Current Drug Safety - Volume 4, Issue 3, 2009

In this issue of Current Drug Safety, there is a single case report of topiramate-induced epistaxis in a 36 year old woman who was being treated for migraine [1]. The dose was increased gradually to 100 mg over one month. 35 days after starting the topiramate and five days after having been on the dose of 100 mg she had repeated prolonged epistaxis. The epistaxis resolved within 12 hours of discontinuing the topiramate. Page et al. [2] previously reported a 61 year old woman treated with topiramate 25 mg daily for lower limb neuropathy. Seven days after starting treatment she had severe epistaxis lasting 8 days, requiring emergency treatment. The epistaxis resolved one week after the topiramate was stopped. Three months later the topiramate was recommenced and she again developed intractable epistaxis. She was treated with two units of packed red cells. One week after stopping the topiramate, for a second time, the epistaxis stopped. She had no subsequent recurrence. No other cases could be located in the literature, although Page et al. have pointed out that epistaxis was reported on 1-4% of patients receiving topiramate in clinical trials. It has been suggested that topiramate might affect platelet function through modulation of L type calcium ion channels.

The risks and benefits of hormone therapy (HT) in the treatment of postmenopausal women remain controversial. In this population-based, observational study, we documented health outcomes among postmenopausal Australian women using HT. Women aged 60-80 years were recruited into the Geelong Osteoporosis Study 1994-7 and followed over a median period of 6.6 years. Mortality, and the development of vascular events, breast and colorectal cancers were documented for 67 HT-users and 521 non-users. Median duration of HT-use was 5.0 years (IQR 3.0-10.0). There was no excess in all-cause mortality associated with HT-use. Based on 92 deaths (six HT-users, 86 non-users), the adjusted odds ratio (OR) for all-cause mortality was 0.79 (95%CI 0.32-1.97). With 99 reports of vascular events (13 HTusers, 86 non-users), the adjusted OR for vascular events was 1.30 (95%CI 0.66-2.57). There were insufficient numbers of breast or colorectal cancer cases (21 breast cancer cases, all non-HT users; and 7 colorectal cancer cases, one HT-user and six non-users) to adequately calculate the risk associated with exposure to HT. Although the sample size was small, these results do not support an association between HT and mortality, despite a possible link between HT and increased risk of developing vascular disease.

Objectives: Describe the population characteristics of liver chemistries, the incidence and patterns of liver chemistry abnormalities, and the longitudinal behavior of alanine aminotransferase in mild-to-moderate asthmatic patients. Methods: We undertook a retrospective analysis of comparator arm data from a long-term safety surveillance study of a leukotriene inhibitor. Results: Several liver chemistry elevations relative to the upper limit of normal were observed. We identified three other types of outliers: liver chemistry elevations relative to screening values, persistent liver chemistry elevations, and unusually variable alanine aminotranferase. Conclusions: In the absence of any common drug therapy, there are considerable within-population differences of liver chemistry profiles including substantial outliers. This ordinary variability should be taken into account in the design of clinical trials and analysis of drug-induced liver injury therein.

Purpose: This study describes the current etiologies, demographic characteristics, incidence of acute renal insufficiency and correlation between peak creatine kinase (CK) and peak creatinine in hospitalized patients with rhabdomyolysis. Methods: A retrospective chart review of patients with creatine kinase (CK) values greater than 5000 IU/L during a nine month period identified 106 cases of rhabdomyolysis. Results: The most common contributing etiologies were recreational drug and/or alcohol use in 28%, trauma in 23%, compression in 19%, shock in 17%, statin-use in 13%, seizure in 8% and quetiapine-use in 8%. 37% of cases involved multiple etiologies. Renal insufficiency occurred in 49% of cases and modestly but significantly correlated with CK (R2 = 0.41, p < 0.0001). Myoglobinuria and a pre-renal state were associated with renal insufficiency in 49% and 52% of cases, respectively. Conclusions: Rhabdomyolysis should be defined with CK values exceeding 10-25 times the upper limit of normal irrespective of renal function. Using a laboratory marker such as CK can aid diagnosis of rhabdomyolysis and identify adverse drug events.

Evidence in the literature is contradictory regarding the precise role of nitric oxide (NO) in modulating systemic inflammatory response induced by cardiopulmonary bypass (CPB). We studied the impact of inspired NO gas on physiological function and markers of inflammation-oxidative stress for subjects (n = 15, age 62+4.5 and 12/3 M/F) scheduled for coronary artery bypass graft (CABG) operation. Outcomes from subjects that received 5 ppm and 20 ppm of inspired NO (n = 5/group) were compared to those not given NO gas. Breath-to-breath measurement commenced at the start of intubation and continued up to 4h later. Indices of cardiovascular function, alveolar-capillary gas exchange and haematological parameters were not significantly different in outcomes for the inspired NO groups as compared with control. We observed a reduction in mean systemic arterial in all subjects at 30 min and 4h after bypass when compared with pre bypass values. Markers of systemic inflammatory response and oxidative stress increased during CPB particularly at 4h and 24h after the initiation of bypass. In contrast, we observed a reduction in expired NO, at 24h after surgery in the groups given inspired NO. In addition, there was also a significant reduction in oxidative stress markers in blood at 24h after surgery for the groups given inspired NO as compared with the control group. In contrast, cytokines response remained similar in all the three groups at all time points. The results suggested that inspired NO gas has an antioxidant property that reduces the levels of cell death, and is not associated with significantly worse-off physiological outcomes.

Good medicine labelling practice is vital to ensure safe use of medicines. Non-compliance to labelling standards is a potential source of medication errors. This study was intended to evaluate and compare compliance towards labelling standard for dispensed medications between community pharmacists and general practitioners in Penang, Malaysia. A total of 128 community pharmacies and 26 general practitioners' clinics were visited. Using ‘Simulated Client Method’ (SCM), data were collected on the medications dispensed upon presentation of hypothetical common cold symptoms. The medications dispensed were evaluated for labelling adequacy. Result revealed that majority of the dispensed medications obtained were not labelled according to regulatory requirements. However, general practitioners complied better than community pharmacists in terms of labelling for: name of patient (p<0.001), details of supplier (p<0.001), dosage of medication (p=0.023), frequency to take medication (p=0.023), patient's reference number (p<0.001), date of supply (p<0.001), special instructions for medication (p=0.008), storage requirements (p=0.002), and indication for medication (p<0.001). Conversely, community pharmacists labelled dispensed medications with the words “Controlled Medicine” more often than did general practitioners (p<0.001). Although laws for labelling dispensed medicines are in place, most community pharmacists and general practitioners did not comply accordingly, thereby putting patients' safety at risks of medication errors.

We report a case of hepatotoxicity induced by methimazole treatment in a patient affected by hyperthyroidism. A 54-year-old man, presented to our observation for palpitations, excessive sweating, weakness, heat intolerance and weight loss. On physical examination, his blood pressure was 140/90 mmHg and heart beat was 100/min regular. He had mild tremors and left exophthalmos. Laboratory test revealed a significant increase in serum thyroid hormone levels with a decrease in thyroid stimulating hormone levels. A diagnosis of hyperthyroidism was made and he began treatment with methimazole (30 mg/day). Fourteen days later, he returned for the development of scleral icterus, followed by dark urine, and abdominal pain in the right upper quadrant. Laboratory examinations and liver biopsy performed a diagnosis of cholestatic hepatitis, secondary to methimazole usage. Methimazole was promptly withdrawn and cholestyramine, ursodeoxycholic acid, and chlorpheniramine were given. After five days, abdominal pain resolved and laboratory parameters returned to normal. Naranjo probability scale indicated a probable relationship between hepatotoxicity and methimazole therapy. In conclusion physicians should be aware the risk of hepatotoxicity related with methimazole.

The current case describes epistaxis in a patient treated with a daily regimen of topiramate 100mg for migraine. The patient had not a past medical history of nosebleeds and laboratory parameters were within normal ranges. She was then advised to withdraw topiramate, and the epistaxis resolved within 12 hours after its discontinuation. Since then, the patient never complained other blood clotting disorders. The potential antiplatelet activity of topiramate is discussed.

Statins inhibit 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, which converts HMG-CoA to mevalonate. Statins lower plasma low-density lipoprotein (LDL) cholesterol by causing intracellular cholesterol depletion and upregulating the expression of LDL receptors. Apart from cholesterol, mevalonate is also the substrate for the synthesis of nonsteroid isoprenoids including farnesylpyrophosphate, geranylgeranylpyrophosphate (both attached to small GTP-binding proteins by protein prenyltransferases), coenzyme Q, dolichol, isopentenyladenosine, etc. Depletion of these isoprenoids results in so called “pleiotropic” effects of statins which are independent of cholesterol lowering. Although statins are generally well-tolerated, adverse effects may occur in some patients. These effects result from impaired protein prenylation, deficiency of coenzyme Q involved in mitochondrial electron transport and antioxidant protection, abnormal protein glycosylation due to dolichol shortage, or deficiency of selenoproteins. Myopathy is the most frequent side effect of statins and in some cases may have a form of severe rhabdomyolysis. Less common adverse effects include hepatotoxicity, peripheral neuropathy, impaired myocardial contractility and autoimmune diseases. The risk of these unfavorable effects is largely outweighed by great reduction of cardiovascular events in statin users. However, due to increasing number of patients taking statins, monitoring for any side effects, intense research to recognize their mechanisms and to identify susceptible patients, as well as rational management of these complications are mandatory to further improve safety of these excellent drugs.

Pharmaceutical product labeling as approved by regulatory agencies include statements of adverse event risk. Product labels include descriptive statements such as whether events are uncommon or rare, as well as percentage occurrence for more common events. In addition tables are provided with the frequencies of the latter events for both product and placebo as observed in clinical trials. Competing products are not mentioned in a specific drug's product labeling but indirect comparisons can be made using the corresponding label information for the alternate product. Two types of tools are easily used for this purpose: absolute measures such as number needed to harm (NNH), and relative measures such as relative risk increase (RRI). The calculations for both of these types of quantitative measures are presented using as examples the oral first-line second-generation antipsychotic medications. Among three sample outcomes selected a priori, akathisia, weight gain, and discontinuation from a clinical trial because of an adverse reaction, there appears to be differences among the different antipsychotics versus placebo. Aripiprazole was associated with the highest risk for akathisia, particularly when used as adjunctive treatment of major depressive disorder (NNH 5, 95% CI 4- 7; RRI 525%, 95% CI 267%-964%). Although insufficient information was available in product labeling to calculate the CI, olanzapine was associated with the highest risk for weight gain of at least 7% from baseline (NNH 6, RRI 640% for adults; NNH 4, RRI 314% for adolescents), and quetiapine for the indication of bipolar depression was associated with the highest risk of discontinuation from a clinical trial because of an adverse reaction (NNH 8, RRI 265% for 600 mg/d; NNH 15, RRI 137% for 300 mg/d). In conclusion, with certain limitations, it is possible for the clinician to extract information from medication product labeling regarding the frequency with which certain adverse reactions can be expected. This supplements, but does not replace, information reported directly in clinical trial reports.

Relaxin (RLX) belongs to the relaxin hormone super-family, which in humans includes 3 RLX molecules and 4 insulin-like peptides. Of these, luteal RLX is the main circulating form in animals and man. RLX, formerly known for its effects on reproduction and pregnancy, has been demonstrated to act on numerous other targets, including the cardiovascular, central and peripheral nervous, respiratory, tegument, excretory and digestive systems. Most of these effects have been studied in animal models, but there is compelling evidence that RLX also acts in the human. Over time, RLX, as a crude or purified extract from corpora lutea or as a pure molecule produced by chemical synthesis or recombinant DNA technology, has been the object of clinical studies aimed at identifying its possible therapeutic fields of application. The availability of human recombinant RLX and the most recent achievements on its biological effects, especially on connective tissue remodelling and cardiovascular physiopathology, have sparkled a novel peak of interest of clinicians to the therapeutic potential of RLX. This review of the existing clinical studies with RLX is focused at its pharmacological and toxicological features, with the aim to support interest of clinicians and pharmaceutical companies to continue the pathway which may eventually succeed in translating RLX from the laboratory bench to the bedside.