A review of oxaliplatin and its clinical use in colorectal cancer

Colorectal cancer is one of the leading causes of death from malignant diseases in the Western world. Worldwide, approximately 50% of patients who present with colorectal cancer will develop metastatic disease and eventually die from this malignancy. Recently, significant advances have been made in the medical treatment of advanced colorectal cancer with the introduction of novel cytotoxic drugs, such as irinotecan and oxaliplatin. Based on the results of recent Phase III trials, combination regimens of infusional 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX) have emerged as a new standard of care in the palliative and adjuvant treatment of colorectal cancer. The addition of biological agents targeting angiogenesis or oncogenes such as epidermal growth factor receptor (EGFR) to FOLFOX will conceivably further enhance the activity of treatment regimens. Making use of all available active therapeutic options in the course of disease has significantly improved median overall survival of metastatic colorectal cancer into a chronic disease, with implications for treatment strategies and pharmacoeconomic considerations.     

A review of oxaliplatin and its clinical use in colorectal cancer

Colorectal cancer is one of the leading causes of death from malignant diseases in the Western world. Worldwide, ～ 50% of patients who present with colorectal cancer will develop metastatic disease and eventually die from this malignancy. Recently, significant advances have been made in the medical treatment of advanced colorectal cancer with the introduction of novel cytotoxic drugs, such as irinotecan and oxaliplatin. Based on the results of recent Phase III trials, combination regimens of infusional 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX) have emerged as a new standard of care in the palliative and adjuvant treatment of colorectal cancer. The addition of biological agents targeting angiogenesis or oncogenes such as epidermal growth factor receptor (EGFR) to FOLFOX will conceivably further enhance the activity of treatment regimens. Making use of all available active therapeutic options in the course of disease has significantly improved median overall survival of metastatic colorectal cancer into a chronic disease, with implications for treatment strategies and pharmacoeconomic considerations.     

A review of the carbapenems in clinical use and clinical trials

Despite alarming data showing the ever increasing number of bacteria becoming resistant to different classes of antibiotics through various mechanisms, the carbapenems remain a unique class of antibiotics that possess the broadest spectrum against Gram-positive, Gram-negative, aerobic and anaerobic organisms. However, bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, carry mechanisms that can inactivate the carbapenems. This article gives a review of the carbapenems that are currently in clinical use as well as discusses the new carbapenems that are in clinical trials. These new carbapenems show promising potential to overcome the resistance against the presently existing carbapenems. The present article shows the recent patents using carbapenems as an effective antibiotic.     

Zonisamide: A review of the clinical and experimental evidence for its use in Parkinson's disease

The limitations of currently available therapies in addressing the non motor symptoms of Parkinson''s disease (PD) have egged on the search for newer options. Zonisamide has been in use for epilepsy and it was serendipitously found to improve the symptoms of PD in a patient who had both epilepsy and PD. Thereafter, various trials were designed to assess the use of zonisamide in PD. The present article investigates the evidence for use of zonisamide in PD from the various clinical trials that were designed to address this issue. Furthermore, the article also summarizes the various mechanisms of its use in PD as described in various animal experiments. A search protocol was designed with predefined inclusion and exclusion criteria. The databases searched were Pubmed, Ovid medline, Cochrane and clinicaltrials.gov. The data thus generated, was fed into a predesigned format. Most of the clinical trials on zonisamide in PD have come from Japan. Most of these trials used the changes in the Unified Parkinson''s Disease Rating Scale (UPDRS) score as the endpoints and the most conclusive evidence is for a dose of 25-50 mg, which caused a change in UPDRS part III (motor symptoms). These patients were on levodopa and other drugs used for PD during the trials. One of the clinical trials conducted in Spain investigates the use of zonisamide in impulse control disorders among 15 patients of PD. Among the many mechanisms postulated, a reduction in levodopa induced quinone formation, protection against mitochondrial impairment and an increase in astroglial cysteine transport, an inhibition of microglial activation, monoamine oxidase-B (MAO-B) inhibition, an increased dopamine release and blockade of calcium channels are the most cited. There is evidence for use of zonisamide in PD in addition to levodopa and other therapies for control of motor symptoms. For now, the evidence for its use in control of non motor symptoms in PD is not enough and needs to be investigated further.KEY WORDS: Neuroprotection, Parkinson''s Disease, Zonisamide     

伏立康唑及其临床应用

伏立康唑是最新上市的第2代三唑类广谱抗真菌药物,能有效抑制真菌羊毛甾醇14α去甲基化酶,阻断麦角甾醇生物合成,从而影响细胞膜的流动性、通透性,在体内、外具有广泛的抗真菌活性临床研究结果表明,伏立康唑可用于念珠菌感染和其他药物治疗无效的克柔念珠菌及烟曲菌感染。本文综述了伏立康唑的药效学、药动学特性及临床应用等研究进展。     

Goserelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical use in sex hormone-related conditions.

Goserelin is a synthetic analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH); or gonadorelin] which stimulates gonadotrophin and sex hormone release in the short term, and then causes suppression with continued administration. Goserelin is given as a subcutaneous biodegradable depot incorporating 3.6 mg of the drug, which is released continuously at an average rate of 120 micrograms/day over 4 weeks. Monthly goserelin depot therapy produces partial disease remission or stabilisation in about 75% of men with previously untreated prostatic cancer, a rate equivalent to that achieved with orchidectomy or diethylstilbestrol (stilboestrol). The response to goserelin is more rapid than to diethylstilbestrol, and goserelin is better tolerated. About 30 to 45% of premenopausal women with breast cancer responded to goserelin using objective assessment criteria, suggesting comparability to ovariectomy. In benign hormone-dependent conditions, preoperative goserelin aids surgical removal of uterine leiomyoma (fibroids) and reduces blood loss, and 6 months of therapy relieves the signs and symptoms of endometriosis. The elevation in testosterone at the beginning of goserelin therapy can result in disease 'flare' in men with prostate cancer, and sex steroid suppression with continued treatment results in hot flushes and loss of libido in most patients. Thus, goserelin is an effective alternative to surgery or estrogen therapy in prostatic cancer palliation, and possibly to ovariectomy in premenopausal breast cancer. Other gynaecological conditions reliant on the pituitary-gonadal axis also appear amenable to hormone manipulation with goserelin.     

Sufentanil. A review of its pharmacological properties and therapeutic use

Sufentanil, an opioid analgesic, is an analogue of fentanyl, and has been used for the induction and maintenance of anaesthesia, and for postsurgical analgesia. It has shorter distribution and elimination half-lives, and is a more potent analgesic than fentanyl. In clinical practice, however, intravenously administered sufentanil produces essentially equivalent anaesthesia to fentanyl and is a better anaesthetic than morphine or pethidine (meperidine) for major surgery. It would appear to maintain haemodynamic stability during surgery better than other opioids or inhalational anaesthetics. Postoperative respiratory depression has been reported in a few patients. For outpatient surgery, intravenous sufentanil produces equivalent anaesthesia to isoflurane or fentanyl. Recovery tends to be more rapid after sufentanil and the requirement for postoperative analgesia is less. Initial clinical trials with sufentanil administered epidurally to relieve pain during labour have produced encouraging results, but further studies are required to establish the drug's role in this indication. Epidural sufentanil produces a more rapid onset and better initial quality of analgesia than morphine, buprenorphine or hydromorphine when administered postoperatively, but the duration of analgesia is shorter. Thus, sufentanil's primary place in therapy at this time would appear to be as high dose anaesthesia for major surgery such as cardiac surgery, and as low dose supplement to balanced anaesthesia in general surgery. In addition, low doses administered epidurally seem to have a potential role for analgesia during labour or after surgery although further studies are required to clarify this situation.     

Acitretin. A review of its pharmacology and therapeutic use.

Acitretin (etretin), a second generation monoaromatic retinoid for use in the treatment of severe psoriasis and other dermatoses, is the major active metabolite of etretinate and possesses a similar therapeutic index; i.e. a similar ratio of clinical efficacy to adverse effects. When used alone at a maintenance dosage of 30 to 50mg daily, acitretin is effective in the treatment of psoriasis, causing a reduction in the severity of scaling, erythema and induration. Efficacy appears to be further enhanced by combination with psoralen-ultraviolet A photochemotherapy (PUVA) or ultraviolet B irradiation (UVB). These combinations reduce the time to lesion clearance and reduce the total radiation dose, improving overall safety. Comparative studies have confirmed the equivalence of acitretin and etrtinate with regard to efficacy and toxicity. Adverse reactions are dose-related and generally typical of hypervitaminosis A. Alopecia and mucocutaneous symptoms such as cheilitis and drying of the mucous membranes are particularly prevalent. Hypertriglyceridaemia and elevation of cholesterol levels also occur. Examination of the pharmacokinetic profile of acitretin reveals its main advantage over etretinate. Acitretin is less lipophilic than etretinate, and its lack of sequestration into 'deep' fatty storage sites is reflected in a comparatively short terminal elimination half-life of 50 to 60 hours, compared with 120 days for etretinate. Due to its teratogenic potential, acitretin is strictly contraindicated in women of childbearing potential unless effective contraceptive measures are employed. Etretinate has been identified in plasma samples of some patients treated with acitretin. Thus, acetretin has an established place in the treatment of keratinising disorders, although its use in women of child-bearing potential must be accompanied by effective contraceptive measures, with a further 2-year contraceptive period after therapy completion.     

The retinoids. A review of their clinical pharmacology and therapeutic use

With the introduction of the synthetic retinoids, oral therapy with an acceptable risk/benefit ratio became possible for a variety of skin diseases including severe acne, psoriasis and numerous genodermatoses. This article reviews the clinical pharmacology, mechanisms of action and therapeutic use of the retinoids, particularly isotretinoin (13-cis-retinoic acid) and etretinate. The free aromatic acid of etretinate, etretin, and the new polyaromatic retinoid compounds (arotinoids) are also discussed. Isotretinoin is used clinically for oral therapy of severe acne, but is also recommended for severe Gram-negative folliculitis and rosacea not responding to traditional therapy. The results of several studies have established that acne therapy should be started with 1.0 mg/kg/day for 2 to 3 months after which the daily dosage should be lowered to 0.2 to 0.5 mg/kg/day for another 2 to 3 months. This therapeutic regimen of isotretinoin has proven to be the most successful in preventing relapses. Etretinate is particularly useful for oral therapy of widespread plaque-like, pustular and erythrodermic psoriasis, and of generalised lichen planus, Darier's disease and severe congenital ichthyoses. Whereas pustular forms of psoriasis require a high daily dosage of 1.0 mg/kg/day, erythrodermic psoriasis should be treated with a lower dosage of 0.25 to 0.35 mg/kg/day. In chronic plaque-like psoriasis, a mean daily dosage of 0.5 mg/kg/day over several weeks to months, usually combined with photo(chemo)therapy, tar or dithranol, is recommended. Other indications for oral etretinate therapy are adequately treated with a moderate dosage of 0.4 to 0.75 mg/kg/day. Etretin differs from etretinate in having a much shorter elimination half-life of 2 to 3 days, in contrast to 80 to 100 days after long term administration of etretinate. Moreover, it has not been shown to increase serum cholesterol levels. However, its clinical efficacy is not yet clearly established. Among the arotinoids, arotinoid ethylester (Ro 13-6298) has revealed the best anti-psoriatic and anti-inflammatory effects at extremely low dose levels. Furthermore, no significant elevations of serum lipids have been observed. Taking its prolonged elimination half-life and its efficacy/side effect ratio into account, the drug is comparable to etretinate. The free arotinoid carboxylic acid (Ro 13-7410) is currently undergoing clinical investigation. Another arotinoid, the parent compound Ro 15-0778, has not demonstrated any convincing clinical efficacy in acne or psoriasis, but topical anti-inflammatory effects were evident in some models.(ABSTRACT TRUNCATED AT 400 WORDS)     

聚维酮碘的临床应用

聚维酮碘的临床应用胡兆勇屈安＊丛新德（山东省威海康达制药厂威海２６４２０７）聚维酮碘（ＰＶＰ－Ⅰ）是一种前体药物制剂，系由聚乙烯吡咯烷酮与碘结合形成的一种无定形复合物。与碘酊（或碘溶液）相比，具有性质稳定、水溶性好、无刺激性和挥发性、作用缓和持久、使...     

Lamotrigine. A review of its use in childhood epilepsy

Lamotrigine is an antiepileptic agent that blocks use-dependent voltage-sensitive sodium channels, thereby preventing excitatory neurotransmitter release. However, this mechanism does not explain the broad range of clinical efficacy of this agent. In noncomparative trials, adjunctive lamotrigine (< or = 15 mg/kg/day) improved seizure control in children and adolescents with various refractory seizure types, with about 29 to 90% of patients showing a > or = 50% reduction in seizure frequency after > or = 3 months' treatment. Lamotrigine was particularly effective in generalised seizures, especially absence seizures and those related to the Lennox-Gastaut syndrome. In one placebo-controlled study, 33% of children and young adults (aged 3 to 25 years) with refractory Lennox-Gastaut syndrome had a reduction in seizure frequency of > or = 50% after 16 weeks of adjunctive lamotrigine treatment, compared with 16% of placebo recipients (p = 0.01). Significant reductions in seizure frequency when compared with placebo were also observed in patients with refractory generalised and partial seizures. The use of lamotrigine has also been associated with beneficial effects on cognition and behaviour. Adverse events associated with lamotrigine are primarily neurological, gastrointestinal and dermatological and are typically mild or moderate and transient with the exception of a potentially serious rash. Maculopapular or erythematous skin rash occurred in approximately 12% of paediatric patients (aged < 16 years) treated with lamotrigine and was the most common reason for treatment discontinuation. More severe forms of rash, including Stevens-Johnson syndrome, occasionally occurred, with a 3-fold higher incidence in children (approximately 1%) than adults (approximately 0.3%). However, lamotrigine treatment in paediatric trials was generally given at higher initial doses and faster dose escalations than recently revised recommendations. These factors, as well as concomitant use of valproic acid (valproate sodium), are associated with an increased risk of rash. CONCLUSION: Although published clinical evidence is still limited in paediatric populations, lamotrigine is an effective and generally well tolerated broad-spectrum agent for adjunctive treatment of refractory seizures in children, most notably in those with Lennox-Gastaut syndrome. Results of direct comparisons with other antiepileptic agents are needed to determine more clearly the place of lamotrigine, particularly relative to newer agents, in the treatment of childhood epilepsy. The potential for serious rash in recipients of lamotrigine should also be kept in mind. Nonetheless, lamotrigine is a welcome addition to the available treatments for refractory childhood epilepsy, particularly Lennox-Gastaut syndrome.     

Mirtazapine. A pharmacoeconomic review of its use in depression

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). The antidepressant efficacy of mirtazapine has been established in randomised, double-blind comparative studies. Mirtazapine has generally shown similar efficacy to other antidepressants. There is evidence for a faster onset of action with mirtazapine than with the selective serotonin (5-hydroxytryptamine; 5-HT) re-uptake inhibitors (SSRIs) on the basis of mean depression rating scale scores. Data from a long term (mean 240 days) clinical trial that was subsequently used in pharmacoeconomic analyses showed that mirtazapine was associated with significantly higher sustained remission rates and rates of discontinuation because of improvement than amitriptyline and placebo. Although differences were not statistically significant, mirtazapine had higher response rates at 6 weeks than the SSRI fluoxetine in an analysis that was also used as the basis of pharmacoeconomic studies. Mirtazapine improved quality of life to a similar extent to fluoxetine, citalopram and paroxetine in unpublished studies of 6 and 8 weeks' duration. Pooled analyses suggest that mirtazapine may be associated with greater improvement than fluoxetine and citalopram in quality of life after 2 and 4 weeks, although confirmation is required. In a decision analytical model of approximately 6 months' duration, mirtazapine was associated with a higher proportion of successfully treated patients and lower total direct costs than amitriptyline. The direct cost per successfully treated patient with mirtazapine was lower than that with amitriptyline by 33,112 Austrian schillings (S; year of costing not stated), 24,212 French francs (FF; 1995/1996 values), 13,851 Swedish kronor (SEK; 1997 values) and 553 Pounds (1997/1998 values) in Austrian, French, Swedish and UK analyses, respectively. Compared with fluoxetine, mirtazapine was associated with higher per-patient costs in all 4 countries but a higher proportion of successfully treated patients. Mirtazapine was more cost effective than fluoxetine: the direct cost per successfully treated patient was lower by S32,046 in Austria, FF25,914 in France, SEK9796 in Sweden and 327 Pounds in the UK. The additional cost of mirtazapine versus fluoxetine for each additional successfully treated patient at 6 months was S11,732, SEK17,229, 750 Pounds and FF3342 in the Austrian, Swedish, UK and French analyses, respectively. Mirtazapine was generally associated with lower indirect costs (for lost productivity of employed patients) than amitriptyline and similar indirect costs to fluoxetine in the analyses. CONCLUSIONS: Available data suggest that mirtazapine is a cost-effective alternative to amitriptyline and fluoxetine for the treatment of depression. Mirtazapine also has similar effects to SSRIs on quality of life with possibly a shorter time to onset of action, although published trial results are required to confirm these preliminary data.     

Risedronate: a review of its pharmacological properties and clinical use in resorptive bone disease

Risedronate is a novel orally administered pyridinyl bisphosphonate indicated for the prevention or treatment of postmenopausal and glucocorticoid-induced osteoporosis and Paget's disease. The drug reduces bone turnover and decreases resorption chiefly through osteoclastic effects, with no undesirable effects on cortical porosity or thickness or on cancellous bone volume. Four randomised, double-blind trials have been carried out in 4873 patients with postmenopausal osteoporosis. In 2 of these studies, the primary end-point of vertebral fracture incidence was reduced by risedronate 5mg once daily by up to 65 and 49% relative to placebo after 1 and 3 years, respectively. Across all 4 trials, risedronate improved lumbar spine, femoral neck and femoral trochanter bone mineral density (BMD) statistically significantly relative to placebo. The drug also prevented bone loss in a study in 383 women with recent menopause, and reduced the risk of hip fracture in elderly women with confirmed osteoporosis in a trial involving a total of 9331 patients. Risedronate 5 mg/day plus estrogen has been shown to be superior to estrogen alone in a 12-month double-blind study in 524 women with at least 1-year's history of menopause. Two randomised, double-blind and placebo-controlled 12-month studies in a total of 518 patients have shown risedronate 5 mg/day to prevent or reverse bone loss in patients receiving glucocorticoid therapy. Risedronate 30 mg/day was associated with statistically significant reductions in mean serum levels of alkaline phosphatase (ALP) in noncomparative studies in patients with Paget's disease. ALP normalisation rates ranged from 53.8 to 65% across two 84-day treatment cycles in 2 of these trials in 180 patients. In a randomised, double-blind study in 123 patients, risedronate 30 mg/day for 2 months evoked significantly greater serum ALP responses than etidronate 400 mg/day for 6 months. The overall tolerability profile of risedronate was similar to that of placebo in clinical studies, with no evidence of acute-phase reactions or mineralisation defects, or excess incidence of upper GI lesions, in patients receiving the drug. CONCLUSIONS: Risedronate is an effective and well tolerated novel bisphosphonate that is suitable for first-line therapy in Paget's disease. The rapid and sustained reductions in vertebral fracture incidence and BMD changes seen in patients with postmenopausal and glucocorticoid-induced osteoporosis indicate the drug to be a valuable treatment option with first-line potential, particularly in patients for whom hormonal therapy is inappropriate. The effects of the drug on hip fracture incidence in elderly women with confirmed osteoporosis point to a particular role in older patients, or those with more advanced disease.     

A review of pramipexole and its clinical utility in Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder characterised by selective loss of dopaminergic neurones in the substantia nigra and resulting in progressive disability. Therapy has focused on replacing depleted dopamine (DA) via supplementation with levodopa or DA agonists. Pramipexole (Mirapex), Pharmacia Corp.) has recently been approved for the treatment of PD. Evidence from preclinical studies and clinical trials have proven the effectiveness of this agent in ameliorating the symptoms of PD. There is also non-human evidence that pramipexole may be neuroprotective and could therefore possibly slow disease progression; however, this has yet to be proven in humans. The use of pramipexole may be limited by its side effect profile compared to standard therapies and its relatively higher cost compared to levodopa. Despite these concerns, pramipexole does have a role in the treatment of PD in all stages of the illness and may arguably be the treatment of choice in early disease. In addition to its use in PD, pramipexole has shown some utility in the treatment of restless legs syndrome (RLS), depression and schizophrenia.     

Nabilone. A preliminary review of its pharmacological properties and therapeutic use

Nabilone is a new orally active cannabinoid for the treatment of severe gastrointestinal toxicity associated with cancer chemotherapy. The pharmacological profile of nabilone suggests that it acts primarily by preventing emesis controlled by the medulla oblongata, although its secondary mild anxiolytic activity may contribute to the overall efficacy. Nabilone 2mg twice daily starting 12 hours prior to, and continued for the duration of, chemotherapy produces significant reduction in the severity and duration of nausea and the frequency of vomiting in about 50 to 70% of patients with severe symptoms refractory to conventional therapy. Nabilone has proven to be more effective in controlling symptoms and preferred by more patients than prochlorperazine 10mg 2 to 4 times daily in a limited number of studies, despite a higher incidence of side effects. Comparative trials against other new antiemetic agents, such as high dose metoclopramide, and use of nabilone in combination with other antiemetics remain to be undertaken. The incidence of side effects is high with nabilone; drowsiness, dizziness and/or vertigo occur in 60 to 70% of patients, but rarely lead to drug withdrawal, although more troublesome effects, such as postural hypotension, ataxia, vision disturbance and toxic psychoses, may cause discontinuation of therapy. Thus, nabilone offers an effective alternative to the treatment options available in a difficult therapeutic area - those patients with severe gastrointestinal side effects from cancer chemotherapy who are refractory to conventional therapy.