Anthony Markham

Valsartan. A review of its pharmacology and therapeutic use in essential hypertension.

Valsartan competitively and selectively inhibits the actions of angiotensin II at the AT1 receptor subtype which is responsible for most of the known effects of angiotensin II. In clinical trials in patients with mild to moderate essential hypertension valsartan was as effective as losartan, lisinopril, enalapril, amlodipine and hydrochlorothiazide. Addition of the latter reduced blood pressure in patients who did not respond sufficiently to valsartan monotherapy. Preliminary data also suggest valsartan may be effective in patients with severe essential hypertension. The drug was as effective as lisinopril as treatment for mild to moderate essential hypertension in patients with renal insufficiency and did not worsen renal function. Headache, dizziness and fatigue were the most common adverse events in placebo-controlled studies; the incidence of these adverse events was not significantly different between placebo and valsartan recipients. Compared with ACE inhibitors, valsartan was associated with a significantly lower incidence of dry cough. Thus, valsartan is an effective treatment for mild to moderate essential hypertension and may be particularly useful in patients who experience persistent cough during ACE inhibitor therapy.

Levobupivacaine : A review of its pharmacology and use as a local anaesthetic

UNLABELLED Based on findings that the cardiotoxicity infrequently observed with racemic bupivacaine shows enantioselectivity, i.e. it is more pronounced with the R(+)-enantiomer, the S(-)-enantiomer (levobupivacaine) has been developed for clinical use as a long acting local anaesthetic. The majority of in vitro, in vivo and human pharmacodynamic studies of nerve block indicate that levobupivacaine has similar potency to bupivacaine. However, levobupivacaine had a lower risk of cardiovascular and CNS toxicity than bupivacaine in animal studies. In human volunteers, levobupivacaine had less of a negative inotropic effect and, at intravenous doses >75 mg, produced less prolongation of the QTc interval than bupivacaine. Fewer changes indicative of CNS depression on EEG were evident with levobupivacaine. Levobupivacaine is long acting with a dose-dependent duration of anaesthesia. The onset of action is < or = 15 minutes with various anaesthetic techniques. In studies of surgical anaesthesia in adults, levobupivacaine provided sensory block for up to 9 hours after epidural administration of < or = 202.5 mg, 6.5 hours after intrathecal 15 mg, and 17 hours after brachial plexus block with 2 mg/kg. Randomised, double-blind clinical studies established that the anaesthetic and/or analgesic effects of levobupivacaine were largely similar to those of bupivacaine at the same dose. Sensory block tended to be longer with levobupivacaine than bupivacaine, amounting to a difference of 23 to 45 minutes with epidural administration and approximately 2 hours with peripheral nerve block. With epidural administration, levobupivacaine produced less prolonged motor block than sensory block. This differential was not seen with peripheral nerve block. Conditions satisfactory for surgery and good pain management were achieved by use of local infiltration or peribulbar administration of levobupivacaine. Levobupivacaine was generally as effective as bupivacaine for pain management during labour, and was effective for the management of postoperative pain, especially when combined with clonidine, morphine or fentanyl. The tolerability profiles of levobupivacaine and bupivacaine were very similar in clinical trials. No clinically significant ECG abnormalities or serious CNS events occurred with the doses used. The most common adverse event associated with levobupivacaine treatment was hypotension (31%). CONCLUSIONS Levobupivacaine is a long acting local anaesthetic with a clinical profile closely resembling that of bupivacaine. However, current preclinical safety and toxicity data show an advantage for levobupivacaine over bupivacaine. Clinical data comparing levobupivacaine with ropivacaine are needed before the role of the drug can be fully established. Excluding pharmacoeconomic considerations, levobupivacaine is an appropriate choice for use in place of bupivacaine.

Mycophenolate mofetil : a review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation

SynopsisMycophenolate mofetil is an ester prodrug of the active immunosuppressant mycophenolic acid. It is a noncompetitive, selective and reversible inhibitor of inosine monophosphate dehydrogenase, an important enzyme in the de novo synthesis of guanosine nucleotides in T and B lymphocytes. Mycophenolate mofetil and/or mycophenolic acid inhibit the proliferation of lymphocytes and the production of antibodies induced by a variety of mitogens and antigens. Mycophenolate mofetil is also active in several animal models of transplantation and has produced effects in animals that indicate that it may inhibit the chronic rejection process.Mycophenolate mofetil has been compared with azathioprine or placebo in 3 large, randomised, double-blind, multicentre trials as part of combination immu-nosuppression therapy with cyclosporin and corticosteroids. Compared with either placebo or azathioprine (1 to 2 mg/kg/day or 100 to 150 mg/day), mycophenolate mofetil 2 or 3 g/day was associated with a significantly lower proportion of patients experiencing acute rejection or treatment failure during the first 6 months after transplantation. Mycophenolate mofetil also tended to be associated with a lower proportion of patients who required a full course of antirejection therapy. However, the proportion of patients who died or who had graft loss was similar between all of the treatment groups.There are currently no data regarding the effects of mycophenolate mofetil on long term patient or graft survival, which are important clinical outcomes in assessing its place in the management of renal transplantation. Clinical trials are also needed to evaluate mycophenolate mofetil in specific patient populations (e.g. repeat renal transplant patients or highly sensitised patients), to determine its efficacy in alternative immunosuppressive protocols and to investigate its use in the transplantation of other solid organs.In summary, mycophenolate mofetil appears to be an attractive new agent in the prevention of graft rejection in renal transplant recipients that has shown superior efficacy to azathioprine. Although long term clinical outcome data are required, mycophenolate is a potentially important advance in transplant immunosuppression.Pharmacodynamic PropertiesMycophenolic acid, the active metabolite of mycophenolate mofetil, is a non-competitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). Inhibition of IMPDH blocks the de novo synthesis of guanosine nucleotides which are necessary substrates for DNA and RNA synthesis. Unlike other cell types which can use the salvage pathway, B and T lymphocytes are dependent upon the de novo pathway for the generation of guanosine.Data from in vitro studies indicate that mycophenolic acid and/or mycophenolate mofetil inhibit mixed lymphocyte responses and human peripheral blood lymphocyte proliferation induced by a variety of mitogens and antigens. Mycophenolic acid decreases intracellular pools of guanosine triphosphate (GTP) and deoxyguanosine triphosphate (dGTP) in mitogen-stimulated human peripheral blood monocytes or T lymphocytic cell lines but has no effect on GTP concentrations in human neutrophils.Mycophenolate mofetil has been shown to have efficacy in several animal models of transplantation (including cardiac, hepatic, pancreatic islet and renal). Mycophenolate mofetil was effective in preventing rejection or reversing ongoing rejection in rodent cardiac and canine renal allograft transplantation. However, the drug was only marginally effective in concordant and was ineffective in discordant cardiac xenograft transplantation.In the rat renal allograft model, mycophenolate mofetil effectively attenuated functional, morphological and immunohistological changes (significant reductions in proteinuria, glomerulosclerosis, arterial obliteration, macrophage and lymphocyte infiltration and expression of adhesion molecules and cytokines) associated with chronic rejection. The drug has also been shown to inhibit antibody production in rats and in humans. In rodent studies, mycophenolate mofetil was associated with the induction of donor-specific tolerance to grafted atrial tissue after cardiac allograft transplantation and to grafted thyroid tissue or injected spleen cells after pancreatic islet allograft transplantation.Pharmacokinetic PropertiesMycophenolate mofetil is well absorbed after oral administration and is rapidly converted to the active metabolite mycophenolic acid. The area under the plasma concentration-time curve (AUC) is generally proportional to dosage; however, there is some interpatient variation in values. The AUC and peak plasma concentration (Cmax) of mycophenolic acid are approximately 50% higher in stable renal transplant patients (>3 months post-transplantation) than in patients during the immediate post-transplant period.Mycophenolic acid is primarily eliminated (≈87%) in the urine as mycophenolic acid glucuronide; 6% is eliminated in the faeces. The mean ‘apparent’ half-life and plasma clearance of mycophenolic acid are 17.9 hours and 11.6 L/h, respectively, after oral administration.The AUC of mycophenolic acid and its glucuronide metabolite were higher in patients with renal impairment than in patients with normal renal function following single dose administration. However, the pharmacokinetic s of mycophenolic mofetil after a single dose are not altered in patients with cirrhosis. There are limited data in children but AUC and Cmax of mycophenolic acid appear to rise with increasing age.Clinical EfficacyInitial noncomparative trials helped to determine the efficacy of mycophenolate mofetil and provided the appropriate dosage regimens for use in larger clinical trials. Three randomised, double-blind, multicentre trials have been conducted comparing mycophenolate mofetil with either placebo or azathioprine as part of combination therapy (with cyclosporin and corticosteroids) for the prevention of renal transplant rejection. Acute rejection or treatment failure (premature withdrawal from the study for any reason) during the first 6 months after transplantation occurred in significantly fewer patients receiving mycophenolate mofetil 2 or 3 g/day (range 30.3 to 38.8%) than either placebo (56.0%), or azathioprine 1 to 2 mg/kg/day (47.6%) or 100 to 150 mg/day (50%). The proportion of patients who required full courses of antirejection therapy (corticosteroids and/or anti-lymphocyte therapy) during the first 6 months post-transplant also tended to be lower in patients who received mycophenolate mofetil (range 21.1 to 31%) than either placebo (51.8%) or azathioprine (44.5 and 46%) recipients although the differences were not statistically significant. There were no differences between any of the treatment groups in terms of graft loss or patient survival at 6 or 12 months. There are currently no data on the effect of mycophenolate mofetil on long term patient or renal graft survival.Subgroup analysis of one multicentre study revealed that African-Americans receiving mycophenolate mofetil 3 g/day tended to have a lower rate of biopsy-proven acute rejection and/or treatment failure than those receiving 2 g/day. The use of mycophenolate mofetil in children is limited to a single report involving 14 patients.Data regarding the use of mycophenolate mofetil in the treatment of acute rejection are limited but initial results are promising. In patients with biopsy-proven rejection, mycophenolate mofetil 3 g/day was associated with a significantly lower frequency of subsequent biopsy-proven rejection or treatment failure than high dose intravenous corticosteroids (29 vs 51%).TolerabilityRates of adverse events associated with mycophenolate mofetil appear to be dose related: 2 g/day is generally better tolerated than 3 g/day. Gastrointestinal (diarrhoea, vomiting), haematological and lymphatic (leucopenia, anaemia), and infectious (sepsis, opportunistic infections) events are most common. Diarrhoea and sepsis (most commonly cytomegalovirus viraemia) were slightly more common in patients receiving mycophenolate mofetil than in those receiving azathi-oprine. There was also an increased proportion of patients with leucopenia after treatment with mycophenolate mofetil 3 g/day compared with azathioprine treatment. The overall risk of malignancies associated with mycophenolate mofetil was similar to that of azathioprine.Dosage and AdministrationThe initial recommended dosage of mycophenolate mofetil for the prevention of renal transplant rejection is lg twice daily to be initiated within 72 hours of transplantation as part of a combination regimen with cyclosporin and corticosteroids. Although dosages of up to 3 g/day have been used, they were less well tolerated than 2 g/day and there was no difference in clinical efficacy between these dosages. In patients with glomerular filtration rate <25 ml/min (1.5 L/h)/ 1.73m dosages should not exceed 2 g/day. Dosage adjustments in patients with delayed graft function are not required.

Ciprofloxacin : An updated review of its pharmacology, therapeutic efficacy and tolerability

Ciprofloxacin is a broad spectrum fluoroquinolone antibacterial agent. Since its introduction in the 1980s, most Gram-negative bacteria have remained highly susceptible to this agent in vitro; Gram-positive bacteria are generally susceptible or moderately susceptible. Ciprofloxacin attains therapeutic concentrations in most tissues and body fluids. The results of clinical trials with ciprofloxacin have confirmed its clinical efficacy and low potential for adverse effects. Ciprofloxacin is effective in the treatment of a wide variety of infections, particularly those caused by Gram-negative pathogens. These include complicated urinary tract infections, sexually transmitted diseases (gonorrhoea and chancroid), skin and bone infections, gastrointestinal infections caused by multiresistant organisms, lower respiratory tract infections (including those in patients with cystic fibrosis), febrile neutropenia (combined with an agent which possesses good activity against Gram-positive bacteria), intra-abdominal infections (combined with an antianaerobic agent) and malignant external otitis. Ciprofloxacin should not be considered a first-line empirical therapy for respiratory tract infections if penicillin-susceptible Streptococcus pneumoniae is the primary pathogen; however, it is an appropriate treatment option in patients with mixed infections (where S. pneumoniae may or may not be present) or in patients with predisposing factors for Gram-negative infections. Clinically important drug interactions involving ciprofloxacin are well documented and avoidable with conscientious prescribing. Recommended dosage adjustments in patients with impaired renal function vary between countries; major adjustments are not required until the estimated creatinine clearance is < 30 ml/min/1.73m2 (or when the serum creatinine level is > or = 2 mg/dl). Ciprofloxacin is one of the few broad spectrum antibacterials available in both intravenous and oral formulations. In this respect, it offers the potential for cost savings with sequential intravenous and oral therapy in appropriately selected patients and may allow early discharge from hospital in some instances. In conclusion, ciprofloxacin has retained its excellent activity against most Gram-negative bacteria, and fulfilled its potential as an important antibacterial drug in the treatment of a wide range of infections. Rational prescribing will help to ensure the continued clinical usefulness of this valuable antimicrobial drug.

Infliximab: A review of its use in the management of rheumatoid arthritis

UNLABELLED Infliximab is a chimaeric monoclonal antibody to human tumour necrosis factor-alpha (TNFalpha). It binds to both soluble and transmembrane forms of TNFalpha at picomolar concentrations in vitro. Secondary to inhibition of TNFalpha, infliximab reduces serum levels of inflammatory mediators and vascular endothelial growth factor, decreases the expression of chemokines in the synovial tissue and reduces lymphocyte migration into the joints of patients with rheumatoid arthritis. In 2 multicentre randomised double-blind trials conducted over 26 and 30 weeks, infliximab plus methotrexate was significantly more effective than placebo plus methotrexate according to American College of Rheumatology response criteria in patients with active rheumatoid arthritis. A substantial response to infliximab-containing regimens was evident within 2 weeks. Extension phases of these studies indicate sustained clinical efficacy for up to 54 weeks. Of considerable importance are preliminary 1-year radiographic findings that show zero median progression of joint damage in infliximab plus methotrexate recipients compared with a 7 to 8% deterioration in placebo plus methotrexate recipients. Headache, nausea, upper respiratory tract infection and infusion-related reactions are the most commonly reported adverse events with infliximab. Serious events occurred in 4.4% of infliximab versus 1.8% of placebo recipients. In the largest clinical trial, 2 patients died from disseminated infection and 3 developed new or recurrent malignancies, although the exact relationship between infliximab and these events is unknown. To date, 2 patients with rheumatoid arthritis have developed drug-induced lupus. About 10% of patients may develop antibodies to infliximab, although the clinical significance of these is presently unknown. CONCLUSION Infliximab represents an important advance in the treatment of rheumatoid arthritis, with tolerability concerns raised by early studies having been eased somewhat by more recent data in larger patient numbers. If preliminary results indicating that infliximab is able to arrest joint destruction in patients with rheumatoid arthritis are corroborated, the drug will likely become an integral component of future management strategies for this difficult-to-treat condition.

Cyclosporin: A Review of the Pharmacokinetic Properties, Clinical Efficacy and Tolerability of a Microemulsion-Based Formulation (Neoral®)

The microemulsion-based formulation of cyclosporin (Neoral; referred to as the microemulsion formulation in this review) is a microemulsion preconcentrate which has been developed to overcome problems associated with the poor and unpredictable absorption of the standard oral formulation of this drug. These include marked intra- and interpatient variability in the extent of absorption, a poor correlation between trough blood concentrations of cyclosporin and total systemic exposure, and the need for regular monitoring of blood cyclosporin concentrations. In healthy volunteers and renal or liver transplant recipients, administration of the microemulsion formulation resulted in cyclosporin absorption which was significantly faster, more extensive and more predictable than that seen with the standard oral formulation. Furthermore, measurement of whole-blood trough cyclosporin concentrations provided a better estimate of systemic drug exposure in renal transplant recipients who received the microemulsion formulation than in those who received the standard formulation. Systemic exposure of cyclosporin delivered by the new formulation appears to be relatively unaffected by food intake. Initial data suggest that drug absorption from the microemulsion formulation is enhanced in comparison with that achieved from the standard formulation in liver transplant recipients undergoing biliary diversion or with cholestasis, although absorption from the new formulation does not appear to be completely independent of bile. Preliminary results from other groups that experience cyclosporin malabsorption from the standard formulation (patients with cystic fibrosis or diabetes, and children) are also encouraging. Clinical trials specifically designed to investigate the relative immunosuppressive efficacy of the microemulsion formulation have not been reported; further data are required to fully establish the relationship between the more rapid and extensive absorption of cyclosporin from the microemulsion formulation and the probability of graft rejection or adverse events (including nephrotoxicity and hypertension). However, no statistically significant differences have been noted between the 2 formulations in the incidence of these events in studies to date. The incidence of rejection in new renal or liver transplant recipients treated for a minimum of 3 months was approximately 31 to 50% in those receiving the microemulsion formulation and approximately 24 to 56% in those receiving the standard formulation. Thus, although confirmation of existing efficacy and tolerability data is required, the characteristic pharmacokinetic properties of the microemulsion formulation make it an attractive option for the oral delivery of cyclosporin in transplant recipients, offering more predictable and more extensive drug absorption than the standard formulation. The microemulsion formulation may be of particular benefit in patients who show poor absorption of cyclosporin from the standard oral formulation, such as liver transplant recipients with biliary diversion or cholestasis.

Erratum to: Nimesulide: an update of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy

Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) administered orally or rectally twice daily for a variety of inflammatory and pain states. In mostly short term studies (up to 4 weeks), it was effective in reducing pain associated with osteoarthritis, cancer, thrombophlebitis, oral surgery and dysmenorrhoea in adults, reducing pain associated with general surgery in adults and children, and pain, fever and inflammation accompanying respiratory tract infections, otorhinolaryngological diseases and traumatic injury in adults and children. Nimesulide appeared to be at least as effective as other NSAIDs in all of these indications. Nimesulide has been well tolerated by adult, elderly and paediatric patients in clinical trials and large postmarketing surveillance studies. In general qualitative terms nimesulide exhibits the usual adverse events associated with NSAIDs (gastrointestinal, dermatological and neurological). However, it has a pharmacodynamic profile suggestive of a possibly reduced propensity to cause adverse gastrointestinal effects, although this has not been conclusively demonstrated in comparative clinical trials, many of which showed a similar incidence of such effects for nimesulide and the comparator agent. Additionally, nimesulide has been well tolerated by most aspirin (acetylsalicylic acid)- and/or NSAID-intolerant patients and in patients with asthma. Thus, available evidence indicates that nimesulide is an effective and well tolerated alternative to other NSAIDs in the short term treatment of pain and inflammation of osteoarthritis and various other causes.

Mirtazapine: a review of its use in major depression.

UNLABELLED Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) which has predominantly been evaluated in the treatment of major depression. The drug had equivalent efficacy to tricyclic antidepressants and it was at least as effective as trazodone in the majority of available short term trials in patients with moderate or severe depression, including those with baseline anxiety symptoms or sleep disturbance and the elderly. A continuation study also showed that sustained remission rates were higher with mirtazapine than with amitriptyline and that the drugs had similar efficacy for the prevention of relapse. There is some evidence for a faster onset of action with mirtazapine than with the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). Mirtazapine was more effective than the SSRI fluoxetine at weeks 3 and 4 of therapy and it was also more effective than paroxetine and citalopram at weeks 1 and 2, respectively, in short term assessments (6 or 8 weeks). Preliminary data suggest that the drug may be effective as an augmentation or combination therapy in patients with refractory depression. Anticholinergic events and other events including tremor and dyspepsia are less common with mirtazapine than with tricyclic antidepressants. There was a greater tendency for SSRI-related adverse events with fluoxetine than with mirtazapine, but, overall, mirtazapine had a similar tolerability profile to the SSRIs. Increased appetite and bodyweight gain appear to be the only events that are reported more often with mirtazapine than with comparator antidepressants. In vitro and in vivo data have suggested that mirtazapine is unlikely to affect the metabolism of drugs metabolised by cytochrome P450 (CYP)2D6, although few formal drug interaction data are available. CONCLUSIONS Mirtazapine is effective and well tolerated for the treatment of patients with moderate to severe major depression. Further research is required to define the comparative efficacy of mirtazapine in specific patient groups, including the elderly and those with severe depression. Clarification of its efficacy as an augmentation therapy and in patients with refractory depression and its role in improving the efficacy and reducing the extrapyramidal effects of antipsychotic drugs would also help to establish its clinical value. The low potential for interaction with drugs that are metabolised by CYP2D6, including antipsychotics, tricyclic antidepressants and some SSRIs, may also make mirtazapine an important option for the treatment of major depression in patients who require polytherapy. Mirtazapine also appears to be useful in patients with depression who present with anxiety symptoms and sleep disturbance.

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

SYNOPSIS The enantiomerically pure (S-enantiomer) amide local anaesthetic drug ropivacaine blocked nerve fibres responsible for transmission of pain (Aδ and fibres) more completely than those that control motor function (Aβ 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 post-operatively 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. wound 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 with ropivacaine relative to bupivacaine at lower concentrations (≈5 mg/ml) will be advantageous in certain applications. PHARMACODYNAMIC PROPERTIES Ropivacaine is an enantiomerically pure (S-enantiomer) amide local anaesthetic drug. In in vitro preparations of animal nerves ropivacaine was more selective for nerve fibres responsible for transmission of pain (AS and C fibres) than those that control motor function (Aβ fibres). The drug also induced profound blockade of other animal nerves in vitro and appeared to be more potent than equimolar concentrations of bupivacaine in this regard. Small volumes of ropivacaine injected intradermally have a vasoconstrictive effect. Similarly, in human tissues in vitro, low concentrations of ropivacaine induced vasoconstriction; however, in keeping with the biphasic vascular effects of amide local anaesthetic drugs, this was reversed at higher concentrations. In anaesthetised pigs, a high intra-arterial dose of ropivacaine (5.33mg) significantly decreased mean arterial pressure and left ventricular dP/dT, and increased left ventricular end-diastolic pressure. In guinea-pig cardiac muscle in vitro, ropivacaine-induced blockade of sodium channels was less potent than that induced by bupivacaine. In rabbit Purkinje fibres, ropivacaine depressed cardiac excitability and conduction to a lesser extent than bupivacaine but more so than lidocaine (lignocaine). Ropivacaine was less cardiotoxic than equivalent concentrations of bupivacaine in isolated perfused rabbit hearts. In vivo studies in pigs and dogs indicate that ropivacaine has less effect on cardiac rhythm than equianalgesic doses of bupivacaine but affects cardiac rhythm more than lidocaine. Studies evaluating the effects of epidural administration of ropivacaine to volunteers indicate that the duration of sensory anaesthesia is dose dependent. The effects of the drug on lower extremity motor function clearly increased as the dose increased. PHARMACOKINETIC PROPERTIES Intravenous infusion of ropivacaine 50mg over a 15-minute period produced a mean maximum plasma concentration (Cmax) of 1.5 mg/L. The mean volume of distribution of unbound drug (6%) was 742L, plasma clearance was 0.5 L/h and the terminal elimination half-life was 1.85 hours. In patients undergoing orthopaedic surgery, epidural injection of ropivacaine 100, 150 or 200mg produced Cmax values of 0.53, 1.07 and 1.53 mg/L, respectively after 96 (100mg) or 40 (150 or 200mg) minutes (tmax). Mean residence time was inversely proportional to the dose but the area under the plasma concentration versus time curve was not dose-dependent. Similar trends were observed in patients undergoing other types of surgery including hysterectomy, hernia repair or varicose vein stripping. Compared with bupivacaine, ropivacaine has a signifi-cantly shorter elimination half-life (≈5 vs ≈10 hours) but is cleared at a similar rate (apparent plasma clearance ≈18 L/h). Continuous infusion of ropivacaine over a 21-hour period was associated with a continuous increase in plasma concentration. Compared with data from bolus dose studies, the apparent plasma clearance of the drug was higher and the half-life shorter. THERAPEUTIC USE Most studies evaluating the efficacy of ropivacaine have involved epidural administration of the drug to patients undergoing surgery and, to a lesser extent, women in labour. Apart from one study in women undergoing hysterectomy, ascending dose studies in patients undergoing a wide range of surgical procedures did not detect any dose-related trends in terms of the time taken to reach the maximum level of analgesia. However, the duration of anaesthesia and the degree of motor blockade increased as the dosage of ropivacaine increased. Overall, double-blind comparisons in patients undergoing a variety of surgical procedures show that ropivacaine is less potent than bupivacaine in terms of motor blockade and, to a lesser extent, sensory blockade. Several studies in women undergoing caesarean section reported a significantly longer time to onset of motor blockade in ropivacaine recipients compared with bupivacaine recipients. Differences between the 2 drugs in terms of sensory blockade were less pronounced. All studies used equivalent dosages of each drug. In contrast, a study in patients undergoing urological surgery, which also compared equivalent dosages of ropivacaine and bupivacaine [150mg (7.5 mg/ml)], reported a similar time to onset of motor blockade with both drugs, but a significantly lower frequency of second and third degree motor block in ropivacaine recipients. Importantly, studies that compared ropivacaine and bupivacaine at a dose ratio of approximately 1.5 to 1 (for example ropivacaine 7.5 mg/ml vs bupivacaine 5 mg/ml) reported very similar patterns of motor and sensory blockade in both groups. All of 3 noncomparative trials conducted to evaluate the anaesthetic efficacy of ropivacaine 150 or 165mg administered via the subclavian perivascular approach found the drug to induce satisfactory brachial plexus block in patients scheduled to undergo upper limb surgery. In all of these studies 50% of patients received epinephrine. Anaesthesia of brachial plexus dermatomes was achieved in between 86 and 100% of patients. In a randomised double-blind dosage comparison, the extent of brachial plexus nerve block achieved with ropivacaine 2.5 mg/ml (100mg dose) was significantly less useful than that provided by ropivacaine 5 mg/ml (200mg dose). The drug was as effective as bupivacaine in comparative studies in this indication. Direct comparisons indicate that epidurally administered ropivacaine has generally similar efficacy to bupivacaine when given for pain relief during labour. In one study, a significantly shorter time to onset of analgesia was noted in bupivacaine than in ropivacaine recipients, and motor blockade was slightly less intense after ropivacaine in another. In all of these studies, neonatal outcome, assessed using Apgar scores, was not significantly affected and was similar with both drugs. A further trial, designed specifically to compare the effects of maternal epidural ropivacaine (mean dose 75mg) and bupivacaine (mean dose 85mg) on neonatal neurobehavioural status and outcome, reported no significant differences between the 2 groups. In contrast, a meta-analysis reported significantly higher neurological and adaptive capacity scores at 24 hours in infants born to mothers given epidural ropivacaine than in those born to mothers given bupivacaine. The postsurgical analgesic efficacy of continuous epidural infusion of ropivacaine 10, 20 and 30 mg/h has been compared with that of placebo (saline) in patients undergoing upper or lower abdominal, or orthopaedic surgery. In all studies the drug was infused postoperatively. Pain became proportionally less severe and morphine consumption (when measured) decreased as the dosage of ropivacaine increased. Indeed, all studies reported a significant difference between higher doses of ropivacaine placebo. Motor blockade became more intense as the dosage of ropivacaine

Ondansetron. A review of its pharmacology and preliminary clinical findings in novel applications.

The use of ondansetron, a selective serotonin 5-HT3 receptor antagonist, is well established in patients with nausea and vomiting associated with cancer chemotherapy, radiotherapy or anaesthesia and surgery. The wide distribution of 5-HT3 receptors in the body and the role of these receptors in disease have provided the rationale for investigation of ondansetron in novel applications. Preliminary data have shown ondansetron to have clinical benefit in patients with nausea and vomiting associated with drug overdosage or poisoning, anti-infective or antidepressant therapies, uraemia or neurological trauma, and in patients with pruritus. Patients with gastrointestinal motility disorders (e.g. carcinoid syndrome, irritable bowel syndrome, diarrhoea associated with cryptosporidiosis or diabetes, and chronic refractory diarrhoea) have also shown some improvement when treated with ondansetron, as have patients with certain pain or CNS-related disorders [e.g. alcohol (ethanol) dependence, opiate withdrawal, vertigo, cerebellar tremor and Parkinsons disease treatment-related psychosis]. In contrast to conventional antiemetics, ondansetron is generally well tolerated with a lower incidence of sedation and only isolated case reports of extrapyramidal reactions. Furthermore, unlike dopamine receptor-blocking neuroleptics, ondansetron does not appear to worsen the symptoms of Parkinsons disease. Thus, in addition to its established indications, preliminary results suggest that ondansetron may be beneficial in a number of novel applications. This drug may represent a treatment alternative in patients with refractory disease, or an effective treatment of conditions for which current therapies are either poorly tolerated or not available. Further investigation of ondansetron in a range of potential new applications appears to be warranted.