Mark Naunton

Valproate: a simple chemical with so much to offer

The debate exists amongst clinical pharmacologists as to unlimited supplies of which drug would be most useful when stranded on a deserted island. The tricyclic antidepressants have always rated highly because of their variety of useful therapeutic effects, but valproate also deserves to be high on the list. Of course, it will protect against seizures, if they arise, but it could also be useful for analgesia, preventing migraine and stabilizing the mood particularly if one becomes mentally unbalanced on the island. It might even help to prevent the development of cancer. It would not be an overstatement to suggest that valproate is truly a remarkable drug – a multitude of therapeutic effects from such a simple chemical structure (2-propylpentanoic acid; Fig. 1) – with a remarkable story; it was discovered by chance and is now well-established in the management of a number of neurological conditions and psychiatric disorders. An American chemist (Burton) first synthesized valproate as an organic solvent in 1882 (1). It is a clear, colourless to pale yellow liquid at room and body temperature, and only slightly soluble in water, but highly soluble in organic solvents. The current generic name (valproic acid) was derived from the more descriptive name 2-propylvaleric acid (2). Valproate had been used infrequently as a solvent until its therapeutic properties were serendipitously discovered in 1962 by French researchers, when it was being used as a solvent for other compounds (khelline derivatives) that were being tested for potential anticonvulsant activity (2–4). Eynard and colleagues had encountered difficulty in dissolving some of the derivatives in water or common organic solvents. Valproate was then used to solubilize these compounds and anticonvulsant activity was subsequently observed for the entire test compounds at all doses. Laboratory studies demonstrated anti-seizure activity with valproate (5) and the first clinical trial in epilepsy using the sodium salt of valproic acid was reported in 1964 (6, 7). It was released in France in 1967 (as ‘Depakine’), in Great Britain in 1973 and was approved by the US Food and Drug Administration (FDA) in 1978. It was the only new anticonvulsant drug marketed for many years, beforehand and afterwards. Valproate is currently marketed in over 100 countries and is well established as a first-line and widely used antiepileptic agent, with a very broad spectrum of activity against both generalized and partial seizures in adults and children (4, 8, 9). It is effective against absences and myoclonic, and generalized tonic-clonic seizures. In addition, the drug is useful in the treatment of partial seizures, with or without secondary generalization (2–4, 8, 9). Intravenous valproate has also been shown to be effective against status epilepticus (10). Results from numerous clinical trials suggest that valproate probably has the widest spectrum of anticonvulsant activity of all current antiepileptic drugs in adults and children with epilepsy (4, 8, 9). Received 9 May 2005, Accepted 19 May 2005 Correspondence: Gregory Peterson, Unit for Medication Outcomes Research and Education, School of Pharmacy, University of Tasmania, Locked Bag 26, Hobart TAS 7001, Australia. Tel.: 61 3 62262197; fax: 61 3 62267627; e-mail: g.peterson@utas.edu.au OH H3C H3C

Impact of pharmacist-conducted home visits on the outcomes of lipid-lowering drug therapy

Objective:  To evaluate a pharmacist‐conducted educational and monitoring programme, designed to promote dietary and lifestyle modification and compliance with lipid‐lowering drug therapy, for patients with dyslipidaemia.

Safe to crush? A pilot study into solid dosage form modification in aged care

To observe medication solid dosage form modification in aged care facilities (ACFs), and assess staff levels of self‐perceived knowledge of medication modification and the types of resources available to them.

Estradiol gel : review of the pharmacology, pharmacokinetics, efficacy, and safety in menopausal women

Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of a gel containing estradiol that is applied to the skin. Design: MEDLINE and EMBASE searches were conducted from 1966 to March 2005. Additional references were identified from bibliographies from selected studies in addition to approved product information. Results: Estradiol gel is indicated for the relief of moderate to severe vasomotor symptoms in menopausal women, and moderate to severe symptoms of vulvar and vaginal atrophy. Women who are intolerant of the oral route, have had previous hypersensitivity skin reactions, or have had difficulties with adhesive patches are ideal candidates for estradiol gel. Conclusions: Estradiol gel can effectively reduce menopause symptoms with minimal side effects. Long-term safety data of estradiol gel are required.

PPI use in patients commenced on clopidogrel : a retrospective cross-sectional evaluation

Background/Aims:  Antiplatelet therapy with aspirin and clopidogrel is an important component of the management of acute coronary syndrome, but it also increases the risk of bleeding. There are no formal guidelines about the use of a proton pump inhibitor (PPI) for gastroprotection in patients on clopidogrel. This study assessed how many patients in the Royal Darwin Hospital (RDH) and the Royal Hobart Hospital (RHH) prescribed clopidogrel and at risk of bleeding were co‐prescribed PPIs.

Pharmacist-Provided Quantitative Heel Ultrasound Screening for Rural Women at Risk of Osteoporosis

Background: Osteoporosis is underdiagnosed, and rural communities often have limited technical resources for the assessment of osteoporosis. Objective: To evaluate the impact of a pharmacist, trained in the use of a portable heel ultrasound device, in screening elderly rural women for risk of osteoporosis and determine whether those found to be at risk seek further help and treatment from their general practitioner (GP) following screening. Methods: Following promotion of the service, 345 women were recruited from 6 rural community pharmacies in Tasmania, Australia, and underwent quantitative heel ultrasound screening. Women were comprehensively educated on risk factors for osteoporosis and completed a calcium intake questionnaire. Results were forwarded to each womans GP, and the participants were followed up 3 months later to assess outcomes from the screening procedure. Results: Approximately 20% of women were shown to be at high risk for osteoporosis; 201 (58%) of these were referred to their GP for further assessment. Sixty-eight percent of women who were screened discussed their results with their GP, and 11% underwent further investigation. Over one-third of women screened began medication (30% calcium, 6% bisphosphonate, 6% vitamin D) for osteoporosis. Conclusions: Pharmacist-provided screening for osteoporosis in rural areas is a potentially useful method to identify women at risk for fracture and a convenient time point for discussion of preventive therapy.

Therapeutic Potential of Tea Tree Oil for Scabies

Globally, scabies affects more than 130 million people at any time. In the developed world, outbreaks in health institutions and vulnerable communities result in a significant economic burden. A review of the literature demonstrates the emergence of resistance toward classical scabicidal treatments and the lack of effectiveness of currently available scabicides in reducing the inflammatory skin reactions and pyodermal progression that occurs in predisposed patient cohorts. Tea tree oil (TTO) has demonstrated promising acaricidal effects against scabies mites in vitro and has also been successfully used as an adjuvant topical medication for the treatment of crusted scabies, including cases that did not respond to standard treatments. Emerging acaricide resistance threatens the future usefulness of currently used gold standard treatments (oral ivermectin and topical permethrin) for scabies. The imminent development of new chemical entities is doubtful. The cumulative acaricidal, antibacterial, antipruritic, anti-inflammatory, and wound healing effects of TTO may have the potential to successfully reduce the burden of scabies infection and the associated bacterial complications. This review summarizes current knowledge on the use of TTO for the treatment of scabies. On the strength of existing data for TTO, larger scale, randomized controlled clinical trials are warranted.

Doctors’ beliefs and knowledge on corticosteroid‐induced osteoporosis: identifying barriers to improve prevention

What is known and Objective:  Despite the availability of effective treatments for the management of corticosteroid‐induced osteoporosis (CIOP), the condition is undertreated. Our objective was to assess prescribers’ knowledge and likely prescribing patterns concerning the diagnosis and treatment of CIOP. Another goal was to identify key barriers to the use of preventive therapy in patients using long‐term corticosteroids.

Lasofoxifene: Selective Estrogen Receptor Modulator for the Prevention and Treatment of Postmenopausal Osteoporosis

Objective: To review literature evaluating the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of lasofoxifene (CP-336156), a selective estrogen receptor modulator (SERM) that is not approved for use in the US. Data Sources: Literature was accessed through the MEDLINE and EMBASE databases (1985-June 2010) using the terms lasofoxifene and selective estrogen receptor modulators. Reference lists from retrieved articles were also manually reviewed. The Food and Drug Administration and Pfizer provided additional information. Study Selection and Data Extraction: All clinical trials evaluating lasofoxifene were included in (his review. In addition, all articles evaluating the pharmacology, pharmacokinetics, and safety of lasofoxifene in humans were reviewed. DATA SYNTHESIS: Lasofoxifene is a third-generation SERM with markedly higher in vitro and in vivo potency and oral bioavailability than other SERMs. The drug has produced significant improvements in bone density and biochemical markers of bone turnover in preclinical studies and in Phase 2 and 3 clinical trials. In these trials, lasofoxifene has shown a favorable safety profile, with adverse events including hot (lushes, leg cramps, and increased vaginal moisture. One 2-year major comparative study in postmenopausal women determined that lasofoxifene and raloxifene were equally effective at increasing total hip bone mineral density (BMD), while lasofoxifene had a significantly greater effect on lumbar spine BMD. Conclusions: Osteoporosis is a significant health problem. While the results of further clinical trials are needed to define the risks and benefits of treatment, particularly relating to fractures, lasofoxifene may prove to be an effective and well-tolerated therapeutic option for the prevention of bone toss in postmenopausal women.

Topical Ivermectin 0.5% Lotion for Treatment of Head Lice

Objective: To investigate the pharmacology, pharmacokinetics, efficacy, adverse effects, and place in therapy of a single application of topical ivermectin 0.5% lotion for head lice treatment. Data Sources: Literature was obtained by searching MEDLINE, PubMed, CINAHL, and Scopus (January 1980 to January 2013). Abstracts were searched for the terms ivermectin AND (head lice or pediculus or pediculosis), topical ivermectin, ivermectin lotion, ivermectin AND (pharmacology OR pharmacokinetics). The New Drug Application filed with the Food and Drug Administration and the product data sheets for ivermectin were obtained. Study Selection and Data Extraction: All English-language articles retrieved from the search were evaluated for relevance to the objective. Data Synthesis: The recommended first-line head lice treatments in the United States are permethrin 1% or pyrethrins, with malathion 0.5% lotion used as a second-line treatment. Significantly more of the 289 head lice–infested participants using topical ivermectin 0.5% lotion were lice-free at day 15 when compared with vehicle control (73.8% vs 17.6%; P < .001) in 2 studies. Although this rate is lower than other third-line treatments (eg, spinosad 0.9% or benzyl alcohol 5%), topical ivermectin 0.5% lotion is well tolerated (pruritus, the most common adverse event, 0.9%) and requires only a single application. Conclusions: Topical ivermectin 0.5% lotion kills head lice by increasing chloride in muscle cells, causing hyperpolarization and paralysis. Only 1 application is required; when the treated eggs hatch, the lice are not viable because they cannot feed as a result of pharyngeal muscle paralysis. Minimal systemic absorption occurs following topical application. Studies have demonstrated that topical ivermectin 0.5% is a safe and efficacious treatment for head lice. Although it has no documented resistance, there is limited clinical experience, it requires a prescription, and it is expensive. Therefore it should be reserved as a third-line treatment for head lice in the United States.