Chapter II:

Review of Related Literature and Studies.

The focus of this study is to identify the jeopardy and advantageous effects of
pharmaceutical drugs to vigorous humans, a vague question still left unanswered. Some studies
were conducted in relation to this topic. The results suggested that pharmaceutical drugs may
pose benefits as well as recognizable risks to human health depending on respective
consumption. Dosage is a factor that hugely influences pharmaceutical effects.

Related Foreign Literature:

As exposed by a Hungarian study (Orsolya Somogyi et al. 2019) patients consumed on

average 7.9 ± 3.1 medications and other products. 571 DRPs were detected in 540 patients,
averaging 1.06 DRPs per patient (SD = 1.07). The highest frequency category was DRP5 (non-
quantitative safety problem; 51.0%). The most common root cause was an interaction (42.0%)
and non-adherence (19.4%.). The most commonly used intervention was education (25.4%) and
medication replacement by the pharmacist (20.1%). The changing of the frequency and dosage in
any direction were negligible. The same study showed that pharmacists need some good
conversation with patients to come up with concrete conclusions based from honest feedbacks.
Through this communication they help each other in regards with the medicine’s content.
Pharmacists have been conducting medication review at each consultation. They look at it from
the point of the necessity, safety and effectiveness to the consumers or patients. In the process of
assessing drug-related problems, the pharmacist classified the DRPs into six classes and
identified the root cause. A lot of the data, the quantity, causes and intervention from anonymous
patients were statistically analyzed by the pharmacists at their meetings. Qualified pharmacists
conducted the project. The data were handled by pharmacy and health data management
according to Act XLV11 of 1997. Data were transmitted without personal information to process
the results. The personal and health data of the patients included in the study were not damaged.

Medical cannabis is widely used as a controller for strong chronic pains, post-surgical
pains and is known for it’s effectiveness. In spite of being a medically employed product
throughout the ages. A legal study from (Caroline A. MacCallum et al. 2018) that the recent
legal prohibition, biochemical, complexity and variability, quality controlled trials and lack of
pertinent education have conspired to leave clinicians in the dark as to how to advise patients
pursuing such treatment. Additionally, in result of the advert of this pharmaceutical cannabis-
based, medicines emancipated access in settled nations, the ignorance of cannabis pharmacology
and therapeutic has become untenable. However, the authors of this study has strived to present
compact data based on cannabis pharmacology. Adverse events of cannabis medicine pertain
primarily to THC, whose total daily dose-equivalent should generally be limited to 30 mg/day or
less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of
tolerance.
 For being used as a pain medicine with other medications for anesthesia, a scrutiny
regarding to the effects of Fentanyl depression from (Rob Hill et al., 2019) has expound their
investigation about a drug called Fentanyl. According to the article, there has been a dramatic
rise in acute opioid overdose deaths involving new synthetic opioids, primarily the fentanyls
(fentanyl and structurally related medicinal and illicit drugs), in North America (NIH, 2019). Of
the over 60,000 opioid overdose deaths in the United States in 2017, almost 30,000 involved
fentanyls, exceeding those involving heroin (diacetyl morphine) or prescription opioids such as
oxycodone and hydrocodone. Elsewhere, in Europe, fentanyl deaths have been recorded in
Estonia (for some time, fentanyls were the main street opioids available in that country), and
there have been sporadic outbreaks of fentanyl‐related deaths in the United Kingdom, Germany,
and Finland (EMCDDA, 2018).

A lot of factors have proved why this drug is considered to be deadly. It is due to their
high potency which means even a small amount can produce definite effects. Which also shows
that a tiny inexact dosage could cause too much, such as rapid penetration into the brain can
result in overdose levels being reached more quickly than with heroin. Deaths in heroin overdose
may take more than 30 min to occur after injection (Darke & Duflou, 2016), providing a window
of opportunity for intervention (administration of the opioid antagonist naloxone). In contrast,
fentanyl overdose deaths can occur very quickly before there is an opportunity to administer
naloxone (Burns, DeRienz, Baker, Casavant, & Spiller, 2016). Fentanyls induce muscle stiffness
(Benthuysen, Smith, Sanford, Head, & Dec‐Silver, 1986; Streisand et al., 1993) including in
intercostal and diaphragm muscles, often referred to as “wooden chest,” and this is likely to
make it harder to breathe. The overdose from this drug has been considered as an “epidemic”
level in North America. Fentanyl had the fastest rate of onset and morphine the slowest. The rate
of onset of respiratory depression correlated with the lipophilicity of each drug.

Related Local Literature:

Shown from a local literature of (Mark Lloyd G. Dapar et al., 2020) that the Philippines
is one of the species-rich country culturally. Yet, the ethnopharmacological studies are still
narrow especially in most tribal parts and locations of the country. Which resulted of lacking
understanding and knowledge about the modern pharmaceutical invented drugs. This aims to
document the traditional practices, medicinal plant use, and knowledge; to determine the relative
importance, consensus, and the extent of all medicinal plants used; and to integrate molecular
confirmation of uncertain species yet to be discovered with the help of the ethnic Agusan
Manobo tribe. This study enumerated the ethnopharmacological use of 122 medicinal plant
species, distributed among 108 genera and belonging to 51 families classified in 16 use
categories. Statistically, the medicinal plant knowledge among respondents was significantly
different (p < 0.001) when grouped according to education, gender, social position, occupation,
civil status, and age but not (p = 0.379) when grouped according to location. This study recorded
the first quantitative ethnopharmacological documentation coupled with molecular confirmation
of medicinal plants in Mindanao, Philippines, of which one medicinal plant species has never
been studied pharmacologically to date. Conventional pharmaceutical medicines and therapeutics
may serve as an effective remedy, but some people still prefer the native way of healing and
treating health condition problems. The WHO has accounted about 60% of the world’s
population relying on traditional medicine and 80% of the population in developing countries
depend almost entirely on traditional medical practices, in particular, herbal remedies, for their
primary health care. The Philippines has 1500 medicinal plants discovered and 120 of them are
approved for it’s fascinating efficacy to people. Due to the increasing demand for drug
development, the application of a quantitative approach in ethnobotany and ethnopharmacology
is rising continuously in the last few decades including multivariate analysis.

Local native plants are widely used and known by a lot of people regarding their
effectiveness and natural quantities to treat unstable health issues and problems. A group of
researchers have stated that Phaeanthus ophthalmicus (Roxb. ex G.Don) J.Sinclair (previously
known as P. ebracteolatus (Presl) Merr) is a Philippine medicinal plant, locally known as
“Kalimatas” occurring as an evergreen shrub in the lowland forests of Luzon islands. It is used
traditionally by Filipinos to treat bacterial conjunctivitis, ulcer and wound infections. Based on
previous investigations where cyclooxygenase-2 (COX-2) functions as immune-linked factor in
infectious sensitivities to bacterial pathogens by triggering pro-inflammatory immune-associated
reactions, we investigated the antimicrobial and COX inhibitory activities of the extracts and
tetrahydrobisbenzylisoquinoline alkaloids of P. ophthalmicus in vitro and in silico to validate its
ethnomedicinal uses. (Hilbert D. Magpantay et al., 2021). The resurgence of infections caused by
multi-drug resistant bacterial pathogens poses great threats globally and constitutes a major crisis
plaguing societies in the past years. Many pathogenic bacteria such as Staphylococcus aureus
and Pseudomonas aeruginosa exhibit multi-drug resistance (MDR). Recently, a “pan-resistant”
strain of the Gram-negative bacterium P. aeruginosa emerged and caused alarming consciousness
of its infectivity. Therefore, new drugs and treatment regimens are increasingly needed to catch
up with the rise of bacterial resistance. While there are available antibiotics used to treat bacterial
infections, the need for antimicrobials that regulate host immune response and diminish
inflammation incidences are also increasing in demand. Recent efforts illustrate COX-2
inhibitors (i.e., celecoxib) confer increased bacterial sensitization and reversal of drug resistance
(Ivane M. Malaluan et al., 2021).

This discovery has pushed a great movement of finding remedies through plants and
other natural resources to be obtained to treat any anti-inflammatory-related infections such as
corneal ulcers. Consequently, the efforts on finding these remedies needed a warrant leading
researchers to take native medicinal plants as their easiest option. As to their fortune, any plant-
based products have been considered safe to use as an anti-bacterial remedy. Due to the wide use
of the pharmaceutical drug Antihistamines, inspired the local group to identify some allergic
causes occurring on the users of this known medicine. The second generation antihistamines are
believed to be the first-line treatment option when it comes to the activity of allergic rhinitis
(Recto et al., 2017). It served as a concurrence to several countries like Hong Kong, Malaysia,
Philippines, Singapore, Thailand, and Vietnam. Which they strive to identify and discuss the
needs and challenges pertaining to this pharmaceutical medicine. As a stepping stone, they have
conducted specialists such as allergologists, dermatologists, and otorhinolaryngologists which
they surveyed on a practical way regarding the allergic issue. This survey has resulted that
clinicians felt the need for additional tools for diagnosis of these diseases and a single drug with
all preferred features of an antihistamine. Challenges in treatment include lack of clinician and
patient awareness and compliance, financial constraints, and treatment for special patient
populations such as those with concomitant disease. Selection of optimal second-generation
antihistamines depends on many factors, particularly drug safety and efficacy, impact on
psychomotor abilities, and sedation. Country-specific considerations include drug availability
and cost-effectiveness. Survey results reveal bilastine as a preferred choice due to its high
efficacy and safety, suitability for special patient populations, and the lack of sedative effects.
(Recto et al., 2017)

Related Foreign Studies:

Humira, Abbvie’s single and largest selling product which originated from a joint venture
between Cambridge Antibody Technology and BASF in the UK. It has been approved by Food
and Drug Administration (FDA) in 2003. The mentioned medicine is known for its effectiveness
on treating several kinds of autoimmune diseases, most commonly, arthritis and plaque psoriasis
in the United States, Europe, Mexico and Canada. It is also considered approve by Japan for
treating intestinal Bechet’s disease. The tumour necrosis factor inhibitor Humira (adalimumab,
AbbVie) is an established biologic treatment for a number of immune-mediated inflammatory
diseases, including rheumatoid arthritis (RA), psoriatic arthritis and inflammatory bowel disease.
A former study has objectified Humira’s efficacy, safety and immunogenicity from tested
patients. According to the article, the primary objective of the study was to demonstrate
equivalent clinical efficacy of BI 695501 and Humira. Coprimary endpoints were the percentage
of patients achieving the American College of Rheumatology 20% response criteria (ACR20) at
week 12 (requested by FDA) and week 24 (requested by EMA). The patients are believed to be
(18-60 years old) with rheumatoid arthritis for more than 6 months. They must receive 15-25mg
per week and will have a background treatment for more than 12 weeks. However, some patients
appeared to have missing data in spite of not stopping the intake, multiple imputation has been
used. As a result, The first patient was screened on 4 February 2015. Patients discontinued the
trial prematurely. Last patient, last visit occurred on 18 October 2016. There were no differences
in the rate of treatment or trial discontinuation between treatment groups. Patient disposition and
geographical distribution are presented in figure 1B and online supplementary table S1,
respectively. (Alberto Alonzo-Ruiz et al.,2018).

Ensuring the safety of medicines especially for the children. As a human, their immunity
is weaker than adults, their bodies are sensitive when it comes to chemicals. Thus, one of the
pharmaceutical drug that are used by most adolescents is Albuterol. Knowing the benefits of this
mentioned drug commonly used for nebulization is a large concern to adults mainly parents.
However, the dropper bottle of benzalkonium chloride (BAC), which is a preservative of an
albuterol is believed to cause bronchospasm. This lead to hypothesized that it reduces the
therapeutic efficacy of albuterol on patients with acute asthma exacerbations. The aim of this
study was to determine if the change to BAC-containing albuterol products resulted in clinical
consequences in children with severe acute asthma exacerbations. On the basis of the literature
and the expected exposure to a large cumulative dose of BAC during continuous nebulization,
we hypothesized that the use of albuterol formulations containing BAC would prolong the
duration of continuous nebulization, an indirect measure of adverse effect. To justify this issue
regarding the one of the mainly used pharmaceutical product, researchers have conducted several
kinds of testing on patients less than 18 years old to nebulize them both with and without the
influence of BAC. As to their results, A total of 477 patients were included in the analysis (236
exposed to BAC and 241 controls). The duration of continuous nebulization was significantly
longer in the BAC group than in the control group and 43% more likely to stop additional
respiratory support (hazard ratio 1.43; 95% confidence interval: 1.16 to 1.75; P < .001).
(Matthew C. Pertzborn et al., 2020). Overall, the results of this retrospective analysis have
revealed that BAC is significantly associated with an increase in dose and duration of continuous
albuterol nebulization and needs a longer duration of respiratory support needed mainly among
children hospitalized with severe asthma exacerbations which requires continuous nebulized
albuterol. On the other hand, with an increased duration of 3 hours of nebulizing and 8 hours of
needing respiratory support would cause a more respiratory distress with the BAC group
patients.

In concern with one of the most popular diseases in humanity, Gastric ulcer is now being
analyzed with it’s known cure Nexium. Nexium (Esomeprazole) is a pharmaceutical drug known
for it’s loftier activity against the mentioned disease. However, various clinical studies tried to
conduct a conclusion that may suggest clarified efficacy of this drug. Using the method of short-
listing the randomized records which includes the tract results of esomeprazole on patients with
gastric ulcer. The data and assessments were analyzed independently. In consequence, After
critically analyzing four major important related clinical trials (n=3837), it was found that at 24
weeks, patients maintained on esomeprazole 20 mg OD (167/173) were gastric ulcer free, in
comparison to placebo group (112/168). Similar results were obtained with 26 weeks treatment
of esomeprazole at doses of 20 mg, 40 mg (808/818), and (798/804), respectively. While,
outcome of another trial at the same dose, for the duration of 52 weeks, 125 out of 130 patients
showed recovery from gastric ulcer, compared to 40/799 in placebo group. Similarly, in the other
trial, patients who were given esomeprazole in combination with naproxen (500 mg), displayed
positive effect in 166 out of 218 patients. Adverse events were observed only in 5/218 and 6/216,
respectively. (Nimra Mujeeb et al., 2019)

However, another study has also stated the effects of esomeprazole on other random
patients. Drug exposure and corresponding antisecretory effects increase over the first 4–5 days
of esomeprazole treatment. To date, this effect has not been correlated with symptomatic
improvement. Therefore, the efficacy of esomeprazole was evaluated on days 1–4 and 5–14
(David Puera et al., 2019). Frequent heartburn sufferers treated with esomeprazole 20 mg had
significantly more heartburn-free days relative to placebo throughout the studies. Maximal
clinical benefits coincided with the estimated timing of maximal pharmacokinetic and
pharmacodynamic effects and duration of acid control on days 5–14.

Related Local Literatures

At one of the Island of Mindanao, where most people are still relying on their knowledge
pertaining to the medicinal plants throughout the archipelago as their health care. Despite of the
several researches, there are still many of these plants remained untouched. The target diseases
of these plants are some of the main and severe diseases that occur in the human body. It is also
believed that medicinal plants are valuable sources of the modern pharmaceutical drugs (Chen et
al., 2016). According to the World Health Organization (WHO), 80% of the world’s population
still rely on traditional medicine for treatments for patients who have lacked access to
conventional modern medications (Hamilton 2004; Zarsuelo et al., 2018). Due to pharmaceutical
drug side effects and expensiveness in the world market, many countries in Africa, North
America, Europe, and Australia have tended to stick into the therapeutic uses of herbal plants
despite the modernization of medicine and technology. Meanwhile, in some parts of Asia, the
use of therapeutic plant items were still being questioned by some of the medical experts.
Therefore, the present study on ethnomedicinal plants is essential to the ongoing search of an
effective organic and low-cost natural product (Montero, JC et al., 2021). In the Philippines,
most of the people especially ethnic groups still put their hopes in healing naturally. This study
pursued researchers to study the plants more to also prevent the extinction of these natural
resources due to modernization (Pizon et al., 2016). In order to preserve the herbal medications
of most people. Based on the interviews conducted among the 30 respondents in Tina and Libas
Gua village of San Miguel, Surigao del Sur, a total of 46 plant species belong to 31 families were
documented. Each plant collected from the field determined in terms of its family, scientific
name, local name, plant part used, forms of preparation and mode of application, and
disease/ailment to be treated (Table 1). Of the 31 families, Gramineae/Poaceae (5 species),
Fabaceae (4 species), Lamiaceae and Zingiberaceae, (3 species) were the most frequent number
of plant species. These are followed by the Compositae, Verbenaceae, Liliaceae, and Malvaceae
with two (2) plant species each, and the rest of the remaining families had one species. Family
Gramineae/Poaceae was the highest and most abundant representative plant species that had
occupied a diversity of medicinal plants. These plant families were frequently present in the
household surroundings as ornamental plants, inferring that these plants were the most part
utilized for medicinal purposes.

The recorded variety of ailments and diseases believed to have treated using medicinal
plants. Based on the conversations with the respondents, medicinal plants have an innate power
to cure a variety of illnesses and diseases which depend on the kind of plant species. These
include gastrointestinal ailments (n=17), cold sore, measle, wound, and skin infection/diseases
(n=15), fatigue, fever, headache, infant torticollis and body pain (n=10), high blood, leukemia
and diabetes (n=10), cancer and tumor/cysts (n=10), respiratory illnesses (n=9), and renal
diseases (n=8).
 According to a local article, antibiotics are one of the most used type of drug in the
Philippines. Due to untidy environment, people commonly obtain diseases caused by bacteria.
Self‐medication with antibiotics is problematic, as it is a major contributor to antibiotic
resistance (Daniel A. Barber et al., 2017). 2, Recent meta‐analyses have estimated that 38% of
the world's population engages in self‐medication and sharing of antibiotics but self‐medication
varies globally, with the highest prevalence in Southeast Asia and the Western Pacific Region of
WHO (58–64%). With the exception of two studies that described prophylactic use of antibiotics
by Filipino commercial sex workers (CSWs) to prevent sexually transmitted infections (STIs)
and four studies that described non‐prescription access and use of antibiotics research on
antibiotic misuse in the Philippines is scarce. Evidence from the Southeast Asian region more
broadly has suggested that self‐medication may be associated with cultural misconceptions
premature termination of antibiotic courses insufficient regulations and enforcement of
pharmaceutical law and antibiotic knowledge and or attitudes. This study also showed the
possible changes between prescribed antibiotics and sari-sari store antibiotic. As one of the most
used pharmaceutical product in the mentioned country, researches had this urge to ensure the
safety of taking a shared antibiotic.As been medically reviewed by a pharmacist, taking different
kinds of antibiotic can also cause varieties of side effects while doing its job. He concluded
vomiting, runny nose, common cold and flu as some of the basic signs. However, your immune
system can change over time. It’s possible that your allergy will weaken, go away, or get worse.
So, it’s important always to follow your doctor’s instructions on how to manage a drug.
Participants who reported sharing antibiotics most often shared them with family (37%) and
children (33%), followed by neighbours (18%), elderly family (18%), spouse or sex partner
(16%), friends (14%) and others (4%). Among those employed (65%), a small percentage
indicated they shared antibiotics with co‐workers (7%). Of note, percentages do not total to
100% because response options were not mutually exclusive (Barber et al., 2017).

In regards to the diabetic patients chiefly here at the Philippines, the pharmaceutical drug
that is essential to cure this disease called Metformin is used with a proper diet and healthy living
program, to also be able to control high blood sugar while also used to people with type 2
diabetes. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems,
loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk
of a heart attack or stroke (webmd.com 2015). According to the data gathered, diabetic people
are believed to be more contractible of CoVid19 and the prognosis is known to be quite poor.
Governments have to face tough challenges in getting needed treatments as well as the required
support of specialists and other health-care professionals, all fully engaged in the COVID-19
battle. At the same time, in such a difficult health crisis, they likely are not receiving the most
appropriate management when hospitalized. Diabetes mellitus is a serious metabolic disorder
affecting millions of people worldwide. Phenformin and metformin are biguanide antidiabetic
agents that are conveniently synthesized in a single‐step chemical reaction. Phenformin was once
used to lower blood glucose levels, but later withdrawn from the market in several countries
because it was frequently associated with lactic acidosis. Metformin is still a widely prescribed
medication for the treatment of type 2 diabetes despite the introduction of several newer
antidiabetic agents (Yendapally et al., 2020). A research had stated that a diabetic person taking
metformin while also struggling from CoVid19 is a very risky and is suggested to be avoided.
Due to an anticipated fear of lactic acidosis in the background of multi-organ dysfunction
including hepatic and renal impairment (A.K. Singh 2020). Metformin’s mechanism can reduce
inflammation risks and can improve immunity response. The gathered data below shows the
result of conducting varieties of tests to diabetic persons with CoVid19 and the possibilities
when it does. The former groups, compared to the latter (2.9 vs. 12.3% respectively; p = 0.01).
Interestingly, this significant reduction in mortality in metformin users was observed despite a
significantly higher baseline fasting glucose, compared to the non-users (9.19 vs. 7.36 mmol/L
respectively, p < 0.01). Notably, in the multi-variate analysis more than 4-fold decrease in in-
hospital death was observed in metformin users, as compared to the non-users (OR 4.36; 95%
CI, 1.22–15.59, p = 0.02). This retrospective study underscores the benefit of metformin in
patients with diabetes and COVID-19. Table 1 summarizes the effects of metformin on various
outcomes including lung diseases and mortality in patients with diabetes with or without
COVID-19 (S.Gubbi et al., 2020).

Synthesis:

Overall, these studies have showed different types, angles and perspective towards their main
goals. And it is to ensure the safety for people taking different kinds of pharmaceutical medicines
and herbal medicines. They have proved each side that every drug has both potentials and risks
to people especially to vigorous ones. Firstly, the dosage when taking a prescribed medicine. For
there are extremely strong drug that can damage our internal organs. Somehow, these researches
have stated that both herbal and modern pharmaceutical medicines are essential to human for
there are pharmaceutical medicines that couldn’t cure a disease but herbals can and vice versa.
These researches tended to remind us to know our limits and consult a doctor in regards from
your own point and communicate with them truthfully and detailed if you want to be
independently knowledgeable about your own health.