Nocturnal Dosing Research Articles

Pulsatile Drug Delivery Systems: A Comprehensive Review

sigmoidal drug release profile is formed when a pulsatile drug delivery system (PDDI) initiates drug administration and follows it up with rapid and complete drug release. It ensures the correct dosage of the drug is delivered at the right time and place. Pulsatile drug delivery is effective for treating asthma, arthritis, cancer, diabetes, epilepsy, hypertension, ulcers, and hypercholesterolemia, among others. There are many types of delivery systems in the pharmaceutical industry, including capsular, osmotic, single and multi-unit designs and membranes that are soluble and erodible. Innovations are directed toward conditions such as those requiring nocturnal dosing, high first-pass effects, and site-specific absorption in the gastrointestinal tract. In particular, these systems make dosing more convenient for patients, resulting in better compliance. As a result of the use of chronomodulated drug delivery systems, pharmaceutical therapy is more effective with a personalized approach.

Meds before bed? Nocturnal dosing of antihypertensive medications improves cardiovascular mortality

Dickman, Michael M. DO, FAAFP; Bury, David C. DO, FAAFP; Meisenheimer, Erica S. MD; Oh, Robert C. MD, MPH, FAAFP; Rogers, Tyler S. MD; Tiglao, Samuel M. DO, FAAFPAuthor Information

Randomized Crossover Trial of the Impact of Morning or Evening Dosing of Antihypertensive Agents on 24-Hour Ambulatory Blood Pressure.

Some data suggest that nocturnal dosing of antihypertensive agents may reduce cardiovascular outcomes more than daytime dosing. This trial was designed to evaluate whether ambulatory blood pressure monitoring levels differ by timing of drug dosing. Patients aged 18 to 80 years with reasonably controlled hypertension (≤150/≤90 mm Hg) on stable therapy of ≥1 antihypertensive agent were recruited from 2 centers in London and Thessaloniki. Patients were randomized to receive usual therapy either in the morning (6 am-11 am) or evening (6 pm-11 pm) for 12 weeks when participants crossed over to the alternative timing for a further 12 weeks. Clinic blood pressures and a 24-hour recording were taken at baseline, 12, and 24 weeks and routine blood tests were taken at baseline. The study had 80% power to detect 3 mm Hg difference in mean 24-hour systolic blood pressure (α=0.05) by time of dosing. A 2-level hierarchical regression model adjusted for center, period, and sequence was used. Of 103 recruited patients (mean age, 62; 44% female), 95 patients (92%) completed all three 24-hour recordings. Mean 24-hour systolic and diastolic blood pressures did not differ between daytime and evening dosing. Similarly, morning and evening dosing had no differential impact on mean daytime (7 am-10 pm) and nighttime (10 pm-7 am) blood pressure levels nor on clinic levels. Stratification by age (≤65/≥65 years) or sex did not affect results. In summary, among hypertensive patients with reasonably well-controlled blood pressure, the timing of antihypertensive drug administration (morning or evening) did not affect mean 24-hour or clinic blood pressure levels. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT01669928.

Evaluation of 24-Hour Blood Pressure and Arrhythmias through Simultaneous Ambulatory Blood Pressure Monitoring and Holter Monitoring in Type 2 Diabetes Mellitus Patients with Hypertension

We studied 1200 (Males=868, Females =332) hypertensive, T2DM hospitalised for 24 hours to analyse the association of hypertension and arrhythmias simultaneously for three years (January 2015-December 2017), as part of the PREDICT protocol, a mixed methods approach, developed as a standard care of management at three tertiary care hospitals. We used Trillium 3000 Holter recorder (Forest Medical) and DynaPulse 5000A Ambulatory Blood Pressure monitoring (ABPM) and the Trillium Gold software, respectively for the recording and the data analysis. ANOVA, Graphpad was used for statistical analysis. The mean age was 51.2 ± 7.9 years (range 41-82 years). The tertile in the triad of age > 60 years, duration of diabetes > 20 years and HbA1c > 11% had the highest incidence of arrhythmias (p<0.0001). The socioeconomic status was high in 401 patients (43%), middle income in 436 (36.3%) and low income in 363 cases (30%). The commonest risk factors were sedentary lifestyle (64%), obesity (56%), dyslipidemia (37%), smoking (23%), sleep apnea (21%). The mean 24-hour BP was 143 ± 12 mmHg for the SBP and 92.6 ± 12.2 mmHg for DBP. The awake and asleep BP mean were respectively 147 ± 11 mmHg and 137 ± 13.7 mmHg for SBP, 89.5 ± 10.2 and 83.1 ± 8.9 mmHg for DBP. Arterial pressure variability and bradyarrhythmia were significantly associated with sleep apnea (p<0.0001). Patients with ST-T wave depression > 1 mm (26%) and tachycardia (31%) as a sub-group were significantly associated with both the reverse dippers and non-dippers. (p<0.0001). Chronotherapy in concurrence with the circadian rhythm to reduce the side effects, optimise the dosage, reduce the pill burden would be a suitable option to achieve a better BP control in T2DM. Nocturnal anti-hypertensive dosing to target the nocturnal hypertension would be an appropriate management approach. Disclosure V. Redkar: None. S. Redkar: None. S. Redkar: None. A. Inamdar: None. M. Inamdar: None. S. Rane: None. D. Khanolkar: None. M. Jagtap: None. D. Yeralkar: None. N. Wadhwa: None.

Protocol for assessment of sleep quality and duration in the Treatment In Morning versus Evening (TIME) study: a randomised controlled trial using online patient-reported outcome measures

IntroductionWe will use the existing online mechanisms of the Treatment in Morning versus Evening (TIME) study to collect patient-reported outcome measures of sleep quality to determine whether nocturnal dosing of...

Noctural dipping status and left ventricular hypertrophy: A cardiac magnetic resonance imaging study.

We investigate the impact of dipper status on cardiac structure with cardiovascular magnetic resonance (CMR). Ambulatory blood pressure monitoring and 1.5T CMR were performed in 99 tertiary hypertension clinic patients. Subgroup analysis by extreme dipper (n=9), dipper (n =39), non-dipper (n =35) and reverse dipper (n =16) status was performed, matched in age, gender and BMI. Left ventricular (LV) mass was significantly higher for extreme dippers than dippers after correction for covariates (100±6g/m2 vs 79±3g/m2 , P=.004). Amongst extreme dippers and dippers (n =48), indexed LV mass correlated positively with the extent of nocturnal blood pressure dipping (R=.403, P=.005). On post-hoc ANCOVA, the percentage of nocturnal dip had significant effect on indexed LV mass (P=.008), but overall SBP did not (P=.348). In the tertiary setting, we found a larger nocturnal BP drop was associated with more LV hypertrophy. If confirmed in larger studies, this may have implications on nocturnal dosing of anti-hypertensive medications.

Treatment in the Morning versus Evening (TIME) Study: Feasibility of an Online Study

Aims: The Treatment in Morning versus Evening (TIME) pilot study sought to establish the feasibility of an onlineonly study detecting whether evening dosing of antihypertensives is more cardio protective than morning dosing. Methods: The TIME study uses a prospective, randomised, open-label, blinded end-point (PROBE) design. In response to various forms of advertising, patients from primary and secondary care, and databases of patients who had previously consented to being contacted about research in the UK, enrolled on the study website (www.timestudy.co.uk). Furthermore, 1,794 hypertensive subjects were written to in three primary care practices as a form of targeted advertising. Participants had to be over 18, prescribed at least one hypertensive drug and have a valid email address. Subjects self-registered, consented, and entered demographics and drug treatments online, before being randomised to taking their antihypertensive therapy in the morning or evening. Automated email followup was used to track patient reported cardiovascular outcomes for the year-long pilot study. Result: 355 participants were randomised and followed up for ≥ 12 months. During this period, 14 participants withdrew from the randomised time of treatment. 59 patients were randomised from 3 practices which wrote to patients publicising the study, giving a rate of 33 randomised per 1,000 patients written to. The 10-year ASSIGN cardiovascular risk of the randomised participants varied by age; 21% for all ages (n=355), 25% for >55 yrs (n=269), 27% for >60 yrs (n=227) and 30% for >65 yrs (n=150). Based on participant cardiovascular risk during the pilot, a full trial with 80% power to detect a 20% improved outcome of nocturnal dosing would require 631 events to occur. Conclusion: The TIME study pilot achieved recruitment efficiently. Based on the pilot data, the TIME study appears viable and has been funded by the British Heart Foundation to recruit over 10,269 subjects and to follow them up for 4 years.

Intrathecal Pharmacology Update: Novel Dosing Strategy for Intrathecal Monotherapy Ziconotide on Efficacy and Sustainability.

Intrathecal drug delivery is a well-defined strategy to treat malignant and nonmalignant pain. Ziconotide is a well-studied intrathecal medicine option that has many attractive qualities, as it is non-granulomagenic, overdose or underdose is not associated with cardiopulmonary compromise or death, and is a non-opoid analgesic. However, it has had slow adoption into pain care algorithms because it has been historically plagued with the connotation of having a narrow therapeutic window and a low sustainability rate. We introduce a novel dosing strategy to improve patient outcomes and sustainability. Patients were identified as being an intrathecal candidate and trialed with ziconotide based on the current standard of care. Patient demographics, diagnosis, previous treatment failures, and pre-implant visual analog scale (VAS) scores were recorded. Once the trial was deemed successful, based on the dual bolusing strategy, the patient underwent device implantation. Consecutive patients were prospectively followed. Ziconotide was then initiated with a flex dosing strategy, weighted during nocturnal dosing. Outcome endpoints included: reduction in VAS, side effects, durability of therapy, and systemic opioid use prior to implant and at last visit were noted (calculated to daily morphine equivalents). Primary endpoint was tolerability of ziconotide at three months following new dosing strategy. No industry support or funding was obtained for this project. All enrolled patients met the endpoint of the study of tolerability of ziconotide at three months. Numbers declined to 75% of patients at four months, and 70% of patients at six months. The discontinuing side-effects were most commonly urinary retention and visual hallucinations. There were no serious adverse events and no unresolved complications reported. Numerical rating scale (NRS) decreased on average from 9.06 to 1.8. Opioid reduction in morphine equivalents averaged 91.5% The efficacy and tolerability of monotherapy ziconotide may be improved by using a weighted bolus flex dosing strategy as compared with slow continuous infusions. We present a novel strategy to deliver ziconotide using a unique continuous infusion flex dosing strategy. Further randomized, prospective, higher-powered studies are needed to critically evaluate the conclusions suggested by this limited prospective case series.

Chronotherapeutic Drug Delivery Systems

Recent advances in chronotherapeutics led to the development of pulsatile drug delivery systems which effectively delivered the drug at specified time. Diseases like asthma, arthritis, cancer, diabetes, hypertension, ulcer, hypercholesterolemia, congestive heart failure, stroke etc. show different day night pattern in onset and symptoms exacerbation. Pulsatile drug delivery systems deliver the drug at right time in desired levels providing the multiple benefits over the conventional dosage forms. According to the circadian rhythms of the body drug is facilitated to completely release after a lag time especially for drugs eliciting higher first pass effect and where nocturnal dosing is required these systems are highly beneficial. This review epitomizes the special focus on chronotherapeutics, various approaches in chronotherapeutic drug delivery and applications.

C12 Measurement With Nocturnal Dosing of Tacrolimus Extended-Release Formulation Shows High Correlation to Daily Exposure.

C12 Measurement With Nocturnal Dosing of Tacrolimus Extended-Release Formulation Shows High Correlation to Daily Exposure.

Evolution of glomerular filtration rate in patients with essential hypertension: impact of type 2 diabetes

groups. In addition, night time BP medication dose was increased with the objective to achieve 10% nocturnal drop in SBP in those randomized to the chronotherapy arm. iGFR was repeated at 12 months. Results are presented in a tabular format. Conclusions: In kidney transplant recipients without OSA and with acceptable kidney function and abnormal circadian BP pattern at 1 month from tx only a minority will achieve normal day-night BP pattern at 1 year from tx despite nocturnal dosing of BP medications.

New insights—from risk factors to treatment implications

The results of several hypertension studies published in 2011 have contributed to our knowledge on the risks of and treatment for this condition, including the effects of slow-wave sleep, nocturnal dosing of medication, variability in post-stroke blood-pressure reduction, and the impacts of a low-sodium diet.

Recent technologies in pulsatile drug delivery systems

Pulsatile drug delivery systems (PDDS) have attracted attraction because of their multiple benefits over conventional dosage forms. They deliver the drug at the right time, at the right site of action and in the right amount, which provides more benefit than conventional dosages and increased patient compliance. These systems are designed according to the circadian rhythm of the body, and the drug is released rapidly and completely as a pulse after a lag time. These products follow the sigmoid release profile characterized by a time period. These systems are beneficial for drugs with chronopharmacological behavior, where nocturnal dosing is required, and for drugs that show the first-pass effect. This review covers methods and marketed technologies that have been developed to achieve pulsatile delivery. Marketed technologies, such as PulsincapTM, Diffucaps®, CODAS®, OROS® and PULSYSTM, follow the above mechanism to render a sigmoidal drug release profile. Diseases wherein PDDS are promising include asthma, peptic ulcers, cardiovascular ailments, arthritis and attention deficit syndrome in children and hypercholesterolemia. Pulsatile drug delivery systems have the potential to bring new developments in the therapy of many diseases.

Nocturnal dosing and chronic kidney disease progression: new insights

Several studies have identified the presence of altered diurnal blood pressure patterns, specifically elevated nighttime blood pressure in patients with chronic kidney disease. The lack of nocturnal decline in blood pressure is associated with markers of hypertensive target organ damage and predictive of long-term clinical outcomes. The purpose of this review is to summarize the literature in this area and explore the potential for use of nighttime blood pressure for improving risk stratification and as a therapeutic target. The mechanisms of persistent elevation of blood pressure at night in chronic kidney disease are likely to be multifactorial, including altered sodium handling and sympathetic activation among others. Elevated nocturnal blood pressures have been shown to be associated with increased adverse clinical outcomes. Recent studies demonstrate that it is feasible to lower nocturnal blood pressure by modifying the time of administration of antihypertensive medications. Currently, clinical blood pressure measurements are assessed and targeted for drug therapy. This article shows the importance of measuring ambulatory blood pressures, specifically nocturnal blood pressures to improve risk stratification. More research needs to be done to identify interventions that lower nighttime blood pressure, and test their efficacy in improving clinical outcomes.

Nocturnal therapy with famotidine for 1 year is effective in preventing relapse of gastric ulcer

A multicentre, double-blind, randomized, placebo-controlled trial was undertaken to investigate the therapeutic efficacy of a nocturnal dose of famotidine 20 mg to reduce the 1 year relapse rate of recently healed gastric ulcers. Twenty investigators in eight countries randomized 202 patients with endoscopically confirmed healed gastric ulcers. Repeat endoscopies were performed at 6 and 12 months or for symptoms compatible with ulcer relapse. A per protocol analysis of cumulative life table relapse at 12 months showed that famotidine 20 mg was superior to placebo in reducing gastric ulcer relapse, 24 versus 50%, respectively (P less than 0.01). Both placebo and famotidine were well tolerated. Since nocturnal dosing with famotidine 20 mg is effective in preventing gastric ulcer relapse over a 1-year period and is well tolerated, it offers a therapeutic option for the long-term treatment of patients with gastric ulcer.

Challenges in acid/peptic disorders: a symposium overview

Before 1977, the treatment of peptic ulcer disease consisted primarily of dietary, antacid, and anticholinergic programmes. There were heated controversies regarding rigid vs. liberal ulcer diets, a variety of antacids and dosing patterns to choose from, and conflicting claims over the benefit of various anticholinergic therapies. It was hoped that the dramatic introduction of the H2-receptor antagonists would simplify our approach to the treatment of peptic ulcer and reflux oesophagitis. Standard doses of H2-receptor antagonists are effective for acid/peptic disorders, yet it has become clear that some subsets of patients present special management problems, including recurrent ulcers, non-steroidal anti-inflammatory drug (NSAID)-induced disease, stress ulcers, and refractory oesophagitis. New regimens, such as maintenance therapy and once-daily nocturnal dosing, have been indicated for peptic ulcer disease. New drugs have been introduced, such as sucralfate, misoprostol, and omeprazole, each with a different mechanism of action. Therefore, while we have learned considerably more about the pathogenesis of peptic disease, treatment decisions have become more complicated. The Transatlantic Conference on Acid/Peptic Disorders was held on 19-21 January 1990, in Wesley Chapel, Florida. A faculty from the United Kingdom, the United States, and Canada reviewed pathophysiology and the role of pharmacologic agents in the treatment of acid/peptic disorders and outlined clinically useful treatment strategies. The conference was organized into five segments: acid suppression and ulcer healing; acid suppression and control of reflux disease; NSAID-induced ulceration; stress ulceration, rationale for control of rebleeding, and drug interactions; and controversies. The proceedings of the symposium are presented in this supplement.

Comparison of nocturnal dosing of diltiazem er and ramipril on early morning blood pressure, heart rate and the rate-pressure product

Comparison of nocturnal dosing of diltiazem er and ramipril on early morning blood pressure, heart rate and the rate-pressure product

Effects of nocturnal doses of mirtazapine and mianserin on sleep and on daytime psychomotor and driving performance in young, healthy volunteers

Eighteen healthy volunteers participated in a randomized, double blind, cross-over trial. They received mirtazapine, mianserin or placebo during separate periods of 15 days. Mirtazapine and mianserin were respectively administered in doses of 15 mg and 30 mg nocte for the first 7 days and doses of 30 mg and 60 mg nocte for the remaining 8 days. Assessments were made at baseline and on days 2, 8, 9 and 16 of each period to compare effects of drugs and placebo on mood, psychomotor (CTT, CRT, CFF and Vigilance) and ‘actual’ driving performance. Sleep quality and duration and side-effects were assessed at baseline and every treatment day. Mirtazapine 15 mg and mianserin 30 mg slightly impaired psychomotor and driving performance on day 2 of treatment. On day 8, the effects were virtually gone, although some driving impairment could still be observed in the mianserin condition. No drug effects on performance were found on day 9 despite the dose escalation. On day 16 of treatment, driving performance and vigilance slightly decreased in, respectively, the mirtazapine and the mianserin conditions. These effects indicate that tolerance to the drugs' adverse effects was not complete. This observation was also supported by subjective data. Similar increments in sleep duration and feelings of lethargy, drowsiness and weakness were observed throughout treatment with both drugs. Alertness and contentedness was always lower during both drug treatments than with placebo. Spontaneously reported adverse events were similar to self-rated side-effects and more of both were recorded during mianserin treatment. It is concluded that the acute and subchronic effects of nocturnal doses of both drugs were similar and equally low in magnitude. Effects on performance were much less than those seen in other studies after administration during the day. Full daily doses of both drugs should be prescribed in nocturnal dosing regimens, and not in divided doses over the day, for avoiding excessive sedation and performance impairment. © 1998 John Wiley & Sons, Ltd.

A chronotherapeutic approach to the management or hypertension

Patients with hypertension have a characteristic circadian pattern of blood pressure (BP) variability in a 24-h period, characterized by a wide range while awake and active, and a narrower range during sleep and inactivity. Blood pressure in the untreated hypertensive individual declines by approximately 10% to 20% during sleep compared with the mean awake BP values. Early in the morning (assuming a typical day-night activity cycle), the BP rises sharply on awakening, when physical and mental activities increase. Antihypertensive therapy has been traditionally dosed in the morning after awakening, and in recent years most of the newly developed antihypertensive agents have been once-daily, long-acting preparations. However, theoretically, this pattern of drug dosing may be suboptimal since pharmacodynamic activity is attenuated at the end of the dosing period, when a large rise in BP may occur. Presently, only a few studies have been performed to evaluate the effects of nocturnal dosing of standard long-acting drugs. Consequently, we undertook an assessment of the effects of a new formulation of verapamil--controlled onset extended release verapamil HCl (COER-24)--that is dosed nocturnally and has a controlled onset of delivery (4 to 5 h postdose) and an extended release for the remainder of the dosing period. Through ambulatory BP monitoring, evaluation revealed that this verapamil formulation produced changes in BP that followed the circadian rhythm of BP: lower reductions during sleep, when the BP is intrinsically lowest, and appropriately larger reductions during the early morning and daytime hours, when ambulatory BP values accelerate and plateau to their highest levels. These data demonstrate that it is possible to design antihypertensive therapy for once-nightly dosing, thereby providing a chronotherapeutic regimen for patients with hypertension.

A Chronotherapeutic Approach to the Management of Hypertension

Patients with hypertension have a characteristic circadian pattern of blood pressure (BP) variability in a 24-h period, characterized by a wide range while awake and active, and a narrower range during sleep and inactivity. Blood pressure in the untreated hypertensive individual declines by approximately 10% to 20% during sleep compared with the mean awake BP values. Early in the morning (assuming a typical daynight activity cycle), the BP rises sharply on awakening, when physical and mental activities increase. Antihypertensive therapy has been traditionally dosed in the morning after awakening, and in recent years most of the newly developed antihypertensive agents have been once-daily, long-acting preparations. However, theoretically, this pattern of drug dosing may be suboptimal since pharmacodynamic activity is attenuated at the end of the dosing period, when a large rise in BP may occur. Presently, only a few studies have been performed to evaluate the effects of nocturnal dosing of standard long-acting drugs. Consequently, we undertook an assessment of the effects of a new formulation of verapamilontrolled onset extended release verapamil HC1 (COER-24)—that is dosed nocturnally and has a controlled onset of delivery (4 to 5 h postdose) and an extended release for the remainder of the dosing period. Through ambulatory BP monitoring, evaluation revealed that this verapamil formulation produced changes in BP that followed the circadian rhythm of BP: lower reductions during sleep, when the BP is intrinsically lowest, and appropriately larger reductions during the early morning and daytime hours, when ambulatory BP values accelerate and plateau to their highest levels. These data demonstrate that it is possible to design antihypertensive therapy for once-nightly dosing, thereby providing a chronotherapeutic regimen for patients with hypertension. Am J Hypertens 1996;9:29S–33S