Candesartan Cilexetil

Candesartan cilexetil is the orally administered prodrug of candesartan, an angiotensin II subtype 1 receptor antagonist. The pharmacokinetics (area under the plasma concentration-time curve and maximum plasma concentration) of candesartan do not appear to be affected by age, sex, or weight, with a similar exposure observed in children aged 1 to <6 years or >6 years and adults. Therapy with candesartan cilexetil 0.05, 0.20, and 0.40 mg/kg/day for 4 weeks was effective in the treatment of hypertension in children aged 1 to <6 years, inducing significant dose-dependent reductions from baseline in sitting SBP (SSBP) [primary endpoint] and sitting DBP (SDBP) in the double-blind phase of a randomized, parallel-group, multinational, dose-ranging clinical study. The criteria for antihypertensive response (SBP and DBP values that were less than the 95th percentile) were met by 28–66% of patients. The beneficial antihypertensive effects of candesartan cilexetil therapy were sustained for up to 160 weeks. No significant difference from zero in the slope of the placebo-adjusted change in SSBP (primary endpoint) and SDBP was observed across the three candesartan cilexetil treatment groups (candesartan cilexetil 2,8, or 16 mg/day in patients weighing <50 kg and candesartan cilexetil 4, 16, or 32 mg/day in patients weighing ≥50 kg) during the double-blind phase of a randomized, double-blind, parallel-group, placebo-controlled, multinational, dose-ranging study in children and adolescents aged 6 to <17 years. Nonetheless, candesartan cilexetil demonstrated significantly greater changes from baseline to the end of the double-blind phase than placebo in SSBP and SDBP, with a significantly higher proportion of patients receiving candesartan cilexetil meeting the criteria for antihypertensive response than those receiving placebo. Antihypertensive response rates were sustained for 52 weeks. Candesartan cilexetil therapy for up to 160 weeks was generally well tolerated in clinical studies in children and adolescents aged 1 to <17 years with hypertension.     

The effects of scopolamine,lorazepam, and glycopyrrolate on classical conditioning of the human eyeblink response

Human eyeblink conditioning, a relatively simple form of learning and memory, has previously been shown to be impaired by the central and peripheral anticholinergic scopolamine. The present study compared the behavioral effects of scopolamine with the benzodiazepine lorazepam and a peripherally active anticholinergic, glycopyrrolate. Thirty-six healthy normal volunteers (mean age: 23.7 years) were studied with 12 assigned double-blind to each of three drug conditions (0.5 mg scopolamine IV, 2 mg lorazepam PO, or 0.2 mg glycopyrrolate IV). Subjects underwent classical conditioning of the eyeblink response in which the conditioned stimulus was an 80 dB binaural tone, and the unconditioned stimulus was a 2 psi airpuff to the right eye. Ten trials of unpaired stimulus presentations were followed by 60 paired trials and finally by an extinction period of five tone-alone presentations. An eyeblink response that occurred during the tone but before the airpuff was scored as a conditioned response (CR). Subjects treated with lorazepam (43% mean CRs) and scopolamine (51% mean CRs) exhibited a significantly lower asymptotic level of conditioning than those treated with glycopyrrolate (85% mean CRs;P<0.01). However, during extinction, lorazepamtreated subjects (35% CRs) showed a lower overall level of responding to the tone than either scopolamine (60% CRs) or glycopyrrolate (62% CRs) treated subjects (P<0.05). It seems unlikely that these differences could be accounted for by drug-induced alterations in motor responses because there were no significant differences between the three drug conditions in the frequency, latency, or amplitude of unconditioned responses to the airpuff. Overall, our data indicate that scopolamine and lorazepam impair eyeblink conditioning and suggest that some of the effects of benzodiazepines and anticholinergics on learning and memory can be differentiated using this paradigm.     

Valsartan: in children and adolescents with hypertension

Valsartan is an oral angiotensin II subtype 1 receptor antagonist with well established antihypertensive efficacy in adults. It is now approved in the EU and the US for the treatment of hypertension in children and adolescents. In two, randomized, double-blind trials, a once-daily regimen of valsartan reduced the blood pressure (BP) of children and adolescents with hypertension. In one trial in hypertensive children and adolescents aged 6-16 years, significant dose-dependent reductions from baseline in mean sitting systolic BP (msSBP) were observed for recipients of valsartan following 2 weeks' treatment (primary endpoint). There were corresponding dose-dependent and significant reductions in mean sitting diastolic BP. Following 2 further weeks of treatment, the reduction in msSBP was maintained in patients who were re-randomized to continue receiving the same dosage of valsartan but not in those re-randomized to placebo. In the other trial in hypertensive children and adolescents aged 6-17 years, valsartan was no less effective than enalapril in reducing BP. Following 12 weeks' treatment, the least square mean reduction from baseline in msSBP (primary endpoint) in recipients of valsartan was noninferior to that in recipients of enalapril. In addition, the proportion of patients achieving an msSBP <95th percentile for age, sex, and height at week 12 was not significantly different between recipients of valsartan and enalapril (67% vs 70%). Treatment with valsartan for up to 52 weeks was well tolerated in children and adolescents with hypertension.     

Glycopyrrolate treatment of drooling in an adult male patient with cerebral palsy

1. The aim of the study was to assess the effect of glycopyrrolate on drooling in an adult male patient with cerebral palsy. 2. After a thorough medical examination and consent in writing by the responsible guardian, a baseline sum score for frequency and seriousness of drooling was established over a 2 week period in addition to data on shifts of handkerchiefs, urination, defecation and observation of behaviour. Glycopyrrolate (1 mg) tablets were then administered, starting with one tablet daily the third week and increasing the daily dose by one tablet per week until a maximum of four tablets during week six and 4 days of week seven when the daily dose was reduced to two tablets for 3 days. For the four weeks 8-11 three tablets were given daily. In week 12 the dose was reduced to two tablets and for the weeks 13-15 no tablets of glycopyrrolate were given. 3. For as long as the patient received three to four tablets of glycopyrrolate daily, drooling was markedly reduced and handkerchiefs were not necessary on some days. After the tablets were withdrawn drooling increased to approximately the same level as it was before treatment. No adverse medical, psychological, or social effects were observed. 4. For shorter periods, glycopyrrolate can be given in controlled doses provided that an adequate medical assessment has been undertaken.     

Results of an independent oncology review board of pivotal clinical trials of gemcitabine in non-small cell lung cancer

Response rates reported in early phase II clinical trials are often not reproduced in subsequent larger or phase III studies. Independent review of claimed partial or complete responders to gemcitabine was undertaken in four pivotal, open-label phase II studies of advanced, non-small cell lung cancer (NSCLC) to provide accurate, consistent, reproducible response rates. Patients were chemonaive and had stage III or IV NSCLC. In three trials, gemcitabine (800 and 1250 mg/m2) was administered once-weekly for 3 weeks followed by a rest week. In the fourth, gemcitabine (90 mg/m2) was given twice-weekly for 3 weeks in every 4 weeks. The primary endpoint was response rate. Of the 374 evaluable patients, 114 (30%) were claimed as responders. Independent review reduced this to 79 (21%). The response range was reduced from 25-35 to 20-23% after validation; 95% confidence intervals did not overlap. Consistent application of response criteria by an independent panel significantly reduced response rates but produced greater consistency and reproducibility. These results confirm that gemcitabine is active against NSCLC. Subsequent larger-scale studies have produced comparable response rates, vindicating the use of independent review. Independent review is recommended for all trials using response rate as a primary endpoint.     

Trastuzumab : in HER2 and hormone receptor co-positive metastatic breast cancer

Trastuzumab is a humanised IgG1 monoclonal antibody, which selectively binds to the human epidermal growth factor receptor 2 (HER2), inhibiting cell proliferation and survival in HER2-dependent tumours. In a randomised phase III trial in postmenopausal women with HER2 and hormone receptor (HR) co-positive metastatic breast cancer, median progression-free survival (primary endpoint) was significantly longer in patients receiving intravenous trastuzumab plus oral anastrozole than in those receiving anastrozole alone. Overall response rate and clinical benefit rate were also significantly higher, and median time to disease progression was significantly longer with trastuzumab plus anastrozole versus anastrozole alone. There were no reports of new or unexpected adverse events with trastuzumab plus anastrozole combination therapy in the randomised phase III trial. In a noncomparative phase II study of trastuzumab plus letrozole in postmenopausal women with HER2 and HR co-positive metastatic breast cancer, the majority of adverse events were mild or moderate in severity.     

Spontaneous baroreflex sensitivity as a dynamic measure of cardiac anticholinergic drug effect

1 In this study, the analysis of spontaneous baroreflex sensitivity (BRS) was applied to the dynamic assessment of cardiac anticholinergic drug effect in healthy male volunteers. 2 The anticholinergic effects of single intravenous (i.v.) injections of atropine (10 μg kg^–1), glycopyrrolate (5 μg kg^–1) and scopolamine (5 μg kg^–1), as well as a 2‐h infusion of glycopyrrolate (5 μg kg^–1 h^–1) were investigated. Baroreflex sensitivity, a validated measure of cardiac parasympathetic reflex regulation, was repeatedly measured from 5‐min recordings of electrocardiogram (ECG) and continuous blood pressure by using the sequence technique, a method based on detection of spontaneous fluctuations in blood pressure and heart rate. 3 Single injections of atropine, glycopyrrolate and scopolamine decreased the mean BRS by 71 ± 32, 68 ± 23 and 27 ± 45%, respectively, whereas the slow glycopyrrolate infusion gradually decreased BRS (up to 83 ± 11% reduction) and increased both systolic (SAP) and diastolic arterial pressures (DAP) (on an average, by 9 mmHg). 4 During the withdrawal of the parasympathetic blockade (indicated by increasing BRS), the proportion of baroreflex sequences in the recordings increased transiently from 10 up to 20–25%, probably reflecting the restoration of the baroreflex integrity and the baroreflex‐induced attempt to counteract the blood pressure increase. 5 The sequence method to study BRS seems to be feasible in the assessment of cardiac anticholinergic drug effects, and it also provides good time resolution for the dynamic measurements.     

Effects of scopolamine on immediate postural changes in heart rate and R—R variance in humans

To examine the anticholinergic effects of scopolamine, postural tests were performed in nine healthy male volunteers after they received intravenous infusions of 0.2mg of scopolamine, 0.4 mg of glycopyrrolate, or placebo on separate days under double-blind randomized conditions. Compared to the placebo and glycopyrrolate conditions, scopolamine produced a significantly exaggerated HR response to standing from supine posture. Scopolamine also produced a significant increase in R-R variance during supine deep breathing and standing conditions as compared to glycopyrrolate and placebo conditions. At the same time, scopolamine also produced a significant dry mouth. These findings suggest that the effects of scopolamine in low doses on the above cardiac variables are vagomimetic.     

MSI-78 Magainin Pharmaceuticals

Magainin is developing MSI-78, a 22-amino acid peptide, based on compounds discovered in frog skin, as a topical anti-infective. It has broad-spectrum activity, covering Gram-positive and -negative bacteria, anaerobic bacteria and Candida albicans. The compound also has potential for the treatment of impetigo and healing wounds with various infections. In July 1998, Magainin filed an NDA with the US FDA for the treatment of infections in diabetic foot ulcers [292671]. It expects to launch the drug during the second quarter of 1999 [275844]. A completed pivotal, 584 patient, phase III trial demonstrated statistical equivalence between MSI-78 and orally-administered ofloxacin, for the treatment of infection in diabetic foot ulcers. MSI-78 was comparable to ofloxacin with respect to the primary endpoint of clinical response of infection at day ten of treatment, and at subsequent time points through to day 28, and at follow-up [220339]. These data were confirmed by the company's second phase III trial for the same indication, for which successful results were announced in March 1997 [239274]. Additional data from this second trial, presented at the 37th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), demonstrated that both drugs were comparable in terms of eradication rate of individual organisms and wound healing [264410]. Between 10% and 15% of wounds in patients treated with a combination of both drugs reached closure within four weeks. After six weeks, the closure rate increased to between 18% and 30%. This suggested that additional studies should be performed to evaluate the wound-healing effects further [275279]. The side-effects of both treatments were well-tolerated, although treatment with ofloxacin was associated with a significant excess of insomnia compared to MSI-78 [275844]. Further phase III trials are planned for treatment of surgical wounds, decubitus ulcers, venous stasis ulcers and infections associated with burns [173293]. The primary clinical endpoint is the cure of the infection and the secondary endpoint is the eradication of the organism. The first study has enrolled approximately 400 patients [195065]. The drug was also being developed for impetigo, but proved no better than placebo in phase III trials for the treatmentprimarily because 75% of controls showed clinical improvement as a result of better hygiene [293751]. Magainin is attempting to develop a recombinant process for commercial synthesis of MSI-78 to allow it to compete on price with conventional antibiotics [174944], [176153]. Magainin has a contract with Abbott for the manufacture of the drug [174944]. In February 1997, Magainin entered into a development, supply and distribution agreement in North America with SmithKline Beecham (SB) for Cytolex [234035]. Magainin has retained all rights to the drug outside of North America [275844], although it has also signed an agreement with Ambalal Sarabhai Enterprises (ASE) to commercialize MSI-78 (as Cytolex) in India [274544], [275556]. Analysts estimate the potential revenues of this compound, including off-label usage is between $200 and $250 million in the US and up to half as much again outside the US [191231].     

Live attenuated influenza vaccine (FluMist®; Fluenz™): a review of its use in the prevention of seasonal influenza in children and adults

Live attenuated influenza vaccine (LAIV) is an intranasally administered trivalent, seasonal influenza vaccine that contains three live influenza viruses (two type A [H1N1 and H3N2 subtypes] and one type B). LAIV was effective in protecting against culture-confirmed influenza caused by antigenically matched and/or distinct viral strains in children aged ≤71 months enrolled in three phase III trials. LAIV was superior to trivalent inactivated influenza vaccine (TIV) in protecting against influenza caused by antigenically-matching viral strains in a multinational phase III trial in children aged 6-59 months. LAIV was also significantly more effective than TIV in decreasing the incidence of culture-confirmed influenza illness in two open-label studies (in children with recurrent respiratory tract illnesses aged 6-71 months and in children and adolescents with asthma aged 6-17 years). LAIV did not differ significantly from placebo in preventing febrile illnesses in adults (primary endpoint) enrolled in a phase III trial. However, LAIV significantly reduced the incidence of febrile upper respiratory tract illnesses (URTI), severe febrile illnesses, febrile URTI-related work absenteeism and healthcare provider use. In another well designed trial in adults, LAIV significantly reduced the incidence of symptomatic, laboratory-confirmed influenza compared with placebo (but not intramuscular TIV). LAIV was generally well tolerated in most age groups, with the majority of adverse events being mild to moderate in severity, and runny nose/nasal congestion being the most common. In a large phase III trial, LAIV, compared with TIV, was associated with an increased incidence of medically significant wheezing in vaccine-naive children aged <24 months and an increased incidence of hospitalization in children aged 6-11 months; LAIV is not approved for use in children <24 months. LAIV was not always associated with high rates of seroconversion/seroresponse, particularly in older children and adults, or in subjects with detectable levels of haemagglutination-inhibiting antibodies at baseline. However, LAIV did elicit mucosal (nasal) IgA antibody responses and strong cell-mediated immunity responses. Only one confirmed case of LAIV virus transmission to a placebo recipient (who did not become ill) occurred in a transmission study conducted in young children. The immunogenic response to LAIV in young healthy children was not affected by concomitant administration with other commonly administered childhood vaccines. In conclusion, intranasal LAIV seasonal influenza vaccine is effective and well tolerated in children, adolescents and adults. LAIV was more effective than TIV in children, although this advantage was not seen in adults. In the US, LAIV is indicated for the active immunization of healthy subjects aged 2-49 years against influenza disease caused by virus subtypes A and type B contained in the vaccine.     

Studies on a soft glycopyrrolate analog, SG-1

A short-acting soft drug analog (SG-1) of glycopyrrolate (G) was developed by retrometabolic design in order to minimize systemic side effects and optimize the therapeutic index. SG-1,3-(1'-hydroxycyclopentyl)phenylacetoxy-1-methyl-1- methoxycarbonylpyrrolidinium bromide, was synthesized by: (a) esterification of phenylacetic acid with N-methyl-3-pyrrolidinol by DCC to obtain N-methyl-3-pyrrolidinyl phenylacetate; (b) reaction of lithium salt of above phenylacetates with cyclopentanone to obtain N-methyl-3-pyrrolidinyl 3-(1'-hydroxycyclopentyl)phenylacetate; and (c) quarternization with methyl bromoacetate in acetonitrile to give the designed product. To evaluate the pharmacological effect of SG-1, its mydriatic activity in rabbit eyes was compared to that of glycopyrrolate. At the pharmacodynamically equivalent doses (the lowest dose that induces the maximum response) of SG-1 (1%) and glycopyrrolate (0.1%), the mydriatic activities lasted for 5 and 100 h, respectively. Compared to glycopyrrolate, the intrinsic pupil dilation potency of SG-1 was lower (approximately 1/10th) but the duration of action was much shorter (< 1/20th) as SG-1 is susceptible to facile enzymatic hydrolysis/deactivation in the rabbit eyes. In vitro metabolism and stability investigations further supported this finding. In vitro half lives of SG-1 in rat plasma, blood, and 20% liver and lung tissue homogenates were 15.62, 53.86, 263.43, and 318.35 min, respectively. In human plasma and blood, half-lives were 19.93 and 88.32 min, respectively. SG-1 was relatively stable under acidic conditions (pH 5 and lower). SG-1 is a promising, clinically useful short acting anticholinergic.     

Clonidine extended-release: in attention-deficit hyperactivity disorder

Clonidine, an α(2)-adrenergic agonist, is approved in the US as an extended-release (XR) tablet for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents (aged 6-17 years). In two, randomized, double-blind, multicenter, phase III trials of 8 weeks' duration, clonidine XR improved the symptoms of ADHD in children and adolescents. Significantly greater reductions from baseline in ADHD rating scale IV (ADHD-RS-IV) total scores at week 5 (primary endpoint) were achieved by recipients of clonidine XR 0.2 and 0.4?mg/day monotherapy than by recipients of placebo. When added to patients' normal stimulant regimen, significantly greater reductions from baseline in ADHD-RS-IV total scores at week 5 (primary endpoint) were achieved with a flexible dose of clonidine XR 0.1-0.4?mg/day than with placebo. Symptomatic improvement of ADHD was achieved following 2 weeks' treatment with clonidine XR. In both trials, significantly greater reductions from baseline in ADHD-RS-IV total scores were apparent at week 2 onwards for recipients of clonidine XR than for recipients of placebo. Clonidine XR was generally well tolerated as monotherapy and as adjunctive therapy with stimulant regimens in clinical trials in children and adolescents.     

Belimumab: in systemic lupus erythematosus

Belimumab is a fully human recombinant IgG1λ monoclonal antibody that inhibits the binding of soluble B lymphocyte stimulator to B cells and hence prevents the survival and differentiation of selected B-cell subsets. It is available in the US, the EU and Canada for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity despite receiving standard therapy. At 52 weeks, a significantly greater proportion of belimumab 10?mg/kg than placebo recipients experienced a response as assessed by the SLE Responder Index (primary endpoint) in the randomized, double-blind, multinational, phase III BLISS-52 and BLISS-76 trials in patients with active seropositive SLE receiving standard therapy. A significantly greater proportion of belimumab than placebo recipients achieved a ≥4 point reduction in the SELENA-SLEDAI score at week 52 in both BLISS trials. However, the SLE Responder Index response rate was not significantly different between belimumab and placebo at 76 weeks in BLISS-76. Belimumab was generally well tolerated in the BLISS trials. During the double-blind periods of these trials and the phase II trial, twice as many deaths were reported with belimumab than placebo (six vs three). There were no meaningful differences between the incidence of serious infections and malignancies with belimumab or placebo.     

Olmesartan medoxomil: in children and adolescents with hypertension

Olmesartan medoxomil is an orally administered angiotensin II receptor antagonist, selective for the angiotensin II type 1 receptor, which has established antihypertensive efficacy in adults. In children and adolescents with hypertension (n?=?302), oral olmesartan medoxomil significantly and dose-dependently reduced seated systolic blood pressure (BP) and seated dystolic BP from baseline (the primary endpoint) in a 3-week, dose-response period in a well designed phase II/III clinical trial. Patients received olmesartan medoxomil high dose (20 or 40?mg once daily depending on bodyweight) or low dose (2.5 or 5.0?mg once daily depending on bodyweight). The response was significant for both cohorts, which were stratified by race (cohort A was mixed race [62% White] and cohort B was 100% Black). In addition, BP control was maintained in olmesartan recipients relative to placebo recipients in cohort A and the combined cohort A?+?B, but not for patients in cohort B, during a placebo-controlled withdrawal period of this trial. Oral olmesartan medoxomil was generally well tolerated in children and adolescents with hypertension. The majority of adverse events were of mild to moderate intensity.     

Efficacy and safety of elbasvir/grazoprevir for 12 weeks in people with hepatitis C virus infection aged 35 years or younger compared with older people: a retrospective integrated analysis

Abstract

Background: In the United States, the number of new cases of hepatitis C virus infection has risen in recent years, driven largely by transmission among young white adults in their 20s and 30s. Herein, we report an integrated analysis of participants with hepatitis C virus infection aged ≤35?years from 12 phase II/III clinical trials of elbasvir/grazoprevir.

Methods: Treatment-naive and -experienced adults with hepatitis C virus genotype 1 or 4 infection received elbasvir (50?mg/day)/grazoprevir (100?mg/day) for 12?weeks without ribavirin. Analyses were stratified according to participant age (≤35?years vs >35?years). The primary endpoint was sustained virologic response (hepatitis C virus RNA?<?lower limit of quantitation at 12?weeks after completion of therapy).

Results: Sustained virologic response was achieved by 98.9% (271/274) of participants aged ≤35?years and by 96.9% (2093/2160) aged >35?years. Three participants aged ≤35?years with genotype 1b infection relapsed. Eight participants with genotype 1a infection and baseline non-structural protein 5?A resistance-associated substitutions achieved sustained virologic response. Similarly, all 85 participants aged ≤35?years with genotype 1a infection and no baseline non-structural protein 5?A resistance-associated substitutions achieved sustained virologic response. Safety was favorable, with the incidence of drug-related adverse events similar in younger and older participants (30.1% vs 30.6%). One participant (0.4%) aged ≤35?years and 15 participants (0.7%) aged >35?years discontinued treatment owing to adverse events.

Conclusions: Elbasvir/grazoprevir for 12 weeks was safe and highly effective in participants aged ≤35?years with hepatitis C virus genotype 1 or 4 infection.     

Acute extrapyramidal side effects: Serum levels of neuroleptics and anticholinergics

An assay technique for measuring anticholinergic drugs in human serum based upon their inhibition of the specific binding of [³H]-quinuclidinyl benzilate to rat brain muscarinic receptors is described. The assay was validated by demonstrating a close correlation (r=0.99) between serum levels of nortriptyline measured by the radioenzymatic assay and a GLC technique. The assay measures free anticholinergics, and under standard assay conditions, approximately 95% of benztropine is bound to serum protein. Marked variation in serum anticholinergic levels in patients receiving the same oral dose was observed, and in individual patients there was a non-linear relationship between increasing oral dose and serum anticholinergic levels.In a cross-sectional study of 109 patients receiving concurrently neuroleptics and antichlinergics, there was no correlation (r=0.029) between serum neuroleptic levels measured by a radioreceptor assay and extrapyramidal side effects (EPS). In the patients whose serum anticholinergic levels were also determined, there was a significant inverse correlation (r=0.44) between anticholinergic levels and EPS. In this cohort of patients, there was no significant correlation between serum anticholinergic and serum neuroleptic levels (r=0.16) and the ratio of serum anticholinergic to serum neuroleptic was a poor predictor of EPS (r=0.26).The results suggest a marked variation in sensitivity of patients to the EPS-inducing of neuroleptics; nevertheless, the incidence of EPS decreases with increasing serum levels of anticholinergics. An optimal serum anticholinergic level of 10 pmole atropine equivalent per ml was associated with a low incidence of EPS and is relevant to drug action at the striatal muscarinic receptor.     

Pharmacokinetic–pharmacodynamic model for the anticholinergic effect of glycopyrrolate

OBJECTIVE: The purpose of this study was to develop and test a pharmacokinetic-pharmacodynamic (PK-PD) model for the anticholinergic effect of glycopyrrolate in eight healthy male volunteers. METHODS: First, arterial drug concentration (Cp) data after a single intravenous (i.v.) bolus injection (5 micrograms/kg) were individually fitted to a three-compartment PK model. Second, the effect of a 2-h glycopyrrolate i.v. infusion (5 micrograms/kg/h) on the mean R-R interval (RRI) and the Hayano index of the high frequency variability of RRI (HF CCV) was modelled using an effect-compartment, inhibitory sigmoidal Emax model, with the individual PK parameters from the first part as constants. Third, the developed model was tested using a computer-driven infusion which aimed at two ascending steady-state effect-site concentrations (Ce) at 1-h intervals, corresponding to 20% and 80% of the maximal effect (Emax) observed in the second part. RESULTS: Modeling of the HF CCV data yielded the following mean (+/- SD) estimates: concentration at 50% of Emax (EC50), 2.46 +/- 0.58 ng/ml, equilibration half-time (t1/2 ke0), 42.5 +/- 7.7 min, and sigmoidicity factor (gamma), 7.26 +/- 2.82. The corresponding values for RRI data were 2.79 +/- 0.52 ng/ml, 58.3 +/- 17.2 min, and 4.75 +/- 1.56. During the computer-controlled two-step infusion (performed using HF CCV as the effect variable), the measured Cp approached the targeted Ce in most of the subjects, while the observed effect appeared to surpass the targeted levels. CONCLUSION: Although we were able to develop individual PK-PD models for glycopyrrolate, maintaining a stable anticholinergic effect in the computer-driven infusion appeared to be difficult. This is probably due to intra-individual variability in the PK-PD parameters and the extremely steep concentration-effect relationship of glycopyrrolate.     

Posaconazole

Posaconazole is a triazole antifungal agent, administered as an oral suspension, with an extended spectrum of in vitro activity. Posaconazole 800 mg/day demonstrated clinically relevant activity against a range of fungi in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal therapy in an open-label, multicentre, phase III study (330 patients received posaconazole and 279 patients served as external controls). In aspergillosis, the global response success rate at the end-of-therapy visit (primary endpoint) was significantly higher in posaconazole recipients than in external controls (42% vs 26%). Posaconazole was also associated with overall success rates of 54% in zygomycosis, 46% in fusariosis, 43% in Pseudallescheria infection, 80% in phaeohyphomycosis and 100% in histoplasmosis. Success rates were 48% in refractory candidiasis, 69% in refractory coccidioidomycosis, 48% in refractory cryptococcal infection and 82% in refractory chromoblastomycosis or mycetoma. Posaconazole also demonstrated potential in febrile neutropenia in an open-label phase II study (success rate of 81% 7 days after the end of treatment). In a noncomparative, multicentre, phase III study in patients with advanced HIV infection who had azole-refractory oropharyngeal and/or oesophageal candidiasis, posaconazole 400 or 800 mg/day resulted in a clinical response in 132 of 176 patients (75%). Oral posaconazole suspension was generally well tolerated in patients with invasive fungal infections, including patients who received treatment for >or=1 year.     

Mannitol dry powder for inhalation: in patients with cystic fibrosis

Mannitol dry powder for inhalation has been developed for the treatment of patients with cystic fibrosis. Two randomized, double-blind, multinational, 26-week, phase III trials (CF-301 and CF-302) examined the efficacy of inhaled dry powder mannitol in patients aged ≥ 6 years with cystic fibrosis who were receiving standard care (with a substantial proportion of patients receiving dornase alfa and antibacterials at baseline). Good compliance was seen in both studies. A sustained, significant (p<0.001) improvement in forced expiratory volume in 1 second (FEV(1)) [mean absolute change from baseline over 26 weeks; primary endpoint] was seen in patients with cystic fibrosis who received inhaled mannitol, compared with the control group, in the CF-301 trial, but not in the CF-302 trial (p=0.059). In both CF-301 and CF-302, the relative increase from baseline in percent predicted FEV(1) and the improvement from baseline in forced vital capacity were significantly greater in patients receiving inhaled mannitol than in the control group. In a pooled analysis of the CF-301 and CF-302 trials, the relative risk of a pulmonary exacerbation requiring intravenous antibacterials was significantly reduced by 29% for inhaled mannitol recipients versus the control group (relative risk 0.71; 95% CI 0.51, 0.98) [p=0.039]. Inhaled dry powder mannitol was generally well tolerated in adults with cystic fibrosis in the CF-301 and CF-302 studies, with most treatment-emergent adverse events being of mild to moderate severity.