Once-daily Basis Research Articles

Pre- and perioperative prophylaxis of anti-VEGF therapy in patients with exudative macular degeneration

Macular degeneration is one of the leading causes of blindness worldwide. Nowadays, the gold standard treatment for its exudative form is intravitreal injections with vascular growth factor inhibitor preparations performed on a once-daily basis. Great importance is now attached to the appropriate prophylaxis in the pre- and perioperative period in order to minimise the risk of complications, which often lead to irreversible damage to vision.

Once-daily dosing is appropriate for extended-release divalproex over a wide dose range, but not for enteric-coated, delayed-release divalproex: Evidence via computer simulations and implications for epilepsy therapy

Divalproex sodium extended-release (divalproex-ER), administered once-daily, maintains plasma valproic acid (VPA) concentrations for 24h, whereas enteric-coated, delayed-release divalproex sodium (divalproex) requires multiple-daily doses to do the same. We hypothesize that a once-daily divalproex regimen should not be administered to epilepsy patients requiring high total daily doses, e.g., 35.6-56 mg/kg/day, due to the potential for high (>125 mg/L) maximum VPA concentrations (C(max)). We examined the impact of once-daily dosing, divalproex vs. divalproex-ER, on steady-state plasma VPA concentration-time profiles at commonly used doses in monotherapy (uninduced) and polytherapy (hepatic enzyme-induced) virtual adult patients. Only the 1125 mg once-daily divalproex dose had mean C(max)<100mg/L; >or=2000 mg produced mean C(max)>or=125 mg/L. Mean divalproex C(min) was approximately 50 mg/L at two of four doses tested, whereas mean ER C(min) was >73 mg/L at all doses tested. Once-daily divalproex peak-trough fluctuation was 4.4-6.2-fold greater than once-daily divalproex-ER. We predict that excursions beyond the conventional recommended VPA plasma concentration range will commonly occur with high total mg daily doses (>or=2000 mg) of enteric-coated divalproex, if dosed once-daily, potentially producing clinical toxicity. This divalproex formulation should not be dosed once-daily at high total mg daily doses due to this risk. Divalproex-ER is the appropriate formulation for administration on a once-daily basis, especially if large total mg/day doses are required for the control of seizure activity.

Loss of GABAergic Signaling by AgRP Neurons to the Parabrachial Nucleus Leads to Starvation

Neurons in the arcuate nucleus that produce AgRP, NPY, and GABA (AgRP neurons) promote feeding. Ablation of AgRP neurons in adult mice results in Fos activation in postsynaptic neurons and starvation. Loss of GABA is implicated in starvation because chronic subcutaneous delivery of bretazenil (a GABA(A) receptor partial agonist) suppresses Fos activation and maintains feeding during ablation of AgRP neurons. Moreover, under these conditions, direct delivery of bretazenil into the parabrachial nucleus (PBN), a direct target of AgRP neurons that also relays gustatory and visceral sensory information, is sufficient to maintain feeding. Conversely, inactivation of GABA biosynthesis in the ARC or blockade of GABA(A) receptors in the PBN of mice promote anorexia. We suggest that activation of the PBN by AgRP neuron ablation or gastrointestinal malaise inhibits feeding. Chronic delivery of bretazenil during loss of AgRP neurons provides time to establish compensatory mechanisms that eventually allow mice to eat.

Paliperidone-ER: first atypical antipsychotic with oral extended release formulation

Paliperidone-extended release (ER) is an antipsychotic medication newly introduced in the USA and Europe in 2007. It is the first oral atypical antipsychotic with an extended release, which is achieved by the osmotic-controlled release oral delivery system (OROS®), a well-established technology already in use for CNS drugs (e.g., methylphenidate and hydromorphone). Paliperidone was in the focus of investigations for years, as it is the major metabolite (9-hydroxyrisperidone) of the widely used atypical antipsychotic risperidone. Paliperidone-ER has demonstrated clinical efficacy, safety and good tolerability on a once-daily basis in three randomized, double-blind, placebo-controlled, 6-week-studies including patients with acute schizophrenia and one randomized, double-blind, placebo-controlled long-term study assessing recurrence of psychotic symptoms in patients with schizophrenia. Key features are predominant renal elimination, therefore low risk of interaction with other drugs, good efficacy against psychotic symptoms based on D2-receptor and 5HT2A-receptor antagonism and very low affinity for muscarinic receptors resulting in absence of anticholinergic side effects. The OROS-ER technology leads to considerably lower plasma peak levels compared with nonextended-release formulations, thus possibly reducing side effects.

Can famotidine and omeprazole be combined on a once-daily basis?

Objective. Prompt and long-standing acid control following once-daily administration of antisecretory drugs is desirable. The objective of this study was to determine whether co-administration of a well-characterized H2-receptor antagonist, famotidine, can be combined with the proton-pump inhibitor omeprazole. Material and methods. Intragastric 24-h pH-metry was performed in healthy, Helicobacter pylori-negative volunteers on day 1 and after 8 days of daily administration of 20 mg omeprazole, 10 mg famotidine, or a combination of these in a three-way crossover design. Results. A combination of famotidine and omeprazole raised the gastric pH level to >4 in less than 1 h. The percentage of daytime with pH > 4 on day 1 was significantly higher with the combination of omeprazole and famotidine (median: 37%) than that with omeprazole alone (22%; p < 0.05). On day 8, daytime intragastric pH > 4 following treatment with omeprazole (median: 55%) or a combination of omeprazole and famotidine (61%) was superior (p < 0.05) to that with famotidine (21%). On day 1 treatment with both famotidine and the combination (famotidine and omeprazole) showed a significantly shorter time to reach a pH of 4 (medians: 93 and 63 min, respectively) compared with treatment with omeprazole alone (173 min; p < 0.05). Conclusions. Compared with treatment with omeprazole alone, on day 1 famotidine and omeprazole in combination improved the duration of and time to reach intragastric pH > 4. With regard to duration with pH > 4, the combination therapy was superior to famotidine alone on day 8. The rapid acid control with an H2-receptor antagonist may be combined with the long-lasting antisecretory effect of a proton-pump inhibitor.

Antihypertensive Effect of Manidipine

Manidipine is a lipophilic, third-generation, highly vasoselective, dihydropyridine (DHP) calcium channel antagonist, which, when given on a once-daily basis, effectively reduces blood pressure (BP) in patients with mild-to-moderate essential hypertension. Manidipine has a gradual onset and a long duration of action, effectively maintaining reduced BP levels throughout the 24-hour dosing period, and is effective in the long term with no evidence of intolerance. The BP-lowering capacity of manidipine is similar to that of other established DHPs and of angiotensin-converting enzyme inhibitors. Diabetic patients and very elderly patients with mild-to-moderate hypertension also respond favourably to treatment with manidipine. Manidipine has neutral effects on glucose and lipid metabolism and is generally well tolerated. Manidipine thus represents a first-line option for lowering BP in patients with mild-to-moderate hypertension.

Methods for evaluating the duration of action of once-daily antihypertensive therapy.

There are several methods available to determine the duration of action of an antihypertensive drug. Traditional approaches involve measurements of blood pressure (BP) at the end of the dosing interval (trough). Ambulatory BP monitoring can be used to obtain additional information on the time course and magnitude of the decrease in BP over a standard dosing interval. Use of the 'missed dose' technique makes it possible to demonstrate persistent reductions in BP beyond 24 h for drugs given on a once-daily basis.

Pharmacodynamics of abacavir in an in vitro hollow-fiber model system.

Abacavir is a potent new carbocyclic nucleoside analogue. We employed our hollow-fiber pharmacodynamic modeling system to examine the antiretroviral effects of different abacavir exposures, as well as the impact of the schedule of drug administration on efficacy. Dose ranging of abacavir revealed that a concentration of four times the 50% effective concentration (EC(50)) (approximately the EC(95)) was required to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) (strain MN) either in a continuous-infusion hollow-fiber experiment or in a classical tissue culture flask experiment. In contrast to earlier work with another drug class (HIV-1 protease inhibitors), addition of physiological amounts of the human drug binding proteins albumin and alpha(1) acid glycoprotein revealed that there was little impact on the antiviral effect of the drug. Comparison of equivalent exposures (an area under the concentration-time curve [AUC] developed by approximately 500 mg per day of orally administered abacavir), either in a continuous-infusion mode or as a single oral dose of abacavir, demonstrated no difference in the ability to suppress either strain III(B) or strain MN. Comparison of administration of 250 mg every 12 h (q12h) versus once-daily administration of 500 mg for strain MN again showed no significant difference in suppressive effect. These experiments were carried out over 8 to 15 days. Because of these promising initial results, we extended the experiment to 30 days and examined three different schedules of administration that generated the same AUC at 24 h (AUC(24)): 300 mg q12h, 600 mg q24h, and 1,200 mg q48h. The aim of the last of these regimens was to definitively demonstrate schedule failure. There was little difference between the 1,200-mg q48h treatment group and the untreated control at 30 days. Likewise, there was little difference between the 600-mg q24h and 300-mg q12h treatment groups. However, at circa day 18 of the experiment, there was a small increase in viral output of p24 in the once-daily dosing unit. Examination of virus from all groups demonstrated no phenotypic or genotypic differences. The small difference in hollow-fiber unit p24 in the once-daily dosing group was not due to emergence of resistance over the 30-day single-drug exposure. We conclude that the dose of abacavir currently being studied in clinical trials (300 mg orally q12h) will be efficacious for the majority of sensitive clinical isolates of HIV-1. These in vitro data also suggest that this drug may be able to be administered to patients on a once-daily basis at a dose of 600 mg.

Discussion

Discussion

Olanzapine: Psychopharmacology, Clinical Efficacy, and Adverse Effects

Olanzapine is an atypical antipsychotic that has a pharmacological profile similar that of clozapine. It is biotransformed by hepatic enzymes and can be dosed on a once-daily basis. In large, double-blind, placebo-controlled trials, olanzapine was shown to be efficacious in the treatment of schizophrenia relative to placebo. Many trials showed superior efficacy to haloperidol, especially against negative symptoms. Olanzapine is FDA-approved for the treatment of psychotic disorders, though data suggest possible use in depression, bipolar disorder, psychogenic polydipsia, and developmental disabilities. Olanzap-ine appears to be well-tolerated. Commonly reported adverse effects include orthostatic hypotension, sedation, hepatic transaminase elevations, weight gain, headache, agitation, dizziness, and constipation. The incidence of extrapyramidal symptoms and tardive dyskinesia is low. Few drug interactions have been reported. The recommended starting dose is 10 mg once daily. One trial indicated that the higher cost of this agent might be offset by a reduction in overall hospitalization costs.

Teicoplanin

Teicoplanin, a new glycopeptide antibiotic similar to vancomycin, has proved effective in the treatment of various gram-positive infections in both the normal and the immunocompromised host. In vitro activity against most gram-positive organisms is equal to or greater than that of vancomycin. In both open and comparative clinical trials, teicoplanin has been well tolerated, rarely prompting discontinuation of treatment. Nephrotoxicity caused by teicoplanin is uncommon, even when used concomitantly with aminoglycosides or cyclosporin A. Favorable pharmacokinetics allow for intramuscular administration as well as intravenous bolus dosing, and, after appropriate loading doses, maintenance therapy may be given on a once-daily basis. The combination of all of these factors makes teicoplanin an effective, safe alternative to vancomycin in the treatment of gram-positive infections.

Response to Growth Hormone in Children with Idiopathic Short Stature

A multicentre randomized trial of human growth hormone (GH) treatment was carried out in 121 children with short stature who did not meet the classic criteria for GH deficiency. In the first year of the trial, half of the children received treatment with recombinant somatropin 0.1 mg/kg (0.27 IU/kg) three times weekly and showed a significant increase in mean growth velocity from a pretreatment value of 4.6 +/- 1.1 to 7.5 +/- 1.2 cm/year (mean +/- SD). The growth velocity of the untreated children did not change significantly. The growth velocity of the control group (including 10 pubertal children) increased from 4.2 +/- 1.3 to 5.0 +/- 1.4 cm/year. In the second year, half of the control group received treatment with somatropin, 0.1 mg/kg (0.27 IU/kg) three times weekly, while the remainder received the same weekly dose on a once-daily basis. The mean growth velocity increased in both cases to 8.2 +/- 1.4 and 9.0 +/- 1.6 cm/year, respectively. The group treated during the first year was also divided into two groups in the second year. One group continued with the original treatment regimen, resulting in a mean growth velocity of 6.8 +/- 1.8 cm/year. The other group changed to once-daily treatment at the same weekly dose and the mean growth velocity for this group in the second year was 7.8 +/- 1.4 cm/year. The gain in height age in both of these groups exceeded the bone age in both the first and second years of treatment, suggesting a gain in predicted adult height.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodipine pretreatment and the ischemic heart

Amlodipine is a long-acting dihydropyridine-based Ca 2+ channel blocker, developed for use on a once-daily basis. Experiments using hearts from amlodipine-pretreated rats were undertaken to further test the hypothesis that Ca 2+ channel blockers can be used as prophylactic therapy to reduce the severity of the mechanical and biochemical consequences of ischemia and reperkhsion. Amlodpine was given intravenously, 0.25 mg/kg, 5 hours before excising the hearts. Ischemia (global) was induced at 37°C for 10, 30 or 60 minutes, and was followed by reperfusion. Protection was quantitated in terms of functional recovery, adenosine triphosphate and creative phosphate retention, tissue acidosis and Ca 2+ gain. The results show that amiodipine pretreatment supplied. protection, provided that the ischemic episode did not exceed 30 minutes. The protection resulted in improved recovery of peak developed tension on reperfusion, reduced Cat+ gain, retention of tissue adenosine triphosphate and creative phosphate, and reduced acidosis.

Tyrosine administration to pregnant rats induces persistent behavioral modifications in the male offspring

Pregnant rats were given, by stomach intubation, 1-tyrosine (20 or 500 mg/kg), beginning on day 11 post-coitus. Tyrosine or saline solution administrations were continued on a once-daily basis until day 20 of gestation. When male offspring were seventy days old, the spontaneous locomotor activity, open field test, swim test and motor ability test were performed. The offspring treated with large tyrosine doses showed a marked increase in both spontaneous locomotor activity and open field locomotion as adults. However, activity in the swim test decreased. The number of defecation boluses produced in the open field test and the motor ability in the rotating rod test diminished. The behavior of the rats treated with small doses of tyrosine was similar, in all tests performed, to that of rats treated with saline solution. These findings strongly suggest that a large increase in diet tyrosine during pregnancy modifies the behavior of male offspring.

Fundamental mechanisms of action of calcium antagonists in myocardial ischemia

The mammalian myocardium exhibits a spectrum of damage during an ischemic episode. After relatively short periods of ischemia the damage is reversible, but with longer periods of ischemia the number of cells that are lethally injured increases. When coronary flow is restored the lethally injured cells become overloaded with Ca ++ and fail to regenerate adenosine triphosphate. The calcium antagonists provide protection under these circumstances, but only if used prophylactically. When added only upon reperfusion the calcium antagonists slow, but do not inhibit, the excessive gain in Ca ++ that occurs during postischemic reperfusion. Nicotine, in a concentration equivalent to that found in the plasma of smokers (0.15 μg/ml), exacerbates the reperfusion-induced Ca ++ gain. Treatment with the longacting calcium antagonist, anipamil, on a once-daily basis attenuates the reperfusion-induced Ca ++ gain in spontaneously hypertensive rats and its exacerbation by nicotine in Sprague Dawley rats. The prolonged oral administration of at least 1 calcium antagonist, verapamil (50 mg/kg body weight/day), causes a significant (p < 0.001) depletion of left ventricular norepinephrine.

Respiratory tract infections: Goals for 1995

Goals to be identified for 1995, a decade hence, in the prevention, diagnosis, and management of respiratory tract infections may conveniently be divided into diagnostic goals and goals in therapy and prophylaxis. Major diagnostic goals for bacterial, viral, and mycoplasmal infections of the respiratory tract focus on the development of systems to identify microbial components, such as specific antigens or segments of DNA, using monoclonal antibody techniques or DNA probes for hybridization. Sputum cultures, in the traditional sense, should ultimately become obsolete. Management goals include the development of algorithms to identify patients who should be hospitalized, in contrast to those who can safely be treated on an outpatient basis. New antibiotic drug development should include drugs active against methicillin-resistant staphylococci, broad-spectrum beta-lactam drugs that are orally active against gram-negative bacilli, and drugs that can be used parenterally on a once-daily basis in settings other than the acute care hospital. There are certainly needs to enhance the present spectrum of antiviral drugs and to develop therapeutically useful immunomodulators. There are promising prospects for vaccine development, including live attenuated influenza virus vaccine, parainfluenza virus vaccine, respiratory syncytial virus vaccine, and a Mycoplasma pneumoniae vaccine. With major research support, such vaccines could possibly be fully developed by 1995. Finally, of greatest importance is the need to achieve greater utilization of existing vaccines, that is, inactivated influenza vaccine and the current 23-valent pneumococcal vaccine. A legitimate goal for 1995 would be to achieve 70 percent or greater utilization of these vaccines within the recommended target populations.

Once-daily administration of acebutolol in treatment of hypertension

A comparison of once-daily and twice-daily regimens of treatments with a beta-adrenoceptor-blocking agent, acebutolol, was carried out in patients with mild to moderate essential hypertension. Following an initial placebo phase, all patients entered an open 9-week period during which the dose of acebutolol, given on a twice-daily basis to all patients, was titrated to reduce seated diastolic blood pressure to less than 90 mm Hg or to decrease it by at least 10 mm Hg. After a further 4-week maintenance period, patients whose blood pressure had been successfully controlled entered a 3-month double-blind study in which they were randomly divided into three groups: those receiving continuation of twice-daily treatment (n = 47); those receiving once-daily treatment (using the same total daily dose as in the earlier twice-daily phase (n = 97); and those receiving placebo twice daily (n = 48). By the end of the study, 78% of the once-daily treatment group were still under control, a result similar to that of 72% in the twice-daily treatment group. In contrast, only 39% of the placebo patients remained under control. Moreover, the blood pressure in this group was significantly higher than in the other two groups. Acebutolol is an efficacious antihypertensive agent when used on a once-daily basis.

Clinical pharmacology of tamoxifen in patients with breast cancer: correlation with clinical data.

Blood tamoxifen levels were determined for patients with metastatic breast cancer following initial and chronic dosing at twice daily 10 mg/m2 or a 20 mg/m2 single dose. Median time to response was six weeks. Blood tamoxifen levels at that time were ten-fold greater than those obtained after an initial single dose; however, steady-state values were not achieved until 16 weeks of chronic dosing. On a loading dose schedule of 40 mg/m2 twice daily for seven days and 20 mg/m2 daily thereafter, blood levels greater than or equal to 10 mg/m2 twice daily steady-state values were reached in one week. Levels drawn at peak and trough times suggest that tamoxifen may be given on a once-daily basis. Tamoxifen half-life was 9-12 hours after the initial dose and seven days after chronic dosing.

A hospital out-patient study of timolol/bendrofluazide combination ('Prestim') in essential hypertension.

A study was carried out in 44 patients with mild to moderate essential hypertension attending a hypertension clinic in a general hospital. Treatment was administered using fixed-dose combination tablets of timolol maleate (10 mg) and bendrofluazide (2.5 mg) taken twice daily for 16 weeks, in order to assess the efficacy and side-effects of this combination and to monitor changes in serum electrolytes and other biochemical indices. Blood pressure control (supine diastolic blood pressure less than or equal to 95 mmHg) was achieved in 38 (86%) patients on a mean dose of 2.6 tablets daily (range 1 to 4 tablets). Adverse effects were uncommon, 3 (6%) patients being withdrawn at an early stage. In a complementary investigation, 14 patients who completed the 16-weeks' treatment were changed onto a regimen in which the drug dosage remained unchanged but was taken on a once-daily basis for a further 16 weeks to assess the efficacy of once-daily dosing and to monitor any further long-term changes in biochemistry. The trend of changes in biochemical indices which were observed in the 16-week study tended to reverse during the second 16 weeks so that, overall, changes in biochemistry were minimal. The combination of timolol maleate and bendrofluazide was effective in controlling blood pressure in most mild to moderate hypertensives and the dose range allowed accurate titration of dosing for each patient. The effect was equal on a once-daily or a twice-daily dosage.