Dean M. Robinson

Drospirenone/Ethinylestradiol 3mg/20µg (24/4 Day Regimen)

SummaryAbstractDrospirenone 3mg with ethinylestradiol 20µg (Yaz®) is a low-dose combined oral contraceptive (COC) administered in a regimen of 24 days of active tablets followed by a short hormone-free interval (4 days; 24/4 regimen). Drospirenone, unlike other synthetic progestogens used in COCs, is a 17α-spirolactone derivative and a 17α-spironolactone analogue with antimineralocorticoid and antiandrogenic properties. Drospirenone/ethinylestradiol 3mg/20µg (24/4) is approved in the US for the prevention of pregnancy in women, for the treatment of the symptoms of premenstrual dysphoric disorder (PMDD) and for the treatment of moderate acne vulgaris in women who wish to use an oral contraceptive for contraception.Drospirenone/ethinylestradiol 3mg/20µg (24/4) provided 99% contraceptive protection over 1 year of treatment in two large studies. The same treatment regimen over three treatment cycles also significantly improved the emotional and physical symptoms associated with PMDD, and improved moderate acne vulgaris over six treatment cycles in double-blind trials. It was generally well tolerated, with adverse events generally typical of those experienced with other COCs and which were most likely to occur in the first few cycles. Clinical trials indicate that drospirenone/ethinylestradiol 3mg/20µg (24/4) is a good long-term contraceptive option, and additionally offers relief of symptoms that characterise PMDD and has a favourable effect on moderate acne vulgaris.Pharmacological PropertiesThe pharmacological properties of ethinylestradiol are well established. Drospirenone is a 17α-spirolactone derivative and an analogue of 17α-spironolactone that resembles endogenous progesterone and has antimineralocorticoid and antian-drogenic properties. Drospirenone/ethinylestradiol 3mg/20µg administered as a 24/4 (Yaz®) or 21/7 regimen for two treatment cycles suppressed ovarian activity during daily recommended use; however, stronger suppression of ovarian activity was observed with the 24/4 regimen during intentional dosing errors (three active tablets replaced with placebo at the start of a third treatment cycle).Like natural progesterone, drospirenone induces mild natriuresis, which counteracts estrogen-stimulated fluid retention and weight gain. The effects of drospirenone/ethinylestradiol 3mg/20µg on metabolic parameters, including lipoproteins, were generally neutral or favourable, although, as with other COCs, the serum glucose response to an oral glucose tolerance test in healthy women volunteers increased from baseline. As drospirenone is a spironolactone analogue with antimineralocorticoid activity, it has the potential to induce hyperkalaemia in high-risk patients (those with conditions that predispose them to hyperkalaemia [i.e. renal insufficiency, hepatic dysfunction and adrenal insufficiency] or those receiving other medications that may increase serum potassium).Both drospirenone and ethinylestradiol are rapidly absorbed, with maximum serum concentration reached after 1.5 hours. Both are ≥97% plasma bound, with volumes of distribution of ≈4–5 L/kg. Steady-state levels of drospirenone are reached on day 8, and of ethinylestradiol in the second half of the cycle. Metabolism of both components, including first pass metabolism of ethinylestradiol, is extensive. The elimination half-life of drospirenone is ≈30 hours andthat of ethinylestradiol is ≈24 hours. Drospirenone exposure is slightly increased in women with renal impairment and markedly increased in those with hepatic dysfunction, with drospirenone/ethinylestradiol 3mg/20µg (24/4) contraindicated in both of these groups.Therapeutic EfficacyIn two 1-year (13 contraceptive treatment cycles), noncomparative, international and EU trials enrolling 1027 and 1101 healthy women aged 17–36 years, oral drospirenone/ethinylestradiol 3mg/20µg (24/4) provided 99% contraceptive protection. The uncorrected Pearl index (PI) in the international trial was 1.29 and the PI adjusted for noncompliance was 0.72; in the EU trial, the uncorrected PI was 0.49. The cumulative pregnancy rates were 1.26% and 0.5% in the international and EU trials. Subjective satisfaction ratings (overall satisfaction, emotional and physical well-being, and interest in continuing medication if available) assessed in the international trial were positive in 73–88% of women.The drospirenone/ethinylestradiol 3mg/20µg (24/4) regimen was shown to improve the emotional and physical symptoms associated with PMDD over three treatment cycles in two double-blind, parallel-group (n = 449) or crossover (n = 64) studies. In both trials, the improvement in overall luteal phase Daily Record of Severity of Problems (DRSP) scores (primary outcome) versus baseline was significantly greater in drospirenone/ethinylestradiol 3mg/20µg (24/4) than placebo recipients, while in the parallel-group trial, scores for physical, behavioural and mood subscales were also significantly improved. In both trials, the improvement from baseline in all individual DRSP items, including premenstrual depression, were significantly greater in drospirenone/ethinylestradiol 3mg/20µg (24/4) than in placebo recipients.In the treatment of moderate acne vulgaris, drospirenone/ethinylestradiol 3mg/20µg (24/4) was generally well tolerated and was more effective than placebo in reducing the number of acne lesions and increasing the proportion of patients with ‘clear’ or ‘almost clear’ ratings on an Investigator Static Global Assessment scale in two large (n = 431 and 458) randomised, double-blind, placebo-controlled multicentre trials over six treatment cycles.TolerabilityOnce-daily drospirenone/ethinylestradiol 3mg/20µg in a 24/4 day regimen was generally well tolerated. Irregular bleeding (actively solicited), headache, nausea and breast pain were the most common adverse events; all tended to decrease over time in the 1-year, international trial. There were no clinically significant changes in potassium levels or other laboratory investigations and no abnormalities in adequate-sample endometrial biopsies after 13 cycles.Adverse events were generally similar in the double-blind, 3-month studies in PMDD, although irregular bleeding (spontaneously reported) was more common in the parallel-group trial. The proportion of drospirenone/ethinylestradiol 3mg/20µg (24/4) recipients who discontinued treatment for this reason was <4% in the parallel-group PMDD study and <1% in the international contraceptive trial. Other common adverse events were headache, nausea and breast pain in 13–20% of patients.

Indapamide sustained release: a review of its use in the treatment of hypertension.

SummaryAbstractA low-dose sustained-release (SR) formulation of the thiazide-type diuretic indapamide, indapamide SR (Natrilix® SR), retains the antihypertensive activity of the immediate-release (IR) formulation, with a smoother pharmacokinetic profile.In well controlled 12- to 52-week clinical trials, indapamide SR 1.5 mg/day was well tolerated and reduced blood pressure as effectively as therapeutic dosages of amlodipine, candesartan, enalapril, hydrochlorothiazide or indapamide IR. Indapamide SR was also more effective than enalapril in reducing left ventricular hypertrophy (LVH), and similar reductions in renal end-organ damage, assessed by microalbuminuria, were seen with indapamide SR- and enalapril-based antihypertensive strategies. Indapamide SR provides an effective option for initial antihypertensive monotherapy and a basis for multidrug antihvpertensive strategies.Pharmacological PropertiesIndapamide inhibits sodium chloride cotransport in the cortical diluting segment of the proximal distal tubule, as well as inhibiting a membrane-bound form of carbonic anhydrase.Therapeutic dosages of indapamide have only a mild diuretic activity; the primary antihypertensive activity of low-dose indapamide appears to occur through a direct vasodilatory effect. Indapamide also reduces vascular hypertrophy and LVH in animal models of pressure overload.Serum or plasma sodium and glucose levels in hypertensive patients were unaffected by indapamide SR monotherapy over 12 to 52 weeks; modest reductions in potassium and increases in uric acid levels have been observed.Indapamide SR 1.5 mg/day for 7 days achieved a lower maximum blood indapamide concentration (Cmax) than indapamide IR 2.5 mg/day (58 vs 154 µg/ L) and took longer to reach Cmax (11.0 vs 0.8 hours), while total exposure (area under the concentration-time curve from time 0–24 hours corrected for dose; 726 vs 690 µg · h/L) and minimum concentration (38 vs 41 µg/L) were similar. Indapamide undergoes extensive hepatic metabolism, and elimination occurs in a biphasic manner (terminal elimination half-life 15–24 hours), mainly through renal (≈70%) and biliary (≈22%) pathways.Therapeutic EfficacyIn well controlled clinical trials of 12–52 weeks’ duration, indapamide SR 1.5 mg/ day reduced both mean supine systolic blood pressure (SBP) and diastolic blood pressure (DBP). In patients with essential hypertension or isolated systolic hypertension, the reductions in mean supine SBP and DBP induced by indapamide SR were significantly larger than those seen with placebo, and SBP reductions were greater than those with enalapril 10 mg/day. Reductions in supine SBP and DBP with indapamide SR were similar to those with amlodipine 5 mg/day, candesartan 8 mg/day, indapamide IR 2.5 mg/day and enalapril 20 mg/day. In elderly patients (aged ≥65 years), reductions in mean supine SBP and DBP induced by indapamide SR were equivalent to those with amlodipine 5 mg/day or hydrochlorothiazide 25 mg/day.End-organ damage was also reduced by indapamide SR. LVH was reduced in indapamide SR 1.5 mg/day but not enalapril 20 mg/day recipients after 48 weeks of therapy in patients with essential hypertension. In patients with type 2 diabetes mellitus, multidrug indapamide SR 1.5 mg/day based and enalapril 10 mg/day-based antihypertensive strategies induced similar reductions in urinary albumin: creatinine ratio and fractional albumin clearance; noninferiority was not demonstrated in the reduction of albumin excretion rate.TolerabilityIndapamide SR 1.5 mg/day was generally well tolerated. Headache, back pain, nausea and diarrhoea were observed at relatively low rates (0.2–1.6%), and orthostatic hypotension was observed in 0.4–8.6% of recipients. Hypokalaemia (serum potassium <3.4 mmol/L) occurred in 4–11 % of indapamide SR recipients, while the incidence of moderate to severe hypokalaemia (<3.0 mmol/L) was 0–1.5%.

Albumin-bound Paclitaxel: in metastatic breast cancer.

Abstract▲ A new formulation of paclitaxel, 130-nanometre albumin-bound paclitaxel (nab™ -paclitaxel), solubilises hydrophobic paclitaxel and may increase paclitaxel delivery to tumour cells.▲ Intravenous nab-paclitaxel 260 mg/m2 had a higher maximum whole-blood concentration, shorter time to peak concentration, larger distribution volume and greater clearance than a 175 mg/m2 dose of a conventional polyoxyethylated castor oil (Cremophor® EL) solublised paclitaxel (CrEL-paclitaxel).▲ The reconciled target-lesion response rate was significantly higher in patients receiving intravenous nab-paclitaxel 260 mg/m2 once every 3 weeks than in those receiving CrEL-paclitaxel 175 mg/m2 once every 3 weeks (21.5% vs 11.1%) in a randomised, nonblind, phase III trial in 454 patients with metastatic breast cancer.▲ The objective response rate (ORR) was also significantly greater in nab- paclitaxel than in CrEL-paclitaxel recipients (33% vs 19%).▲ In noncomparative phase II trials, ORRs of 48% and 51% were observed in patients receiving nab-paclitaxel 175 or 300 mg/m2 once every 3 weeks.▲ nab-Paclitaxel 260 mg/m2 caused less grade 4 neu-tropenia than CrEL-paclitaxel 175 mg/m2. The incidence of grade 3 sensory neuropathy was higher in nab-paclitaxel recipients, reflecting the higher dosage of nab-paclitaxel, and improved with treatment interruption. Despite the absence of corticosteroid and antihistamine premedication, no severe hyper-sensitivity reactions were reported.

Spotlight on Bevacizumab in Advanced Colorectal Cancer, Breast Cancer, and Non-Small Cell Lung Cancer

Bevacizumab (Avastin™) is a humanized recombinant antibody that prevents vascular endothelial growth factor (VEGF) receptor binding, and inhibits angiogenesis and tumor growth.In patients receiving an irinotecan plus fluorouracil/leucovorin (IFL) regimen for first-line treatment of metastatic colorectal cancer, the addition of bevacizumab significantly increased overall survival by 4.7 months relative to IFL plus placebo. In the second-line treatment of advanced colorectal cancer, patients who received bevacizumab in combination with a fluorouracil/leucovorin plus oxaliplatin (FOLFOX4) regimen had an overall survival time that was 2 months longer than that in patients receiving FOLFOX4. Preliminary results indicated that bevacizumab significantly extended progression-free survival by 4.9 months in patients receiving paclitaxel for the first-line treatment of locally recurrent or metastatic breast cancer. The addition of bevacizumab to paclitaxel plus carboplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC) significantly prolonged overall survival by >2 months.Bevacizumab has acceptable tolerability in patients with advanced colorectal cancer, breast cancer, or NSCLC, with the majority of adverse events being generally mild and clinically manageable. Thus, bevacizumab provides a highly effective addition to standard chemotherapeutic regimens for advanced colorectal cancer, breast cancer, and NSCLC.

Double-sigmoid model for fitting fatigue profiles in mouse fast- and slow-twitch muscle.

We present a curve‐fitting approach that permits quantitative comparisons of fatigue profiles obtained with different stimulation protocols in isolated slow‐twitch soleus and fast‐twitch extensor digitorum longus (EDL) muscles of mice. Profiles from our usual stimulation protocol (125 Hz for 500 ms, evoked once every second for 100–300 s) could be fitted by single‐term functions (sigmoids or exponentials) but not by a double exponential. A clearly superior fit, as confirmed by the Akaiki Information Criterion, was achieved using a double‐sigmoid function. Fitting accuracy was exceptional; mean square errors were typically <1% and r2 > 0.9995. The first sigmoid (early fatigue) involved ∼10% decline of isometric force to an intermediate plateau in both muscle types; the second sigmoid (late fatigue) involved a reduction of force to a final plateau, the decline being 83% of initial force in EDL and 63% of initial force in soleus. The maximal slope of each sigmoid was seven‐ to eightfold greater in EDL than in soleus. The general applicability of the model was tested by fitting profiles with a severe force loss arising from repeated tetanic stimulation evoked at different frequencies or rest periods, or with excitation via nerve terminals in soleus. Late fatigue, which was absent at 30 Hz, occurred earlier and to a greater extent at 125 than 50 Hz. The model captured small changes in rate of late fatigue for nerve terminal versus sarcolemmal stimulation. We conclude that a double‐sigmoid expression is a useful and accurate model to characterize fatigue in isolated muscle preparations.

Galantamine Extended Release

Abstract▲ Galantamine inhibits acetylcholinesterase (AChE) to slow acetylcholine hydrolysis, and may also modulate presynaptic nicotinic receptor activation, thereby increasing neurotransmitter concentrations in the synaptic cleft.▲ Once-daily galantamine extended release (ER) 24mg and twice-daily galantamine immediate release (IR) 12mg are bioequivalent in terms of the area under the plasma concentration-time curve from time 0 to 24 hours and steady-state minimum plasma concentration.▲ Primary endpoints indicated a significantly greater effect of galantamine ER on cognitive performance than placebo, with efficacy similar to galantamine IR, in a randomised, double-blind trial. While galantamine ER did not show a significant effect on the coprimary endpoint of global change, neither did galantamine IR in this study. Exploratory post hoc analyses of global change correcting for study centre and prognostic factors associated with response (baseline Mini-Mental State Examination, Alzheimer’s Disease Assessment Scale cognitive score, prior cholinomimetic use) indicated nominal significance in the galantamine ER treatment arm.▲ Secondary endpoints indicated an improvement in activities of daily living and memory- and nonmemory-dependent measures of cognitive performance, but not in measures of behaviour or dichotomised rating of global change.▲ Adverse events occurred in similar proportions of galantamine ER, galantamine IR and placebo recipients.

Delayed-Release Multi Matrix System (MMX™) Mesalazine

Abstract▲ Mesalazine appears to act locally on the mucosa of the colon and reduces the inflammation associated with ulcerative colitis.▲ Following oral administration, the majority (≈78%) of a dose of delayed-release Multi Matrix System (MMX™) mesalazine passes unabsorbed through the upper gastrointestinal tract to reach and traverse the entire length of the colon.▲ In a well designed phase III trial in patients with active, mild to moderate ulcerative colitis (n = 262), significantly (p < 0.01) more MMX mesalazine 2.4 (34%) or 4.8 g/day (29%) recipients than placebo recipients (13%) achieved clinical and endoscopic remission after 8 weeks of treatment.▲ In a second phase III trial (n = 341), clinical and endoscopic remission rates with MMX mesalazine 2.4 (40.5%) and 4.8 g/day (41.2%) were significantly (p < 0.01) greater than with placebo (22.1%) after 8 weeks, while the remission rate with non-MMX delayed-release mesalazine (Asacol®) [32.6%] did not differ from placebo.▲ Overall, MMX mesalazine was generally well tolerated in controlled clinical trials, with a similar incidence of treatment-emergent adverse events in placebo (66%) and MMX mesalazine (56%) recipients in a pooled analysis; most adverse events were of mild or moderate severity. Two of 434 MMX mesalazine recipients experienced serious adverse events that were considered treatment related (pancreatitis caused by mesalazine sensitivity).

Fondaparinux sodium: a review of its use in the treatment of acute venous thromboembolism.

SummaryAbstractFondaparinux sodium (fondaparinux) is a synthetic sulfated pentasaccharide anticoagulant developed from the antithrombin binding moiety of heparin. Through the activation of antithrombin it inhibits Factor Xa, the activation of thrombin, and the subsequent coagulation cascade. Fondaparinux is approved in Europe and the US for the treatment of acute venous thromboembolism (VTE), including both deep vein thrombosis (DVT) and pulmonary embolism (PE), when used in conjunction with warfarin.In phase III clinical trials, subcutaneous fondaparinux was noninferior to subcutaneous enoxaparin or intravenous unfractionated heparin (UFH) in the prevention of recurrent symptomatic VTE in patients with acute DVT and PE, respectively, and equally well tolerated. It thus provides a valuable alternative to UFH and low-molecular weight heparins in the treatment of acute VTE, particularly in the outpatient setting.Pharmacological PropertiesFondaparinux, a sulfated pentasaccharide, inhibits Factor Xa by catalyzing a conformational change in antithrombin that potentiates the inhibitory activity of antithrombin →300-fold. Fondaparinux may also inhibit Factors VIIa and IXa, but with a Factor Xa rate constant for inactivation >25-fold higher than that of Factors VIIa and IXa, their inhibition is unlikely to play a role in the pharmacologic actions of fondaparinux.In animal models of venous stasis thrombosis and dynamic thrombus growth, intravenous or subcutaneous fondaparinux inhibited thrombus generation and development in a dose-dependent manner.The pharmacokinetic profile of fondaparinux following subcutaneous administration is characterized by high bioavailability (>100%) and slow elimination (mean terminal elimination half-life 13.1–20.7 hours) allowing once-daily administration. The volume of distribution (8.2–10.2L) suggests that fondaparinux is limited to the vascular compartment. Fondaparinux is highly bound to circulating antithrombin (>94%) and has negligible binding to other plasma proteins.In patients with VTE, the bodyweight-adjusted fondaparinux dose regimen (5.0mg in patients weighing <50kg, 7.5mg in patients weighing 50–100kg, and 10mg in patients weighing >100kg) provided similar drug exposure across all bodyweight categories. At steady state, mean peak plasma concentration (Cmax) was 1.41 mg/L, time to reach Cmax was 2.4 hours, and the minimum plasma concentration was 0.52 mg/L.When administered subcutaneously, 64–75% of fondaparinux in a dose range of 2–10mg is excreted in the urine. Fondaparinux is not metabolized by liver enzymes and does not inhibit cytochrome P450 isoenzymes. In healthy volunteers, fondaparinux clearance is correlated with creatinine clearance.Therapeutic EfficacyIn two large, 3-month, phase III trials, subcutaneous fondaparinux was noninferior to either subcutaneous enoxaparin or intravenous UFH in the prevention of recurrent VTE in patients with DVT or PE. In the double-blind MATISSE (Mondial Assessment of Thromboembolism treatment Initiated by Synthetic pentasaccharide with Symptomatic Endpoints)-DVT trial, the incidence of recurrent VTE in patients with DVT was 3.9% in patients receiving fondaparinux and 4.1% in patients receiving enoxaparin. In the nonblind MATISSE-PE trial, the incidence of recurrent VTE was 3.8% in patients receiving fondaparinux and 5.0% in those receiving UFH.After 3 months in a phase II dose-ranging trial, thrombotic burden, as measured by repeat ultrasound and perfusion scans, was improved in 45.2% of fondaparinux and 48.7% of dalteparin recipients, while recurrent VTE occurred in 2.4% of fondaparinux and 5.0% of dalteparin recipients.TolerabilityFondaparinux was generally well tolerated in patients with DVT or PE. The incidence of major bleeding during initial parenteral anticoagulation therapy was similar in fondaparinux (0.8–2.9%), enoxaparin (1.2%), dalteparin (0%), and UFH (1.1%) recipients. Major or nonmajor bleeding during the initial treatment period occurred with similar incidences in fondaparinux, enoxaparin, and UFH treatment groups, and no differences were observed in the incidence of major or nonmajor bleeding throughout the entire trial period, including subsequent vitamin K antagonist treatment.As a result of increased fondaparinux exposure, patients with impaired renal function had a greater incidence of bleeding-related adverse events than did those with normal renal function. Mortality occurred at similar rates in fondaparinux and comparator treatment groups in the MATISSE-PE and -DVT trials.Thrombocytopenia was observed in 10 (0.9%) fondaparinux recipients and 13 (1.2%) UFH recipients. In the MATISSE-DVT trial, 7 (0.6%) patients in each of the fondaparinux and enoxaparin treatment groups experienced thrombocytopenia.

Ramipril : A review of its use in preventing cardiovascular outcomes in high-risk patients

Ramipril is an oral, non-sulfhydryl ACE inhibitor thought to act in the renin-angiotensin-aldosterone system to decrease vasopressor activity, aldosterone secretion, and bradykinin degradation. Ramipril is generally well tolerated and effective in the treatment of patients aged > or =55 years at high risk for the development of cardiovascular (CV) events, in whom the risk of myocardial infarction (MI), stroke, and CV death can be significantly reduced. The risk of these CV outcomes may also be reduced with ramipril therapy in various subgroups; these include patients with diabetes mellitus, peripheral arterial disease (PAD) or renal insufficiency, and women. Thus, ramipril, in addition to lifestyle interventions, should be considered an important therapy in the prevention of CV outcomes in high-risk patients.

Zoster Vaccine Live (Oka/Merck)

Abstract▴ A subcutaneously administered, live, high-titre (18 700–60 000 plaque-forming units per dose) varicella zoster virus (VZV) vaccine (zoster vaccine) of the Oka/Merck strain has been evaluated for the prevention of herpes zoster and the reduction of zoster-associated pain in adults aged ≥60 years.▴ Zoster vaccine, when compared with placebo, reduced the burden of herpes zoster illness by 61%, the incidence of herpes zoster by 51% and the incidence of postherpetic neuralgia by 67% during more than 3 years of surveillance.▴ The zoster vaccine caused an initial 1.7-fold rise in VZV antibody titre after 6 weeks that declined progressively over 3 years.▴ Increases in γ-interferon-secreting peripheral blood mononuclear cells were 2.2-fold greater with the zoster vaccine than with placebo 6 weeks after vaccination.▴ Zoster vaccine was generally well tolerated. The most frequently reported adverse reactions following vaccination were injection-site reactions; the only systemic adverse event with zoster vaccine that differed significantly in incidence from that with placebo was headache.