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For years, we and others have advocated starting treatment of chronic indolent conditions at doses lower than those typically recommended in the product monographs.1 The approach we recommend is to use a very low dose when starting a new medication if the condition is not life-threatening or producing severe symptoms. Unfortunately, this approach is not used that much in practice. First, we should define “very low dose.” The “start low, go slow” approach when starting medications — which entails starting with the lowest available dose — is generally well accepted in the medical community, especially for elderly patients. However, our approach is different. We are suggesting that it is reasonable in many cases to start with half the lowest marketed dose for older, established products. For newly marketed medications, we suggest starting with half or even one-quarter the lowest available dose, because dose–response studies have either not been done or their findings have not been incorporated into the product monograph. In addition, often only one or maybe two doses are marketed initially. Our approach has several important advantages over the use of initial doses recommended in many product monographs. The use of a very low starting dose (a) would further decrease the risk of adverse effects; (b) engage patients in determining the best dose for them; and (c) would still provide a placebo effect, if present, and mitigate the ethical issues associated with the use of placebos.
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For years, we and others have advocated
starting treatment of chronic indolent con-
ditions at doses lower than those typically
recommended in the product monographs.1The
approach we recommend is to use a very low
dose when starting a new medication if the con-
dition is not life-threatening or producing severe
symptoms. Unfortunately, this approach is not
used that much in practice.
First, we should define “very low dose.” The
“start low, go slow” approach when starting
medications which entails starting with the
lowest available dose is generally well ac -
cepted in the medical community, especially for
elderly pa tients. However, our approach is dif-
ferent. We are suggesting that it is reasonable in
many cases to start with half the lowest marketed
dose for older, established products. For newly
marketed medications, we suggest starting with
half or even one-quarter the lowest available
dose, because dose–response studies have either
not been done or their findings have not been
incorporated into the product monograph. In
addition, often only one or maybe two doses are
marketed initially.
Our approach has several important advan-
tages over the use of initial doses recommended
in many product monographs. The use of a very
low starting dose (a) would further decrease the
risk of adverse effects; (b) engage patients in
determining the best dose for them; and
(c) would still provide a placebo effect, if pre-
sent, and mitigate the ethical issues associated
with the use of placebos.
Rationale
This very-low-dose approach is based on all
three pillars of evidence-based practice: evidence
from clinical trials, clinical experience and
patient preference.
For most conditions seen in general practice
(e.g., insomnia, elevated blood pressure, mild
depression, chronic ob structive lung disease, anxi-
ety, osteoarthritis, menopausal symptoms, ele-
vated cholesterol and elevated glucose), an imme-
diate response to drug treatment is rarely needed.
For many marketed drugs, especially when
originally launched, the recommended starting
doses are too high.2By design, initially marketed
doses are ones that work for most patients. How-
ever, many of those same patients might benefit
equally from lower doses. Rarely have doses on
the true lower end of the dose–response curve
been studied when drugs are first marketed. In a
retrospective review of 354 new molecular entities
available for evaluation that had been approved by
the US Food and Drug Administration (FDA)
between 1980 and 1999, 73 (21%) had had a
labelled dosage change; for 58 (79%) of the 73
medications, the change was a decrease in dosage.
The authors stated that “this pattern may represent
a systematic flaw in pre marketing dosage evalua-
tion; it has been common practice in the pharma-
ceutical industry to undertake phase III trials eval-
uating drug effectiveness at or near maximum-
tolerated doses.”3Perhaps more concerning is that
the need for dose adjustments has increased over
time: they were three times more common during
1995–1999 than during 1980–1984.3
At a minimum, a very low starting dose will
yield the potential benefits such as the placebo
effect and other nonspecific effects that are seen
in the placebo groups of clinical trials.4Recently,
a number of authors called for the return of place-
bos to clinical practice,5but this can be fraught
with a number of ethical dilemmas. Using a very
low dose provides a possible compromise in cap-
turing the placebo effect yet still providing a rea-
sonable therapeutic intervention.
Clinicians cannot reliably predict how any one
patient will respond to a drug (pharmacodynam-
ics). They can adjust for some of the pharmaco -
kinetic variability seen between patients by bas-
ing the dose of a medication on the patient’s
Is bigger better? An argument for very low starting doses
James P. McCormack PharmD, G. Michael Allan MD, Adil S. Virani PharmD
Competing interests:
Adil Virani receives
honoraria for educational
work done in conjunction
with or on behalf of the
Therapeutics Initiative. He
receives royalties in relation
to his role as lead editor for
the handbook Clinical
Handbook of Psychotropic
Drugs. No competing
interests declared by James
McCormack or Michael
Allan.
This article has been peer
reviewed.
Correspondence to:
Dr. James P. McCormack,
jmccorma@interchange
.ubc.ca
CMAJ 2011. DOI:10.1503
/cmaj.091481
Analysis
CMAJ
The recommended starting doses for many medications are too high
for many patients.
Unless the condition is severe or life-threatening, drug treatment can
be started at a very low dose (half or one-quarter the recommended
starting dose).
Potential advantages of this approach include a further decrease in the
risk of adverse events, enhanced patient participation, improved
adherence and reduced long-term costs.
Key points
© 2011 Canadian Medical Association or its licensors CMAJ, January 11, 2011, 183(1) 65
big-mccormack_Layout 1 22/12/10 9:11 AM Page 65
weight and renal/hepatic function; however,
pharmacodynamic variability, which typically
exceeds pharmacokinetic variability,6is not really
taken into account by these adjustments.
In a meta-analysis of 39 prospective studies,
about three-quarters of reported side effects of
medications were dose related.7In a recent random-
ized controlled trial of colchicine, a dose of 1.8mg
was found to be as effective as 4.8 mg for the treat-
ment of acute gout; the incidence of diarrhea was
77% (19% severe) in the high-dose group and only
23% (0% severe) in the low-dose group.8
A cross-sectional study showed that patients
reduced their doses to reduce their costs.9As
clinicians, we have all had patients tell us they
have done the same to avoid side effects. They
take their medication every other day or take
half or sometimes even a quarter of the pill, and
they report that it works just fine. Many patients
are comfortable taking portions of tablets, and
these doses frequently strike the right balance of
benefit to cost and adverse events.
In animal research, in which breeding is
highly controlled to the point that the animals
are virtually genetically identical, there is still a
wide dose–response relation.10 In the less con-
trolled human environment, genetic and envi-
ronmental variability likely leads to an even
more varied dose–response effect.
Are initially marketed doses
too high?
When medications are first marketed, the recom-
mended starting doses are typically much higher
than those eventually found to be effective.
There appear to be a number of reasons for this
predicament.11 First, health protection agencies
require drug companies to show that a medica-
tion has an “effect” before it can be approved. In
general, the easiest way to show an effect is to
use doses that will generate a response in as
many patients as possible. These doses then
become the recommended dose. As Sheiner
states, “The dose studied is a dose almost guar-
anteed to be excessive.”12
A second reason is encompassed by the nat-
ural desire to have the medication work quickly
and completely. To ensure success of their prod-
uct, the manufacturer would prefer as many
patients as possible to have a clinical response on
first use. The clinician and patient are also keen
to see an immediate resolution of the clinical con-
cern. Although this approach has definite appeal,
it is not without potential complications. As noted
previously, about 16% of all new products will
have their doses officially decreased because of
safety issues.3Therefore, for one in every six new
medications, the initially recommended starting
dose is later found to be excessive and to have an
unfavourable risk–benefit profile. Even for med-
ications that do not require a later adjustment to
the labelled dosage, a number of patients would
benefit equally from a lower dose and a reduced
risk of adverse events. These patients may be
unnecessarily tolerating side effects or may stop a
medication that might otherwise have been help-
ful without adverse events at a lower dose.
A recent example shows how organizations
such as the FDA may play a role in advocating
doses that are higher than necessary. Varenicline
is a recently released drug for smoking cessation.
Based on two comparative dosing studies of
1 mg twice daily versus 0.5 mg twice daily, the
FDA stated that “varenicline 0.5 mg BID
appears to work as well as varenicline 1.0 mg
BID, so that subjects who cannot tolerate vareni-
cline 1.0 mg BID should take varenicline 0.5 mg
BID.”13 If 0.5 mg twice daily produces the same
effect as 1 mg twice daily, why is the lower dose
not recommended for all patients? The right dose
for a number of patients may be even lower, but
by advocating doses higher than necessary for
the majority of patients, the FDA has encouraged
physicians to start too high.
Evidence for effective lower doses
A number of randomized controlled trials have
examined the effect of lower doses (Table 1).8,14−25
Most of the studies showed no differences in
effect when half or one-quarter of the usual dose,
or even a smaller amount, was used. In the stud-
ies that showed a difference in response between
doses, the lower doses still typically produced a
clinically important response. However, these
studies did not look at the effect of doses lower
than those mentioned. In other words, these simi-
larly effective lower doses likely do not reflect
the lower part of the dose–response curve. Even
lower doses would probably have produced a
clinical response in a reasonable number of
patients. So, although evidence from randomized
controlled trials is helpful in showing that certain
low or very low doses work, this sort of evidence
is not definitively required to adopt an approach
of starting with very low doses.
Advantages of starting with very
low doses
One advantage is that patients would get the
potential placebo effect because they know they
are receiving something, albeit at a very low
Analysis
66 CMAJ, January 11, 2011, 183(1)
big-mccormack_Layout 1 22/12/10 9:11 AM Page 66
dose. This is all done without the need for
deception.
Another advantage is that patients would be
engaged in finding the best dose for them. Some
will appreciate the concept of “just a little bit to
start.” Although not specifically associated with
this approach to dosage, shared decision- making
has been associated with improved health-related
behaviours and clinical outcomes.26,27
In addition, cost savings would be consider-
able, as found in a retrospective review of phar-
macy claims.28 For example, the use of half a
tablet of a medication that normally would cost
$1/day amounts to more than $175 in cost sav-
ings per year. This savings would exceed the
cost associated with two or even three additional
office visits that may be needed to optimize the
target dose for a patient. Further cost savings
may be garnered because of improved clinical
outcomes owing to improved adherence to treat-
ment regimens that are better tolerated and
because of reduced adverse events.
Finally, most clinically relevant drug interac-
tions could be avoided. Even if a patient was
given a drug that led to a doubling of the concen-
tration of the drug started at a very low dose, by
using say a quarter of the normal starting dose,
the increased concentration would still be well
below that achieved with typical starting doses.
Limitations
The very-low-dose approach we propose does
not apply to acute life-threatening conditions or
when an immediate effect is desired (e.g., acute
alcohol withdrawal, moderate to severe pain
from osteoarthritis or reflux esophagitis, moder-
ate to severe asthma, angina, status epilepticus),
nor does it apply when the consequences of
underdosing are potentially dangerous (e.g.,
acute bacterial infections). In these cases, it is
better to err on the side of giving at least the rec-
ommended dosage immediately rather than using
a slow upward titration. In addition, the very-
low-dose approach (other than the initial titra-
tion) cannot be used in conditions for which a
therapeutic effect or outcome cannot easily be
determined (e.g., reduction in the frequency of
seizures in a patient who has seizures only once
or twice a year).
For some situations, such as the use of
angiotension- converting-enzyme (ACE) inhibitors
in patients with heart failure, guidelines recom-
mend starting treatment at target doses. However,
the main evidence showing a difference in out-
come between a high-dose and a low-dose ACE
inhibitor for heart failure came from a randomized
controlled trial in which the high dose was 7 to 14
times higher than the low-dose comparator.29
Although we are not recommending lower doses
as a target, this serves as an example of how some
dosing studies without mid-dose options create
uncertainty: Would half or one-quarter the high
dose be as effective as the high dose? We do not
know because these lower doses were not studied.
Regardless, there are potential advantages to start-
ing with a low dose and working upward from
there, to reduce the risk of side effects. In addi-
tion, if patients can tolerate half or one-quarter the
target dose, that is likely better than abandoning
the drug completely.
Undoubtedly some patients will end up
requiring higher doses. In these patients, the
strategy of starting with a very low dose could
result in some delay or inconvenience; this is a
counterbalance to the cost savings and reduced
risks of adverse events for all patients as well as
Analysis
CMAJ, January 11, 2011, 183(1) 67
Table 1: Examples of the effect of lower doses reported in randomized
controlled trials*
Medication
Lower dose
studied Result
Hydrochlorothiazide 6.25 mg/d Effective at lowering blood pressure;
first marketed at 50 to 200 mg/d14
Captopril 6.25 mg Effective at lowering blood pressure
as a single dose and when given twice
daily over a longer term; captopril
25 mg three times daily is still
commonly recommended as a starting
dose for hypertension15
Sildenafil 25 mg As effective as 50–100 mg for erectile
dysfunction16
Sumatriptan 25 mg Virtually as effective as 100 mg; most
drugs in this class have a flat dose
response curve at the doses studied17
Fluoxetine 5 mg/d Effects at this dose were similar to
those at 20 mg/d and 40 mg/d18
Ezetimibe 0.25 mg 1/40th of the recommended starting
dose of 10 mg provided 50% of the
effect of lowering low-density
lipoprotein levels achieved with 10 mg19
Elemental iron 15 mg/d As effective as 50 mg and 150 mg for
treating anemia in elderly patients,
with fewer side effects20
Bupropion 150 mg/d Rate of smoking cessation at one year
was the same as that with 300 mg/d21
Atorvastatin 10 mg Produced two-thirds the effect on
cholesterol as that with 80 mg22
Ibuprofen 200 mg As effective as 400 mg for migraine
headache23
Ranitidine 25 mg As effective as 125 mg for heartburn
relief24,25
Colchicine 1.8 mg As effective as 4.8 mg for acute gout,
with fewer adverse events8
*The use of lower doses recommended for drugs that affect surrogate markers such as cholesterol
or blood pressure may not always translate into a decreased risk of cardiovascular events.
big-mccormack_Layout 1 22/12/10 9:11 AM Page 67
the clear advantage for patients requiring only
the lowest doses. A very-low-dose approach is
not meant to be dogmatic. Clinicians and pa -
tients should discuss the right starting dose
based on the patient’s individual characteristics
and history.
Starting with a very low dose may add some
complexity to treatment initiation and take more
time both in developing a treatment plan with the
patient and reaching the best dose for the patient.
During titration, some patients (and perhaps clini-
cians) may lose patience with the process and
assume the medication is ineffective after only a
few dose increases. Clinicians need to educate
patients about how the best dose for them may be
higher than the starting dose and that it may take
a few increases to find the right dose. For some
patients, our proposed strategy will take time,
particularly as titration plans are developed and
clarified, but we feel that the time will not exceed
that spent in normal, informed decision- making.
As well, time spent reaching the right dose may
result in increased adherence and may reduce the
time spent dealing with the consequences of too-
high doses or stopped medications.
Another limitation is that, although most side
effects are dose-related, some of the more seri-
ous life-threatening idiosyncratic allergic reac-
tions are often not dose-related and could still
occur despite starting with very low doses.
Finally, given that “side effects” are reported
in placebo groups of clinical trials, patients re -
ceiving very low starting doses may still report
side effects that may or may not be caused by
the drug.
Practical suggestions
A discussion with the patient about the ratio-
nale and approach to starting drug treatment at
a very low dose is essential. Clinicians should
explain how individuals respond differently to
different doses and determine whether the
patient prefers to start at a lower or higher dose,
after discussing the benefits and limits of each.
When starting with a very low dose, patients
should be advised that they may not respond
immediately and that, with upward titration, the
right dose that im proves the condition while
minimizing the risk of dose-related adverse
events will be found.
Not all drugs come in forms that allow small
doses to be used. However, the majority of
tablets can be split, especially with a pill cutter.
Although splitting tablets does not always result
in perfect sized pieces,30 patients need not be too
concerned if every piece is not exactly the same
size, even for drugs with a low therapeutic index.
Some capsules can be opened and the dose
reduced that way. Alternatively, the interval
between doses could be increased; for example, a
proton pump inhibitor could be taken every two
to three days instead of daily. Finally, a number
of drugs come in liquid form; for example, fluox-
etine is available as a liquid (20 mg per 5mL).
Conclusion
For most conditions that are not life-threatening
or severe, there are few legitimate reasons not to
start with a very low dose and titrate upward.
Dose titration will likely improve tolerability,
may improve adherence if side effects are re -
duced, and will reduce drug costs if a low or
very low dose is found to be effective. An alter-
native approach to determining the best dose for
a patient is to start with a higher dose, get a
response and then reduce the dose to the lowest
effective dose. Some patients may prefer this
approach, but it increases the risk of dose-related
side effects, and both the clinician and the pa -
tient may be reluctant to decrease the dose once
an effect has been achieved.
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Affiliations: From the Faculty of Pharmaceutical Sciences
(McCormack, Virani), University of British Columbia, Van-
couver BC; the Faculty of Medicine (Allan), University of
Alberta, and the Toward Optimized Practice program
(Allan), Edmonton, Alta.; and the Fraser Health Authority
(Virani), Surrey, BC
Contributors: All of the authors contributed substantially to
the conception and design of the article. James McCormack
drafted the article; all of the authors revised it critically for
important intellectual content and approved the final version.
Acknowledgement: The concept for this paper was inspired
by Dr. Robert Rangno, who regularly provided us with a
“high dose” of his clinical experience with very low doses.
Analysis
CMAJ, January 11, 2011, 183(1) 69
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... The intricate pharmacokinetics and pharmacodynamics of efpeglenatide may be the reason why smaller dosages of the medication produce glycemic control that is comparable to or greater than larger doses. Efpeglenatide might best activate the GLP-1 receptor at lower dosages, helping to modulate glucose metabolism effectively without saturating it [22,27]. Additional factors that may be involved include individual variability in responsiveness, metabolic changes, and receptor desensitization at higher dosages. ...
... Additional factors that may be involved include individual variability in responsiveness, metabolic changes, and receptor desensitization at higher dosages. In addition, small dosages could provide steady and prolonged receptor activation, which might eventually improve glycemic control [22,27]. Lastly, when compared to other GLP-1 RAs like liraglutide, efpeglenatide showed either a comparable or even better impact on glucose metabolism and beta-cell functioning [23,24]. ...
Article
Background Efpeglenatide, a novel GLP-1 receptor agonist, has shown promise in improving glycemic control and inducing weight loss in individuals with type 2 diabetes (T2DM). This meta-analysis assessed its therapeutic potential and safety profile. Methods A literature search was conducted on PubMed, SCOPUS, and Cochrane Central from inception until September 2023. We selected patients with T2DM and identified and compared those receiving efpeglenatide to placebo. Outcomes assessed included fasting plasma glucose (FPG), HbA1c, body weight, BMI, and cardiometabolic parameters. Data were analyzed using a random-effects model, with results presented as mean differences (MD) for continuous outcomes and risk ratios (RR) for safety analysis, along with their respective 95% confidence intervals. Quality assessment was conducted using the Cochrane risk of bias tool. Results We included 11 studies in our analysis. Efpeglenatide demonstrated significant reductions in FPG (MD = -1.53 mmol/L, 95% CI = [-2.86, -0.66], p < 0.01), HbA1c (MD = -0.84, 95% CI= [-1.08, -0.60], p < 0.01), body weight (MD = -2.24 kg, 95% CI = [-4.20, -2.00], p < 0.01), and BMI (MD = -1.61 kg/m2, 95% CI= [-2.12, -1.09], p < 0.01). However, efpeglenatide was associated with a moderate increase in the risk of gastrointestinal adverse events, nausea, diarrhea, and vomiting. There was a non-significant elevated risk of hypoglycemia. Conclusions Efpeglenatide significantly improves glycemic outcomes and promotes weight loss in individuals with diabetes. However, it is associated with moderate adverse effects related to the gastrointestinal system. Thus, further trials are warranted to comprehensively assess its safety and efficacy to derive a robust conclusion.
... Low-dose research has gained considerable momentum and attraction over the last decade as drugs of increasing potency are being developed. Small dosage amounts show high safety with minimal adverse effects or overloading phenomena, fewer drug-drug interactions, and reduced dependencies, while demonstrating high levels of efficacy in maintaining low disease activity [8,9]. From a regulatory perspective, it is stated [9] that one in six new products will need to have their doses officially decreased due to safety concerns. ...
... Small dosage amounts show high safety with minimal adverse effects or overloading phenomena, fewer drug-drug interactions, and reduced dependencies, while demonstrating high levels of efficacy in maintaining low disease activity [8,9]. From a regulatory perspective, it is stated [9] that one in six new products will need to have their doses officially decreased due to safety concerns. Colchicine is a good example, where a lower-dose tablet had to be produced due to safety concerns arising from the marketed product [10]. ...
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Purpose To evaluate the use of resonant acoustic mixing (RAM) technology for homogenous blending of a morphologically challenging model API in low-dose concentrations (<0.1% w/w), and assess the potential for blend uniformity (BU) optimization. Methods Caffeine (CAF) mixing was carried out using a LabRAM I benchtop mixer. Uniformity was assessed under a range of mixing conditions and sample preparation procedures in order to optimize system performance. The capacity for microscale mixing was evaluated from final parameters for 0.05% and 0.0125% CAF blends. Results Upon optimization, RAM was able to accurately prepare homogeneous mixtures of <0.1% CAF in dilutions of up to 1 part per 8,000. Results from a 0.05% blend targeting 125 μg CAF dosage amounts revealed an AV score of 8.8 while a 0.0125% w/w blend accurately prepared 25 μg of CAF with 99.3% accuracy (98.7% label claim) and AV of 10.1. Microscale mixing in the 0.05% w/w blend was confirmed from plots of BU data against sample size demonstrating a slope of 0.05 within the range of 250–10 mg sample (125–5 μg CAF). L1 BU criteria only failed at the level of 2 μg CAF, despite target precision to 26 nanograms (98.7% label claim). Conclusions This study presents the first instance of a homogenously mixed <0.1% (w/w) blend using RAM technology and demonstrate the suitability for reproducible dosing of single-digit microgram drug amounts. Uniformity is documented for API amounts 60x smaller than a recent report has shown and 10,000x smaller than achieved previously with CAF.
... The rationale for the reduction or cessation of antipsychotic medication is that not all patients benefit from their use, whilst a variety of adverse effects are common; these include metabolic complications [18][19][20] and probable brain shrinkage, even on top of any effect attributed to the condition of schizophrenia itself. 21 Adverse effects can lead to service user dissatisfaction and increased risk of patient-led discontinuation of medication, [22][23][24] compromising the therapeutic relationship between clinician and patient. One randomised controlled trial demonstrated that reducing and stopping antipsychotic medication has been shown to improved long-term prognosis by increasing the likelihood of recovery through symptomatic and functional remission in people with psychotic conditions. ...
... 25 Prescribing any medication should centre around the principles of using the lowest required dose for the shortest duration of time. 24 Therefore, clinicians should always consider when medications, including antipsychotics, can be reduced in dose and eventually discontinued. While the risk of relapse can be high if dose reductions are performed too rapidly, a meta-analysis of randomised controlled trials suggests that this risk is reduced when tapering takes place over months. ...
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Gradual, hyperbolic tapering has been proposed as a method to reduce the risk of withdrawal effects and potential relapse of an underlying condition by minimising disruption of existing equilibria. We applied hyperbolic tapering principles in silico to long-acting aripiprazole to generate regimens for withdrawal in clinical practice. We derived thresholds for taper rates using existing studies and consensus. Using pharmacokinetic data for aripiprazole long-acting injectable antipsychotic (ALAI), we conducted in silico modelling to examine the impact of abrupt cessation of long-acting injectable antipsychotic (LAI) medication and the effect of prolonging inter-dose interval on plasma aripiprazole levels and consequent D 2 occupancy. We also modelled transitions from LAI medication to oral medication. Regimens were designed to afford a rate of reduction between 5 and 12.5 percentage points of D 2 occupancy per month. Abrupt discontinuation of ALAI was shown to lead to a maximal D 2 occupancy reduction of 16.8 percentage points per month; prolongation of the inter-dose interval of ALAI produced a slower reduction. Specifically, hyperbolic tapering was afforded by prolongation of a 400 mg ALAI inter-dose interval from 4 to 7 weeks, before reducing the dose to 300 mg ALAI. This could then be administered at up to 4-week (for 6% maximal D 2 occupancy change), 6-week (9% change) or 7-week (11% change) intervals. Switching to oral medication – 5, 2.5 and 1.25 mg for the three regimens, respectively – is required for ALAI to complete full cessation to prevent too rapid a reduction in D 2 occupancy. Oral medication should probably be maintained at a consistent dose for 3–6 months before further reductions to account for residual LAI being concurrently eliminated. Hyperbolic dose tapering is possible with ALAI through prolongation of the inter-dose interval and may reduce the risk of relapse compared to abrupt discontinuation of LAI medication.
... Більшість з них, 27%, склали психотропні препарати. [40]. ...
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Importance. Despite the fact that in recent decades a large number of new psychotropic medication have been developed and investigated, psychotherapy and other treatments for mental disorders, it became apparent that many patients are resistant to treatment or response only after repeated changes in therapy or its combinations. Having a diagnosis of mental disorder itself was not sufficient to choose the best treatment. In the medical field, there is a new approach to the treatment of mental disorders - "personalized approach", which will treat not "diagnosis" but "patient". Materials and methods. In order to observe the prospects of using low doses of psychotropic drugs (and their combinations) to achieve more effective treatment results, a content analysis was conducted using Ukrainian and English publications for the last 15 years. The search was performed on the databases Pubmed, CrossRef. Results. The most effective drug is selected by the doctor based on the clinical condition and symptoms of the patient, but the most important factor in achieving successful results is the individually selected effective dose. Timely dose adjustment to achieve the desired clinical response, combined with the prevention of adverse reactions, is an important factor in maintaining patient's adherence to treatment. Reducing the dose of psychotropic drugs to levels below those recommended in the instructions for use can lead to significant positive results due to: improved health care in general with more effective therapeutic results, reduced side effects and reduced patient`s costs. Personalized approach and judicious use of psychotropic drugs for other purposes is considered an integral part of the continuous development of science, taking into account the clinical experience of the use of drugs. Conclusions. There is a need to adjust the dosage of psychotropic drugs to the minimum effective dose that will meet the individual needs of the individual patient, and will help to find a balance between efficacy and risk of side effects and will be a necessary basis for developing an effective personalized approach in psychiatric practice. Optimizing the dosage of a psychotropic drug is an important factor in improving the efficiency of the health care system as a whole.
... An alternative technique to determine the optimal efficacy of one sample, according to McCormack et al. (2011), is to start with a higher dose, wait for a response, and then drop the amount to the lowest effective dose. Some tests may prefer this strategy, but it raises the risk of dosage-related adverse effects, and both the clinician and the patient may be hesitant to reduce the dose once a result is obtained. ...
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The golden apple snail Pomacea canaliculata (L) is one of the most pervasive pests in rice farms in the Philippines. Synthetic molluscicidal formulations are one of the most widely used pest control methods. However, this affected the non-target organisms and the environment adversely. Thus, there is a need to find a viable alternative in the form of a plant-based pesticide that is commonly available and less costly. The garlic Allium sativum (L.) and the makabuhay plant Tinospora crispa (L.) are widely known for medicinal purposes. According to studies, these plants' bioactive components can also be a potential pesticide for snails in lowland rice fields. Thus, this study sought to determine whether a singly or binary combination of these fermented plants' extracts could demonstrate the molluscicidal effect in P. canaliculata. The mortality rate of P. canaliculata after applying different extracts in varying concentrations within 24-hour exposure time was collected and tested using ANOVA. Among the various extracts and concentrations tested, 60 percent of the garlic and makabuhay individual plant fermented extract were the most effective, with the highest mortality recorded for golden apple snails.
... The lower hypoglycemic effect in the higher dose (500 A) group was consistent with previous studies on several other indigenous plants, including Murraya koenigii and Aegle marmelos (Kesari et al., 2005(Kesari et al., , 2006. This phenomenon might be possibly affected by the maximum-tolerated dose effect where improved treatment adherence and effectiveness are often observed at lower dosage regimens in chronic disease treatments (McCormack et al., 2011). Overall, the results clearly showed that AE extract has anti-hyperglycemic potential for use in managing diabetes. ...
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Ethnopharmacological relevance: Ardisia elliptica Thunb. (AE) (Primulaceae) is a medicinal plant found in the Malay Peninsula and has been traditionally used to treat diabetes. However, limited studies to date in providing scientific evidence to support the antidiabetic efficacy of this plant by in-vitro and in-vivo models. Aim of the study: To investigate the anti-hyperglycemic potential of AE through in-vitro enzymatic activities and streptozotocin-nicotinamide (STZ-NA) induced diabetic rat models using proton-nuclear magnetic resonance (1H-NMR)-based metabolomics approach. Materials and methods: Anti-α-amylase and anti-α-glucosidase activities of the hydroethanolic extracts of AE were evaluated. The absolute quantification of bioactive constituents, using ultra-high performance liquid chromatography (UHPLC) was performed for the most active extract. Three different dosage levels of the AE extract were orally administered for 4 weeks consecutively in STZ-NA induced diabetic rats. Physical assessments, biochemical analysis, and an untargeted 1H-NMR-based metabolomics analysis of the urine and serum were carried out on the animal model. Results: Type 2 diabetes mellitus (T2DM) rat model was successfully developed based on the clear separation observed between the STZ-NA induced diabetic and normal non-diabetic groups. Discriminating biomarkers included glucose, citrate, succinate, allantoin, hippurate, 2-oxoglutarate, and 3-hydroxybutyrate, as determined through an orthogonal partial least squares-discriminant analysis (OPLS-DA) model. A treatment dosage of 250 mg/kg body weight (BW) of standardized 70% ethanolic AE extract mitigated increase in serum glucose, creatinine, and urea levels, providing treatment levels comparable to that obtained using metformin, with flavonoids primarily contribute to the anti-hyperglycemic activities. Urinary metabolomics disclosed that the following disturbed metabolism pathways: the citrate cycle (TCA cycle), butanoate metabolism, glycolysis and gluconeogenesis, pyruvate metabolism, and synthesis and degradation of ketone bodies, were ameliorated after treatment with the standardized AE extract. Conclusions: This study demonstrated the first attempt at revealing the therapeutic effect of oral treatment with 250 mg/kg BW of standardized AE extract on chemically induced T2DM rats. The present study provides scientific evidence supporting the ethnomedicinal use of Ardisia elliptica and further advances the understanding of the fundamental molecular mechanisms affected by this herbal antidote.
... Semen quality is one of the most important markers in male reproductive system to diagnose infertility and associated causes of infertility. [38] In general, the characteristic of a sperm is evaluated based on its count in one single ejaculate, motility, viability, and abnormality. The present study showed dose-dependent effects on sperm characteristics following the administration of methanolic extract of B. monosperma flower. ...
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Background: Search for an effective, feasible, and safe male contraceptive has been one of the major public health challenges. The present contraceptive methods are either permanent or impractical. Herbal methods are considered safe, and thus, their acceptability is higher than other prospective methods. Aims: In the present study, oral administration of methanolic extract of Butea monosperma (Lam.) Taub. flower was investigated for its potential role in the modulation of fertility in male albino rats. Materials and methods: Healthy male albino rats were randomly distributed into three groups, i.e., a control and two groups administered with 50 and 500 mg/kg body weight/day of methanolic extract of B. monosperma flower for 30, 90, and 180 days, respectively. Fertility records were maintained throughout the experimental period. At the end of experiment, animals were sacrificed and the weight of reproductive organs, sperm characteristics, and histopathology of testicular and epididymal tissues were evaluated. A 45-day withdrawal period was also investigated for parameters as described above for each group. Results: A 40% decline in fertility rate was evident in rats administered with 500 mg/kg of B. monosperma flower extract for 180 consecutive days. A significant reduction in testicular and epididymal weight was observed in these animals. Sperm count, motility, and viability were also reduced significantly in animals treated for 180 days. Histological evaluation of testicular cells indicated distortions in germ cell arrangements at various stages of spermatogenesis. Following 45 days of withdrawal, the resumption of normal functional and histological characteristics was apparent. Conclusion: Based on the abnormalities present in the sperm characteristics and damages in testicular histology, it was confirmed that methanolic extract of B. monosperma flower contain antifertility potential.
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As more bacteria develop antibiotic resistance, bioenhancers – substances that enhance antibiotic performance – are emerging as potential solutions. However, the effectiveness of bioenhancers has not been measured on highly antibiotic-resistant pathogens. We hypothesized that the bioenhancer piperine, derived from black pepper, combined with the drug ampicillin-sulbactam, would lead to decreased growth of Acinetobacter baumannii, a highly resistant bacterium, compared to the drug alone. Broth dilution was used to find the minimum concentration of drug needed to inhibit three strains of A. baumannii, with Escherichia coli as a control, providing a baseline for the strain’s resistance levels. The strains were exposed to four treatments: varying concentrations of ampicillin-sulbactam alone, piperine alone, a combination of ampicillin-sulbactam and piperine, and no treatment to analyze the antibiotic-bioenhancer synergy. Treatments were also incubated with macrophages, cells of the mammalian innate immune response, measure drug efficacy under conditions mimicking early stages of infection. The results indicated that combining piperine with ampicillin-sulbactam at 64 mg/L and 32 mg/L reduced bacterial growth for two A. baumannii strains compared to treatment with antibiotic alone. However, the third strain had no significant difference in bacterial growth. However, at a drug concentration of 16 mg/L, the addition of piperine led to significantly reduced bacterial growth for all three strains (p < 0.001, p < 0.0001, p < 0.0001). These studies showed that piperine enhanced ampicillin-sulbactam efficacy against A. baumannii. The addition of piperine led to lower minimum inhibitory concentrations of the antibiotic against drug-resistant A. baumannii.
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Tumor necrosis factor-α (TNF-α) contributed to the insulin resistance which leads to type 2 diabetes. The A. altilis plant has traditionally been used by the Indonesian people to treat diabetes mellitus. The purpose of this study was to determine the parameter of TNF-α level in obese mice (Rattus norvegicus). This study was used experimental laboratory with Randomized Controlled Trial (RCT) design. It’s divided into 5 groups, and each group consisted of 5 rats that have been given a 45% fat (open source) high fat diet for fattening itself. Measurement of body weight to assess obesity and examination of fasting blood sugar (GDP) were used of DR glucose test kits. Group I was negative control, group II as positive control using metformin HCl, group III using A. altilis 5%, group IV A. altilis with 10% and group V A. altilis with 15%. Treatment was carried out for 14 days in each group and TNF-α levels was assessed with ELISA test. Nonparametric test was used to see the differences between each groups with a 95% confidence level. There was a significant effect of A. altilis with 10% extract toward TNF-α levels, where the value of p = 0.018. While the administration of extracts of 5% and 15% did not show a significant effect. The administration of 10% A. altilis extract showed a significant decrease of TNF-α levels in obese mice who had hyperglycemia.Keywords: A. altilis, obesitas, TNF-α, insulin resistance
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Background: Damage to the periodontium tissue requires a regenerative treatment to increase the dimensions of the lost bone. This research was conducted to find another regenerative material with the use of type 1 collagen peptides derived from gourami fish scales. This study was conducted to test the viability of gourami scales collagen peptides on Human Gingival Fibroblast cells for 24 hours. Purpose: To determine the viability of Human Gingival Fibroblasts (HGF) after the administration of collagen peptides of gourami fish scales. Method: HGF was taken from healthy gingiva and planted in 96 well plates. The type 1 collagen peptides of gourami fish scales with concentrations of 0.32 mg / ml, 0.16 mg / ml, 0.04 mg / ml, 0.02 mg / ml and 0.01 mg / ml were inserted into each well and incubated for 24 hours. MTT Assay was performed to see the viability of fibroblast cells. Results: There was an increase in the viability value from a concentration of 0.32 mg/ml to 0.01 mg/ml. The concentration of 0.01 mg/ml showed the highest viability. Conclusion: The collagen peptide is a potential substance for tissue engineering. The concentration of 0.01 mg/ml collagen peptides shows the highest HGF viability.
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Background. Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure. It is unclear, however, if low doses and high doses of ACE inhibitors have similar benefits. Methods and Results. We randomly assigned 3164 patients with New York Heart Association class II to IV heart failure and an ejection fraction ≤ 30% to double-blind treatment with either low doses (2.5 to 5.0 mg daily, n=1596) or high doses (32.5 to 35 mg daily, n=1568) of the ACE inhibitor, lisinopril, for 39 to 58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients with the high-dose group had a nonsignificant 8% lower risk of death (P=0.128) but a significant 12% lower risk of death or hospitalization for any reason (P=0.002) and 24% fewer hospitalizations for heart failure (P=0.002). Dizziness and renal insufficiency was observed more frequently in the high-dose group, but the 2 groups were similar in the number of patients requiring discontinuation of the study medication. Conclusions. These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor (if any) is likely to be very small.
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Objectives: To present a methodology for identifying specific medications for which pill splitting is clinically appropriate and cost saving, to present data from a commercial managed care population on current pill-splitting practices, and to estimate additional cost savings from extended use of this strategy. Study Design: Retrospective pharmacy claims analysis Methods: Pharmacy claims data from a commercial managed care health plan covering 19,000 lives and national drug data were used to compile a list of frequently prescribed medications. Excluding medications in which packaging, formulation, and potential adverse pharmacologic outcomes prohibited splitting, we performed a cost analysis of medications amenable to splitting. Results: Eleven medications amenable to pill splitting were identified based on potential cost savings and clinical appropriateness: clonazepam, doxazosin, atorvastatin, pravastatin, citalopram, sertraline, paroxetine, lisinopril, nefazadone, olanzapine, and sildenafil. For these medications, pill splitting is currently infrequent, accounting for annual savings of 6200(or6200 (or 0.03 per member per month), just 2% of the potential 259,500(or259,500 (or 1.14 per member per month) that more comprehensive pill-splitting practices could save annually. Conclusions: Pill splitting can be a cost-saving practice when implemented judiciously using drug- and patient-specific criteria aimed at clinical safety, although this strategy is used infrequently.
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Objective.—To evaluate the efficacy and safety of ibuprofen, 200 mg and 400 mg, compared with placebo and each other for the treatment of pain of migraine headache. Background.—Migraine headache is a common illness with significant social and economic impact. Design.—Randomized, placebo-controlled, double-blind trial of 6 hours' treatment duration. Methods.—Fifteen investigators at 17 private practice and referral centers in the United States participated in this study of 660 outpatient adults aged 18 to 84 years with migraine headache of moderate to severe intensity. Each patient was randomly assigned to a single dose of study medication: ibuprofen 200 mg (n=216) or 400 mg (n=223), or placebo (n=221). The percentage of patients with a reduction in baseline headache intensity from severe or moderate to mild or none 2 hours after treatment and the headache pain intensity difference from baseline at 2 hours were the primary efficacy measures. Secondary outcomes included other measures of pain relief, severity differences from baseline for migraine-associated symptoms of nausea, photophobia, phonophobia, and functional disability, and percentage of patients with migraine-associated symptoms reduced to none. Results.—Significantly (P.006) more patients treated with ibuprofen, 200 mg or 400 mg, reported mild to no pain after 2 hours (41.7% and 40.8%, respectively), compared with those treated with placebo (28.1%). The mean pain intensity difference from baseline measured at 2 hours was significantly (P .001) greater for patients treated with ibuprofen 200 mg or 400 mg (0.68 and 0.65, respectively), compared with those treated with placebo (0.39). Statistically significant differences in favor of both doses of ibuprofen over placebo were observed for mean pain intensity difference at 1 hour after treatment. In patients with severe baseline pain intensity, ibuprofen, 400 mg, was significantly (P .048) superior to placebo for the primary efficacy end points, while ibuprofen, 200 mg, was not. Ibuprofen, 200 mg and 400 mg, were statistically significantly more effective than placebo for all clinically important secondary pain relief outcomes. Mean severity changes of migraine-associated symptoms of nausea, photophobia, phonophobia, and functional disability at 2 and 6 hours were significantly (P .03) in favor of both doses of ibuprofen over placebo, and results for the percentage of patients with symptoms reduced to none consistently, although less often statistically significant, favored ibuprofen. No statistically significant differences in adverse events were found among treatment groups. Conclusions.—Ibuprofen at doses of 200 mg and 400 mg is an efficacious, cost-effective, well-tolerated, single-ingredient nonprescription treatment for pain of migraine headache. In addition, while not always statistically significant, ibuprofen provided a beneficial effect on associated symptoms of migraine including nausea, photophobia, phonophobia, and functional disability.
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Despite widespread use of colchicine, the evidence basis for oral colchicine therapy and dosing in acute gout remains limited. The aim of this trial was to compare low-dose colchicine (abbreviated at 1 hour) and high-dose colchicine (prolonged over 6 hours) with placebo in gout flare, using regimens producing comparable maximum plasma concentrations in healthy volunteers. This multicenter, randomized, double-blind, placebo-controlled, parallel-group study compared self-administered low-dose colchicine (1.8 mg total over 1 hour) and high-dose colchicine (4.8 mg total over 6 hours) with placebo. The primary end point was > or = 50% pain reduction at 24 hours without rescue medication. There were 184 patients in the intent-to-treat analysis. Responders included 28 of 74 patients (37.8%) in the low-dose group, 17 of 52 patients (32.7%) in the high-dose group, and 9 of 58 patients (15.5%) in the placebo group (P = 0.005 and P = 0.034, respectively, versus placebo). Rescue medication was taken within the first 24 hours by 23 patients (31.1%) in the low-dose group (P = 0.027 versus placebo), 18 patients (34.6%) in the high-dose group (P = 0.103 versus placebo), and 29 patients (50.0%) in the placebo group. The low-dose group had an adverse event (AE) profile similar to that of the placebo group, with an odds ratio (OR) of 1.5 (95% confidence interval [95% CI] 0.7-3.2). High-dose colchicine was associated with significantly more diarrhea, vomiting, and other AEs compared with low-dose colchicine or placebo. With high-dose colchicine, 40 patients (76.9%) had diarrhea (OR 21.3 [95% CI 7.9-56.9]), 10 (19.2%) had severe diarrhea, and 9 (17.3%) had vomiting. With low-dose colchicine, 23.0% of the patients had diarrhea (OR 1.9 [95% CI 0.8-4.8]), none had severe diarrhea, and none had vomiting. Low-dose colchicine yielded both maximum plasma concentration and early gout flare efficacy comparable with that of high-dose colchicine, with a safety profile indistinguishable from that of placebo.
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Statins are the most commonly prescribed agents for lowering levels of low-density lipoprotein (LDL) cholesterol. Although dose-dependent reductions in levels of atherogenic lipids are observed with all statins, the impact of increasing dose has not been fully elucidated. An individual patient data pooled analysis was performed of 32,258 patients in studies comparing the efficacy of rosuvastatin with that of atorvastatin or simvastatin. The impact of increasing dose on lowering LDL cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B was investigated. Doubling the dose of each statin was accompanied by a 4% to 7% greater degree of lowering of all atherogenic lipids. A stronger correlation was observed between changes in LDL cholesterol and non-HDL cholesterol (r = 0.92, p <0.001) or apolipoprotein B (r = 0.76, p <0.001) than triglycerides (r = 0.14, p <0.001). On multivariate analysis, baseline lipid level (p <0.0001) and increasing statin dose (p <0.0001) were strong predictors of achieving treatment goals in high-risk patients. Increasing age was a strong independent predictor of achieving goal for all atherogenic lipids (p <0.0001). Achieving LDL cholesterol goals was also more likely in women (p <0.0001), patients with diabetes (p <0.0001), and patients without atherosclerotic disease (p = 0.0002). In contrast, normal triglyceride levels were more often observed in men (p <0.0001) and patients without diabetes mellitus (p = 0.03). In conclusion, doubling statin dose was associated with greater lowering of LDL cholesterol by 4% to 6% and non-HDL cholesterol by 3% to 6%. Greater lipid goal achievement with increasing dose supports the use of high-dose statin therapy for more effective cardiovascular prevention.