Drugs

Indinavir is a protease inhibitor used in the treatment of patients with HIV infection. Combination antiretroviral therapy with indinavir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is associated with greater reductions in viral load, greater increases in CD4+ cell counts, and reduced morbidity and mortality when compared with 2 NRTIs alone. In the landmark clinical trial ACTG 320, the rate of progression to AIDS or death (primary end-point) among zidovudine-experienced patients treated with indinavir, zidovudine and lamivudine was approximately half that of patients who received only zidovudine plus lamivudine (6 vs 11%; p < 0.001). The durability of an indinavir-containing regimen was demonstrated in Merck protocol 035, an ongoing trial in which a significant proportion of patients had sustained viral suppression for up to 3 years. Merck protocol 039, also an ongoing trial, showed a greater effect on surrogate markers of HIV disease progression with indinavir-based triple therapy than with zidovudine plus lamivudine or indinavir monotherapy in patients with advanced disease (median baseline CD4+ count 15 cells/µL). Numerous additional clinical trials have established the beneficial antiviral and immunological effects of indinavir in both antiretroviral-naive and -experienced patients with HIV infection. Indinavir is associated with various drug class-related adverse events, including gastrointestinal disturbances (e.g. nausea, diarrhoea), headache and asthenia/fatigue. A lipodystrophy syndrome has been commonly reported with indinavir and other protease inhibitors combined with NRTIs, but it has also been reported in many protease inhibitor-naive patients, and a definitive causal link has not been established between the syndrome and protease inhibitors. Nephrolithiasis may develop in about 9% of patients receiving indinavir but does not appear to be associated with other protease inhibitors; <0.5% of patients receiving indinavir discontinue the drug because of nephrolithiasis, which may be the extreme end of a continuum of crystal-related renal syndromes. Additional renal problems (e.g. nephropathy) have been reported in small numbers of patients receiving indinavir. In summary, indinavir is a protease inhibitor with well documented efficacy when used as part of combined therapy in patients with HIV infection. Both US and UK treatment guidelines continue to recommend protease inhibitor-based regimens including indinavir as a first-line option. Indinavir is being studied as a twice daily and once daily regimen with a low dosage of ritonavir as a way to alleviate tolerability, drug interaction and patient compliance/adherence issues. Indinavir-containing triple therapy has demonstrated positive effects not only on surrogate markers of disease progression, but also on clinical end-points of mortality and morbidity in patients with HIV disease. Protease inhibitors are a significant advance in the care of patients with HIV infection, and, in an era of vidence-based medicine, indinavir represents an important component of anti-retroviral treatment strategies. Indinavir is an HIV protease inhibitor. It acts by binding to the HIV protease active site and inhibiting post-translational processing, thereby resulting in the formation of immature noninfectious viral particles and interruption of viral spread. Indinavir inhibited HIV replication by 95% at concentrations ranging from approximately 25 to 100 nmol/L in vitro, and an additive or synergistic antiviral effect was demonstrated in most studies combining indinavir with other antiretroviral agents in cell culture. Amino acid substitutions of HIV protease are the primary determinants of resistance to protease inhibitors, and there are at least 11 substitutions which may contribute to resistance to indinavir. However, ≥3 amino acid substitutions are required and only certain combinations of substitutions confer resistance to indinavir. Cross resistance can develop among the entire protease inhibitor class. Indeed, a high degree of cross resistance with other protease inhibitors has been demonstrated in indinavir-resistant clinical isolates of HIV selected during indinavir therapy. After oral administration, indinavir is rapidly absorbed in the fasting state. Time to achieve maximum plasma drug concentration is approximately 0.8 hours. Steady-state peak plasma drug concentration (Cmax), minimum plasma drug concentration (Cmin) and area under the plasma drug concentration-time curve (AUC) values are 12.6 µmol/L, 0.25 µmol/L and 30.7 µmol/L · h with indinavir 800mg every 8 hours. The rate but not the extent of absorption is reduced when indinavir is taken with a low-fat meal. Administration of indinavir with a high-fat meal markedly reduces the rate and extent (by approximately 35 to 75%) of drug absorption; however, food has little effect on indinavir pharmacokinetics when the drug is administered with a low dose of ritonavir. Indeed, concurrent administration of ritonavir appears to improve the overall pharmacokinetic profile of indinavir, by increasing plasma trough concentrations of indinavir and providing more consistent indinavir exposure throughout the dosage interval (such that twice daily, rather than every 8 hour, administration of indinavir is possible). Plasma protein binding of indinavir is approximately 60% and the elimination half-life is approximately 1.8 hours. Indinavir undergoes extensive metabolism by cytochrome P-450 (CYP) 3A4 isoenzymes to several metabolites (the activity of which is unknown). Approximately 11% of an administered dose is eliminated unchanged in the urine, the remainder is eliminated in the faeces as indinavir metabolites and unabsorbed indinavir. Indinavir is associated with a number of pharmacokinetic drug interactions, some of which are clinically significant and necessitate dosage modifications or avoidance of concomitant administration. Drug interactions appear to be more common with ritonavir and less common with saquinavir than with indinavir on the basis of inhibitory effects of the drugs on cytochrome P-450 (CYP) 3A4 isoenzymes. In the landmark ACTG 320 trial, progression to AIDS or death (primary end-point) occurred in 6% of patients randomised to receive indinavir, zidovudine and lamivudine compared with 11% of those who received zidovudine plus lamivudine (p < 0.001), i.e. a relative reduction of ≈50%. The intention-to-treat analysis included 1156 zidovudine-experienced patients who received study treatment for a median duration of 38 weeks. Overall mortality, a secondary outcome measure, was 1.4 and 3.1%, respectively (p = 0.04). Numerous clinical trials have evaluated the effects of indinavir-containing regimens on surrogate markers of HIV disease progression, i.e. serum or plasma (hereafter simplified to ‘plasma’) HIV RNA levels (viral load) and CD4+ cell counts. In studies in antiretroviral therapy-experienced or both-experienced and -naive patients (mean or median baseline plasma HIV RNA4.39 to 5.12 log10copies/ml), ≥24 weeks of indinavir-containing double or triple therapy was associated with reductions from baseline plasma HIV RNA levels ranging from 1.6 to 2.7 log10copies/ml. The percentage of patients with plasma HIV RNA levels below the limit of detection (LOD; typically 400 or 500 copies/ml) ranged from 45 to 90%. CD4+ counts ranged from 15 to 344 cells/µL at baseline and increased by 86 to 243 cells/µL after ≽24 weeks of therapy. These results were broadly similar to those in studies which included only antiretroviral treatment-naive patients. Intention-to-treat analysis in 2 pivotal, randomised, double-blind, multicentre trials (Merck protocols 035 and 039; both are ongoing) showed that triple therapy with indinavir, zidovudine and lamivudine was significantly more effective at improving surrogate markers of disease progression than a combined regimen of zidovudine plus lamivudine or indinavir monotherapy in zidovudine-experienced patients with HIV infection. In the Merck protocol 035 trial, the antiviral/immunological effect was sustained for up to 3 years in approximately two-thirds of patients, thus demonstrating good durability. Median baseline CD4+ cell count in the Merck protocol 039 trial was just 15 cells/µL; thus, efficacy with indinavir-containing triple therapy has been demonstrated even in patients with very advanced disease. In general, the proportion of patients with plasma HIV RNA level below the LOD after 12 to 36 weeks of therapy ranged from 61 to 83% in studies involving small numbers of patients with HIV infection (antiretroviral therapy-experienced or naive) who received indinavir in conjunction with another protease inhibitor [(with or without nucleoside reverse transcriptase inhibitors (NRTIs)]. One trial showed a much lower proportion of patients achieved HIV RNA levels below the LOD, but these patients had previously received extensive antiretroviral therapy. Concurrent protease inhibitor treatment included nelfinavir, saquinavir (soft-gelatin capsule or formulation not stated), ritonavir or amprenavir. Mean changes from baseline in CD4+ cell counts and plasma HIV RNA levels were broadly similar to those observed in studies in which indinavir was combined with 2 NRTIs. Several nonrandomised trials of 8 to 78 weeks’ duration have evaluated indinavir (usually in combination with zidovudine and lamivudine) in children infected with HIV, but most have included small numbers of patients. In general, indinavir-containing regimens have demonstrated similar effects on surrogate markers of HIV disease progression in paediatric patients to those in adult patients. All prospective studies in ≥15 children showed at least a modest improvement from baseline in CD4+ cell count and/or viral load. Indinavir, like other protease inhibitors, is associated with a number of adverse events, including gastrointestinal symptoms (nausea, abdominal pain, vomiting), headache and asthenia/fatigue. In comparative clinical studies, there was at least a trend towards a lower incidence of serious adverse events with indinavir-containing regimens than with ritonavir-containing regimens. Saquinavir-containing regimens tended to be associated with fewer adverse events than both of these protease inhibitor-containing regimens. When indinavir was used in combination with other protease inhibitors (e.g. ritonavir), adverse events were usually mild and transient in nature and most frequently included diarrhoea, nausea, rash, headache, fatigue and perioral tingling/numbness (the latter related specifically to ritonavir). Nephrolithiasis has been seen to occur in approximately 9% of patients receiving indinavir (193 of 2071 patients according to pooled clinical trial data; duration of therapy not stated) and does not appear to be associated with other protease inhibitors. Most patients who develop nephrolithiasis are able to continue indinavir therapy after adequate hydration and temporary interruption of indinavir (e.g. 1 to 3 days); less than 0.5% of patients treated with indinavir discontinue therapy because of nephrolithiasis (7 of 2071 patients). Thus, approximately 4% of those who develop indinavir-induced nephrolithiasis (7 of 193 patients) need to discontinue the drug. Indinavir-associated crystalluria appears to be more common than nephrolithiasis and is sometimes accompanied by urological symptoms. It is possible that indinavir may be associated with a continuum of crystal-related renal syndromes ranging from frank nephrolithiasis (e.g. renal stones and flank pain with or without haematuria) to asymptomatic crystalluria. Other renal problems, such as renal insufficiency or nephropathy, have been reported with indinavir in small numbers of patients. Indirect hyperbilirubinaemia occurs in about 10% of patients treated with indinavir, although there are no known clinical consequences or sequelae. Less than 1% of patients receiving the drug have hyperbilirubinaemia accompanied by elevations in serum ALT or AST levels. Lipodystrophy or a lipodystrophy syndrome involving body fat redistribution and metabolic effects appears to be another common adverse event among patients with HIV infection treated with antiretroviral therapy including protease inhibitor-containing combination therapy, although a direct causal link between protease inhibitors and the syndrome has not been established. There is currently no consensus case-definition for the syndrome and, consequently, the reported incidence has varied significantly and is also seen with antiretroviral regimensnot containing a protease inhibitor. The recommended dosage of indinavir is 800mg orally every 8 hours. Trials show that, for optimal absorption, indinavir should be administered with water 1 hour before or 2 hours after a meal. Indinavir may be administered with a light meal such as dry toast with jelly/jam or corn flakes with skim milk and sugar. Patients taking indinavir must drink at least 1.5L of liquids each day (24-hour period) to ensure adequate hydration and reduce the risk of nephrolithiasis. In patients with mild to moderate hepatic insufficiency due to cirrhosis, the dosage of indinavir should be reduced to 600mg every 8 hours. Pharmacokinetic and clinical data suggest that, for patients who would otherwise creceive the standard recommended dosage of indinavir 800mg every 8 hours, the dosage interval may be extended to twice daily when indinavir is used with a low dose of ritonavir (total daily dosage of indinavir has varied in trials). In addition, there are no food restrictions with regimens of indinavir plus a low dose of ritonavir.

Spontaneous intracerebral hemorrhage (ICH) constitutes 10–15% of all strokes, and is a significant cause of mortality and morbidity. Survivors of ICH, especially those with atrial fibrillation (AF), are at risk for both recurrent hemorrhagic and ischemic cerebrovascular events. A conundrum in the field of vascular neurology, neurosurgery, and cardiology has been the decision to initiate or resume versus withhold anticoagulation in survivors of ICH with AF. To initiate anticoagulation would decrease the risk of ischemic stroke but may increase the risk of hemorrhage. To withhold anticoagulation maintains a lower risk of hemorrhage but does not decrease the risk of ischemic stroke. In this narrative review, we discuss the evidence for and against the use of antithrombotics in ICH survivors with AF, focusing on recently completed and ongoing clinical trials.

Significant advances in the pharmacological prophylaxis of venous thromboembolism have occurred since warfarin and unfractionated heparin were introduced for this indication nearly 60 years ago. Despite these advances, coumarin derivatives such as warfarin remain the only orally active anticoagulants available for prophylaxis in venous thromboembolism. Although administered orally, coumarin derivatives are not convenient to use, because they have narrow therapeutic indexes and require routine coagulation monitoring and dose adjustment. This is inconvenient for patients and physicians and costly for the healthcare system. Low-molecular-weight heparins, which are administered in fixed or weight-adjusted doses and do not require monitoring, are widely used for the prevention of venous thromboembolism in patients in both the hospital and the outpatient setting. However, these drugs must be given subcutaneously, which can be difficult for outpatients and resource-intensive for in-hospital use. Likewise, fondaparinux, the synthetic pentasaccharide, must be administered subcutaneously. Consequently, there remains a need for new orally active anticoagulants that can be given in fixed doses and do not have a narrow therapeutic index, so that coagulation monitoring is unnecessary. Because such agents would be more convenient for patients and physicians, they would probably expand the use of prophylaxis in venous thromboembolism in those at risk, and would simplify treatment of patients with established venous thromboembolism.

Sustained-release bupropion (bupropion SR) is a unique, non-nicotine smoking cessation aid that is hypothesised to act upon neurological pathways involved in nicotine dependence. Pharmacokinetic and metabolism studies reveal that bupropion SR is metabolised by multiple pathways with no single pathway predominating. When one pathway is inhibited, others are available to compensate. Therefore, only a few clinically relevant drug-drug interactions involving bupropion SR have been observed, although the potential for interactions exists, as with any extensively metabolised drug. Population pharmacokinetic/pharmacodynamic analyses of data from patients receiving daily oral doses of 100mg, 150mg, or 300mg reveal that the anti-smoking efficacy of bupropion SR is directly related to dose. The incidences of dry mouth and insomnia were directly related to bupropion plasma concentrations while the incidence of anxiety was inversely proportional to bupropion plasma concentrations. To maximise efficacy (with an acceptable safety profile), the optimal daily dose for the majority of patients is 300mg.

The sudden development of a red painful eye with blurred vision may be an acute attack of angle closure glaucoma which requires emergency attention. Once the attack is controlled with medication, surgical intervention with a peripheral iridectomy is indicated to relieve relative pupillary block. Eyes subject to angle closure glaucoma are anatomically different with ‘crowded’ anterior segments. In contrast, open angle glaucoma (the more common form) may progress to near blindness without symptoms. Routine screening of intraocular pressure is, therefore, necessary to make the diagnosis before extensive irreparable damage has occurred. Surgery for open angle glaucoma carries risks of cataract and infection, and is unpredictable. Open angle glaucoma patients are usually treated chronically with specific medications. β-Adrenoceptor blocking agents appear to provide a significant new addition to the currently available antiglaucoma medications.

Of 1,593 subjects admitted to the Australian National Blood Pressure Study 1 to 2 years ago, a substantial number (391 or 24.5%) ceased attending, in 85% of cases voluntarily. Withdrawal rates were very high in the first 4 months, settling to 5% per annum by the second year. Extrapolation to clinical practice is hazardous but contributory factors elicited by questionnaire suggest certain management strategies: maximisation of efforts to enlist subject co-operation at the onset of treatment; management of treatment by family doctor or health centre with appointments flexible in time and infrequent in number; minimisation of doctors’ ambivalence about treatment effectiveness and the withholding of information from the subject. It is inevitable that a proportion of subjects will reject long-term drug treatment. This adds further weight to the need for research on alternatives such as low salt diets.

Linzagolix (Yselty®) is an orally administered, selective, non-peptide small molecule gonadotrophin releasing hormone (GnRH) receptor antagonist that is being developed by Kissei Pharmaceutical for the treatment of uterine fibroids and endometriosis in women of reproductive age. Linzagolix binds to and blocks the GnRH receptor in the pituitary gland, modulating the hypothalamic pituitary-gonadal axis and dose-dependently reducing serum luteinising hormone and follicle-stimulating hormone production and serum estradiol levels. In June 2022, linzagolix was approved for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age in the EU. Linzagolix is under regulatory review the USA for this indication and is in phase 3 clinical development in the treatment of pain associated with endometriosis. This article summarizes the milestones in the development of linzagolix leading to this first approval for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.

Between 15 and 35% of pharyngeal infections are attributable to Group A β-haemolytic streptococci. Streptococcal pharyngitis is one of the most common infections in adolescents and children. A specific diagnosis of pharyngitis can be obtained only by isolating organisms in culture. The current treatment of choice for streptococcal pharyngitis/tonsillitis is a 10-day course of phenoxymethylpenicillin (penicillin V); however, unresolved problems concerning the use of penicillin include the timing of therapy, appropriate therapy for treatment failures, chronic carriers and those with frequent recurrences. In addition, failure rates of 10 to 35% have been reported with oral phenoxymethylpenicillin. Effective treatment alternatives in this indication include oral cephalosporin agents or penicillin/β-lactamase inhibitor combinations. The oral cephalosporins offer the advantage of an improved pharmacokinetic profile, once- or twice-daily administration, a shorter (7-day) regimen, and a low incidence of adverse effects, although these advantages must be balanced against the broad spectrum of these agents (broader than is necessary) and their cost. Clinical trials conducted with cefetamet pivoxil, a new oral third generation cephalosporin, in both adults and children with pharyngitis/tonsillitis indicate that this agent offers an effective alternative for phenoxymethylpenicillin in this indication.