Ranolazine sustained-release tablets were recently approved in the EU for chronic stable angina as add-on therapy when symptoms are not controlled with first-line agents. The mechanism of action is thought to involve inhibition of late sodium influx in the heart, which can reduce abnormalities of contractility and repolarisation associated with ischaemia. Ranolazine increases the exercise capacity, reduces angina, and diminishes the use of nitroglycerine. The drug has an excellent safety profile and may be a valuable addition to the treatment of chronic stable angina.

The search for a peripheral neuropathy must be systematic when a toxic medicament for the peripheral nervous system is prescribed as well as the search for a drug induced neuropathy is part of the screening of any peripheral neuropathy, but for numerous drugs, the imputability is not strictly demonstrated. A drug induced neuropathy must be differentiated from a neuropathy related to the disease for which the drug was prescribed. It is the case in the course of some cancers and or AIDS. Moreover, the intake of a neurotoxic drug can aggravate a pre-existing neuropathy. Electrophysiological study is important to confirm the neuropathy, to specify the type, more often axonal, and the severity, and also to detect infraclinical signs of neuropathy before the beginning of the treatment. Many of these drug induced neuropathies are reproducible in animals, that is useful to try to diminish the neurotoxicity in human beings. Antineoplastic chemotherapies and antibiotics are most often implicated in drug induced neuropathies.

There was limited knowledge about drug-induced ILD(DILD), when safety reports of acute ILD-type events in gefitinib-treated patients appeared in Japan. There is a need to better understand DILD including event incidence on different treatments and risk factors for developing DILD. Some studies using recent advances in imaging, molecular examination, and pathology are designed and conducted by an independent academic team to define the risk and increase understanding of ILD of various agents in a postmarketing surveillance. These studies may help to shed light on the underlying mechanisms of DILD and appropriate strategies for such events.

A 25-year-old woman, known to have schizoaffective disorder, presented with symptoms that had arisen a few weeks earlier. The symptoms indicated that she had a toxic clozapine blood level. The probable cause of the toxicity was a pharmacokinetic interaction between citalopram and clozapine at the level of the cytochrome P450 system. A literature search reveals the importance of monitoring the interactions between selective serotonin reuptake inhibitors and clozapine, a procedure which should, if possible, be accompanied by blood level measurements. Caution is called for, particularly when non-smokers are involved.

The data from 5 clinics concerning 8 infants, who had developed severe lactic acidosis and hyperglutamic acidaemia were reviewed. Blood-lactate levels were up to 15 mmol/l (reference level:< 2) and plasma-glutamate levels up to 1632 pmol/l (reference level: 14-78), and there was no concomitant hyperglutaminaemia (levels up to 1032 micromol/l (reference level: 333-809)). A positive correlation between the amount of calcium levulinate administered and the degree of hyperglutamic acidaemia was found. Replacement of the calcium levulinate by another calcium salt caused a reversal of the biochemical abnormalities of the patients. Two of the infants had a 22q11 microdeletion. This development of severe acidosis in infants who had been given a calcium supplement in the form of calcium levulinate may be related to genetic predisposition. The paradoxal hyperketonaemia and generalized aminoaciduria in 4 other patients suggested disturbed function ofthe mitochondrial respiratory chain. The hypothesis of the occurrence of an underlying defect of the mitochondrial respiratory chain was tested in the muscle tissue of one 22q11 patient, but this showed no abnormalities. Excessive accumulation of glutamate because of dysfunction ofglutamine synthetase, which forms glutamate from glutamine seems unlikely because of the relatively low values of plasma glutamate compared to the glutamine plasma levels. Calcium levulinate should no longer be used in neonates as it may lead to lactic acidosis.

INTRODUCTION: Pemetrexed is a chemotherapeutic drug with good tolerance, used as first line treatment for malignant pleural mesothelioma in association with cisplatin, and alone as second line treatment in resistant or relapsing non-small cell lung cancer (NSCLC). However, cutaneous toxicity has been described, principally as a rash. Cutaneous toxicity of all grades has been observed in up to 14%, and grade 3 or 4 toxicity in 0.8-1.3% of cases. CASE REPORT: We report the case of an 85 year old man treated for NSCLC presenting 15 days after administration of the second cycle of pemetrexed with cutaneous lesions including erythema, bullae, and desquamation, associated with deterioration in his general condition; a skin reaction corresponding to Lyell's syndrome. Treatment with steroids and gammaglobulins led to local resolution and improvement in his general condition. CONCLUSION: Cutaneous toxicity from pemetrexed should be recognised on account of its potential severity. The appearance of skin lesions is an indication for careful follow-up for evidence of Lyell's syndrome for which intensive management is needed.

The significant inhibitory capacity of gastric acid secretion of PPIs makes them the drugs of choice for treating acid-related diseases. The considerable prevalence of these diseases and the need for maintaining the administration of the drug during considerably long periods results in this therapeutic group being one of the most widely used. However, in spite of their extensive use, there continue to emerge concerns about their potential toxicity; concerns surrounding the specificity of their mechanism of action and a consequential suspicion that something so potent must involve harmful effects. PPIs act selectively on the final stage of the process of gastric acid secretion, namely the H+/K+-ATPase or proton pump. This enzyme represents an essential step in the process of secretion of H+, and PPIs exert a very specific action on the parietal cell, as they need an environment with very low pH levels, which only exist in this cell. In the present article, the adverse effects of PPIs are reviewed, with special emphasis on those related to their continued administration and on the special circumstances of patients, as in the case of the elderly, those with liver failure, pregnant and breastfeeding mothers and children. All the PPIs on the market share a common chemical basis and there are no great differences in their potential adverse effects, the possibility of them promoting opportunist infections or their capacity to generate pharmacokinetic interactions with other drugs, which, if occur, are generally insignificant. After two decades of use, PPIs have proved to be very effective and safe drugs.

Inosine 5'-monophosphate dehydrogenase (IMPDH) is a key enzyme in the de novo biosynthesis of guanine nucleotides. Proliferation of T- and B-lymphocytes, a hallmark of many autoimnunne diseases, is heavily dependent on access to a large pool of guanine nucleotides. To support this activity IMPDH is upregulated. The clinical benefit observed with mnycophenolic acid, a potent IMPDH inhibitor, in a number of autoimmune diseases, including those associated with organ transplantation, rheumatoid arthritis, psoriasis, systemic lupus erythenmatosus and inflammatory bowel disease, has validated IMPDH as an immunosuppressive target, and triggered the search from the pharmaceutical industry for IMPDH inhibitors with best-in-class status. This review will highlight recent advances in the IMPDH field, with a focus on the discovery and development of non-nucleoside IMPDH inhibitors.

A 56-year-old woman was admitted to our hospital for treatment of non-specific interstitial pneumonitis (NSIP). The patient started prednisone treatment, but one month later treatment with voglibose, an alpha-glucosidase inhibitor (alpha-GI), was started because of prednisone-induced diabetes mellitus. One week later, a massive volume of free air below the diaphragm was detected by a chest X-ray examination. An abdominal CT examination demonstrated pneumatosis coli and the patient was diagnosed with pneumatosis cystoides intestinalis (PCI). Voglibose was discontinued and parenteral nutrition and oxygen inhalation were initiated. Radiographic findings of PCI disappeared within 7 days. We encountered a rare case of PCI, that was associated with alpha-GI treatment.

The pharmacokinetics of tenatoprazole (CAS 113712-98-4), a newly synthesized proton pump inhibitor, and its metabolites TU-501 (sulfide form) and TU-502 (sulfone form) were investigated in an ascending-dose parallel-group study at the dose levels of 10, 20, 40, 80 and 120 mg. A total of 30 healthy Caucasian male volunteers (6 in each dose group) received a single dose at Day 1 (fasted state) and repeated doses from Day 14 to Day 20. CYP2C19 genotype status was determined in all subjects. Concentrations of tenatoprazole, TU-501 and TU-502 in plasma and urine were measured by a validated HPLC/MS/MS method. The single and multiple-dose study provided reliable tolerance. After the single administrations, plasma concentrations reached a maximum between 2.5 and 4.3 h post dose, and thereafter decreased according to a terminal half live (T1/2) ranging from 4.8 to 7.7 h. Similar T1/2 were obtained on first and the last administration, and the steady state was reached after 5 days. Cmax and AUC increased linearly between 10 to 80 mg. However, with the 120 mg dose, the observed Cmax was higher than expected, especially at steady state. For TU-501 and TU-502 metabolites, Cmax and AUC increased linearly after repeated administration between 40 and 120 mg.

BACKGROUND: Anaemia caused by iron deficiency is common in children younger than age 5 years in eastern Africa. However, there is concern that universal supplementation of children with iron and folic acid in areas of high malaria transmission might be harmful. METHODS: We did a randomised, placebo-controlled trial, of children aged 1-35 months and living in Pemba, Zanzibar. We assigned children to daily oral supplementation with: iron (12.5 mg) and folic acid (50 mug; n=7950), iron, folic acid, and zinc (n=8120), or placebo (n=8006); children aged 1-11 months received half the dose. Our primary endpoints were all-cause mortality and admission to hospital. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59549825. FINDINGS: The iron and folic acid-containing groups of the trial were stopped early on Aug 19, 2003, on the recommendation of the data and safety monitoring board. To this date, 24 076 children contributed a follow-up of 25,524 child-years. Those who received iron and folic acid with or without zinc were 12%(95% CI 2-23, p=0.02) more likely to die or need treatment in hospital for an adverse event and 11%(1-23%, p=0.03) more likely to be admitted to hospital; there were also 15%(-7 to 41, p=0.19) more deaths in these groups. INTERPRETATION: Routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. In the presence of an active programme to detect and treat malaria and other infections, iron-deficient and anaemic children can benefit from supplementation. However, supplementation of those who are not iron deficient might be harmful. As such, current guidelines for universal supplementation with iron and folic acid should be revised.

Acceptable adverse effects and a clinical relevant weight loss of 3 to 5 kilograms have been found in long-term randomized clinical trials for sibutramine (Reductil) and orlistat (Xenical); these drugs may be prescribed for treatment of obesity for a duration of one and four years, respectively. This also seems to be the case for rimonabant (Acomplia), which is expected to receive approval in 2005 or 2006. However, until data on morbidity and mortality are available from RCTs, there is no absolute indication for prescribing drugs for treatment of obesity.