Current Clinical Pharmacology - Volume 7, Issue 4, 2012

In the present study, a novel, fast, sensitive and robust method to quantify clozapine in human plasma using quetiapine as the internal standard (IS) is described. The analyte and the IS were extracted from plasma using a single protein precipitation extraction technique with methanol and analyzed by high performance liquid chromatography coupled to the electrospray ionization tandem mass spectrometric (HPLC-ESI-MS/MS). The method was linear over the range 20 to 1500 ng.mL-1. The intra-assay precisions ranged from 3.8 to 5.9%, while inter-assay precisions ranged from 4.2 to 6.0%. The intra-assay accuracies ranged from 99.3 to 107.5%, while the inter-assay accuracies ranged from 98.9 to 101.7%. This method agrees with the requirements proposed by the US Food and Drug Administration of high sensitivity, specificity and high sample throughput and was used to evaluate the pharmacokinetic profiles and bioequivalence of the two clozapine formulations in twenty six schizophrenic patients affected by refractory schizophrenia under steady-state conditions. During the hospitalization period the patients received the 100 mg clozapine formulation tablets corresponding to the same dose they were using 14 days before hospitalization. The clozapine pharmacokinetic did not differ significantly after administration of both test and the reference formulations. The Tmax and T1/2 for the test formulation were 2.26 and 10.92 h, respectively. In addition, the Tmax and T1/2 for the reference formulation were 2.44 and 11.08 h, respectively. The 90% confidence interval of the mean ratio of lnAUC0-t was within 0.80-1.25 range which indicates that the test formulation was bioequivalent to the reference formulation when orally administered to schizophrenic patients regarding both the rate and extent of absorption.

Over the years Renal Transplant has become increasingly successful and fairly routine in terms of availability to prospective patients. More effective and better tolerated medications have led to decreased adverse immunologic events after transplant leading to improved graft survival. Moreover, since the last few years renal transplant is being offered to a wider range of patients with variety of comorbidities, thus making the surveillance of long term complications of immunosuppression (IS) medications critical for both graft and patient survival. As the use of newer and more potent medications becomes more wide spread, their adverse effects, interactions amongst themselves as well as with other medications, are necessary to recognize and follow closely specially in patients with other comorbidities. Although infections resulting from IS are common; other noninfectious complications cause significant problems in a transplant patient. Post-transplant, several preexisting risk factors like hypertension (HTN), dyslipidemia and hyperglycemia usually get exacerbated resulting in accelerated atherosclerosis causing cardiovascular disease which is the most common cause of death in transplant patients. Some IS medications have been implicated as a cause for certain malignancies and their close surveillance and timely intervention is an important aspect of care for these patients. Therefore an understanding of these medications and their adverse effects is of paramount importance for the successful medical management of these patients. In this manuscript we review the transplant IS and systematically outline their various noninfectious adverse effects.

Patent ductus arteriosus is a common problem in very low birth weight infants. Prostaglandin synthesis inhibitors such as indomethacin and ibuprofen are widely used preferred medications for ductal closure but the question of which one should be preferred is controversial. There are some studies in the literature comparing their pharmacokinetics, efficacy, side effects and long-term outcomes. In this review we aimed to focus on prostaglandin synthesis inhibitors with their pharmacodynamic and pharmacokinetic in relation to oral and intravenous forms. Oral ibuprofen seems to be an effective and cheap alternative to the intravenous forms. Studies in extremely low birth weight infants that also evaluate the neurodevelopment will clarify its use.

Interleukin (IL)-1 is a pivotal proinflammatory cytokine consisting of two molecular species, IL-1α and IL-1β. Anakinra (Kineret), a recombinant human IL-1 receptor antagonist, is regarded as a biological agent which blocks the inflammatory effects of IL-1. The aim of this review was to search the literatures and summarizes in vivo, in vitro and human studies on anakinra uses in dermatological disorders. The results show that anakinra is currently used clinically for the treatment of a variety of skin conditions such as psoriasis, atopic dermatitis, photoagaing, melanoma, Schnitzler syndrome, pyoderma gangraenosum, PAPA syndrome, hidradenitis suppurativa, lamellar ichthyosis, Sweet's syndrome, panniculitis, Muckle-Wells syndrome, familial Mediterranean fever, SAPHO syndrome and other disorders. Notably, anakinra is expensive to produce and administer. Injection is the route of therapy and allergic reaction is most possible.

Drug-related problems (DRPs) can reduce the potential clinical benefits of treatment with medicines and waste valuable resources. No previous studies were published to examine the nature and frequency of drug related problems among hospitalized patients in Palestinian hospitals. Methodology: Prospective observational study was conducted to report and record the natural and frequency of drug related problems in two general hospitals. Results: The study included 212 patients, 54.4 % female, with a mean age 62.2 (±10.6 SD). 88% of the patients were reported with one or more DRPs, with an average of 1.9 DRPs per patient were found. The most prevalent DRP was incorrect dosing regimen which was represented by (22.2%), followed by drug-drug interaction (19.4%), drugs need laboratory tests (15.2%). Ceftriaxone, warfarin, enoxapirin and dogixin were the drugs causing most frequent DRPs. The drug groups causing most DRPs were anti-infective agents, anti-thrombotic agents and non-steroidal anti-inflammatory agents. Once discovered, the majority of DRPs (71.6%) were accepted by the physicians and solved immediately, while 11.5 % of pharmacist advice was not approved. Multiple regression analysis indicated that the number of medications (RR 1.99; 95% CI 1.31-3.76) and the number of medical conditions (RR 1.81; 95% CI 1.11-3.13) independently predicted the number of DRPs. Conclusion: DRPs in general hospitals are frequent, serious and predictable. Most of the problems identified as DRPs by the pharmacists were accepted by the physicians and solved. Pharmacists in the hospital setting are well suited to identify and resolve DRPs.

This review describes the most important new generations of pharmaceutical systems: medicines with extended release, controlled release pharmaceutical systems, pharmaceutical systems for the targeted delivery of drug substances. The latest advances and approaches for delivering small molecular weight drugs and other biologically active agents such as proteins and nucleic acids require novel delivery technologies, the success of a drug being many times dependent on the delivery method. All these dosage forms are qualitatively superior to medicines with immediate release, in that they ensure optimal drug concentrations depending on specific demands of different disease particularities of the body. Drug delivery of these pharmaceutical formulations has the benefit of improving product efficacy and safety, as well as patient convenience and compliance. This paper describes the biopharmaceutical, pharmacokinetic, pharmacologic and technological principles in the design of drug delivery systems with modified release as well as the formulation criteria of prolonged and controlled release drug delivery systems. The paper presents pharmaceutical prolonged and controlled release dosage forms intended for different routes of administration: oral, ocular, transdermal, parenteral, pulmonary, mucoadhesive, but also orally fast dissolving tablets, gastroretentive drug delivery systems, colon-specific drug delivery systems, pulsatile drug delivery systems and carrier or ligand mediated transport for site specific or receptor drug targeting. Specific technologies are given on the dosage forms with modified release as well as examples of marketed products, and current research in these areas.

Autoimmune hepatitis is an immune-mediated disease targeting hepatocytes. It is more common in middleaged Caucasian females, although may affect other patient populations and age groups. The diagnosis is made according to criteria based on the alkaline phosphatase: ALT ratio, IgG, the presence of autoantibodies, liver histology, response to therapy, and the absence of a viral, alcohol or drug etiology. More recently a simplified scoring system has been proposed. In the absence of treatment, the prognosis is very poor with a 60% three year mortality. There are guidelines on the indications for treatment and some groups of patients may not require treatment. The main element of treatment is prednisolone which decreases the 3 year mortality to 10%. Prednisolone is tapered down to 5-10 mg per day, as monotherapy or in combination with azathioprine. Approximately 80% of patients will respond to therapy with prednisolone with or without azathioprine and this should be given for at least 2 years. Remission is defined as an asymptomatic patient with serum aminotransferases that are normal or less than two-fold elevated, a normal level of IgG and inactive liver histology. Relapse occurs in up to 90% of patients following drug withdrawal. The sensitivity and specificity of liver histology to predict relapse off treatment is not high. Other treatments that have been proposed include mycophenolate mofetil, budesonide, cyclosporine A, tacrolimus, 6-MP, methotrexate, ursodeoxycholic acid, rapamycin and rituximab although experience with all these agents is limited.

This paper describes the main development steps of pharmacokinetics that paralleled the development of analytical bioassay methods. From the first stirrings on 1950s, with very sensitive but not specific radiotracing measurements using 14C or 3H labelled drugs, to further developments with more specific methods like gas chromatography, high pressure liquid chromatography, to the last achievement with tandem mass spectrometry, pharmacokinetics has supported all the development procedures of both NDA (New Drug Application) and ANDA (Abridged New Drug Application). The discovery of new therapeutic active molecules is now concentrated in a few very big companies, and requires pharmacokinetic support from the first screening procedures to the last clinical developments. Medium and small pharmaceutical companies largely use pharmacokinetics for various new applications of existing drugs now out of patent, that require only or mainly pharmacokinetic, bioavailability, bioequivalence investigations in compliance with the ANDA procedure. In spite of guidelines published by US FDA and EU EMA, some open problems on bioequivalence would still require more attention from regulatory authorities, like how to manage the puzzle of endogenous substances, ethical problems against the repeated-dose regimen with some drugs and how to manage Cmax in the presence of the multiple-peak phenomenon.

DNA methylation is a major epigenetic mechanism that leads to inhibition of gene transcription and is known to be involved in the pathogenesis of cancer. The effectors of DNA methylation are DNA methyltransferases (DNMTs) that catalyze either de novo or maintenance methylation of hemimethylated DNA after DNA replication. DNA methylation patterns in cancer are distorted, with three ways by which DNA methylation contributes to cancer: hypomethylation of the cancer genome, focal hypermethylation of the promoters of tumour suppressor genes, and direct mutagenesis. Drugs that inhibit DNMTs are proving to be useful in the treatment of cancer with a few such drugs approved for clinical use. These drugs include nucleoside inhibitors, non-nucleoside inhibitors, oligonucleotides, and noncoding RNAs that target messenger RNAs of genes encoding DNMTs. The major value of DNMT inhibitors could be that at low doses they can induce the re-expression of aberrantly silenced tumour suppressor genes, allowing cancer cells to revert to a normal phenotype and/or reacquire cellular pathways needed for cell cycle regulation and apoptosis induction. They could also be useful in combination with other anticancer drugs.