ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

With the increased spread of chloroquine-resistantPlasmodium falciparummalaria and mounting evidence of lack of efficacy and toxicity of alternative drugs, it has become extremely difficult to propose simple, widely applicable and uniformly acceptable recommendations for malaria chemoprophylaxis.With regard to specific drugs, it is clear that because of its toxicity amodiaquine should no longer be used for chemoprophylaxis, and that pyrimethamine/sulfadoxine should, for the most part, be used only as a presumptive therapy. The pyrimethamine/dapsone combination is promising, but data on its efficacy are limited. Although proguanil (chloroguanide) is recommended by several sources because of its safety, disturbing reports of chemoprophylaxis failure in Africa and a well-documented lack of efficacy in South East Asia would suggest that its usefulness may be limited. However, a recent study has documented the efficacy of a proguanil-sulphonamide combination in Thailand, an area of high grade chloroquine resistance. Although long term studies of drug safety are not yet available, doxycycline and mefloquine appear to be the drugs of choice in areas whereP. falciparumshows multidrug resistance.Regardless of the drug regimen recommended for chemoprophylaxis, travellers must be informed that no present-day antimalarial agent guarantees protection against malaria.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Based on published reports of controlled double-blind studies, the efficacy of &bgr;-receptor blockers and calcium antagonists in the prophylactic treatment of migraine is reviewed. Taking into consideration problems in trial design and evaluation of the effects of treatment, and the amount of documentation, it may be concluded that propranolol, metoprolol, timolol, nadolol and atenolol have been shown to reduce the frequency of migraine attacks in patients with common as well as classical migraine. The effect on duration and intensity of migraine attacks is less clear. Treatment effect is generally seen within 4 weeks, but seems to increase with time. Nonselective &bgr;-receptor blockers as well as drugs selective for &bgr;1-receptors may be effective, and their efficacy is comparable to that of other active antimigraine drugs. Available studies do not exclude the fact that &bgr;-receptor blockers with partial agonist activity (intrinsic sympathomimetic activity) have an effect, but suggest that their efficacy is inferior to that of blockers lacking this property.Among the calcium antagonists tested for prophylactic effect in migraine, the effects of verapamil, nifedipine and diltiazem seem promising, but available documentation does not allow any definitive statements of efficacy to be made, particularly not for nifedipine and diltiazem. The ability of flunarizine to reduce the frequency of migraine attacks in patients with common and classical migraine is well documented; its effect on attack duration and intensity is less well established. The response rate is similar to that for &bgr;-receptor blockers, and to that, for example, for pizotifen (pizotyline). Nimodipine also appears to reduce the frequency of migraine attacks, but the efficacy of this drug, compared with other alternatives, remains to be definitely established.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Patients with elevated serum cholesterol concentrations, particularly men, should be treated to lessen their chance of subsequent morbidity from coronary heart disease. Reduction of elevated triglyceride levels is more contentious, but is justified in severely affected individuals. The levels requiring treatment can only be judged by consideration of the overall clinical setting, including patient age and sex, the presence of other risk factors and the particular lipoprotein abnormality. In general, relative youth, male sex, a low level of high density lipoprotein (HDL) cholesterol and a strong family history of coronary heart disease will favour vigorous therapy. The possibility that hyperlipoproteinaemia is secondary to some other metabolic disorder should be considered, particularly in regard to elevated triglyceride levels.Appropriate dietary counselling plays a central role in the clinical management of the hyperlipoproteinaemias. If diet is unsuccessful in controlling lipid levels consideration should be given to the use of pharmacological agents. For isolated hypercholesterolaemia, appropriate choices include bile acid sequestering resins, nicotinic acid, fibric acid derivatives, HMG CoA reductase inhibition and probucol. Severely affected individuals may require combination therapy or the use of nondietary, nonpharmacological methods (e.g. plasmapheresis) for cholesterol reduction. For patients with predominantly elevated triglyceride levels fibric acid derivatives, nicotinic acid (niacin) and marine oils should be considered.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

General considerations in planning therapy of heart failure include identification of the cause, rapidity of onset, and the age of the patient. Neonates and young infants with acute onset heart failure frequently develop acidaemia, respiratory compromise or failure, and metabolic derangements such as hypoglycaemia, hypocalcaemia or hypomagnesaemia. These complications require early recognition and urgent therapy.The diagnosis of heart failure in neonates with ductal dependent congenital cardiac lesions (such as coarctation of the aorta, hypoplastic left heart syndrome or pulmonary valve atresia) allows the early institution of alprostadil (prostaglandin E1) therapy to maintain patency of the ductus arteriosus, which stabilises these infants before surgical therapy.Classic therapy for infants with heart failure due to a large left-to-right shunt consists of salt restriction, diuretics and digoxin. If this treatment is inadequate an angiotensin converting enzyme (ACE) inhibitor (e.g. captopril) is added to therapy. The question then arises whether captopril and diuretics should be the initial therapy and digoxin added if this treatment fails.Acute heart failure may occur in the immediate postoperative period after cardiac surgery or may complicate acute overwhelming infections. Therapy consists of volume loading, vasodilator or inotropic agents. Heart failure due to various forms of chronic dilated cardiomyopathy usually responds to treatment with salt restriction, diuretics, digoxin and captopril. Acute deterioration requires treatment with vasodilators and/or inotropic agents.Heart failure in fetuses may occur from sustained supraventricular tachyarrhythmias, and may respond to treatment of the mother with antiarrhythmic agents such as digoxin or procainamide.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Recent innovative research into the physiology and pharmacology of erection and the introduction of intracavernous injection of vasoactive agents have revolutionised our approach to the diagnosis and treatment of impotence. A thorough understanding of the rationale, indications, precautions and potential complications of intracavernous self-injection is essential for successful management.The commonly used drugs for injection are papaverine, either alone or in combination with phentolamine, and alprostadil (prostaglandin E1). The major adverse effects include priapism, prolonged erection, and fibrosis of the erectile tissue. With the proper technique and appropriate dosage, this is a safe, minimally invasive, and highly effective treatment.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisThe gonadotrophin releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH); gonadorelin] agonist buserelin is a promising new agent in the treatment of a variety of disorders in gynaecology and andrology, paediatrics and oncology, While a single dose of buserelin stimulates the release of pituitary gonadotrophins, multiple doses produce reversible pituitary desensitisation, and this specific blockade of gonadotrophin support to the gonads provides the basis for the drug's efficacy in conditions dependent on sex hormone secretion. Thus, buserelin provides comparable efficacy to orchidectomy or high dose estrogens in the treatment of hormone-sensitive prostate cancer and exhibits a lower incidence of adverse effects. During the early phase of treatment it may be particularly useful in combination with antiandrogens. Buserelin also appears promising in hormone-sensitive premenopausal breast cancer. Extensive studies have proven the value of buserelin in endometriosis, where it produces a transient remission with gradual recurrence of the disease on cessation of treatment. Surgical intervention is necessary in severe disease after buserelin-induced involution of the lesions. In patients with uterine leiomyoma, preliminary data suggest that buserelin may be beneficial in rendering surgery more conservative by reducing fibroid size, although it appears unlikely to preclude surgical intervention.The use of buserelin to induce a state of reversible hypogonadotrophism before administration of exogenous gonadotrophins is a promising strategy in the treatment of infertility associated with polycystic ovary syndrome and other conditions of infertility with underlying ovarian dysfunction; such a strategy also clearly enhances the efficiency ofin vitrofertilisation programmes. Initial studies suggest its potential usefulness as a female contraceptive when administered intermittently in conjunction with a progestogen. Buserelin represents a first-line treatment of central precocious puberty. In endometriosis the adverse effect profile of buserelin is generally favourable, with hypoestrogenic effects such as hot flushes and vaginal dryness, and decreased libido, predominating. There is no apparent detrimental effect on lipid metabolism. The potential for adverse hypoestrogenic effects on bone mineral content with long term administration remains to be clarified.Thus, the GnRH agonist buserelin represents an advance in the treatment of a variety of gynaecological and andrological as well as paediatric and oncological conditions, infertility and other sex-hormone dependent conditions, with a low incidence of adverse treatment effects.Pharmacodynamic StudiesBuserelin is a synthetic analogue of GnRH which is an agonist at pituitary GnRH receptors. When administered as a single dose, buserelin stimulates pituitary gonadotrophin release, whereas multiple doses result in dose-dependent depletion of gonadotrophins.Peak serum luteinising hormone (LH) and follicle-stimulating hormone (FSH) responses to a single dose of buserelin administered intranasally 6 to 12 days after the midluteal phase in healthy women were observed at 4 and 6 hours, respectively, all levels returning to baseline at 24 hours. Estradiol and progesterone are temporarily increased 10 hours after a dose. Thereafter as gonadotrophin response is blocked, levels of both steroids begin to decrease. At doses of 500&mgr;g or more, significant decreases in sex steroid levels and a shortened luteal phase were noted. When given in the early luteal phase, buserelin can induce a deficient luteal phase, while administration in the mid-luteal phase induces luteolysis, leading to early menses. Postovulatory administration does not cause luteolysis in normal women and buserelin has no abortifacient activity in humans. Subcutaneous buserelin 5&mgr;g daily starting from days 1 to 3 of the cycle resulted in inhibition of ovulation in healthy women, with decreased pituitary responsiveness preventing the preovulatory gonadotrophin surge; a further study indicated a clear dose response to intranasally administered buserelin.On daily administration of subcutaneous or intranasal buserelin ovulation is inhibited in normally menstruating women by mechanisms related to suppression of pulsatile LH secretion, and to a reduction in the pituitary LH content which occurs after treatment for 10 to 14 days. Several studies report consistent responses of initially increased LH, followed by sustained decreases in gonadotrophin secretion, reduced sex steroid levels, a state of anovulation, and rapid resumption of normal cycles after discontinuation, following buserelin dosage regimens including 10&mgr;g intramuscularly from days 1 to 4, 2.5 to 10&mgr;g subcutaneously daily, and 800 to 1200&mgr;g intranasally daily, Estrogen provocation in women undergoing long term therapy with intranasal buserelin 400 to 600&mgr;g daily produced no gonadotrophin responses, indicating blockade of the effects of endogenous GnRH at pituitary level, which may partially explain the inhibition of ovulation observed with buserelin.Several studies have noted the effects of low dosages of buserelin on the healthy endometrium. One group has reported an inactive or weakly proliferative endometrium, with no hyperplasia present, after intranasal buserelin 200 to 400&mgr;g daily for 2 to 17 months, However, a second group has detected moderate or marked proliferation in about 45% of 92 biopsies from 56 women treated similarly for 1 to 6 months. High dosages of buserelin leading to estrogen suppression usually result in atrophy of the endometrium.In healthy men, intravenous doses of buserelin 1. 2.5. 5 and 10&mgr;g resulted in significant LH but not FSH release at the 2 lower doses, while with the 2 higher doses both LH and FSH increased, and remained elevated for 8 to 10 hours. There was a late stimulating effect on testosterone and estradiol secretion, but no effect on growth hormone, thyroid-stimulating hormone (TSH), prolactin or cortisol. Intravenous buserelin 5&mgr;g has been reported to be equipotent, in terms of serum LH release, with intravenous GnRH 25&mgr;g or subcutaneous GnRH 100&mgr;g. In a series of experiments, single doses of buserelin produced transient increases in serum levels of 17-hydroxyprogesterone, 17&bgr;-estradiol and testosterone, followed by a loss of diurnal cyclicity and decreased steroid levels, which returned to normal after several days. Chronic subcutaneous infusion of buserelin to 2 groups of men receiving mean dosages of 118 and 230 &mgr;g/day, respectively, resulted in initial rises in LH. FSH and testosterone followed by decreases, which occurred more rapidly in the high dose group. Despite pituitary desensitisation and impaired testicular function, azoospermia did not develop. Similar results were obtained in a further study of long term buserelin treatment, with prolactin levels observed to be unaffected.Buserelin binds to GnRH receptors with greater affinity and a more prolonged duration of binding than synthetic GnRH. In homogenates of human luteal tissue, binding of buserelin was determined to be of much lower activity than in pituitary membranes, and to vary depending on the stage of the luteal phase in which samples were taken.The effect of buserelin on the estrogen-sensitive MCF-7 human breast cancer cell line has been investigated in several studies. Buserelin has inhibited cell proliferationin vitro, and in the athymic nude mouse inhibited tumour formation and produced a 30% regression of mature tumours in intact but not ovariectomised animals. Buserelin has also inhibited growth of the prolactin-sensitive T-47-D breast cancer cell line, indicating an inhibition of the prolactin effectin vitro. In male rats with the Dunning R3327 prostatic tumour, buserelin decreased the weights of ventral prostate, seminal vesicles and testes, and tumour. Combination with the antiandrogen nilutamide (anandron) produced further weight reduction and almost complete arrest of tumour growth. Animal studies indicate that antibody formation to buserelin does not occur after long term continuous administration.Teratogenicity studies in mice and rabbits have revealed no abnormalities in the off-spring of either species after subcutaneous administration of buserelin. No evidence of carcinogenicity was apparent in a 2-year study in rats. Chronic toxicity studies over 26 weeks revealed dose-dependent decreases in testis weight in male rats and dogs, and increased corpora lutea in female rats.Pharmacokinetic PropertiesIn healthy volunteers single intranasal doses of buserelin 150, 300 and 450&mgr;g, and subcutaneous injection of 5&mgr;g resulted in mean maximum plasma concentrations of 66, 117, 111 and 120 ng/L, respectively, 39 to 58 minutes after administration. A single intravenous injection of 500&mgr;g in women with endometriosis produced a mean maximum plasma concentration of 101 &mgr;g/L, while concentrations of 41.7 and 1.39 &mgr;g/L followed repeated administration of 1000&mgr;g subcutaneously and 300&mgr;g intranasally. In girls with precocious puberty, maximal subcutaneous infusion of 400&mgr;g daily produced an average buserelin serum concentration of 1.15 &mgr;g/L. Systemic availability after intranasal instillation was 2.5 or 3.3% depending on the formulation studied, and absorption was not influenced by experimental rhinitis. 29 and 57 days after subcutaneous implantation of buserelin 3.3 and 6.6mg in a biodegradable poly (d,L-lactide-co-glycolide) polymer, serum concentrations were 0.38 and 0.43 &mgr;g/L, respectively.In women with endometriosis who were administered buserelin 500&mgr;g intravenously, serum analysis showed intact buserelin was the main constituent (90% after 10 minutes, 74% after 2 hours and 52% after 6 hours). The main serum metabolite is the inactive buserelin (5-9) pentapeptide. In urine collected 6 to 24 hours after buserelin treatment, intact buserelin and buserelin (5-9) pentapeptide accounted for 67 and 32% of the recovered dose, respectively. The mean percentage of a dose recovered in urine as immunoreactive buserelin within 24 hours after administration was 16.7%, 12.6% and 0.17% after intravenous, subcutaneous (5&mgr;g) and intranasal (300 or 450&mgr;g) administration, respectively. Mean elimination half-life has generally been about 72 to 80 minutes regardless of route of administration.Therapeutic TrialsSeveral noncomparative trials of buserelin in endometriosis have been conducted, and consistent results have been obtained; buserelin has usually been administered intranasally at a dose of 300&mgr;g 3 times daily for 6 months. During treatment there was a progressive disappearance of dysmenorrhoea, pelvic pain and dyspareunia. Repeat laparoscopy at the end of treatment showed a 70 to 80% reduction in active endometrial implant scores. Within a 6-month post-treatment follow-up, symptoms recurred in some patients, mostly those with initially severe disease. Planned pregnancy occurred in 10 to 54% of previously infertile women during the 6-month follow-up, and in 14 to 62% over a longer period. Trials comparing buserelin 900 or 1200 &mgr;g/day intranasally or 200 &mgr;g/day subcutaneously with oral danazol 400 to 800 mg/day have demonstrated similar relief of symptoms and percentage decrease in implant score. However, adverse effects with buserelin caused by estrogen deprivation have generally been better tolerated than the anabolic and androgenic effects due to danazol. Pregnancy rates were similar following treatment with either drug, but there was an opposite effect on serum lipids. Whereas danazol increased low density lipoprotein (LDL)- and decreased high density lipoprotein (HDL)-cholesterol, buserelin caused either no change or an increase in the HDL fraction. Buserelin is now established as an alternative to danazol in the medical treatment of endometriosis. Buserelin produces a transient remission with gradual recurrence after stopping treatment, and surgical intervention is necessary in severe endometriosis. In less severe disease repeated treatment courses with intranasal buserelin can be undertaken.In the treatment of uterine leiomyoma buserelin 200 to 600&mgr;g daily has been administered subcutaneously by conventional injection, infusion using a minipump, by intranasal administration of 900 to 1200&mgr;g daily and by subcutaneous implantation of a depot preparation containing 6.6mg. By either route buserelin reduced uterine volume by an average of 30 to 49%, fibroid volume by 50 to 71% and uterine cavity by 35%. The major symptoms of menorrhagia, pelvic pain and dysmenorrhoea have consistently been relieved in most patients during treatment. Fibroids often return to pretreatment size within 6 months of stopping buserelin. There is some evidence that buserelin treatment could facilitate surgery by reducing vascularity of the tumour.Limited investigation of buserelin treatment of polycystic ovary syndrome has been conducted. LH and estrogen levels have been markedly reduced, as well as androstenedione and testosterone levels. Some clinical results are available. Induction of reversible hypogonadotrophism with buserelin plus timed ovarian stimulation with exogenous gonadotrophins appears a promising approach to treatment of infertility associated with polycystic ovary syndrome.Buserelin is used extensively in the treatment of infertility, suppressing pituitary function and premature luteinsation during regimens based on administration of exogenous gonadotrophins.Comparative studies have shown that the addition of buserelin to FSH/human chorionic gonadotrophin (HCG) regimens improves oocyte retrieval, fertilisation and pregnancy rates, while direct and indirect comparisons of buserelin/menotropin (human menopausal gonadotrophin)/HCG and clomifene/menotropin/HCG have demonstrated improved oocyte retrieval and embryo transfer, and in some studies, higher pregnancy rates with the buserelin-containing regimens. It is now apparent that pituitary suppression by buserelin followed by gonadotrophin stimulation enhances the success ofin vitrofertilisation programmes.In the treatment of central precocious puberty (mostly in girls), intranasal buserelin 400 to 1800&mgr;g daily and subcutaneous administration of 6 to 30 &mgr;g/kg daily has often resulted in a reduction in growth rate, decreased progression of bone maturation, arrest of breast development or decreased breast size and cessation of menses in girls, and arrest of testicular and penile development or a reduction of testicular volume in boys. Although some less favourable results have been reported, buserelin should be considered a first-line treatment in children with central precocious puberty, with therapy being individualised according to clinical response.Treatment of previously untreated patients with prostate cancer stage C and D with subcutaneous or intranasal buserelin is associated with good response rates (in the order of 50 to 95%) according to National Prostatic Cancer Project criteria. Prospective and retrospective comparisons of buserelin 1200&mgr;g intranasally (preceded by subcutaneous injections for 3 to 7 days) with diethylstilbestrol (stilboestrol) 3mg daily or orchidectomy have revealed similar complete and partial response rates and no statistically significant differences in progression-free survival, although buserelin was better tolerated. In order to obviate the ‘flare’ of disease which occurs as a result of initially raised plasma testosterone levels with buserelin, and in an attempt to improve overall success, some studies have used buserelin in combination with an antiandrogen. Although disease ‘flare’ has not occurred during combined drug treatment, an advantage for buserelin plus antiandrogen over conventional treatment, with respect to median survival or extent of progression over 12 months, has not been demonstrated. Good results have been obtained in initial studies of subcutaneous implants of buserelin in the treatment of prostate cancer.To date published clinical evidence on the use of buserelin in premenopausal women with advanced breast cancer is limited. High initial subcutaneous doses of up to 3mg daily, followed by subcutaneous or intranasal maintenance therapy, have elicited objective responses (complete plus partial) in 39 to 42% of patients. One study, which used buserelin 1200 &mgr;g/day intranasally in conjunction with antineoplastic therapy, considered the response rate of 82% to be comparable with that historically achieved with surgical castration and antineoplastic therapy. Initial studies of buserelin in postmenopausal breast cancer have produced low response rates.Intranasal buserelin has been administered daily continuously to healthy women at doses of 200 to 1200 &mgr;g/day for up to more than 2 years to assess its potential as a contraceptive agent. In these studies ovulation was inhibited in a total of around 96% of cycles. Regular bleeding was induced by intermittent administration and combination with a progestogen in the second half of the cycle; the most appropriate regimen was buserelin 200&mgr;g twice daily or 300 &mgr;g once daily for 21 days, in conjunction with a progestogen on days 16 to 22 of the menstrual cycle. Postpartum contraception in breast-feeding women was studied in a few women using continuous daily intranasal administration of buserelin 300 &mgr;g/day.Adverse EffectsAdverse effects of buserelin treatment of endometriosis and uterine leiomyoma were due mainly to estrogen deprivation and included hot flushes (78%), vaginal dryness (19%) and decreased libido (12%). Other effects include headache, nausea, premenstrual syndrome, breast pain, and depression and emotional lability. Withdrawal of treatment due to adverse effects was necessary in about 5% of patients. Loss of bone mineral density, particularly in trabecular bone, occurs after 6 months' continuous daily administration of buserelin 900 or 1200&mgr;g intranasally, but this loss is regained 6 months after stopping treatment. When used as a ‘cyclic’ contraceptive agent, mild local irritation of the nasal mucosa and headaches are the main adverse effects. In the treatment of prostate cancer hot flushes and loss of libido and potency occur in many patients.Dosage and AdministrationBuserelin is normally administered intranasally or subcutaneously, at a variety of dosages depending on the condition treated. These are in general up to 1500 &mgr;g/day in divided doses with subcutaneous administration, and normally 900 or 1200 &mgr;g/day with intranasal administration. A continuous subcutaneous infusion regimen and depot formulation have also been employed.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisEtoposide is a podophyllotoxin derivative which delays progression of the cell cycle through the late S or early G2phase.In vitroantitumour activity is dose and administration schedule-dependent and synergy, notably with cisplatin, has been demonstrated. The clinical profile of etoposide has been well characterised in small and non-small cell lung cancer and testicular cancer. The combination of etoposide and cisplatin has demonstrated substantial antineoplastic activity in the treatment of small cell lung cancer, testicular cancer, and promising activity in non-small cell lung cancer and acute myelogenous leukaemia. Etoposide and cisplatin provide a useful combination that is particularly beneficial as salvage chemotherapy in a variety of tumours resistant to other combination regimens. The therapeutic potential of the synergistic combination of etoposide with cisplatin or carboplatin continues to be explored and the optimum dosage schedule remains to be determined. Etoposide in combination with other cytotoxic drugs has shown substantial activity in the treatment of small cell lung cancer and testicular cancer, both seminomatous and nonseminomatous, as well as in the treatment of adult and childhood acute nonlymphoblastic leukaemia. Hodgkin's and non-Hodgkin's lymphoma, some childhood solid tumours and trophoblastic disease. The adverse effect profile of etoposide is well characterised with myelosuppression, predominantly leucopenia, as the only major dose-limiting toxicity.Thus, etoposide, administered as an intravenous infusion or orally, in conjunction with other cytotoxic drugs produces favourable remission rates as a first-line agent and as salvage chemotherapy in a variety of cancers, especially small cell lung and testicular cancer.Pharmacodynamic PropertiesThe cytotoxicity of etoposidein vitrois both concentration- and time-dependent. Various animal and human carcinoma cell lines are sensitive to etoposide, and synergism has been demonstrated in tumours in mice with doxorubicin (adriamycin), cisplatin, 4-hydroxyperoxycyclophosphamide and vindesine. The sensitivity of cell lines to etoposide is also increased by verapamil.In vivoetoposide is particularly active against Lewis lung carcinoma and leukaemias in mice. The activity of etoposide is increased with multiple dosing and with certain frequencies of administration. Etoposide is thus dose schedule-dependent, with treatment every third or fourth day being optimal against murine leukaemias.Certain metabolites of etoposide may be cytotoxic, probably from oxidation-reduction with a dehydrogenase enzyme. The mechanism by which etoposide or its metabolites, or both, causes DNA damage is probably from stabilisation of a DNA topoisomerase II complex such that the strand-rejoining activity of the enzyme is impaired. The number of single- and double-strand breaks is proportional to the concentration and length of incubation with etoposide, with more double-strand breaks occurring at higher concentrations and longer incubation times. Crossresistance has been demonstrated between other cytotoxic drugs that share a similar action on DNA topoisomerase II.Etoposide delays progression of the cell cycle through late S or early G2phases, and is without effect on tubulin assembly or accumulation of cells during metaphase. Inhibition of thymidine uptake as well as that of uridine, adenosine and guanosine, into isolated tumour cells is both concentration- and time-dependent. Recovery of granulocyte-macrophage colony-forming units (CFU-GM), an indicator of the haematopoietic reconstitution capacity of purged bone marrowin vitro, is also concentration- and time-dependent following addition of etoposide, Various leukaemia and lymphoma cell lines are sensitive to etoposide at concentrations which allow recovery of CFU-GM within 1 to 2 weeks.Other mechanisms, however, are involved in resistance and crossresistance such as reduced drug uptake, and deactivation of etoposide or its metabolites.Pharmacokinetic PropertiesThe plasma decay of etoposide usually fits a 2-compartment model. The peak plasma concentration of etoposide and area under the concentrationversustime curve (AUC) show an approximately linear relation to increasing intravenous dose. After intravenous infusion of etoposide 100 mg/m2over a period of 30 to 60 minutes, a plasma concentration of 21 mg/L was observed within 5 minutes of completing administration. No evidence of drug accumulation is seen with daily infusions of etoposide 100 mg/m2. After oral administration peak plasma concentrations are achieved within 2 to 3 hours, but a linear relation of peak plasma concentration and AUC to increasing oral dose has not been clearly established although there is some evidence that such a dose-proportional relationship does exist up to 250 mg/m2but not at higher dosages. The mean bioavailability of orally administered etoposide is approximately 50%.The median apparent volume of distribution after a single intravenous dose and at steady-state is 9.7 and 8.3 L/m2, respectively; slightly higher values are found after oral administration. Penetration of etoposide into cerebrospinal fluid has been variable but generally low, while distribution into other tissues is poorly documented. Etoposide is highly bound to plasma albumin (approximately 94%).Renal clearance accounts for up to 40% of the administered dose, and the principal metabolites recovered from urine are the hydroxy acid and the glucuronide. Biliary excretion plays a minor role in the elimination of etoposide. The median terminal phase elimination half-life of etoposide from studies in healthy adults evaluated using 2-compartment models is 5.6 hours after intravenous administration; similar half-lives are reported for the oral route.Renal impairment decreases the plasma clearance and increases volume of distribution and elimination half-life of etoposide; a good correlation of plasma clearance with creatininc clearance is observed. Hepatic impairment appears to have less influence on etoposide pharmacokinetics. Prior administration of cisplatin increased etoposide AUC. Apart from this, disposition of etoposide is not altered by concomitant administration of a number of other cytotoxic agents often used in chemotherapy regiments, although the Tween 80 component of the intravenous formulation of etoposide may alter the pharmacokinetics of doxorubicin.Therapeutic TrialsEtoposide alone, administered intravenously, has demonstrated single agent cytotoxic activity with a response rate of at least 20% in the treatment of small cell lung cancer, nonseminomatous testicular cancer, non-Hodgkin's lymphoma, acute nonlymphocytic leukaemia and neuroblastoma. Consequently, etoposide has been added to standard chemotherapy regimens shown to be active in these tumours in an attempt to improve response rates. The dose-schedule dependency of etoposide was shownin vitroagainst various human malignant cell lines and animal models of leukaemia, and the various schedules used in early studies were prompted by this awareness. Recent studies of etoposide as primary treatment of patients with previously untreated small cell lung cancer have clearly demonstrated that efficacy of etoposide is related to administration schedule, although the optimum schedule remains to be established.Etoposide has proved to be a very active cytotoxic agent in combination with cisplatin and the synergy of the 2 drugs is clinically relevant in small cell lung cancer, germ cell tumours and various other malignancies. Etoposide has been studied extensively in the initial treatment of small cell lung cancer. Nonrandomised studies of intravenous etoposide-containing regimens for primary treatment of limited disease small cell lung cancer showed the most active combinations to be etoposide with cyclosphosphamide, doxorubicin and vincristine (CAV) or etoposide/cisplatin alternating with CAV or ifosfamide. In limited disease, complete responses (CR) were achieved in up to 76% of patients and overall responses [CR + partial responses (PR)] in 88 to 93%. In extensive disease these combination regimens achieved complete responses in 27% and 34% of patients, and overall responses in 65% and 78%, respectively, Randomised studies in patients with small cell lung cancer also show intravenous etoposide and cisplatin is an effective combination either alone or alternating with CAV. Etoposide also effectively substitutes for doxorubicin in the CAV regimen, and to improve response and, in one study, survival, when added to this regimen (CAVE) in patients with extensive disease. Used in intensification or consolidation therapy, etoposide in combination with cisplatin has demonstrated activity in patients with limited small cell lung cancer. Generally, lower overall response rates (27 to 75%) are observed with etoposide and cisplatin as salvage chemotherapy in relapsed or resistant small cell lung cancer than when used in previously untreated patients.In non-small cell lung cancer, etoposide and cisplatin induced complete remission in 2 to 16% and partial remission in a further 24 to 53% of patients, with a median survival of 11 to 15 months. Addition of other drugs to this combination did not improve the response and survival rates. These results have been confirmed in randomised studies where complete remission in 1 to 11% and an overall response rate of 10 to 38% has been achieved with etoposide/cisplatin, or with etoposide combined with cyclophosphamide and/or doxorubicin (ACE).Etoposide in combination with other cytotoxic drugs has also shown considerable activity in the treatment of testicular cancer. Complete remission rates achieved with cisplatin, bleomycin and vincristine were similar to those with cisplatin, bleomycin and etoposide in patients with seminoma (74vs68%), embryonal carcinoma (88vs93%) and teratocarcinoma (70vs78%), with a 2-year survival rate of approximately 80% in both treatment groups. Etoposide and cisplatin produced a 93% CR rate in seminomatous testicular cancer, and addition of bleomycin to this combination achieved 83 to 100% complete remission rate in nonseminomatous patients. As salvage chemotherapy, etoposide as monotherapy or in combination is of variable activity inducing CR in 11 to 71% of patients.In acute nonlymphoblastic leukaemia (ANLL), etoposide in combination with standard therapy of daunorubicin and cytarabine (cytosine arabinoside) improved remission duration and disease-free survival compared with doxorubicin and cytarabine. As salvage chemotherapy, etoposide has shown promising activity in combination with doxorubicin and cytarabine, and with amsacrine or azacitidine, or both, in children or adults with ANLL.In Hodgkin's disease, etoposide as first-line chemotherapy in combination with standard chemotherapy consisting of vincristine, chlorambucil and prednisolone, and etoposide alternated with these drugs plus procarbazine, was active as induction (77% CR). As salvage therapy, when combined with cyclophosphamide and carmustine, or combined with vinblastine, doxorubicin and prednisone and alternated with chlorambucil, vincristine, procarbazine and prednisolone, etoposide was effective (CR) in 23 to 67% of patients. In non-Hodgkin's lymphoma, induction with etoposide as monotherapy or in combination with CAV as first line therapy achieved response rates of 56 to 100%, while as salvage chemotherapy etoposide-containing regimens induced complete response in up to 29% of patients with refractory or relapsed lymphomas.Etoposide in combination with doxorubicin as salvage therapy, induced complete remission in about 10% and overall response in less than 40% of patients with advanced breast cancer. In patients with advanced refractory ovarian adenocarcinoma, etoposide exhibited minimal activity when used intravenously, although better results were achieved when given intraperitoneally. In trophoblastic disease, etoposide as monotherapy or in combination produced complete remission in all of the small number of patients studied. The combination of etoposide and cisplatin has also demonstrated promising activity in small numbers of children with solid tumours including advanced neuroblastoma, advanced germ cell tumours and soft tissue sarcomas, both as induction or salvage therapy.Adverse EffectsThe dose-limiting toxicity of etoposide alone is myelosuppression, predominantly leucopenia. The leucocyte nadir occurs 8 to 10 days after treatment, with recovery usually by day 21. Thrombocytopenia is less common and recovery is evident by 21 to 28 days. Stomatitis is generally reported only occasionally at usual therapeutic dosages, although it is dose-limiting with high-dose regimens, diarrhoea is infrequent, and bronchospasm has occurred rarely. Alopecia, however, is frequent and even universal with some etoposide regimens. Neurotoxicity has seldom been reported, but the possible potentiation of vincristine-induced neurotoxicity by etoposide needs further investigation. Bolus intravenous injection has been associated with hypotension; thus it is recommended that etoposide be administered over a period of 30 to 60 minutes.Dosage and AdministrationThe recommended intravenous dose of etoposide is an infusion of 50 to 100 mg/m2over 30 to 60 minutes on 5 consecutive days, or 100 mg/m2on days 1, 3 and 5. For oral administration, twice the relevant intravenous dose should be given. The dosage should be repeated every 21 or 28 days, but should be adjusted on the basis of both nadir and pretreatment blood counts.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisWhen used to treat patients with Parkinson's disease pergolide acts at dopamine receptors in the corpus striatum to improve locomotor activity, reducing the tremor, gait disturbances, bradykinesia or akinesia and rigidity experienced by such patients. Treatment with pergolide often allows substantial reductions in concomitant levodopa dosage, and occasionally levodopa can be completely replaced by pergolide therapy in short term use. Pergolide has a long duration of action, thus reducing the wearing-off and end-of-dose phenomena frequently seen with long term levodopa therapy, suppressing fluctuations in levodopa response, and increasing total ‘on’ time, Despite a lack of well controlled studies comparing this drug with other dopamine agonist agents, pergolide appears to result in adverse effects and anti-Parkinson responses similar to those of bromocriptine and lisuride.Thus, pergolide would appear to be at least as useful as other dopamine agonists such as bromocriptine or lisuride for the management of patients with Parkinson's disease when administered in combination with levodopa. Future research should be directed towards establishing which patients are most likely to benefit from pergolide therapy, and clarifying the relative efficacy and safety of the anti-Parkinsonian drugs available to the clinician. If pergolide does provide clinical benefit when substituted for levodopa-adjunct drugs that are producing less than optimal control, this will be an advantage in a disease area which at present has few therapeutic options.Pharmacological and Pharmacokinetic PropertiesPergolide is a dopamine receptor agonist which acts at both D1and D2receptors in the nigrostriatal regions of the brain where it affects locomotor activity, exemplified by circling behaviour in lesioned rats. It stimulates adenylate cyclase activity via D1receptors in the corpus striatum in a manner similar to dopamine and has minor &agr;2-stimulating activity which may cause a vasopressor response at high doses.Pergolide initially increases serum corticosterone levels in rats, possibly via central dopamine receptors, but tolerance to this effect develops after as little as 5 days of continuous administration. Pergolide 0.0075 mg/kg reduces blood pressure in normotensive dogs by 17% although 0.03 mg/kg caused an initial 25% increase in pressure; larger reductions of blood pressure occur in hypertensive animals. Similarly, heart rate, blood pressure and plasma dopamine, norepinephrine (noradrenaline) and lactic acid levels are reduced at rest and/or during exercise when pergolide 0.05 mg/day is administered to healthy volunteers. The hypotensive effects of the drug are dose proportionate and tend to diminish with continued treatment of patients. Pergolide appears devoid of effects on glucose metabolism in either animals or patients with Parkinson's disease. Furthermore, pergolide reduces intraocular pressure in healthy volunteers and causes significant reductions in prolactin levels at rest and during exercise. In animal models of Parkinson's disease, pergolide has induced stereotypic behaviour in rats and guinea-pigs by direct stimulation of striatal dopamine receptors. In rats, pre- and postsynaptic dopamine receptors may play a part in decreases and increases in locomotor activity, respectively. Increased locomotion is accompanied by stereotypy and could be sustained for long periods, Effects of the drug on prolactin levels appear to last 24 hours or more and although its duration of activity in Parkinson's disease is shorter, it still exceeds that of levodopa. The onset of action against Parkinson's disease symptoms in 8 patients occurred in 80 minutes and effects lasted a mean of 5.5 hours.Pergolide is rapidly absorbed from the gastrointestinal tract, reaching peak plasma concentrations within 1 to 2 hours. Complete elimination of a single radiolabelled dose from the body is achieved within 4 to 5 days, with a mean elimination half-life of 27 hours. Pergolide is 90% bound to plasma proteins. 55% of a radioactive dose is eliminated via the kidneys, 5% via the lungs and the remainder by the liver. Pergolide appears to concentrate in dopamine-rich areas of the brain such as the corpus striatum.Therapeutic TrialsIn short term noncomparative studies (less than 3 months) in Parkinson's disease, administration of pergolide frequently results in reduced levodopa requirements (complete withdrawal has occasionally been possible), reduced disability and decreased ‘off’ time in patients who no longer respond reliably to bromocriptine and/or levodopa. Placebo-controlled studies demonstrate that mean daily dosages of pergolide 2.5 to 4.6mg result in a 33 to 78% reduction in the requirement for levodopa while improving the duration and extent of response to the latter and reducing the total duration of ‘off’ time by 1.4 to 2.8 hours per day. However, switching from pergolide to placebo results in deterioration of symptoms in all patients. Sleep disturbances tend to be suppressed by pergolide in some patients with Parkinson's disease.Long term (6 months to 7 years) studies of pergolide show that both disability and levodopa dosage tend to be reduced and mobility improved, with the most persistent responses seen in patients who achieved the greatest initial benefit. Peak clinical improvement appears to occur after 2 to 12 months and results may diminish slowly there-after, although some patients continue to respond for up to 7 years without increasing pergolide or levodopa dosages. Previous response to bromocriptine is not predictive of likely outcome with pergolide since, in a small study involving 25 patients, 50% of individuals who did not improve on bromocriptine gained significant benefit when switched to pergolide.When compared with bromocriptine in a double-blind crossover study, pergolide induced similar improvements in gait, tremor, rigidity and dyskinesia, with slightly more patients preferring to continue pergolide at the end of 14 to 20 weeks of study. If efficacy with bromocriptine or pergolide decreases, the substitution of pergolide for bromocriptine appears more likely to be clinically beneficial than the switch to bromocriptine after pergolide therapy. Comparisons of pergolide with lergotrile, lisuride, and mesulergine have usually been of one-way crossover design, and while similar responses have been seen in a small number of patients, some studies show marginally more favourable responses to pergolide. However, given the limited nature of these clinical trials any conclusions regarding relative efficacy must remain tentative.De novomonotherapy with pergolide has shown limited promise. However, use of pergolide combined with levodopa in the early therapy of Parkinson's disease may yet prove to delay the onset of levodopa related adverse effects.Adverse EffectsOverall, pergolide appears to be relatively well-tolerated in patients with Parkinson's disease, although adverse effects have resulted in discontinuation of therapy in 27% of patients in clinical trials. The most frequently reported adverse effects during pergolide treatment have been dyskinesias, nausea, dizziness, hallucinations, rhinitis and other CNS or gastrointestinal symptoms.ECG changes and other cardiac effects have been noted infrequently, but close observation may be required in patients with prior heart disease. Occasional first-dose postural hypotension makes gradual introduction and increments of pergolide dosage advisable. Rarely, abrupt withdrawal of the drug has resulted in confusion or hallucinations, so if pergolide therapy needs to be stopped it is prudent to discontinue the drug gradually if at all possible. In general, long term use of the drug does not adversely alter neuropsychological parameters.Dosage and AdministrationWhen used to treat Parkinson's disease, slow incremental increases in oral dosage of pergolide are recommended, beginning with 0.05 mg/day and increasing by 0.05 to 0.15 mg/day every third day for 2 weeks, then by 0.25 mg/day every third day until an optimum dosage is reached. Reductions in concomitant levodopa dosages may be required. Dosages of 2 to 4 mg/day are most common, administered in 3 to 4 divided oral doses. The effects of dosages above 5 mg/day have not been fully examined.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS