error is normally quite small and hence may be neglected. Broadly speak- ing, the titration essentially comprises of measuring and subsequently recording a cell potential in terms of either mV or pH, after each sequentially known addition of reagents. It is always advisable to allow sufficient time lapse after each addition of titrant so as to attain equilibrium. These various kinds of electrodes will be discussed briefly, along with a diagrammatic representation wherever possible, in the sections that follow : 16. Reference Electrodes In general, reference electrodes exhibit a potential which is absolutely independent of the solution wherein it is used. Besides, it must not display any significant change even when a small quantum of current is passed through it. The metal electrode comprises of a small piece of platinum foil with a finely divided platinum, H2(g)(1. The coated foil is immersed in an acidic medium having a hydrogen ion activity of 0. The foil Pt-black-foil possesses a relatively large-surface-area thereby enabling it to absorb an appreciable amount of H + 2 H (a = 1. Consequently, thePt-electrode attains a potential which is finally estimated Figure 16. It serves as a salt-bridge which allows the entire set-up immersed directly into the solution to be measured. The po- rous ceramic fiber permits establishment of electrical contact between one D side of the salt-bridge and the solution under the examination and serves C as a barrier between the said two solutions. The differ- ent parts of the saturated calomel electrode are as follows : A A = Porous ceramic fiber, B = Small-hole, Figure 16. Indicator Electrodes An indicator electrode is invariably used exclusively in conjunction with a reference electrode the response of which solely depends upon the concentration of the analyte. Metal Indicator Electrode Metal indicator electrodes develop a potential which is usually determined by the equilibrium posi- tion of a redox half-reaction at the electrode surface. These are further classified into the following three types, namely : (i) First order electrodes, (ii) Second order electrodes, and (iii) Inert electrodes. Hence, the reversible half reaction may be represented as : Ag+ + e– Ag(s) E° = 0. However, several other metals like : Fe, Co, Cr and W are not useful due to the following reasons : (i) Non-reproducible potentials largely influenced by impurities, (ii) Irregular crystal structures in the solid-state, and (iii) Formation of oxide layers on their surfaces. Second-order electrodes Sometimes a metal electrode may be directly responsible to the concentration of an anion which either gives rise to a complex or a precipitate with the respective cations of the metal. Therefore, they are termed as second-order electrodes as they respond to an ion not directly involved in the electron transfer process. In this particular instance, the coated Ag wire when dipped in a solution, sufficient AgCl dissolves to saturate the layer of solution just in contact with the respective electrode surface. Inert electrodes Inert electrodes comprise of chemically inert conductors, for instance : Au, Pt and C which do not necessarily take part either directly or indirectly in the various redox processes. However, the potential developed at an inert electrode solely depends upon both the nature as well as the prevailing concentration of the different redox-reagents present in the solution. Membrane Indicator Electrodes (or Ion-Selective Electrodes) The underlying principle of this type of electrode is that the potential developed due to an unequal charge generated at the opposing surfaces of a ‘special’ membrane. The resulting charge at each surface of the membrane is exclusively controlled and monitored by the exact position of an equilibrium involving analyte ions, which in turn, solely depends upon the concentration of those ions present in the solution. Ion- selective electrodes occupy a very important place in the analytical chemistry by virtue of the fact that one may use the acquired skill, expertise and wisdom to design and commercially prepare membranes that are practically selective towards a specific ion besides producing potentials according to the Nernst-type equation. These are classified further into the following four kinds, namely : (i) Glass membrane electrodes, (ii) Polymer (liquid) membrane electrodes, (iii) Crystalline membrane electrodes, and (iv) Gas-sensing electrodes, which will be described below briefly : 16. Glass Membrane Electrodes The diagram of a typical glass-membrane electrode is depicted in Figure 16. The internal element essentially comprises of a Ag-AgCl electrode (B) dipped in a pH 7 buffer saturated with AgCl (A). The thin, ion-selective glass membrane (I) is carefully fused to the bottom of a high resistance non-responsive glass tube (H) so that the entire membrane may be immersed while taking measurements. The half-cell of glass-membrane electrode may be expressed as : Ag (s) | AgCl [saturated], Cl– (inside), H+ (inside) | glass membrane | H+ (outside) According to the Nernst equation, the potential of the electrode is represented by : + 0. It has a close similarity to the glass pH electrode, and it essentially Membrane pH Electrode comprises of an internal Ag-AgCl electrode (B) and an internal reference solution having a fixed composition e. Interestingly, the didecylphosphate anion represents a fixed component of the non-aqueous liquid membrane. As the concentration of Ca+ ions present in the solutions on either side of the membrane varies ; hence, the concentration of didecylphosphate anion at every membrane surface would also vary accordinly, thereby causing a potential that may be expressed by the following equation : 2+ 0. Crystalline Membrane Electrodes The crystalline membrane electrodes have a very close similarity to those of glass-membrane electrodes (see Section 16. In fact, these electrodes offer a means to devise responsive to anions by making use of a membrane containing specific B anionic sites. Gas-Sensing Electrode The schematic diagram of a gas-sensing electrode is illustrated in Figure 16. One end of the plastic tubing is provided with a thin, replaceable, gas-permeable membrane that separates the internal electrolyte solution from the external solution containing gaseous analyte. However, the exact composition and specifications of this gas-permeable G membrane is usually described by its respective D F manufacturers. It is normally made up of a thin microporous film fabricated from a hydrophobic plastic material. D = External solution containing dissolved gaseous analyte, E = Reference electrode (a Ag/AgCl electrode), F = Internal electrolyte solution, and G = Plastic tube. In general, it must fulfil the following requirements, namely : (a) It should act as a 100% barrier for both water and electrolytes i. Notes : (i) None of the electrodes (reference & indicator) ever gets in contact directly with the analyte solution, and (ii) The only substances which may cause interference with the measurement of potential are dissolved gases which may have a free-access through the membrane, and in turn may affect the pH of the internal solution accordingly. Selectivity of Gas-sensing Electrode : The selectivity of the gas-sensing electrode may be enhanced by making use of such an internal electrode which is particularly sensitive enough to certain species other than the H+ ion. In this case a preset equivalence point potentiometer is applied at the two electrodes with the aid of a calibrated potentiometer (I). It will give rise to an “error” signal (C) provided a difference is caused between this potential and that of the electrodes. The feeble signal thus generated is duly amplified (D) and closes an electronic switch (E) which allows the electricity to flow through the solenoid operated value (B) of the burette (J). As the titration proceeds, the error signal (C) starts approaching a zero value, subsequently the *Svehla, G. The solution of the sample is constantly and uniformly stirred with the help of a magnetic stirrer (A). A few typical examples would be described here, namely : Nitrazepam ; Allopurinol ; and Chloridine hydrochloride. If a positive reaction is obtained add a further 2 g of silver oxide and shake for 30 minutes. Repeat this procedure until the mixture is free from iodides, filter through a fine sintered-glass filter and wash the reaction vessel and filter with three 50-ml quantities of toluene. The volume of titrant used in the second titration represents the amount of tetrabutylammonium hydroxide required. Discuss in an elaborated manner the various means of ‘potentiometric titrations’ in the following reaction variants : (a) Neutralization reactions, (b) Redox reactions, (c) Precipitation reactions, (d) Complexation reactions, and (e) Potentiometric titrations in non-aqueous solvents. With the help of a diagramatic neat-sketch of each curve explain and affirm which one gives the most reliable ‘equivalence point’ and why. What are the tow major types of ‘Electrodes’ one may come across in potentiometric method of analysis? Discuss the working of at least one electrode from each category along with its diagramatic description, working and advantages. Do you think an ‘Automatic Titrator’ (Preset End-Point Titrator) is a technological advancement in potentiometric titration? Expatiate its efficacy and advantages in a busy ‘quality assurance laboratory’ with a neat-labelled diagram and its modus operandi. Hence, these measurements may be employed effectively to record the alteration in concentration of an ion in question in the course of a titration, and ultimately the end-point is established. This specific process is commonly referred to as amperometric method or amperometry. In this particular case, the total current flowing shall remain almost equal to the current carried by the ions that undergoes equal electrolytic migration together with the current caused on account of the diffusion of the ions. Thus, we have : I = Id + Im where I = Total current, Id = Diffusion current, and Im = Migration current. An awkward situation arises when dealing with a dilute solution where it has been observed that the depletion of the electrode layer ultimately leads to an enhancement of the resistance of the solution and thereby affecting subsequently an alteration in the Ohm’s Law potential drop (I × R) in the cell. This ulti- mately gives rise to a doubtful observed potential operative at the electrode.

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