Biomedical subjects

D Faulds

Publications and source records attributed to D Faulds.

At least 55 records · Page 3Linked to original sources

PubMed1997

Zalcitabine. An update of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of HIV infection.

Zalcitabine is a dideoxynucleoside antiretroviral agent that is phosphorylated to the active metabolite 2',3'-dideoxycytidine 5'-triphosphate (ddCTP) within both uninfected and HIV-infected cells. At therapeutic concentrations, ddCTP inhibits HIV replication by inhibiting the enzyme reverse transcriptase and terminating elongation of the proviral DNA chain. The results of 3 large pivotal trials comparing zidovudine monotherapy with combination therapy have now clearly established that zalcitabine plus zidovudine combination with an improvement in viral load and CD4+ cell count compared with zidovudine monotherapy. More recently, clinical end-point and surrogate marker data have established the efficacy of zalcitabine in combination with the protease inhibitor saquinavir in zidovudine-experienced patients. Other studies have demonstrated the utility of zalcitabine in combination with ritonavir and the nucleoside analogue lamivudine. Importantly, early use of zalcitabine in the treatment sequence does not appear to limit the therapeutic efficacy of subsequent therapy with other nucleoside analogues such as lamivudine. Peripheral neuropathy is the most frequent dose-limiting adverse effect associated with zalcitabine therapy and is generally reversible on discontinuation of treatment. Stomatitis and mouth ulcers may occur frequently with zalcitabine therapy but tend to resolve with continuing treatment. Haematological toxicity, which is a common adverse effect associated with zidovudine, is reported infrequently with zalcitabine. Overall, combination therapy with zalcitabine plus zidovudine or saquinavir has been shown to have a tolerability profile comparable to that of either agent alone, although treatment with zidovudine plus zalcitabine was associated with a significant increase in the incidence of haematological toxicity compared with zidovudine monotherapy in one study. Therefore, current data suggest that zalcitabine is a useful antiretroviral agent for inclusion as a component of initial double combination therapy with zidovudine or as part of triple combination therapy including zidovudine plus a protease inhibitor in the management of patients with HIV infection.

Adult↗

PubMed1997

Micronised fenofibrate: a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia.

Micronised fenofibrate is a new formulation of the fibric acid derivative fenofibrate. It is indicated for the treatment of patients with type IIa, IIb, III or IV dyslipidaemia who have failed to respond to dietary control or other nonpharmacological interventions. Micronised fenofibrate has improved absorption characteristics compared with the standard preparation, allowing a lower daily dosage and once-daily administration. The lipid-modifying profile of micronised fenofibrate is characterised by a decrease in low density lipoprotein (LDL) and total cholesterol levels, a marked reduction in elevated plasma triglyceride levels and an increase in high density lipoprotein (HDL) cholesterol levels. Consistent with the standard formulation, which is administered as 300mg daily in divided doses, the micronised preparation has demonstrated efficacy in the treatment of type IIa, IIb and IV primary dyslipidaemias but at a lower daily dosage of 200mg once daily. Because of its significant triglyceride-lowering effect, micronised fenofibrate appears to be of greatest benefit in patients with hypertriglyceridaemia (with or without hypercholesterolaemia), including patients with type 2 (non-insulin-dependent) diabetes mellitus and dyslipidaemia. In the comparisons available, micronised fenofibrate 200mg once daily was of similar efficacy to or less effective than the HMG-CoA reductase inhibitors simvastatin 20mg daily and pravastatin 20mg daily at reducing LDL and total cholesterol levels. However micronised fenofibrate produced greater improvements in triglyceride and, generally, HDL cholesterol levels than both simvastatin and pravastatin. Data on the long term tolerability of micronised fenofibrate are limited. However, data from a large short term (3-month) study have indicated that gastrointestinal disorders are the most frequent adverse events associated with therapy. Elevations in serum transaminase and creatine phosphokinase levels have been reported rarely with micronised fenofibrate. In conclusion, available data suggest that the more convenient lower once-daily dosage of micronisedfeno fibrate retains the beneficial lipid-modifying effects of the standard formulation. Further studies are required to determine whether the lipid changes achieved with micronised fenofibrate result in a reduction in cardiovascular morbidity and mortality.

Cardiovascular Diseases↗

PubMed1996

Ebastine. a review of its pharmacological properties and clinical efficacy in the treatment of allergic disorders.

Ebastine is a long-acting nonsedating second generation histamine H1 receptor antagonist which binds preferentially to peripheral H1 receptors in vivo. It has shown antihistamine and antiallergic activity in healthy volunteers and patients with allergies, and protected against histamine-induced bronchoconstriction in patients with asthma. Significant symptom improvement is observed in patients with seasonal or perennial allergic rhinitis or chronic idiopathic urticaria following administration of ebastine 10 mg/day, or 20 mg/day in severe rhinitis. In clinical trials, the efficacy of ebastine 10 or 20 mg/day was generally similar to standard dosages of terfenadine, cetirizine, astemizole and loratadine in patients with seasonal allergic rhinitis, astemizole, terfenadine and ketotifen in patients with chronic idiopathic urticaria, and ketotifen, terfenadine, chlorpheniramine and mequitazine in patients with perennial allergic rhinitis. The most frequent adverse events reported during ebastine therapy are drowsiness, headache and dry mouth, the incidence being similar to that reported in placebo recipients. Serious adverse cardiac events, observed on rare occasions with some other histamine H1 receptor antagonists, have not been reported with ebastine, and there has been no evidence of QTc interval prolongation related to ebastine therapy. Thus, once-daily ebastine offers an effective and well-tolerated alternative to other second generation antihistamines in current use for the first-line treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria.

Animals↗

PubMed1996

Stavudine: a review of its pharmacodynamic and pharmacokinetic properties and clinical potential in HIV infection.

Stavudine is a nucleoside analogue which undergoes intracellular phosphorylation to its active metabolite, stavudine-5'-triphosphate. At clinically relevant concentrations, the active metabolite restricts HIV replication by inhibiting the inclusion of thymidine-5'-triphosphate into proviral DNA by HIV reverse transcriptase, and/or by causing DNA chain termination. Viral resistance to stavudine does not commonly develop during treatment. Where it has developed, up to a 12-fold increase in resistance has been observed in clinical isolates from patients treated with stavudine for long periods. Stavudine 40mg twice daily and zidovudine 200mg 3 times daily were compared in 822 patients at various stages of HIV infection who had previously received long term zidovudine therapy. Stavudine was superior for both primary and surrogate end-points including clinical progression, treatment failure, increase in CD4+ cell counts and bodyweight gain. In a larger study, stavudine 40mg twice daily provided greater benefit than stavudine 20mg twice daily in terms of weight gain, haematological findings and the number of hospitalisations in 11 784 patients intolerant of or resistant to, zidovudine and didanosine. Peripheral neuropathy is the major dose-limiting adverse event associated with stavudine therapy and occurred more frequently with stavudine than zidovudine. However, haematological adverse events were observed less frequently with stavudine than with zidovudine. Thus, stavudine is effective in alleviating signs and symptoms of HIV infection in patients intolerant of or no longer responding to, zidovudine or didanosine. It is also more effective than zidovudine in slowing disease progression in patients previously treated with zidovudine for long periods. The results of studies which will reveal the role of stavudine therapy in untreated patients and in combination with other anti-HIV agents are awaited with interest.

Animals↗

PubMed1996

Saquinavir. A review of its pharmacology and clinical potential in the management of HIV infection.

Saquinavir is a peptide derivative which inhibits the HIV protease enzyme, preventing post-translational processing of viral polyproteins. It was the first agent of its class to become available for the treatment of HIV infection. Well controlled studies have assessed the effects of saquinavir, when used alone or in combination with reverse transcriptase inhibitors, in patients with advanced HIV infection. Analysis of CD4+ cell counts and measures of viral load in the ACTG 229 study suggest that triple therapy with saquinavir, zidovudine and zalcitabine is more effective than double therapy with saquinavir plus zidovudine or zidovudine plus zalcitabine in patients who have previously received long term treatment with zidovudine. Similar assessments from a small study in previously untreated patients suggest that double therapy with saquinavir plus zidovudine is more effective than monotherapy with either agent. Combination therapy with saquinavir and zalcitabine significantly reduced the time to the first AIDS-defining event or death, and the time to death, compared with zalcitabine alone, according to data from a large, long term study (NV 14256) in patients with advanced HIV infection who had previously received zidovudine. Saquinavir is generally well tolerated, either as monotherapy or in combination with reverse transcriptase inhibitors; no change in tolerability profile was reported when saquinavir was added to treatment with nucleoside analogues. In vitro and clinical studies have documented the emergence of saquinavir-resistant HIV strains. Although the possible impact of resistance on the clinical efficacy of saquinavir has yet to be fully characterised, genotypic and phenotypic resistance appear to develop slowly during treatment with saquinavir, and the drug does not appear to have a significant effect on the incidence of mutations associated with cross-resistance to other protease inhibitors. Thus, laboratory and clinical results suggest that saquinavir in combination with reverse transcriptase inhibitors is effective in the treatment of advanced HIV infection. Initial data on the effects of saquinavir on disease progression and mortality are promising, and the apparent absence of mutations conferring cross-resistance to other protease inhibitors is a potentially valuable clinical feature. Additional data on disease progression, mortality and viral resistance, together with information on relative efficacy (in comparison with other protease inhibitors), will need to be assessed before the clinical value of saquinavir can be fully determined. Nevertheless, saquinavir represents a valuable new pharmacological option for the treatment of HIV infection and is likely to be a useful component of combined therapy with reverse transcriptase inhibitors and/or other protease inhibitors.

Anti-Bacterial Agents↗

PubMed1996

Nisoldipine coat-core. A review of its pharmacology and therapeutic efficacy in hypertension.

Nisoldipine coat-core is a long-acting formulation of the dihydropyridine calcium antagonist (calcium channel blocker) nisoldipine, suitable for once daily administration in the treatment of patients with hypertension. In clinical trials in patients with mild to moderate hypertension, nisoldipine coat-core has efficacy and tolerability similar to those of other calcium antagonists, and antihypertensive efficacy equivalent to that of agents from various other drug classes including beta-blockers, thiazide diuretics and ACE inhibitors. Unlike beta-blockers and thiazide diuretics, calcium antagonists (including nisoldipine coat-core) are not associated with clinically significant adverse metabolic effects on the serum lipid profile or glycaemic control. Nevertheless, published guidelines or consensus papers on the pharmacological management of patients with hypertension recommend calcium antagonists (and other drugs) as "alternative first-line' agents, while beta-blockers and diuretics are generally considered to be first-line therapy because of demonstrated benefits in terms of cardiovascular morbidity and mortality in this clinical setting. Nisoldipine coat-core maintains consistent plasma drug concentrations and antihypertensive effects throughout the 24-hour dosage interval, thereby attenuating intermittent reflex increases in sympathetic activity. This pharmacological profile may have important clinical implications; recent retrospective data suggest an association between moderate to high dosages of short-acting dihydropyridine calcium antagonists and adverse cardiovascular events, although this has yet to be confirmed in large prospective trials. In addition, the high degree of vasoselectivity of nisoldipine minimises negative inotropic effects which may be observed with less selective agents such as nifedipine. Nisoldipine coat-core is, therefore, a useful alternative to other antihypertensive agents in the management of patients with hypertension, providing consistent antihypertensive efficacy and good tolerability with once daily administration.

Antihypertensive Agents↗

PubMed1996

Ropivacaine. A review of its pharmacology and therapeutic use in regional anaesthesia.

The enantiomerically pure (S-enantiomer) amide local anaesthetic drug ropivacaine blocked nerve fibres responsible for transmission of pain (A delta and C fibres) more completely than those that control motor function (A beta fibres) in in vitro studies. The drug shares the biphasic vascular effects common to the amide local anaesthetic drug class. In vitro studies indicate that ropivacaine is less cardiotoxic than equimolar concentrations of bupivacaine. Apart from one trial in women undergoing hysterectomy, clinical studies that compared the efficacy of different doses of epidurally administered ropivacaine in patients undergoing various surgical procedures did not reveal any consistent dose-related differences with respect to sensory blockade. However, motor blockade did become more intense as the dose of ropivacaine increased. Overall, direct comparisons show that epidural ropivacaine is less potent than epidural bupivacaine when the 2 drugs are administered at the same concentration. However, this difference is less marked in terms of sensory blockade than motor blockade. The greater degree of separation between motor and sensory blockade seen with ropivacaine relative to bupivacaine is more apparent at the lower end of the dosage scale. Nevertheless, higher doses of ropivacaine than bupivacaine are generally required to elicit equivalent anaesthetic effects. Ropivacaine has been shown to induce successful brachial plexus anaesthesia when given at a concentration of 5 mg/ml, but not 2.5 mg/ml, and was as effective as bupivacaine in comparative studies in this indication. Limited data indicate that continuous epidural infusion of ropivacaine postoperatively reduces postsurgical pain in a dose-related manner. Morphine consumption was also reduced. Higher doses of ropivacaine were significantly more effective than placebo. Similarly, ropivacaine controlled postsurgical pain when infiltrated directly into surgical wound sites (i.e. would infiltration) and was as effective as bupivacaine, and more effective than placebo, in this regard. Adverse events associated with epidurally administered ropivacaine include hypotension, nausea, bradycardia, transient paraesthesia, back pain, urinary retention and fever. The drug appears to have an adverse event profile similar to that of bupivacaine. In animal studies, overdoses of ropivacaine were better tolerated than overdoses of bupivacaine but not lidocaine (lignocaine). Human volunteers tolerated a higher intravenous dosage of ropivacaine than bupivacaine before developing initial signs of toxicity. Thus, ropivacaine, according to animal data, is less cardiotoxic than bupivacaine. Based on available clinical data, ropivacaine appears to be as effective and well tolerated as bupivacaine when equianalgesic doses are compared. The greater degree of separation between motor and sensory blockade seen withropivacaine relative to bupivacaine at lower concentrations (approximately 5 mg/ml) will be advantageous in certain applications.

Amides↗

PubMed1996

Ritonavir.

Ritonavir is a protease inhibitor with an HIV-1 resistance profile similar to that of indinavir, but different from that of saquinavir. Ritonavir has good oral bioavailability, and may increase the bioavailability of other protease inhibitors including saquinavir, nelfinavir, indinavir and VX-478. Clinically significant drug interactions have been predicted between ritonavir and a range of medications. In patients with HIV-1 infection, ritonavir markedly reduced viral load within 2 weeks of treatment onset and also increased CD4+ cell counts. In a large placebo-controlled trial in patients with advanced HIV infection, the addition of ritonavir to existing therapy reduced the risk of mortality by 43% and clinical progression by 56% after 6.1 months. Triple therapy with ritonavir plus zidovudine, in combination with lamivudine or zalcitabine, reduced HIV viraemia to below detectable levels in most patients with acute, and some patients with advanced HIV infection in 2 small trials. Early results suggest combination therapy with ritonavir and saquinavir increases CD4+ cell counts and decreases HIV RNA levels in patients with previously untreated HIV infection.

Administration, Oral↗

PubMed1996

Dexfenfluramine. An updated review of its therapeutic use in the management of obesity.

Dexfenfluramine increases serotonergic activity by stimulating serotonin (5-hydroxytryptamine; 5-HT) release into brain synapses, inhibiting its reuptake into presynaptic neurons and by directly stimulating postsynaptic serotonin receptors. On the basis of the serotonin hypothesis of appetite control, these actions would be expected to reduce appetite and, consequently, bodyweight. Studies conducted in animals and in overweight patients with and without associated disorders have confirmed the weight-reducing efficacy and good tolerability of dexfenfluramine. In 3-month clinical studies in obese patients, weight reductions with dexfenfluramine 15mg twice daily combined with dietary support were significantly higher than those achieved with placebo and similar to those with ephedrine/caffeine 20/20mg 3 times daily, sibutramine 10mg once daily and fluoxetine 60 mg/day. Furthermore, dexfenfluramine recipients with non-insulin-dependent diabetes mellitus, hyperlipidaemia or hypertension consistently show improvements in glycaemic control, blood lipid profiles and blood pressure. 12-month trial results indicate that most weight loss occurs in the initial 6 months and appears to be maintained for a further 6 months. Weight regain after withdrawal of treatment in 12-month studies demonstrates that dexfenfluramine is effective in maintaining a stable bodyweight at a lower level than placebo and in limiting food intake over this time period. Commonly reported adverse events with dexfenfluramine include diarrhoea, tiredness, dry mouth and somnolence; these symptoms are generally mild and transient. Approximately 7 and 10% of dexfenfluramine recipients in short and long term studies withdrew because of adverse events. Dexfenfluramine was better tolerated than ephedrine/caffeine and fluoxetine in short term studies. Obesity is a chronic condition that is accompanied by a number of metabolic complications. It is a significant health problem in developed countries, and as a major risk factor for many chronic diseases, including diabetes and cardiovascular disease, the economic burden of this condition is considerable. As with other chronic conditions, there is a role for pharmacological intervention in patients with severe obesity. However, drugs should be considered as only one component of a weight-control programme, since additional lifestyle modification is required to maintain weight loss. The promising data on the long term efficacy and tolerability of dexfenfluramine as well as its favourable effects on risk factors associated with obesity requires confirmation in long term studies. In the meantime, dexfenfluramine should be considered a valuable adjunct to a reduced-calorie diet in the management of severe obesity, particularly in patients with associated disorders and those unsuccessful with conventional weight loss measures. Available data support the use of the drug for up to 1 year to maintain weight loss and thus dexfenfluramine should be considered for long term administration.

Animals↗

PubMed1996

Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections.

Valaciclovir, the L-valyl ester of aciclovir (acyclovir), is an oral prodrug that undergoes rapid and extensive first-pass metabolism to yield aciclovir and the essential amino acid L-valine. Aciclovir, the active antiviral component of valaciclovir, shows good in vitro activity against the herpesviruses herpes simplex virus (HSV)-1, HSV-2 and varicella zoster virus. The bioavailability of aciclovir from oral valaciclovir is considerably greater than that achieved after oral aciclovir administration. Thus, valaciclovir delivers therapeutic aciclovir concentrations when administered in a less frequent oral dosage regimen than is required for aciclovir. Valaciclovir is an effective treatment for herpes zoster in immunocompetent adults. In a large comparative study that included patients > or = 50 years of age, valaciclovir (1000mg 3 times daily for 7 or 14 days) and oral aciclovir (800mg 5 times daily) were equally effective in achieving resolution of cutaneous zoster lesions. Importantly, valaciclovir was significantly more effective than aciclovir in reducing the duration of zoster-associated pain. Preliminary results of several studies indicate that valaciclovir (500 to 1000mg twice daily for 5 to 10 days) is as effective as aciclovir (200mg 5 times a day for 5 to 10 days) in the treatment of genital herpes. In patients with first or recurrent episodes of genital herpes, valaciclovir reduced the duration of viral shedding, hastened lesion healing and decreased lesion-associated pain. Valaciclovir was also effective in suppressing recurrent episodes of genital herpes and significantly prolonged the time to a recurrent episode of infection compared with placebo. Valaciclovir is a well tolerated drug; in herpes zoster and HSV studies its tolerability profile was similar to that of aciclovir or placebo. Valaciclovir represents and advance in antiherpes drug therapy and is a useful treatment option for patients with herpes zoster or genital herpes. It is at least as effective as aciclovir and is administered in a more convenient oral dosage regimen. Thus, valaciclovir may ultimately succeed aciclovir as a first-line treatment for genital herpes or herpes zoster.

Acyclovir↗

PubMed1996

Filgrastim. A reappraisal of pharmacoeconomic considerations in the prophylaxis and treatment of chemotherapy-induced neutropenia.

Neutropenia is a frequent and often dose-limiting complication of chemotherapy and is associated with considerable patient morbidity and mortality. Standard treatment in patients who become febrile includes hospitalisation and empirical antibiotic therapy. Filgrastim is a recombinant human granulocyte colony-stimulating factor (rHuG-CSF). It significantly decreases the incidence of febrile neutropenia in patients receiving standard-dose chemotherapy, and shortens the duration of febrile neutropenia in patients undergoing autologous bone marrow transplantation (BMT) or peripheral blood progenitor cell (PBPC) infusion after myeloablative chemotherapy regimens. These effects are usually associated with a decrease in hospitalisation and antibiotic requirements. The contribution of filgrastim therapy to beneficial effects on other clinically important end-points (e.g. quality of life, tumour relapse rate, and short and long term survival) remains to be accurately determined. Pharmacoeconomic data concerning the use of filgrastim as an adjunct to standard-dose chemotherapy are derived largely from the results of phase III trials. Cost analyses based on hospital charges suggest that the cost of providing filgrastim therapy can be fully recouped if the drug is used as primary prophylaxis in previously untreated patients, for whom the risk of developing febrile neutropenia is at least 40%. Reserving filgrastim for use in patients who have developed febrile neutropenia in a previous chemotherapy cycle may result in further cost savings. However, careful patient selection is required, since potential cost savings will vary depending upon the risk of hospitalisation in the absence of filgrastim treatment. Infusion of filgrastim-mobilised PBPCs is emerging as a preferred strategy in patients receiving myeloablative chemotherapy, and promising results have been obtained from cost analyses. From a pharmacoeconomic viewpoint, future research should be directed towards defining optimum dosage regimens and hence improving the cost-effective use of filgrastim. Data evaluating patient quality of life and treatment preferences would help define the cost utility of filgrastim therapy. In the meantime, available pharmacoeconomic data support the use of filgrastim as an adjunct to chemotherapy in selected clinical situations.

Antineoplastic Agents↗

PubMed1995

Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterase inhibitor.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that serves as a model for the human disease multiple sclerosis. We evaluated rolipram, a type IV phosphodiesterase inhibitor, for its efficacy in preventing EAE in the common marmoset Callithrix jacchus. In a blinded experimental design, clinical signs of EAE developed within 17 days of immunization with human white matter in two placebo-treated animals but in none of three monkeys that received rolipram (10 mg/kg s.c. every other day) beginning 1 week after immunization. In controls, signs of EAE were associated with development of cerebrospinal fluid pleocytosis and cerebral MRI abnormalities. In the treatment group, there was sustained protection from clinical EAE, transient cerebrospinal fluid pleocytosis in only one of three animals, no MRI abnormality, and marked reduction in histopathologic findings. Rolipram-treated and control animals equally developed circulating antibodies to myelin basic protein. Thus, inhibition of type IV phosphodiesterase, initiated after sensitization to central nervous system antigens, protected against autoimmune demyelinating disease.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1995

Members of the 70 kDa heat shock protein family specifically recognize sulfoglycolipids: role in gamete recognition and mycoplasma-related infertility.

We have previously shown that several mycoplasma species associated with infertility bind specifically to sulfated glycolipids isolated from the mammalian reproductive tract. We now show that a germ cell-specific sulfoglycolipid binding protein (SLIP 1), which is a potent inhibitor of sperm/egg binding in vitro, is immunologically related to the heat shock protein(Hsp) 70 family of stress proteins and that Hsps are surface antigens in male germ cells. Our present data demonstrate that several mycoplasma and mammalian Hsps share this glycolipid binding specificity in vitro, and suggest that surface Hsps can function as adhesins which mediate sulfoglycolipid recognition in infectious disease and normal reproductive physiology.

Animals↗

PubMed1995

Goserelin. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in prostate cancer.

Goserelin is a gonadotrophin-releasing hormone (GnRH) analogue which during long term administration reduces circulating levels of gonadotrophins (luteinising hormone and follicle stimulating hormone) and sex hormones. Goserelin is administered subcutaneously as a biodegradable depot formulation incorporating 3.6mg of the drug, which is released continuously over 4 weeks. In men with untreated advanced prostate cancer, monthly goserelin 3.6mg has been confirmed as similar in efficacy to surgical castration and diethylstilbestrol (stilboestrol) 3mg daily taken orally. Goserelin is better tolerated than diethylstilbestrol and appears to have a more favourable effect on quality of life than surgical castration. Treatment of prostate cancer with a combination of goserelin and an antiandrogen remains controversial as a result of inconsistent findings, despite extended data from a large trial which indicated an advantage for the combined regimen over surgical castration with respect to duration of time to progression and survival. Combination therapy also minimises the initial increase in signs and symptoms (disease flare) that occurs in up to 4% of patients at the beginning of treatment with a GnRH analogue. Surgical castration remains the treatment of choice in patients at risk of metastatic compression of the spinal cord or ureteric obstruction. However, goserelin is an effective alternative to surgery, or estrogen therapy, in men with previously untreated advanced prostate cancer. Goserelin seems to be preferred to surgery by the majority of patients given a choice of treatment, and importantly in a palliative care situation where there are no survival advantages for treatment alternatives, it appears to have a more beneficial effect on the quality of life than surgery.

Absorption↗

PubMed1995

Oral pilocarpine: a review of its pharmacological properties and clinical potential in xerostomia.

Pilocarpine is a cholinergic agonist which stimulates salivary secretion both in individuals with normal salivary gland function and in those with impaired salivary flow (xerostomia or oral dryness). A rapid increase in salivary flow rate is observed following oral pilocarpine administration and peak levels are maintained for at least 1 to 2 hours. Mean salivary flow rates after administration of pilocarpine are 2- to 10-fold higher than after placebo, and no evidence of tolerance to the pharmacological effects of the drug has been observed during prolonged administration for up to 5 months. The clinical efficacy of oral pilocarpine in relieving symptoms of xerostomia (resulting from radiation therapy to the head and neck region or salivary gland dysfunction), including oral dryness and difficulty in chewing, swallowing and speaking, has been demonstrated in double-blind placebo-controlled clinical trials. In these studies, pilocarpine 5 to 10mg 3 times daily increased salivary flow and improved symptoms of xerostomia in a significantly higher percentage of patients than did placebo (54 versus 25% in one study). Preliminary findings indicate that administration of pilocarpine during radiation therapy may reduce the severity of xerostomia; however, this requires further investigation. The majority of patients receiving oral pilocarpine therapy for xerostomia experience adverse events (most commonly sweating); however, these are generally mild and tolerable in nature. Thus, pilocarpine is an effective agent for the treatment of xerostomia, increasing salivary flow and reducing symptom severity to a significantly greater extent than placebo. Further clinical trials should evaluate the potential beneficial effects of pilocarpine on the incidence of dental caries and oral candidiasis during prolonged therapy, its prophylactic efficacy during radiation therapy and its efficacy relative to that of other salivary stimulants.

Controlled Clinical Trials as Topic↗

PubMed1995

Altretamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cancer chemotherapy.

Altretamine (hexamethylmelamine) is a cytotoxic antineoplastic agent which appears to require metabolic activation. Metabolic intermediates may act as alkylating agents; however, altretamine is not directly cross-resistant with classical alkylating agents. Objective response rates to orally administered altretamine as salvage therapy in patients with advanced ovarian cancer were 0 to 33%, with disease stabilisation in a further 8 to 78% of patients. Response rates appear to be higher in patients who have responded to previous alkylating agent or cisplatin-based therapy. There is some evidence that addition of altretamine to platinum-based combination regimens used for induction therapy of advanced ovarian cancer may improve long term survival, particularly in patients with limited residual disease. Although altretamine displays some activity in small cell lung cancer, it is unlikely to have any clinical role in the management of non-ovarian cancer. Altretamine appears to be relatively well tolerated, with gastrointestinal, neurological and haematological toxicities being the main dose-limiting adverse effects. However, assessment of accurate incidence rates for these effects is complicated by the use of altretamine with cisplatin. On the basis of the emerging body of clinical evidence, altretamine appears to have a limited role in the treatment of persistent or recurrent advanced ovarian cancer, primarily in patients who are potentially platinum sensitive yet intolerant of platinum analogues. Additionally, altretamine may be added to platinum-based regimens for induction therapy of advanced ovarian cancer. At the doses currently recommended, altretamine offers a reasonably well tolerated regimen that can be administered orally and is suitable for use on an outpatient basis.

Altretamine↗

PubMed1995

Sulfasalazine. A review of its pharmacological properties and therapeutic efficacy in the treatment of rheumatoid arthritis.

Sulfasalazine was first used for rheumatic polyarthritis in the 1940s and in the past 2 decades has become firmly established as a disease-modifying antirheumatic drug (DMARD). The drug is split by the action of bacterial azoreductases in the large intestine into sulfapyridine and mesalazine (mesalamine, 5-aminosalicylic acid), although whether the parent molecule or the sulfapyridine moiety, or both, is the active principle remains uncertain. Sulfasalazine is an effective treatment for rheumatoid arthritis (RA), producing improvements in disease parameters similar to those seen with penicillamine, hydroxychloroquine or oral or parenteral gold in comparative clinical trials. However, there are no direct comparisons of the drug with methotrexate. Most adverse events associated with sulfasalazine are minor and tend to occur within 3 months of starting therapy. A meta-analysis of studies investigating DMARD therapy, which included almost 5000 evaluable patients, concluded that sulfasalazine was close to methotrexate in terms of efficacy but was slightly less well tolerated. However, unlike sulfasalazine, many DMARDs may be unsuitable for women who are, or may become, pregnant because of their potential to cause teratogenic effects. Sulfasalazine may also offer a more rapid onset of action than other DMARDs and may slow down the radiological progression of RA. Combination therapy with other DMARDs, particularly methotrexate, appears more effective than single DMARD therapy. If the safety of these regimens is shown in large numbers of patients they are likely to become more widely used in the future. Sulfasalazine is a therapy of first choice in patients with RA and may be the DMARD of choice in women who are, or may become, pregnant.

Antirheumatic Agents↗

PubMed1995

Propofol. An update of its use in anaesthesia and conscious sedation.

Propofol is an intravenous sedative hypnotic agent which rapidly and reliably causes loss of consciousness. It is also associated with a quick and 'smooth' recovery, which distinguishes it from many of the more traditional anaesthetic regimens. Like other intravenous agents, propofol is both a cardiovascular and a respiratory depressant; however, the risk of these effects can be lessened by appropriate dosage adjustment or patient management. Anaphylaxis with propofol is rare. Propofol anaesthesia in day case surgery is consistently associated with a quicker early recovery than other intravenous agents and the more traditional anaesthetic regimens. Savings in time to discharge were more variable compared with these regimens, although propofol was commonly associated with less post-operative nausea and vomiting in this period. In the future, the relative benefits of propofol compared with the newer volatile agents (desflurane and sevoflurane) and propofol/volatile agent combinations need to be examined in this clinical setting. There is now clinical experience with propofol in major surgical procedures including cardiac and neurosurgery. Propofol has also been investigated as a sedative accompanying regional or local anaesthesia for diagnostic and therapeutic procedures, and in other clinical settings (ophthalmic surgery, cardioversion and electroconvulsive therapy). The unique antiemetic, antiepileptic and antipruritic effects of propofol may further broaden its appeal. As a result of its favourable recovery profile, propofol holds a central place in day case surgery anaesthesia. Accumulating clinical experience in cardiac and neurosurgery suggests that the full potential of propofol has yet to be realised.

Anesthetics↗