Safety and Efficacy of Medicinal Plants Used to Manufacture Herbal Products with Regulatory Approval in Uganda: A Cross-Sectional Study

Introduction The Uganda National Drug Authority requires phytochemical screening, freedom from microbial contamination, and evidence of safety and efficacy of the constituent plants to register herbal products. Since Uganda has no pharmacopeia, safety, efficacy, and plant processing information are not readily available. We documented the plant materials used to manufacture products in Uganda and established evidence of their safety and efficacy and availability of monographs. Methods The NDA register of herbal products was reviewed, and a product list was extracted. The herbal products were purchased from local pharmacies, and their labels were studied to identify plant ingredients and drug use. Literature was reviewed to document evidence of the safety and efficacy of the plant materials concerning manufacturer's claims. Also, the WHO and available African Pharmacopeia were searched to establish the availability of the plant monographs. Results Of the 84 NDA-registered local products, only 18 were obtained from the market; 82% were indicated for respiratory tract disorders. Thirty-three plant materials were listed with Eucalyptus globulus Labill, being the commonest. Several in vitro and in vivo studies demonstrate efficacy, thus supporting the use of the selected plant species for empirical treatment as stated on the product label. While most plants were safe, some species such as Albizia coriaria Oliv. had dose-dependent toxicities that cannot be predicted in combinations. The WHO, African Pharmacopoeia, and West African Herbal Pharmacopoeia had only 16 plant monographs of the 33 plants of interest. Nevertheless, Aloe vera (L.) Burm.f., Azadirachta indica A.Juss., Zingiber officinale Roscoe, and Allium sativum L. monographs were published by all three pharmacopoeias. Conclusions Preclinical evidence of safety and efficacy exists in the literature for most of the plants used to manufacture registered herbal products in Uganda. More specific bioassays and clinical trials are required for the products to provide conclusive evidence of safety and toxicity. Monographs are urgently needed for the Ugandan plants.

Traditionally, medicinal plant products have been prescribed by traditional healers within communities or selfprescribed. In this regard, assessment of efficacy and safety was based on the history of use and informal knowledge passed on from generation to generation. However, with commercialization, there is a need for scientific proof that the products are effective and safe. Various studies have demonstrated deficiencies in the quality of herbal medicines; from adulteration with conventional medicines to substitution with ineffective or harmful plant materials and contamination with soil, microorganisms, pesticides, aflatoxins, etc. [3].
Consequently, the developed world's regulatory authorities have established policies to regulate herbal and other traditional medicines. e US FDA and the EMA, for instance, have published strict requirements for market authorization of traditional methods; as such, the manufacturer has to demonstrate the efficacy and safety of the product through clinical trials, a quality assurance plan for cultivation and harvesting of the plant materials as well as protocols for good manufacturing practices [4,5].
In contrast, traditional medicines are hardly regulated in developing countries. In a study to evaluate the regulatory framework of traditional medicines, over 60% of developing countries did not have any framework in place [6]. Following this study, the WHO published several guidelines for quality assurance of herbal medicines including, but not limited to, guidelines for registration of traditional medicines in the African region [7], guidelines for assessing the quality of herbal medicines [8], and the guidelines for good manufacturing practices herbal medicines [9].
Many African countries still have weak regulatory frameworks for traditional medicines despite these guidelines. In Uganda, for instance, there are no herbal pharmacopoeial methods for assessing the quality of herbal medicinal products. Consequently, all the locally manufactured herbal products authorized for marketing are not fully registered but rather "notified" [10]. is is because the medicines have not been evaluated fully for quality, safety, and efficacy due to regulatory and manufacturer inadequacies. To notify herbal products, the NDA considers longstanding folk use as evidence for the safety of any herbal plant material and therefore waives thorough toxicological evaluation of the product concerning the plant species used. In addition, there are no specific requirements regarding the product's efficacy. Only a report summarizing results of phytochemical screening of the plant materials used is required [11]. Once evidence for traditional use is established, specific preclinical and clinical studies to establish the safety and efficacy of the herbal products used are not a prerequisite to obtain market authorization.
Unlike in Western medicines in which pure bioactive compounds are used in pharmaceutical products, traditional medicine utilizes crude forms of whole plants or plant parts. e various plants and herbal products utilized in traditional/herbal medicine differ due to differences in climate and culture [12,13]. Consequently, analytical methods for herbal products developed in one country are not applicable in another country. erefore, monographs developed by countries with established herbal medicine regulatory systems such as China and the USA cannot be applied to products that are local to a culturally and climatically different region such as sub-Saharan Africa [14].
is study aimed to document the plant raw materials used in Uganda for the manufacture of herbal products and establish a database of safety and efficacy information. is information can be added to future herbal pharmacopeia/ monographs for routine use in quality assurance and quality assessment by manufacturers and regulators, respectively.

Study Design and Setting.
is was a cross-sectional study of local herbal products registered and sold in Uganda in 2019 and a review of published literature on the safety and efficacy of the herbal raw materials between 1960 and 2021. e products were bought from the busy cities of Mbarara, Jinja, Wakiso, and Kampala. In addition, most of the manufacturers are located in this area. e pharmacies were accessed conveniently, and the only important factor was the presence of the products of interest.

Data Collection
Methods. Data were collected mainly by desk review. Drug registers, product labels, and journal articles were considered. e data were collected as mentioned in the following sections.

Identintification of the Most Common Raw Materials and Indicated Use of the Products.
e most current drug register (August 2019) of herbal medicinal products was obtained from the NDA website (https://www.nda.or.ug/ drug-register-downloads/). en, a list of the notified (partial registration to permit marketing) local herbal medicinal products was compiled. A sample of each of the products on the notified list was purchased from local pharmacies.
After the products were purchased, their labels were studied to identify the indications (use of the drug) and the active ingredients (medicinal plant materials). A database of all the herbal plant materials was then developed, and the materials were ranked according to their popularity (frequency of appearance) in the herbal medicinal products.

Establishment of Evidence for Efficacy and Safety of Plant Materials and Rationale for the Polyherbals.
We conducted a literature review to obtain evidence of biological activity concerning the current traditional use (according to the manufacturers' labels) and safety of all the plant species used. We searched databases and search engines such as PubMed, Google Scholar, ResearchGate, Web of Science, and Scopus. e search terms consisted of the scientific plant names, pharmacological/therapeutic activity of interest, and toxicity. Only full-length articles published in English were reviewed.

Search for Plant Monographs Already Available.
Since there are no Ugandan monographs or pharmacopeia, we were interested in finding out if monographs of the plants used in Uganda have been published in other African countries.
e uses and composition of the plants were considered to be similar due to their similarity in culture and climate. We reviewed the African Pharmacopoeia 2014 [15] and the West African Pharmacopoeia 2013 [16]. Due to the absence of the monographs for most of the plants in the African Pharmacopeia, we also searched WHO monographs on selected medicinal plants volumes I-IV published between 1999 and 2009 [17][18][19][20].

Identification of the Most Common Plant Raw Materials
and Indicated Use of the Products. By 31 st March 2019, the NDA drug register had 4,148 and 214 conventional products and herbal medicinal products, respectively. All the herbal products are not fully registered but rather notified, and the majority (130) was imported, mainly from India and China. 84 locally manufactured herbal products were notified. Of these, 82% (n � 69) were syrups or solutions indicated for systemic treatment of upper respiratory tract disorders, such as cough, asthma, and flu. For skin infections and wound healing, the others were ointments, creams, balms, or soaps. ree products were indicated for the treatment of peptic ulcers (Table 1).
Although there were 84 locally manufactured products, we could only find 18 products in the study areas. We evaluated these products to obtain the most commonly used medicinal plant species in the formulations. Two products that did not indicate the active ingredients were eliminated.
A review of the products revealed that 33 plant species were used as raw materials. Whereas various scientific names of the plant species and/or their synonyms were used on the product information labels, we adopted the approved scientific names and their authorities according to the Kew database; Plants of the World http://www. plantsoftheworldonline.org accessed on 19 th March 2021.
is ensured uniformity and maintained scientific standards. We did not verify from the manufacturers if the plants indicated on the labels were the ones used to manufacture the products. Table 1 summarizes the products found in pharmacies during data collection. Indications are as written on the product label (these are classified into major disease categories ( Figure 1). Where wrongly spelled scientific plant names were found on the product labels, corrected and verified names were used instead.
Of the 33 plants listed, Eucalyptus globulus was by far the most used material. E. globulus was mentioned in 50% (f � 9) of the products, followed by Aloe barbadensis, Albizia coriaria, Mangifera indica, and Warburgia ugandensis tied in the third place ( Figure 2). Most of the plant materials are used for self-limiting conditions, majorly to alleviate the signs and symptoms of upper respiratory tract disorders (URT) and gastrointestinal tract (GIT) disorders ( Figure 1). Figure 1 summarizes the major diseases treated by locally manufactured herbal products. Over 40% of the medicines are used to treat upper respiratory tract disorders (whooping cough, catarrh, sore throat, asthma, bronchitis, cough, flu, measles symptoms, allergic cough, smokers cough, productive cough, lung cleaning, sinusitis, common colds, rhinitis, allergic conditions, bronchial congestion, painful coughing, dry/irritating cough, nasal congestion). e rest of the products are indicated for gastrointestinal disorders (cleanses GIT, gastric ulcers, stomach ulcers, flatulence, constipation, ulcers); immune boosting (boost the immune system, antioxidant); analgesic (pain relief, painful lips); skin disorders (relief of minor skin irritations due to; insect bites, minor cuts, and minor scrapes); and mouth wash (toothache, bad odor, sensitivity, bleeding gums, cavities, tooth decay). Most of these conditions are similar to those the folk/ traditional uses indicated in the pharmacopeia/monographs reviewed (Table 2). Figure 2 shows the popularity of the plant raw materials for manufacture of herbal products. e plants were ranked based on the number of times they appear on the product label as active ingredients. Of the 33 plant raw materials, Eucalyptus globulus was the most common, followed by Aloe vera and Albizia coriaria in the second place, while Albizia coriaria, Mangifera indica, Warburgia ugandensis, Azadirachta indica, and Zingiber officinale tied in the third place. e rest of the plants were only mentioned once.

Establishment of Evidence for Efficacy and Safety of Plant Materials and Rationale for the (Poly) Herbal Products.
Half (n � 8) of the surveyed locally produced herbal products were for the management of diseases of the respiratory system, with label claims such as dry, wet, and whooping cough, sore throat, bronchial asthma, nasal congestion, flu, common cold, sinusitis, and allergies. Digestive system conditions such as gastric ulcers, flatulence, and constipation are also frequently targeted. Others include immune boosters, mouth wash, antioxidants, wounds, allergies, and a lip balm. Nine of the most frequently used plant materials were reviewed in detail, for evidence of safety and efficacy in managing the conditions on the label claim. ese were A. coriaria, M. indica, A. indica, S. aromaticum, A. barbadensis, W. ugandensis, Z. officinale, A. sativum, and E. globulus. e information for the rest of the plant materials is summarized in Table 3.
To establish the safety and efficacy of the plant materials, we adopted the recommendations of the WHO [7] as mentioned in the following sections.

General Requirements for Safety.
In addition to authentication of the plant species, biological information on the safety of the plant/product should be provided. If biological evidence is lacking, data documented from long-term use should be used to assess the risk. However, the absence of toxicity data is not a guarantee of safety. Toxicity studies are required for plants and products thereof with a known toxicological risk.  [79].

Evidence-Based Complementary and Alternative Medicine
To ensure reproducibility of efficacy, the preparation of medicines should be standardized so that each batch contains a defined amount of the active ingredients.
Information on safety and efficacy can be obtained from scientific literature, national or international pharmacopeia, and WHO monographs for selected plant materials.  [81]. Bacteria cause about 15% URTI, and the most implicated bacterium is Streptococcus pyogenes. URTI causes a variety of diseases with overlapping presentations, including acute bronchitis, influenza, rhinitis, pharyngitis, tonsillitis, laryngitis, and other respiratory distress syndromes. Symptoms of URTI commonly include cough, sore throat, runny nose, nasal congestion, headache, low-grade fever, facial pressure, sneezing, malaise, and myalgias. Most viral infections are self-limiting [81]. e goal of treatment is symptom relief, and in case of bacterial infections, antiinfectives can be used [82]. erefore, for the effective management of URTI, the medication should possess one or more of the following activities: antiviral, antibacterial, antiinflammatory, expectorant, and decongestant.

Albizia coriaria
Bioactive compounds such as lupeol, lupenone, betulinic acid, and catechin extracted using ethyl acetate from the stem bark of A. coriaria had activity against Pseudomonas aeruginosa and Escherichia coli [83]. ese bacteria are, however, not commonly implicated in the causation of URTI. No specific studies were evaluating the activity of the bark of A. coriaria against Gram-positive cocci, which are the causative agents of URTI. Lupeol has anti-inflammatory activity [84]. Treatment with lupeol reduces mucus secretion and overall lung inflammation in a murine model [85]. e antiviral activity of lupenone is selective. Lupenone exhibits Evidence-Based Complementary and Alternative Medicine a strong viral plaque inhibitory effect against herpes simplex virus (HSV)-1 and HSV-2 and inhibits African swine fever virus [86], but none of these viruses cause URTI. When studied in experimentally induced polymicrobial sepsis in mice, betulinic acid exhibited a protective effect on the lungs by inhibiting the production of inflammatory mediators. In another study, betulinic acid showed anti-inflammatory and antioxidant properties that protect the lungs against lipopolysaccharide-induced lung inflammation in rats [87].
Herbalists use A. coriaria in very small quantities in polyherbal preparations and boil it for several hours because of its known toxicity. Not surprisingly, the DMSO and ethanol extracts of A. coriaria were highly cytotoxic to the human glioblastoma U87.CD4.CXCR4 cells (CC 50 � 6.4 and <4 μg/ml respectively) [57]. Albizia spp. has a toxic compound, 4-methoxypyridoxine, which antagonizes vitamin B 6 [88].
Other Albizia species have shown different toxicities, including several central nervous system disturbances and other effects on the cardiovascular and respiratory systems. For instance, seed methanolic extracts of Albizia greveana and Albizia bernieri are toxic to mice with LD 50 of 1.13-2.3 and 52 mg/kg body weight, respectively, the former being more than one toxic [89]. However, the methanol and aqueous extracts of A. coriaria have been shown to have very low cytotoxicity (CC 50 >500 μg/ml) against human embryonic lung fibroblast (HELF) cells [90]. In contrast, the methanol, ethanol, ethyl acetate, and diethyl ether extracts of A. coriaria were not toxic to the human keratinocyte cell line (HaCaT) IC 50 > 512 [91].
ere is scientific evidence for the usefulness of A. coriaria in the symptomatic management of respiratory tract conditions. However, specific studies need to be done to assess URTI activity against the causative organisms. Specific toxicity studies on the bark of A. coriaria need to be done to conclude on the safety of the plant.

Mangifera indica L. (Anacardiaceae). Mangifera
indica is also used in many preparations for URTI management from the survey, including Gabogola syrup ® , Kwesiima cough mixture ® , and Yeco cough doctor ® .
M. indica is widely used to manage various infections and as an immune booster in Uganda [80]. Various pharmacological investigations have been carried out to explore the therapeutic potential of the phytochemicals in different plant parts of M. indica [92]. However, for the management of URTI, the antiviral, antibacterial, anti-inflammatory, expectorant, and decongestant activities of M. indica are important. Extracts from the fruit pulp of M. indica possess antiviral activity against influenza virus H9N2 and chicken embryo fibroblast (CEFs) with low cytotoxicity [93]. Mangiferin, extracted from the leaves of M. indica, inhibited herpes simplex virus 2 (HSV-2) replication but did not directly inactivate the virus [94]. Extracts from the stem bark of M. indica have some bacteriostatic activity against S. aureus albeit lower than the activity of the positive control used, ampicillin [95]. Alok et al. [96] demonstrated the antibacterial effects of the aqueous kernel extracts of two M. indica varieties (Bagnapalli and Senthura) from Tamil Nadu (India) against Staphylococcus aureus and Pseudomonas aeruginosa. Acetone, methanol, and water extracts of the leaves on M. indica exhibited lower antibacterial activity against S. aureus, S. pyogenes, S. pneumoniae, Bacillus cereus, E. coli, P. aeruginosa, Proteus mirabilis, Salmonella typhi, and Shigella flexneri using the agar well (cup plate) diffusion method than gentamicin and erythromycin [97].
A toxicological evaluation of M. indica leaf extract containing 60% mangiferin revealed a no-observed-adverseeffect level in male and female rats at 2000 mg/kg body weight/day. Additionally, no evidence of genotoxicity was found in a bacterial reverse mutation test [98]. In vivo acute toxicological studies of the stem bark aqueous extract of M. indica in rats and mice showed no lethality at the limit dose of 2,000 mg/kg body weight and no adverse effects when given by oral or dermal administration. Deaths occurred when the extract was administered intraperitoneally at 200 mg/kg in mice [99]. M. indica extracts were nonirritating on rabbits' skin and ocular and rectal mucosa [99].
ere were no specific studies found evaluating the expectorant and decongestant activities of M. indica. Overall, the antiviral and antibacterial activities of various parts of the plant support its use in URTI management.

3.2.5.
Azadirachta indica A.Juss. (Meliaceae). Azadirachta indica (neem tree) is used in the following products: Muwereza herbal cough remedy ® ; Princess aloe lip balm ® , a lip balm ® ; and Rezalin for ulcer ® , a syrup for management of gastric ulcers, flatulence, and constipation. To support its use in a cough remedy, A. indica should possess expectorant, decongestant, antiviral, and/or antibacterial activities [82]. e bark extract of A. indica significantly blocked HSV-1 entry into cells at concentrations ranging from 50 to 100 μg/ ml [100]. e methanolic extract fraction of leaves of A. indica is virucidal against Coxsackie virus B-4 and interfered with an early event in the viral replication [101].
us, the antiviral activity has been demonstrated but not in the viruses known to commonly cause URTI, such as the rhinovirus, adenovirus, influenza virus, enterovirus, and respiratory syncytial virus. e bark, leaf, seed, and fruit extracts of A. indica showed a concentration-dependent antibacterial activity against bacteria isolated from an adult mouth [102]. e ethanolic extract of neem twigs, barks, and leaves are bactericidal against Streptococcus mutans [103]. e methanol fraction of neem oil possesses bactericidal activity against 9 strains of Helicobacter pylori, the causative agent of gastric ulcers [104]. e extract's minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against the H. pylori strains ranged between 25 and 51 μg/ml and 43-68 μg/ml, respectively. e bactericidal activity was time-and concentration-dependent [104]. is evidence supports the use of neem in Rezalin ® syrup to manage ulcers. e wound-healing effect of neem could be beneficial in the lip balm. e water extract of the stem bark of A. indica promoted wound healing in mice by increasing the rate of wound contraction and levels of hydroxyproline, DNA and protein content, and nitric oxide compared with the vehicle control group. ese effects promote wound healing through increased inflammatory response and neovascularization [105].
Neem oil poisoning is rare in adults. However, one such case was reported in an adult male who presented with vomiting, seizures, metabolic acidosis, and toxic encephalopathy [106]. e patient had a complete recovery from symptomatic management. In vivo evaluation of acute toxicity of water extracts of A. indica leaves and seeds in rats revealed an LD 50 of 6.2 and 9.4 ml/kg, respectively [107].
ere is evidence to support the use of A. indica in URTI management, gastric ulcers associated with H. pylori infection, and wound healing. e use of the oil has the potential to cause adverse events.
S. pyogenes and S. mutans are the most common causes of bacterial URTI and tooth decay, respectively [108]. e essential oil extracted from the dried flower buds of clove has antiseptic, anti-inflammatory, analgesic, and anesthetic activities [109]. is supports its common use in dentistry. Furthermore, eugenol, the main constituent of clove essential oil, showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test in mice, with the effect lasting at least 30 minutes [110]. e methanolic extract of S. aromaticum has potent inhibitory activity against both dental caries pathogens with MIC of 0.2 mg/ml. In addition, S. aromaticum bud essential oil was active against S. mutans at 0.05 mg/ml [111]. Furthermore, the antibacterial activity of clove has been demonstrated in S. aureus, Pseudomonas aeruginosa, E. coli, S. pyogenes, Corynebacterium species, Salmonella species, and Bacteroides fragilis [112].
An in vitro study demonstrated cytotoxic properties of clove oil and eugenol toward human fibroblasts and endothelial cells. Clove oil was highly cytotoxic at concentrations as low as 0.03% (v/v) with up to 73% of this effect attributable to eugenol [113]. Moreover, eugenol produces local irritative and cytotoxic effects and hypersensitivity reactions when in contact with soft tissues [114]. However, Vijayasteltar et al. [115] evaluated the subchronic toxicity of the standardized polyphenolic extracts of clove buds in Wister rats and showed a no-observed-adverse-effect level at 1000 mg/kg bodyweight/day.
is study showed that administration of the extracts did not result in any toxicologically significant changes in clinical/behavioral observations, ophthalmic examinations, body weights, organ weights, feed consumption, urinalysis, hematology, and clinical biochemistry parameters when compared with the untreated control group of animals. Also, no genotoxicity was observed with the extract rather exhibiting significant antimutagenic potential against the known mutagens: sodium azide, NPD, tobacco, and 2-acetamidoflourene. e antibacterial, anti-inflammatory, analgesic, and anesthetic activities of S. aromaticum provide evidence for its value in managing URTI and dental conditions. A wound dressing gel containing acemannan, extracted from the internal leaf aloe gel, reduced radiation-induced skin reactions in mice when applied daily for at least 2 weeks, beginning immediately after irradiation [116]. Furthermore, the extracts of crude A. barbadensis gel prevent suppressing the induction of T cell-mediated responses such as contact and delayed-type hypersensitivity caused by cutaneous exposure to ultraviolet light [117]. is effect is attributed to aloe oligosaccharides that prevent ultraviolet-induced suppression of delayed-type hypersensitivity by reducing keratinocyte-derived immunosuppressive cytokines such as interleukin-10. is evidence supports the use of aloe extracts in lip balm.
Acemannan from A barbadensis extract stimulated macrophage production of monokines, including interleukin-1 and tumor necrosis factor, resulting in the initiation of immune attack, necrosis, and regression of implanted sarcomas in mice [118]. In another study, A. barbadensis stimulated cellular and humoral immune responses in rabbits following immunization against myxomatosis [119].

Evidence-Based Complementary and Alternative Medicine
Furthermore, aloe extracts enhanced the ability of broiler chickens to mount a humoral immune response when challenged with Newcastle disease virus [120]. ese studies support the use of A. barbadensis extract to boost the immune system.
Emodin, an anthraquinone prepared from aloin, was shown to inactivate herpes simplex virus type 1 and type 2, varicella-zoster virus, pseudorabies virus, and influenza virus, not adenovirus and rhinovirus. Electron microscopic examination of the anthraquinone-treated herpes simplex virus demonstrated that the envelopes were partially disrupted [121].
is antiviral activity is important in the management of URTI.
Aloe emodin is also a known stimulant laxative [122], and this could be the basis of the use of A. barbadensis in Damaleo vera tablets for cleansing the GIT. e generative changes in the kidney tissue were significantly reduced in diabetic rats treated with glibenclamide and aloe leaf gel and pulp extracts compared with the untreated group [123]. e treated group also had decreased serum urea and creatinine levels in comparison with diabetic controls. Among the diabetic rats, kidney lipid peroxidation levels were lower in those received aloe extracts than those who received glibenclamide alone. ese findings suggest a protective effect of A. barbadensis on mild damage caused by type-II diabetes on kidney tissue and support its use in Damaleo vera tablets.
Several single case reports have been published on the toxicity of A. barbadensis in humans. Some include massive intraoperative bleeding after consumption of A. barbadensis tablets [124], acute renal failure [125], severe vomiting [126], acute hepatitis [127], and Henoch-Schonlein purpura [128]. Ernst [129] reported on the hypersensitivity and allergic reactions due to A. barbadensis. In another study, rats fed aloe whole-leaf powder for 90 days showed the adverse effect level to be 2 g/kg BW [130]. Aloe inner leaf gel rich in highmolecular-weight fibers and soluble polysaccharides is cytotoxic to the human intestinal cell line Caco-2 (CC 50 � 1 g/ l), even at concentrations below the recommended dose for human consumption [131]. Processing of aloe inner leaf gel or aloe leaf extract by filtration through diatomaceous earth and activated carbon reduces their cytotoxicity and improves their immunomodulatory activity [131].
Literature supports the use of aloe extracts for cosmetic purposes, boosting the immune system, and management of URTI and constipation. However, studies also show that aloe extracts can be toxic, although processing can reduce such toxicities.    e water extracts of W. ugandensis elicited antimicrobial activity against E. coli and S. aureus in the agar well assay, with higher activity against S. aureus than E. coli. is activity was only detectable at high concentrations of the extract, i.e., up to 50 mg/ml of crude extract [132]. In another study, the crude and petroleum ether extracts of W. ugandensis leaves exhibited antimicrobial activity against S. boydii and S. aureus [133]. e biological activities of the plant are attributed to the drimane and colorotane sesquiterpenoids, including polygodial, warburganal, muzigadial, mukaadial, and ugandensial, as well as flavonoids and other compounds [134,135]. e sesquiterpene muzigadial isolated from the ethyl acetate extract of the stem bark of W. ugandensis was the main antibacterial agent (IC 50 � 12.5 μg/ ml) against both S. aureus and Bacillus subtilis [136].
Specific antiviral activity studies could not be found to assess the importance of W. ugandensis in the management of viral URTI. Its usefulness in the management of peptic ulcer disease could also not be established from the literature review. Other reported pharmacological activities of W. ugandensis backed by some scientific evidence include antifungal activity, antimycobacterial activity, anti-inflammatory and antioxidant properties, molluscicidal, antifeedant, antiplasmodial, cytotoxic, anthelmintic, and antileishmanial activities [135]. e diethyl ether extract of W. ugandensis has anti-inflammatory effects and inhibited  Very low toxicity to human HaCaT cells IC 50 � 512 μg/ml [21]. 11. Curcuma longa L.

Gastric ulcers
C. longa extract inhibits gastric acid secretion by competitively blocking H (2) histamine receptors [22] e extract was safe and efficacious in the treatment of painful knee osteoarthritis in a randomized placebo-controlled trial [23].

URT disorders
Curcumin reduced ethanol-induced gastric lesions and significantly increased gastric blood flow and plasma gastrin levels in a dose-dependent manner. is involves endogenous PG, NO, gastrin, and CGRP released from sensory nerves due to activation of the vanilloid TRPV1 receptor.
is protective effect can be attributed to the inhibition of HIF-1a and Cdx-2 expression and the activation of HO-1 and SOD 2 expression [24] 12. Mentha piperita L.

URT disorders
A spray containing essential oils of five plants including M. piperita caused significant and immediate improvement in symptoms of upper respiratory ailment in a randomized clinical trial [25] Short-term and subchronic oral studies reported cyst-like lesions in the cerebellum in rats given high doses of peppermint oil (>200 mg/kg/day). Peppermint oil contains the hepatotoxin pulegone. Isolated clinical cases of irritation and/or sensitization to peppermint oil and/or its constituents have been reported [26].
Immune booster e methanolic leaf extract caused significant immune-stimulatory effects on both cell-mediated and humoral immune systems in the Wistar albino rats [27]. e ethanolic and saline extracts contain antioxidants [28]. e leaf extract increased the antioxidant activity of glutathione (186%), superoxide dismutase (97.8%) and catalase (0.177%) [29]. e leaves are genotoxic at suprasupplementation levels of 3000 mg/kg BW but are safe at levels ≤1000 mg/kg BW in rats (LD 50 � 1585 mg/kg) and thus nontoxic [30].

Carica papaya L. Mouth wash
A randomized, single-blind parallel-design study showed the leaf extract dentifrice/ mouthwash provided an efficacious and natural alternative to sodium lauryl sulfatefree dentifrice ± essential oil-containing mouthwash in reducing interdental gingival inflammation [31] e leaf extract is safe as shown in subacute oral toxicity tests in Sprague Dawley rats at up to 2 g/kg, (14 times the levels used in traditional medicine in Malaysia [32,33]). Short-term leaf consumption in adults is generally safe though cautioned in pregnancy and liver impairment [34] 15. Terminalia catappa L.
Mouth wash e leaf aqueous and methanol extract demonstrated antibacterial activity against different bacterial strains [35] e aqueous leaf extract is relatively nontoxic to the heart in subacute toxicity studies [36] 16. Salvadora persica L.

Mouth wash
S. persica extract caused significant reduction in the plaque score and cariogenic bacterial count, but the score was lower than the positive control chlorhexidine mouthwash [37].
e aqueous and ethanolic extracts were not toxic to mice at doses of up to 1200 mg/kg [38] 17. Zanthoxylum fagara (L.) Sarg Gastric ulcers No specific data for Z. fagara.

Evidence-Based Complementary and Alternative Medicine
Boiling reduces toxicity.
e hydroalcoholic extract of A. calamus is nontoxic but at high dose produces mild but acceptable toxicity potential [43] 20. Xanthium strumarium L.
URT disorders Anti-inflammatory activity through inhibition of IFN-c lipopolysaccharideinduced NO production and TNF-α production and analgesic activity [44] and inhibits histamine, interleukins, and TNF α, which are important in allergic rhinitis [45,46], A decoction caused hepatic injury, symptomatic hypoglycemia, and seizures 7 days after administration [47]. Extracts can induce in vitro DNA damage at cytotoxic concentrations in vitro [48] X. strumarium contains the toxic compounds atractyloside, carboxyatractyloside, and 4′-desulphateatractyloside, which XSF induced significant cytotoxic effects in both L-02 and BRL liver cell lines [49] 21.

Hamamelis virginiana L.
Skin ulcers A shampoo from H. virginiana improved subjective manifestations of skin irritation [50]. Extracts have antifungal and antibacterial effects against Candida albicans and S. aureus [51] Did not cause any toxicity or deaths in rabbits when administered through the rectum at 300 mg/kg for 28 days [52] Skin irritations
Mouth wash A randomized controlled clinical study showed that a flower extract mouthwash of C. officinalis could be effective on reducing the intensity of radiation-induced oropharyngeal mucositis in patients with head-and-neck cancer [53]. In another randomized controlled study, C. officinalis mouth wash was shown to be effective in treating gingivitis by significantly reducing the plaque and gingival index [54] Acute and subchronic toxicity studies indicated that the extracts of C. officinalis have low toxicities in Wistar rats [55] 23. Zanthoxylum chalybeum Engl.
URT disorders e essential oil exhibited strong antibacterial activities against S. typhi, S. agalactia, S. aureus, and E. coli [56] e ethanol extract was weakly cytotoxic (CC 50 � 231.0 μg/ml), whereas the DMSO extract was moderately cytotoxic (CC 50 [58] e aqueous leaf extract is moderately toxic when given to rats intraperitoneally at doses up to 8000 mg/kg [59].
URT disorders e leaves contain flavones and flavanones that inhibits proinflammatory cytokine release [60] No specific data available both COX-2 and COX-1 in vitro with IC 50 values of 13.33 ± 4.36 and 11.05 ± 1.43 μg/ml, respectively [137]. While W. ugandensis is widely used by herbalists in Uganda for treating various infections, it is also known to be toxic if used in high doses [80]. e acute toxicity evaluation of the aqueous stem bark extract of W. ugandensis in mice gave an LD 50 >5000 mg/kg body weight with no mortalities recorded for all dose levels used. e extract was classified as noncytotoxic with 50% cytotoxic concentration (CC 50 ) determined to be >250 μg/ml [138]. W. ugandensis was cytotoxic to intestinal epithelial cells IEC-6, with IC 50 values <50 μg/ml [139]. Both the DMSO (CC 50 � 1.5 μg/ml) and the ethanol (CC 50 � 7.6 μg/ml) root were highly cytotoxic to U87CD4CXCR4 cells [140]. e evidence in the literature is not enough to draw conclusions on the usefulness of W. ugandensis in the e aqueous leaf possesses antiulcer potential with protective and curative effects against gastric lesion [61]. K. africana at a concentration of 450 mg/kg BW gave the best results with a significant decrease in ulcer index (0.67 ± 0.16) on aspirin-induced ulcerogenic animals compared with 3.0 for the reference drug (cimetidine at 300 mg/kg) and control with 1.67 ± 0.27 [62] e aqueous bark extract was safe in rats up to 5 g/kg [63]. At a higher dose of 6400, the extract was toxic in rats [64] 27. Tamarindus indica L.
Gastric disorders (ulcers, flatulence, constipation) e seed extract showed a dose-dependent protective effect on animal peptic ulcer models [65]. e leaf extract exhibited antiulcerogenic and ulcer-healing properties in rats [66].
Even at high concentrations, the extract administered to rats was still safe compared with the 5% concentration usually present in juice consumed by humans [67] 28. Z. officinale contains various phytochemicals including phenolic compounds, terpenes, polysaccharides, lipids, organic acids, and raw fibers. e pharmacological activities of ginger have however been attributed to phenolic compounds such as gingerols and shogaols [141]. Various studies have demonstrated the anti-inflammatory activity of ginger and its bioactive compounds. Orally administered ginger reduced the proinflammatory cytokines (TNF-α, IL-6, and IL-1β) and increased the anti-inflammatory cytokines (IL-10 and IL-22) in mouse colitis models [142]. Z. officinale attenuated post-exercise-induced elevation in several proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in well-trained male endurance runners [143].

Entada abyssinica
Intravenous administration of 6-gingerol (at 1.75-3.5 mg/kg) and 6-shogaol (at 1.75-3.5 mg/kg) and oral administration of both (at 70-140 mg/kg) produced an inhibition of spontaneous motor activity, as well as antipyretic and analgesic effects, the latter producing more intense effects than the former. 6-Shogaol also showed an intense antitussive effect in comparison with dihydrocodeine phosphate [144]. is supports of the use of Z. officinale in herbal cough remedies for their cough-suppressant activity. e ethanolic extract of Z. officinale rhizome was active against common respiratory tract pathogens: S. aureus, S. pyogenes, S. pneumoniae, and Haemophilus influenzae [145]. Furthermore, an herbal extract of Z. officinale inhibited biofilm formation and affected the membrane integrity of multidrug-resistant P. aeruginosa, both of which play a role in the mechanism of infection and antimicrobial resistance [146]. e crude and methanolic fraction of ginger reduced biofilm formation, inhibited glucan synthesis and adhesion, and downregulated the virulence genes in S. mutans [147]. e antiviral activity of ginger has been demonstrated in some viruses not specifically implicated in the causation of common URTI. Fresh Z. officinale dose-dependently inhibited human respiratory syncytial virus (HRSV) and induced plaque formation in human respiratory tract cell lines [148]. Fresh ginger also dose-dependently inhibited viral attachment and internalization and, at high concentration, stimulated mucosal cells to secrete interferon β (IFN-β) that possibly contributed to counteracting viral infection. Other studies have demonstrated antiviral activity of Z. officinale in hepatitis C virus (HCV) [149] and Chikungunya virus that causes an arthritogenic febrile illness [150].
Studies on the safety of different Z. officinale rhizome extracts showed no treatment-related signs of toxicity or mortality in any animals at tested doses [151][152][153][154]. One such study revealed a no-observed-adverse-effect level for a crude ethanolic extract of 5000 mg/kg body weight [151].
ere is scientific evidence in support of the use of Z. officinale extracts in preparations for the management of upper respiratory tract diseases. e rhizome has been established to be safe.

Allium sativum L. (Amaryllidaceae).
From the survey, Allium sativum (garlic) is used in Jenacid negus ® for the management of peptic ulcer disease and in Yeco cough doctor ® for the management of URTI.
An aqueous garlic extract was bactericidal against 16 clinical isolates and three reference strains of Helicobacter pylori. e MIC 90 of the extracts was 5 mg/ml, and the MBC was equal to, or twofold higher than, the MIC. Boiling the garlic extract lowered the efficacy twofold to fourfold the values of MIC and the MBC obtained with fresh extract [155]. Another study in which the aqueous garlic extract was standardized for its thiosulfinate concentration revealed an MIC of 40 μg/ml of thiosulfinate against H. pylori [156].
Orally administered A. sativum juice at 250 and 500 mg/ kg in rats produced a gastric ulcer healing effect in acetic acid-induced chronic gastric ulcer. e extracts also produced a gastric antisecretory effect in pylorus-ligated rats; gastric cytoprotective effect in ethanol-induced and indomethacin-induced gastric ulcer; and a significant reduction in stress-induced gastric ulcers and cysteamine-induced duodenal ulcers with higher effectiveness at 250 mg/kg [157]. Furthermore, aqueous garlic extract increased the pH and reduced the volume of gastric juice in rats [158].
An ethanolic garlic extract was bactericidal against S. pyogenes, which is commonly implicated in bacterial URTI, with an MBC of 1 g/ml [159]. e antiviral activity of garlic has been demonstrated in the following viruses known to cause URTI in humans; adenovirus [160]; influenza A and influenza B virus [161,162]; human rhinovirus-2 [163]; and measles virus, Newcastle disease virus, and parainfluenza virus-3 [164]. Garlic acts by blocking viral entry into host cells, inhibiting viral RNA polymerase, reverse transcriptase, DNA synthesis, and immediate-early gene 1 (IEG1) transcription, as well as through downregulating the extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling pathway [164]. ese activities can be important in the management of URTI of different etiologies. e most commonly reported adverse effects of garlic in randomized clinical trials are garlic breath and gastrointestinal symptoms [165]. Allergic reactions have also been reported in case reports [166][167][168]; contact dermatitis [169] and drug-herb interactions have been reported in patients taking anticoagulant medication (warfarin) and those on antiretroviral therapy [170].
Scientific evidence supports the use of A. sativum in the management of upper respiratory tract conditions and in peptic ulcer disease. e plant can be used with caution as cases of allergic reactions have been reported.
An essential oil blend of E. globulus with other oils was effective against fourteen Gram-positive and Gram-negative bacteria strains tested, including some antibiotic-resistant strains [171]. e organisms tested in the study included those implicated in causation of URTI; for example, S. pyogenes, S. pneumoniae, Listeria monocytogenes, and S. aureus. MICs ranged from 0.01% to 3%. e study also found the blend effective against H1N1 influenza virus, making it suitable for management of influenza and postinfluenza bacterial pneumonia infections [171]. e antibacterial effect of E. globulus has also been demonstrated in the organisms causing dental caries especially S. mutans [172] and Lactobacilli [173,174]. e essential oil of E. globulus exhibited analgesic and anti-inflammatory effects in mice and rat models [175]. e essential oil of E. globulus possesses central and peripheral analgesic effects as well as neutrophil-dependent and neutrophil-independent anti-inflammatory activities [175].
A eucalyptus oil water emulsion had an LD 50 of 3811.5 mg/kg. e oil slowed growth of the male rats and damaged the liver and the kidneys at 792 and 1188 mg/kg BW after oral administration, respectively [176]. In another study, an LD 50 of 1650 mg/kg in mice was determined. In addition, there was no abnormal skin reaction observed when a 5% ointment formulation was administered on the rats' skin, indicating the safety of E. globulus essential oil at a relatively lower concentration [177].
E. globulus is safe for use, at low concentrations, for the management of URTI and dental conditions. Table 3 shows the evidence of safety and efficacy of the plant raw materials used to manufacture herbal products in Uganda.

Availability of Plant Monographs.
We reviewed the WHO monographs, African Pharmacopoeia, and West African Pharmacopoeia to obtain information on the availability of monographs for the plants used to manufacture products in Uganda. Of the 33 plant materials, only ten (10) had monographs published by the WHO, ten (10) by the African Pharmacopoeia, and six (6) (Table 2). e folk and/or traditional uses in these pharmacopoeias are similar to the Ugandan manufacturers' as indicated on the product labels for most of the herbs. In addition to the traditional uses, the monographs reviewed also state the pharmacological evidence, plant parts of interest, methods for preparation, and quality control procedures. erefore, these monographs can be adopted for routine quality control of the materials produced in Uganda. Table 2 summarizes the availability of plant monographs in African Pharmacopoeia, West African Herbal Pharmacopoeia, and WHO monographs on selected herbal materials.
e traditional indications are outlined as they are stated in the monographs for comparison with Ugandan manufacturer indications of the products containing the plant materials to justify adaptability of the monographs.

Conclusion
Several in vitro and in vivo studies have been carried out to establish the safety and efficacy of the plants used for the management of different conditions. For all plant materials, there is some scientific evidence to support the use of the plants in the management of the conditions on the label claim. However, some of these studies lack specificity for the conditions on the label claim and therefore may not be confidently relied upon to support the use of the plant material. More specific bioassays are required in these cases to provide conclusive evidence. Also, studies in humans are few, and therefore, in most cases, results from animal models and human cell lines are extrapolated to humans. Some plant materials have specific dose-dependent toxicities and interactions that should concern the manufacturers and the regulatory authorities before approval of the products. Other plants' toxicity depends on the preparation method, yet there are no GMP requirements for herbal manufacture in Uganda. Pharmacovigilance efforts should be stepped up to identify toxicity cases and establish efficacy of the finished products. Plant monographs are urgently required to standardize uses, processing, and quality assurance of plant materials.
Data Availability e data sets analyzed during the current study are available from the corresponding author on reasonable request.

Ethical Approval
is work was approved by the Mbarara University of Science and Technology, Research and Ethics Committee.

Not applicable
Conflicts of Interest e authors declare that they have no conflicts of interest.