A pharmacokinetic study of paracetamol in Thai β-thalassemia/HbE patients

Background

Thalassemia may alter the pharmacokinetics of several drugs in thalassemic patients. Paracetamol is a commonly used analgesic and antipyretic drug which is extensively metabolized in the liver via glucuronidation. The aim of this study was to compare the pharmacokinetics of paracetamol (PCM) and its metabolites [paracetamol glucuronide (PCM-G), paracetamol sulfate (PCM-S), and paracetamol cysteine (PCM-C)] in 16 patients with 16 normal subjects.

Method

Following an overnight fast, a single dose of paracetamol (1,000 mg of Tylenol®) was given and blood samples were obtained at predose, 0.5, 1, 1.5, 2, 3, 4, 5, 7, and 9 h after dosing for determination of the plasma levels of PCM and its metabolites by high-performance liquid chromatography.

Results

There was no significant difference in maximum concentration of PCM between groups. However, a significantly shorter elimination half-life of PCM was observed in the thalassemic subjects (p<0.001). Total apparent clearance of PCM was significantly faster in thalassemic subjects (p<0.01) while the apparent volume of distribution of PCM did not change. The area under the concentration time curve (AUC_0->∞) of PCM-G and PCM-S increased in thalassemic subjects (p<0.05) whereas this parameter for PCM-C was slightly lower in the patients. The half-lives of PCM metabolites were significantly shorter (p<0.01) in thalassemic subjects.

Conclusion

The results indicate that the elimination of PCM and its metabolites in thalassemic subjects is faster than that in normal subjects. Our pharmacokinetic data provide additional evidence that plasma PCM-G is higher in thalassemic patients with hyperbilirubinemia, which could be a casual relationship in regulating the UDP-glucuronosyltransferase expression.     

Guillain-Barré syndrome in Ethiopian patients

This is a ten years retrospective study conducted to assess the clinical profile and outcome of Guillain-Barré Syndrome (GBS) in Ethiopian patients. The medical records of all patients admitted with the diagnosis of GBS to the Department of Internal Medicine, Tikur Anbessa University Hospital, Addis Ababa, Ethiopia during the period September 1992 to September 2001 were reviewed. During the ten-year review period ninety-five patients were admitted with the diagnosis of GBS, of which eighty-one met the National Institute of Neurological and Communicative Disorders and Stroke diagnostic criteria. The mean age (SD) of patients was 34.4 +/- 14.4 years. The male to female ratio was 1.25:1. History of antecedent event such as upper respiratory tract infection, diarrhea and vaccination was obtained in 47/81 (58.1%) of patients. The majority of the patients 62 (78.5%), presented with an ascending areflexic quadriparesis while 10 (12.7%) presented with a descending type of arefilexic quadriparesis, but in 6 (7.4%) of the patients the weakness was confined to the lower extremities (i.e. Paraparetic variant). Signs of autonomic involvement were seen in 25/81 (30.9%). Cytoalbzuminological dissociation in the cerebrospinal fluid was demonstrated in 62.3%. EMG was done in 47 patients The commonest electrophysiologic abnormality encountered was demyelinating picture in 26 (55.3%) followed by mixed and axonal in 12 (25.5%) and 9 (19.1%) respectively). Nineteen (70.3% of 27 GBS patients for whom serology for HIV was done were seropositive. The clinical findings were similar in both groups, except for a higher frequency of CSF pleocytosis, need for ventilatory support and mortality among HIV-positive patients. The overall mortality was 25.9%. This study highlights the importance of GBS as a cause of peripheral nerve disease in our setup. The higher mortality rate observed in this study appeared to be related mainly to the lack of adequate intensive carefacility and highlights the need to improve these services. Further-more, the finding of high frequency of seropositivity among GBS patients in this study underlines the need for further prospective research on the association and clinical course of GBS and HIV, particularly in Africa where HIV/AIDS has become an important public health problem.     

Intravenous/oral sequential therapy in patients hospitalised with community-acquired pneumonia: which patients, when and what agents?

Cost and pharmacoeconomic aspects are becoming more and more important in antibacterial therapy. Nevertheless, antibacterial therapy is curative and initial use of the right antibacterial with high activity and low resistance rates against the relevant pathogens can help to save costs. A new trend in antibacterial therapy is sequential therapy (intravenous/oral) in hospitalised patients with moderate to severe infections. Large studies comparing intravenous therapy with sequential therapy (intravenous/oral) have shown equivalence in clinical and bacteriological outcome. One main indication investigated is community-acquired pneumonia (CAP). CAP requires prompt and effective antibacterial treatment and conventional therapy for patients hospitalised with CAP has typically been parenteral antibacterial therapy for 7 to 10 days. However, clinical evidence shows that in most patients the objective and subjective indicators of infection are substantially improved within the first 2 to 3 days of treatment. Today a large number of clinical trials in patients with CAP have been undertaken and sequential therapy with appropriate antibacterials used in suitable patients has been proven as a treatment option. This demonstrates pharmacoeconomic benefits without compromising antibacterial efficacy. Recommended antibacterials for intravenous/oral sequential therapy in patients with CAP are second- and third- generation cephalosporins, aminopenicillins plus a beta-lactamase inhibitor, and new fluoroquinolones.     

Relapses in bipolar patients: changes in social rhythm?

The Ramadan month represents a valuable opportunity to test the hypothesis that the course of the illness of bipolar patients can be disrupted by the change in social rhythm which usually occurs during this month. The objectives of this study were to follow up the mood state and blood lithium level of fasting Muslim bipolar patients who had been on lithium therapy for at least 3 months, and were clinically stable before being included in the study. Twenty bipolar patients were enrolled during the month of Ramadan in 1997. Diagnosis of bipolar disorder was according to ICD-10 criteria. Patients were assessed during the week before Ramadan, the second and the fourth weeks of the fasting month and the first week after its end, with the Hamilton Depression and Bech-Rafaelsen scales. The plasma concentration of lithium was also assessed. The main finding of the study was that 45% of the patients relapsed, 70% during the second week and the remaining patients at the end of Ramadan. These relapses were not related to plasma concentration of lithium. Most of the relapses were manic (71.4 %). Patients who did not relapse had insomnia and anxiety during the second and third weeks of the study. Side-effects of lithium increased and were observed in 48% of the sample, mostly dryness of the mouth with thirst and tremor. The result of this pilot study indicates that the Ramadan month may disrupt the mood state of bipolar patients. More studies are needed to confirm this observation and to evaluate the validity of the Ramadan model to study the impact of social rhythms on bipolar patients.     

Pharmacokinetics of some antimicrobials in Asian patients

Ａｍｏｎｇｔｈｅｍａｎｙｆａｃｔｏｒｓｔｈａｔｍａｙａｆｅｃｔｔｈｅｏｕｔｃｏｍｅｏｆａｎｔｉｍｉｃｒｏｂｉａｌｔｈｅｒａｐｙｏｆａｎｉｎｆｅｃｔｉｏｎａｒｅｔｈｅｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ，ｐｈａｒｍａｃｏｄｙｎａｍｉｃｓｏｆｔｈｅｄｒｕｇａ...     

Can monocyte/HDL show inflammatory activity of isotretinoin treatment in acne patients?

Abstract

Aim: There are reports that isotretinoin causes some important diseases such as teratogenicity, inflammatory bowel disease and sacroiliitis by triggering inflammation. (Monocyte/HDL (high density lipoprotein) ratio) MHR is closely related to inflammation and is thought to be an indicator of atherosclerotic development. We aimed to investigate how isotretinoin (ISO) affects the immunoinflammatory response in acne patients.

Materials and Methods: In this study, 116 nodulocystic acne patients who received ISO treatment for at least three months were evaluated retrospectively. ISO treatment was given to patients at a dose of 0.5–1?mg/kg. Pre-treatment and post-treatment white blood cell (WBC), neutrophil, lymphocyte, monocyte, platelet, mean platelet volume (MPV), platelet, plateletcrit, platelet distribution width (PDW), neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), total cholesterol, LDL cholesterol, triglyceride, HDL cholesterol and MHR were evaluated.

Results: MPV and MHR values were significantly increased after 3?month treatment (p?<?0.05). There was no significant change in NLR and PLR values (p?>?0.05). There was a significant decrease in neutrophil count (p?<?0.05). There were no significant changes in WBC, lymphocyte, monocyte, platelet, plateletcrit values (p?>?0.05). Total cholesterol, LDL cholesterol and triglyceride levels were significantly increased after three months of treatment (p?<?0.05). HDL cholesterol levels decreased significantly after three months of treatment (p?<?0.05).

Conclusion: We concluded that ISO treatment may trigger inflammation due to the increase in MPV and MHR value. MHR can show inflammation after ISO treatment.     

Combination therapy in asthma--fixed or variable dosing in different patients?

The introduction of combination products, for the coadministration of an inhaled corticosteroid (ICS) with a long-acting beta2-agonist in a single inhaler, has greatly simplified asthma therapy. The two combination inhalers currently available, Symbicort (budesonide/formoterol in a single inhaler) and Seretide (salmeterol/fluticasone), comply with Step 3 of international guidelines that recommend the addition of a long-acting beta2-agonist to ICS in patients who are inadequately controlled on ICS alone. Importantly, combination inhalers ensure that patients cannot neglect their ICS maintenance therapy in favour of the long-acting beta2-agonist--which may improve adherence and overall asthma control. In vitro experiments suggest that ICS and long-acting beta2-agonists may interact beneficially when they are administered via one inhaler. The efficacy and tolerability of budesonide/formoterol and salmeterol/fluticasone have been demonstrated. There are currently two approaches for treating asthma using combination therapy--fixed and adjustable dosing. Fixed dosing with budesonide/formoterol or salmeterol/fluticasone provides effective asthma control in line with guideline goals. However, given the inherent variability of asthma, there is increasing evidence that adjusting the dose of ICS according to fluctuations in symptoms is beneficial. Findings from a series of studies comparing fixed and adjustable symptom-guided dosing regimens demonstrate that adjustable dosing may improve asthma control at an overall lower steroid dose. Ultimately, if adjustable dosing proves to be an effective treatment option, it may be possible to use budesonide/formoterol for both maintenance therapy and symptom relief, thereby overcoming the need for a separate reliever inhaler. This is because formoterol has a more rapid onset and greater dose-related effects than salmeterol in salmeterol/fluticasone. Given that all patients are different, with different disease severities and treatment preferences, both fixed and adjustable dosing strategies are likely to be important in the long-term management of asthma. It is possible that different treatment options will be used for different patients, depending on their disease severity, personality and ability to adhere to therapy.     

Antibody targeting of TGF-β in cancer patients

The role of TGF-β in tumor development and progression is complex. Genetic mutations that disrupt the antiproliferative signaling effects of TGF-β play a key role in the process of malignant transformation for many types of tumors. Paradoxically, this loss of sensitivity to TGF-β's inhibitory actions often leads to TGF-β overexpression by the tumor cells or by normal cells that are recruited to the tumor microenvironment. Elevated concentrations of TGF-β in the tumor microenvironment have been shown to facilitate tumor growth and metastasis. Numerous published studies have provided evidence that inhibition of TGF-β using antibodies, soluble receptors and small molecule inhibitors of TGF-β signal transduction can have beneficial effects in murine models of cancer. Given the pleiotropic nature of TGF-β and its homeostatic role in numerous biological processes, serious concerns have been expressed regarding the safety of administering TGF-β antagonists to human patients. Interestingly, the results of numerous animal toxicology studies of TGF-β antibodies in normal rodents and primates have shown that administration of neutralizing anti-TGF-β antibodies is well tolerated and any adverse effects were reversible or self-limiting. Likewise, administration of a human anti-TGF-β antibody (fresolimumab) in three separate human phase 1 clinical trials has also been shown to be well tolerated.     

Pharmacokinetics of theophyline metabolites in 8 Chinese patients

目的：研究病人常规剂量茶碱治疗后代谢物的动力学．方法：病人静滴茶碱（６６μｍｏｌ·ｋｇ－１）．ＨＰＬＣ法测定给药前后２４ｈ茶碱及其代谢物：１，３二甲基尿酸（ＤＭＵＡ），３甲基黄嘌呤（３ＭＸ），１甲基尿酸（ＭＵＡ），中间代谢产物１甲基黄嘌呤（１ＭＸ）的浓度．结果：ＤＭＵＡ是代谢物中浓度最高的．３ＭＸ的清除速率最低．１ＭＸ很快转化成ＭＵＡ，体内浓度很低，但是，翌晨，１ＭＸ又回升到一个较高的浓度（从００４μｍｏｌ·Ｌ－１上升到１０５μｍｏｌ·Ｌ－１）．结论：ＤＭＵＡ是茶碱的主要代谢产物；在夜间１ＭＸ浓度积蓄，这是茶碱在夜间消除率下降的原因之一．     

Quality of life in patients with systemic lupus erythematosus in Hong Kong

Ｓｙｓｔｅｍｉｃｌｕｐｕｓｅｒｙｔｈｅｍａｔｏｓｕｓ（ＳＬＥ）ｉｓａｈｅｔｅｒｏｇｅｎｅｏｕｓａｕｔｏｉｍｍｕｎｅｄｉｓｅａｓｅ．Ｔｈｅａｅｔｉｏｌｏｇｙｉｓｎｏｔｆｕｌｙｕｎｄｅｒｓｔｏｄｂｕｔｉｔｍａｙｉｎｖｏｌｖｅｂｏｔｈｇｅｎｅｔｉｃａｎｄｅ...     

Cytochrome p450 phenotyping/genotyping in patients receiving antipsychotics: useful aid to prescribing?

Many antipsychotics, including perphenazine, zuclopenthixol, thioridazine, haloperidol and risperidone, are metabolised to a significant extent by the polymorphic cytochrome P450 (CYP) 2D6, which shows large interindividual variation in activity. Significant relationships between CYP2D6 genotype and steady-state concentrations have been reported for perphenazine, zuclopenthixol, risperidone and haloperidol when used in monotherapy. Other CYPs, especially CYP1A2 and CYP3A4, also contribute to the interindividual variability in the kinetics of antipsychotics and the occurrence of drug interactions. For many antipsychotics, the role of the different CYPs at therapeutic drug concentrations remains to be clarified. Some studies have suggested that poor metabolisers for CYP2D6 would be more prone to oversedation and possibly parkinsonism during treatment with classical antipsychotics, whereas other, mostly retrospective, studies have been negative or inconclusive. For the newer antipsychotics, such data are lacking. Whether phenotyping or genotyping for CYP2D6 or other CYPs can be used to predict an optimal dose range has not been studied so far. Genotyping or phenotyping can today be recommended as a complement to plasma concentration determination when aberrant metabolic capacity (poor or ultrarapid) of CYP2D6 substrates is suspected. The current rapid developments in molecular genetic methodology and pharmacogenetic knowledge can in the near future be expected to provide new tools for prediction of the activity of the various drug-metabolising enzymes. Further prospective clinical studies in well-defined patient populations and with adequate evaluation of therapeutic and adverse effects are required to establish the potential of pharmacogenetic testing in clinical psychiatry.     

Adherence with levodopa/carbidopa/entacapone versus levodopa/carbidopa and entacapone as separate tablets in patients with Parkinson’s disease

Abstract

Background:

Observational studies suggest that single-tablet formulations are associated with improved adherence versus the same components taken as separate tablets. The objective of this study was to compare adherence in patients with Parkinson’s disease (PD) receiving levodopa therapy as levodopa/carbidopa/entacapone tablets (LCE) versus levodopa/carbidopa (LC) tablets and entacapone (E) as separate tablets (LC and E).     

Are experiences of sexual violence related to special needs in patients with substance use disorders? A study in opioid-dependent patients

A history of sexual violence has been related to more complex treatment needs in patients with substance use disorders (SUD). Most of the existing studies, however, included patients with various types of SUD, did not examine gender differences and focused on a small range of clinical domains. Our sample consisted of opioid-dependent outpatients treated during a three-year period in a German metropolitan region. The analysis was based on a local case register and included all patients for whom information on lifetime sexual violence was available (N = 3531; 68.3% males). In a case–control design, patients with a history of sexual violence were compared to patients without these experiences regarding a wide range of clinical and social factors indicative of potential needs. Almost two thirds (65.6%) of the female patients and 10.9% of the males reported experiences of sexual violence. Victims differed from non-victims across a variety of domains, including more psychiatric symptoms and suicide attempts, more legal problems, financial and family problems, as well as a higher use of services. In contrast to a previous study among alcohol-dependent patients, no gender differences became apparent. Our findings suggest that experiences of sexual violence are an indicator for more complex needs in opioid-dependent patients of both genders. In addition to integrated trauma-informed approaches, an effort needs to be made to link addiction facilities to further institutions to meet these complex needs.     

N-acetyltransferase polymorphism in patients with Behçet's disease

OBJECTIVES: The objective of our study was to investigate the possible role of human arylamine N-acetyltransferase 2 (NAT2) polymorphism in susceptibility to Beh?et's disease. METHODS: Eighty-five patients with Beh?et's disease gave their written informed consent to participate in the study. Seven point mutations (G191A, C282T, T341C, C481T, A803G, G590A, G857A) in the NAT2 gene were analysed using polymerase chain reaction/restriction fragment length polymorphism techniques. In addition, each patient received 100 mg dapsone orally to determine their NAT2 phenotype. Dapsone and its metabolite monoacetyl-dapsone were measured in 3-h plasma samples using high-performance liquid chromatography. Subjects with an acetylation ratio (monoacetyl-dapsone/dapsone) less than 0.4 were defined as slow acetylators. RESULTS: Of 85 patients with Beh?et's disease, 54 (63.5%) were identified as genotypically slow acetylators. However, 60% (51 of 85) of patients were diagnosed as slow acetylators according to monoacetyl-dapsone/dapsone ratio. Thus, a low incidence of genotype/phenotype discrepancy (3.5%) was observed in Turkish patients with Behcet's disease. When we compared our results with previous phenotyping and genotyping studies in the Turkish population, frequencies of slow and rapid acetylators were not statistically different in patients with Beh?et's disease. The frequency of the *5B allele was found to be slightly higher in patients with Beh?et's disease than historic controls (44.7 vs 35.6%, P = 0.039). However, there was no significant difference in the frequency of the overall genotypes and alleles of NAT2 between patients and controls. CONCLUSION: Although the frequency of the NAT2*5B allele, responsible for slow acetylation, was slightly higher in patients than historic controls, our results failed to show an association between NAT2-acetylator status and risk for developing Beh?et's disease.     

Leiden mutation in patients with Crohn’s disease

Background. Inherited resistance to activated protein C is a common risk factor of venous thrombosis. In a majority of patients the defect is caused by single-point mutation in the gene for factor V. This mutated form of factor Va is more stable against proteolytic attack by activated protein C. The prevalence of this inherited defect in the European population is at least 5%. The risk of thrombosis is increased in the case of heterozygosity 5- to 10-fold, in homozygous subjects 50- to 100-fold, but even homozygous individuals will not necessarily suffer from thrombosis. The aim of our study was to determine whether the presence of Leiden mutation might play a role in the pathophysiology and clinical manifestation of Crohn’s disease. Materials and methods. Thirty-four patients with Crohn’s disease (mean age 34 years, range 21–72 years) were studied. None of them had a history of thrombotic episodes. We examined the case history for risk factors: use of oral contraceptive, steroids, cigarette smoking. Levels of fibrinogen, APTT, lupus anticoagulant and levels of IgG and IgM class anticardiolipin (ACL) antibodies were determined. The Leiden mutation was detected by PCR method (Denninger et al., 1995). Results. Fibrinogen was elevated in five cases, lupus anticoagulant in one case, but none of the patients had ACL antibodies in the serum. Molecular analyses showed heterozygosity for the Leiden factor V gene mutation in the case of 30 patients (25%). Conclusion. Thromboembolic events frequently complicate the clinical course of patients with Crohn’s disease; however, we do not have enough knowledge about its role in manifestation of the disease. These results suggested the high frequency of Leiden mutation among our patients and suggest a new genetic background of Crohn’s disease.     

Should antiepileptic drugs be withdrawn in seizure-free patients?

Discontinuation of antiepileptic drug (AED) treatment is a valuable option in patients with epilepsy who have been seizure free for 2 years or longer. However, the decision to withdraw AEDs must be based on a balanced view of the overall risk of seizure relapse, the factors most likely to affect that risk, and the medical, emotional and social implications of treatment continuation versus treatment withdrawal. In a critical review of 28 studies accounting for 4571 patients (2758 children, 1020 adults and a combined group of 793), most with at least 2 years of seizure remission, the proportion of patients with relapses during or after AED withdrawal ranged from 12 to 66%. Using life-table analysis, the cumulative probability of remaining seizure-free in children was 66-96% at 1 year and 61-91% at 2 years after withdrawal of AEDs. The corresponding values in adults were 39-74% and 35-57%, respectively. The relapse rate was highest in the first 12 months (especially in the first 6 months) after withdrawal and tended to decrease thereafter. Based on a previously published meta-analysis of data published up to 1992, the pooled relapse risk was 25% (95% CI 21, 30%) at 1 year and 29% (95% CI 24, 34%) at 2 years after AED withdrawal. The factors associated with a higher-than-average risk of seizure relapse included adolescent-onset epilepsy, partial seizures, the presence of an underlying neurological condition, and abnormal EEG findings at the time of AED withdrawal in children. Factors associated with a lower-than-average risk were childhood-onset epilepsy, idiopathic generalised epilepsy and - for children - a normal EEG. Selected epilepsy syndromes (e.g. benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) may be associated with significantly different outcomes after AED withdrawal.All these factors and their combinations may contribute to the development of guidelines for practising physicians to help them in making the best decision related to treatment discontinuation. The decision plan should also take into account social factors (driving license, job and leisure activities) as well as emotional and personal factors, and must be tailored to and discussed with the individual patient and his/her family.