Drug In Many Countries Research Articles

REDUCTION IN SPIKED SULPHADIMIDINE LEVELS IN MILK BY COMMON STORAGE AND PROCESSING TECHNIQUES

ABSTRACT Sulphadimidine (SDM) is widely used as antimicrobial as well as anticoccidial agents on food producing animals, and its violative residues in milk have been reported in many countries. Some common techniques of storage at 27 ± 2, 6 ± 2 and−18 ± 2C temperatures, and processing by heating, curd fermentation, acid coagulation, heat coagulation and spray drying investigated reduced the SDM residue levels in spiked milk to varying extents, but could not eliminate the residue completely. Reduction (P < 0.01) of the spiked SDM levels was enhanced by an increase in storage temperature, storage period, heating period as well as fermentation inoculum level in milk. There were significant (P < 0.01) losses in SDM caused by open as well as microwave heating, curd fermentation, curd storage at 6 ± 2C temperature, acid coagulation, heat coagulation and spray drying. Acid coagulation showed the highest residue reduction among all the methods studied. Heat coagulation by microwave heating showed significantly (P < 0.01) a greater reduction than open heating. Open as well as microwave heating two times with intermittent storage showed significantly (P < 0.01) greater residue reductions than a single time equal period heating. Some of the techniques could be satisfactorily followed to reduce the SDM residue in already contaminated milk less than the prescribed safe limit, ascertaining safe consumption of such milk without discarding it, and thus, having cost as well as nutritional implications in under-developed and developing countries. PRACTICAL APPLICATIONS Several sulphonamides are widely used as broad-spectrum antimicrobials and narrow anticoccidials in many countries in food-producing animals because of their relatively low cost and ease of administration. Their potential tumourgenesis, thyrotoxicity, genotoxicity, embryotoxicity, teratogenicity and hypersensitivity reactions are of much concern, as these show more residue violations than any other drug in many countries. The present study was undertaken for the purpose of eliminating the sulphadimidine (SDM) residue, or bringing its levels less than the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives recommended maximum residue limit (MRL) of 0.025 mg SDM/L milk. Results of the study indicated that the common processing and storage practices could significantly reduce the SDM residue level in spiked milk. This study would help us to utilize, without any appreciable health risk to the consumer, a batch of milk contaminated with the SDM residues more than the prescribed MRL for further processing without discarding it, especially in underdeveloped and developing countries.

Forensic analysis of hallucinogenic mushrooms and khat ( Catha edulisForsk) using cation-exchange liquid chromatography

Hallucinogenic mushrooms (e.g. Psilocybe and Panaeolus species) as well as leaves and young shoots of the khat tree ( Catha edulis Forsk) are illicit drugs in many countries. The exact concentration of the hallucinogenic alkaloids psilocin and psilocybin in mushrooms and the sympathomimetic alkaloids cathinone and cathine in khat is usually essential for jurisdiction. Facing an increasing number of mushroom and khat seizures by German customs authorities, a convenient comprehensive quantitative HPLC method based on cation-exchange liquid chromatography for these rather “exotic” drugs has been developed which avoids time-consuming multi-step sample preparation or chemical derivatization procedures. Using this method a number of different hallucinogenic fungi species and products that are mainly distributed via the internet have been analysed (dried and fresh Psilocybe cubensis Singer as well as P. cubensis collected from “grow boxes”, Panaeolus cyanescens Berkeley and Broome and so-called “philosopher stones” (sclerotia of Psilocybe species)). Highest total amounts of psilocin have been detected in dried P. cyanescens reaching up to 3.00 ± 0.24 mg per 100 mg. The distribution of khat alkaloids in different parts of the khat shoots has been studied. High concentrations of cathinone have not only been detected in leaves but also in green parts and barks of stalks. Additionally, the sample treatment for fresh mushroom and khat samples has been optimised. Highest amounts of alkaloids were found when fresh material was freeze-dried.

Development of a screening method for the detection of analogues of sildenafil and vardenafil by the use of liquid chromatograph coupled with triple quadrupole linear ion trap mass spectrometer

Sildenafil and vardenafil are western drugs used in the treatment of male erectile dysfunction (ED). Prescription is required to use these drugs in many countries including Hong Kong. Recently, health supplements and Chinese herbal drugs claiming to have improvement in male potency were found to be adulterated with these drugs. Even worse, some of these products were found to contain analogues of ED drugs. For regulatory purposes, drug enforcement agencies often use analytical techniques such as HPLC-UV or LC-MS/MS in scheduled multiple reaction monitoring (MRM) mode for routine screening of western drug ingredients. However, drug analogues are expected to have different elution profiles and the ions produced by drug analogues would be different, making them transparent in scheduled MRM conditions. To tackle the problem, an acquisition method that combined precursor ion scan (PIS) with information dependent acquisition (IDA) followed by enhanced product ion (EPI) scan was developed. Results suggested that such an approach could provide a very powerful tool in the detection of analogues of sildenafil and vardenafil.

Immunogloblin E‐mediated immediate allergic reactions to dipyrone: value of basophil activation test in the identification of patients

Pyrazolones are a major cause of immediate IgE-mediated reactions to drugs in many countries. The aim of the study was to evaluate a group of patients with this type of reaction by basophil activation test (BAT), focusing on the influence on positivity of the time between the reaction and this study. The study included 51 patients with selective immediate allergic reactions to pyrazolones and 56 controls. Patients were defined by skin testing or a drug provocation test and BATs with pyrazolones were carried out in all cases. Patients who were BAT positive were followed-up for 30 months to establish the rate of decline in positive tests. BAT was positive in 28 (54.9%) cases. BAT sensitivity was higher in those who were skin-test positive (85.7%) compared with those who were skin-test negative (33.3%). The time between the initial reaction and this study was significantly shorter in those who were skin-test positive (P=0.005) and those who were BAT positive (P=0.017). Follow-up of the BAT-positive patients showed a decrease over time, with 60% of these patients becoming negative after 6 months. BAT is a useful complement to skin testing for the evaluation of immediate allergic reactions to pyrazolones. Although not optimal, BAT sensitivity was also positive in patients with a negative skin test and it is a reasonable alternative in patients with severe reactions who may develop symptoms after skin testing. The time of performance of the test is critical to obtain a positive response.

How to Advise Aspirin Use in Patients Who Need NSAIDs

NSAIDs are widely used all over the world. NSAID use is rising due to increasing availability without a prescription, use of aspirin for prevention of thrombotic disorders and the ageing population. Aspirin is used as an analgesic drug in many countries, but the main current indication is low-dose aspirin for the prevention of cardiovascular events. However, NSAIDs and aspirin use account for approximately 20-25% of all reported drug adverse events. Most of those are gastrointestinal including dyspepsia, hemorrhage, perforation and even death. The COX-2- selective inhibitors (coxibs) have demonstrated equivalent efficacy to nonspecific NSAIDs in the management of arthritis and pain but have less gastrointestinal adverse events, although coxibs and probably all NSAIDs, significantly increase risk of serious thromboembolic events. Concomitant use of low-dose aspirin is present in more than 20% of all patients taking either NSAIDs or coxibs, thus increasing the risk of gastrointestinal side effects. Furthermore, at present, it is not known whether aspirin decreases the cardiovascular risks of COX-2 inhibitors or NSAIDs. Appropriate strategies for gastrointestinal risk reduction with NSAIDs and aspirin must consider the overall health status of our patients including the presence of cardiovascular and gastrointestinal risk factors. Use of the lowest possible dose of these drugs, gastroprotectants, especially proton pump inhibitors and Helicobacter pylori eradication will reduce the risk of gastrointestinal side effects in patients taking low-dose aspirin and NSAIDs or coxibs.

The Genesis and Spread of Reassortment Human Influenza A/H3N2 Viruses Conferring Adamantane Resistance

A dramatic rise in the frequency of resistance to adamantane drugs by influenza A (H3N2) viruses has occurred in recent years -- from approximately 2% to approximately 90% in multiple countries worldwide-and associated with a single S31N amino acid replacement in the viral matrix M2 protein. To explore the emergence and spread of these adamantane resistant viruses we performed a phylogenetic analysis of recently sampled complete A/H3N2 genome sequences. Strikingly, all adamantane resistant viruses belonged to a single lineage (the "N-lineage") characterized by 17 amino acid replacements across the viral genome. Further, our analysis revealed that the genesis of the N-lineage was due to a 4+4 segment reassortment event involving 2 distinct lineages of influenza A/H3N2 virus. A subsequent study of hemagglutinin HA1 sequences suggested that the N-lineage was circulating widely in Asia during 2005, and then dominated the Northern hemisphere 2005-2006 season in Japan and the USA. Given the infrequent use of adamantane drugs in many countries, as well as the decades of use in the US associated with little drug resistance, we propose that the globally increasing frequency of adamantane resistance is more likely attributable to its interaction with fitness-enhancing mutations at other genomic sites rather than to direct drug selection pressure. This implies that adamantanes may not be useful for treatment and prophylaxis against influenza viruses in the long term. More generally, these findings illustrate that drug selection pressure is not the sole factor determining the evolution and maintenance of drug resistance in human pathogens.

Thrombolytics, Anticoagulants, and Antiplatelet Agents

More than 250 articles regarding thrombolytic therapy in acute ischemic stroke were published in the first 10 months of 2005 (Source PubMed). In this section we will focus on some reports that directly affect and improve the treatment of stroke patients, that led to further phase III trials, or that represent a great disappointment after several years of investigation. The key publication on thrombolytic therapy in acute ischemic stroke using recombinant tissue plasminogen activator was published almost 10 years ago, which led to the approval of this drug in many countries.1 Since then, considerable knowledge has been gained about the risks and benefits of thrombolytic therapy. However, 1 major concern is still the limited time window of 3 hours. Many studies have been conducted to extend this time window without increasing the risk for the patients. In addition, more pathophysiologically oriented imaging techniques, such as diffusion- and perfusion-weighted imaging, seemed to be able to detect tissue at risk for further infarction. In January 2005, the results of the Desmoteplase In Acute Ischemic Stroke trial (DIAS) were published.2 DIAS was a dose-finding, phase II, randomized trial designed to evaluate the safety and efficacy of intravenous desmoteplase, a highly fibrin-specific thrombolytic agent, administered within 3 to 9 hours of ischemic stroke onset in patients with perfusion/diffusion mismatch on MRI. It was the first randomized, double-blind, placebo-controlled thrombolysis trial using MRI-based criteria for patient selection and also as an end point. The efficacy end points were rate of reperfusion on MRI after 4 to 8 hours and clinical outcome as assessed by National Institutes of Health Stroke Scale Score (NIHSSS; ≥8-point improvement or scoring of 0 or 1), modified Rankin scale (0 to 2), and Barthel Index (75 to 100) at 90 days. Safety …

Translating research into policy and practice in developing countries: a case study of magnesium sulphate for pre-eclampsia

BackgroundThe evidence base for improving reproductive health continues to grow. However, concerns remain that the translation of this evidence into appropriate policies is partial and slow. Little is known about the factors affecting the use of evidence by policy makers and clinicians, particularly in developing countries. The objective of this study was to examine the factors that might affect the translation of randomised controlled trial (RCT) findings into policies and practice in developing countries.MethodsThe recent publication of an important RCT on the use of magnesium sulphate to treat pre-eclampsia provided an opportunity to explore how research findings might be translated into policy. A range of research methods, including a survey, group interview and observations with RCT collaborators and a survey of WHO drug information officers, regulatory officials and obstetricians in 12 countries, were undertaken to identify barriers and facilitators to knowledge translation.ResultsIt proved difficult to obtain reliable data regarding the availability and use of commonly used drugs in many countries. The perceived barriers to implementing RCT findings regarding the use of magnesium sulphate for pre-eclampsia include drug licensing and availability; inadequate and poorly implemented clinical guidelines; and lack of political support for policy change. However, there were significant regional and national differences in the importance of specific barriers.ConclusionThe policy changes needed to ensure widespread availability and use of magnesium sulphate are variable and complex. Difficulties in obtaining information on availability and use are combined with the wide range of barriers across settings, including a lack of support from policy makers. This makes it difficult to envisage any single intervention strategy that might be used to promote the uptake of research findings on magnesium sulphate into policy across the study settings. The publication of important trials may therefore not have the impacts on health care that researchers hope for.

Developmental exposure to fenproporex: reproductive and morphological evaluation

This study was designed to evaluate the maternal toxicity and teratogenicity of fenproporex, one of the most widely-used anorectic drugs in many countries, including Brazil. Three periods of exposure were evaluated: (a) 30 days before mating; (b) from gestational day (GD) 0 to 14; and (c) 30 days before mating and during pregnancy, until GD 14. Female mice from experimental groups received, by gavage, 15 mg/kg of fenproporex. Treatment with fenproporex increased ambulation of dams in the open-field test and did not influence the mobility in the forced-swimming test. There was no significant difference in maternal weight gain between the controls and fenproporex-treated groups, although fenproporex treatment reduced the gravid uterus weight. No significant difference was observed in postimplantation loss, fetal viability and sex ratio. In addition, this compound did not impair intra-uterine growth. The reduction in the number of implantations in the groups receiving fenproporex indicates that this drug may have an adverse effect on implantation. Fenproporex treatment also increased the number of fetuses presenting small kidneys and cervical ribs. The present results indicate that fenproporex, in the dose and exposure periods tested, appears to exhibit a low maternal toxicity and teratogenic potential in mice.

A five-probe drug cocktail for phenotyping of CYP isozymes with ?high-throughput? LC-MS method

Background This study was performed to validate a five-probe drug cocktail, caffeine, tolbutamide, omeprazole, debrisoquine and midazolam, for simultaneous phenotyping of CYP1A2, 2C9, 2C19, 2D6 and 3A activities. Methods Sixteen healthy male Chinese subjects underwent four study sessions in a cross-over manner, during which they received single oral doses of 500mg tolbutamide (regimen I), 20mg debrisoquine (regimen II), and 10mg caffeine+40mg omeprazole+3.75mg midazolam (regimen III, negative interaction among these three drugs documented in the literature) alone, or a combination of the five drugs (regimen IV). Two blood samples at 2 and 3h and urine at 0–6 and 6–12 h post-dosing were collected. The concentrations of each probe drug and its metabolite were determined by a LC-MS method with one extraction procedure and rapid turn-around time. Results The phenotypic measurements for each enzyme after separate or combined administration are shown below: (see Table) Conclusion The administration of the five-drug cocktail did not result in any significant metabolic interactions. Therefore we conclude that this cocktail can be utilized for simultaneous determination of CYP1A2, 2C9, 2C19, 2D6 and 3A activities in human subjects. In view of the easy availability of these probe drugs in many countries and the relatively “high-throughput” assay, this method may offer a useful approach for pharmacogenetic and drug interaction studies. Clinical Pharmacology & Therapeutics (2005) 77, P35–P35; doi: 10.1016/j.clpt.2004.12.027 CYP Phenotypic index Regimen I/II/III Regimen IV (cocktail) P (t-test) 1A2 paraxathine/caffeine 0.60 ± 0.42 0.69 ± 0.35 0.96 2C9 (hydroxytolbutamide + carboxytolbutamide)/tolbutamide 1084 ± 620 1176 ± 669 0.12 2C19 5-hydroxyomeprazole/omeprazole 0.81 ± 0.43 0.88 ± 0.43 0.42 2D6 4-hydroxydebrisoquine/debrisoquine 0.62 ± 0.56 0.54 ± 0.51 0.11 3A 1′-hydroxymidazolam/midazolam 0.55 ± 0.19 0.53 ± 0.27 0.83

Epidemiology of Nonsteroidal Anti-inflammatory Drug–Associated Gastrointestinal Injury

Nonaspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs in many countries. Use of the majority of NSAIDs increases with age, primarily for symptoms associated with osteoarthritis and other chronic musculoskeletal conditions. Population-based studies have shown that, on any given day, 10–20% of elderly people (≥65 years old) have a current or recent NSAID prescription. Over a 6-month period in Alberta, Canada, 27% of elderly people were prescribed NSAIDs. Furthermore, in Tennessee (USA), 40% of elderly people received at least one NSAID prescription annually, and 6% had NSAID prescriptions for >75% of the year. NSAIDs cause a wide variety of side-effects. The most clinically important side-effects are upper gastrointestinal tract dyspepsia, peptic ulceration, hemorrhage, and perforation, leading to death in some patients. Gastrointestinal side-effects are common; the most common NSAID-associated side-effect is epigastric pain/indigestion. Gastrointestinal side-effects are also a frequent reason both for withdrawal of NSAIDs and for co-treatment with another drug. Indeed, in two population-based studies of people aged ≥65 years, the use of agents to prevent peptic ulcers or relieve dyspepsia was nearly twice as common in regular NSAID users (20–26%) than in non-NSAID users (11%). In Alberta, Canada, it has been estimated that NSAID use accounts for 28% of all prescriptions for antiulcer drugs in people aged at least 65 years. Many studies have now shown that NSAIDs increase the risk of peptic ulcer complications by 3–5-fold, and in several different populations it has been estimated that 15–35% of all peptic ulcer complications are due to NSAIDs. In the United States alone, there are an estimated 41,000 hospitalizations and 3,300 deaths each year among the elderly that are associated with NSAIDs. Factors that increase the risk of serious peptic ulcer disease include older age, history of peptic ulcer disease, gastrointestinal hemorrhage, dyspepsia, and/or previous NSAID intolerance, as well as several measures of poor health.

Morphine formation from ethylmorphine: implications for drugs-of-abuse testing in urine.

In drugs-of-abuse testing, opiates constitute a delicate and controversial task because morphine may occur in urine for several reasons. Ethylmorphine (EtM), which is used as an antitussive drug in many countries, is metabolically converted to morphine. The present study was performed in order to document intra- and interindividual differences in morphine formation after single-dose intake of EtM at two different doses (25 and 50 mg). The urinary excretion of opiates was measured during 48 h with EMIT and gas chromatography-mass spectrometry in 10 healthy volunteers. The mean values of totally recovered EtM and morphine in hydrolyzed urine during 48 h were 42 and 47% of the given dose at high and low dose level, respectively. The ratio between total recovered morphine and EtM ranged from 19 to 131% with a mean value of 48%. The rate of positive outcome in the EMIT opiate-screening assay was 100% during the first 24 h for both doses, and it was still high (> or = 67%) in the 24-48 h time interval. It was found that the decline in urinary EtM is more rapid than for morphine, which leads to an increasing morphine/EtM ratio in urine over time. THe mean value of the morphine/EtM ratio was found to be greater than 1 during the 12-24 h interval and finally increased to greater than 10. There was an intra-individual concordance in morphine/EtM ratio between doses, but there was marked interindividual variation. Morphine/EtM ratios that were greater than 1 were only seen when the concentration of morphine was below 300 micrograms/mmol creatinine. Our results demonstrate that morphine is formed from EtM at a high and variable rate and may be present in urine in concentrations greater than those of EtM even shortly after drug intake.

Amitriptyline tablets reconsidered

We recently noted that three different brands of amitriptyline tablets contain different amounts of drug, even though their labels give the same number of milligrams.1 Laroxyl (Roche) and Saroten (Warner) declare the drug content as amitriptyline base, while Tryptizol (MSD) declares it as the hydrochloride. Laroxyl and Saroten tablets thus appear to contain 13% more drug than Tryptizol. Although there is no good evidence that harm has resulted from this confusion, it seems fair to expect manufacturers to agree among themselves to standardize amitriptyline tablets even before a monograph on the drug appears in the British Pharmacopoeia. Unfortunately agreement will be difficult to reach because each company sells the drug in many countries, and no one company first introduced it in all of them. We understand that the BP Commission is at present considering what convention to adopt in expressing the strength of medicaments. Hitherto most BP standards have been expressed in terms of salts, but some newer drugs have been standardised in terms of the therapeutically active portion of the molecule. The latter method seems preferable, particularly when more than one salt of a drug is used.