The potential of Ethiopian medicinal plants to treat emergent viral diseases.

Ethiopians have deep-rooted traditions of using plants to treat ailments affecting humans and domesticated animals. Approximately 80% of the population continues to rely on traditional medicine, including for the prevention and treatment of viral diseases. Many antiviral plants are available to and widely used by communities in areas where access to conventional healthcare systems is limited. In some cases, pharmacological studies also confirm the potent antiviral properties of Ethiopian plants. Building on traditional knowledge of medicinal plants and testing their antiviral properties may help to expand options to address the global pandemic of COVID-19 including its recently isolated virulent variants and prepare for similar outbreaks in the future. Here, we provide an ethnobotanical and pharmacological inventory of Ethiopian medicinal plants that might contribute to the prevention and treatment of viral diseases. We identified 387 species, about 6% of Ethiopia's known flora, for which records of use by local communities and traditional herbalists have been documented for the treatment of viral diseases. We provide a framework for further investigation and development of this vital resource much anticipated to help combat emergent viral diseases along with existing ones in Ethiopia and elsewhere.

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Reduced Thalamic Volume and Metabolites in Type 1 Diabetes with Polyneuropathy.

OBJECTIVE: Thalamus is essential in processing of sensory information. This study explored the associations between thalamic volume and intra-thalamic metabolites and associations to clinical and experimental characteristics of sensory function in adults with diabetic polyneuropathy. METHODS: 48 adults with type 1 diabetes and confirmed distal symmetric peripheral neuropathy (DPSN) and 28 healthy controls participated in a cross-sectional study and underwent a brain magnetic resonance imaging scan. Estimates for thalamic volume were extracted using voxel-based morphometry and intra-thalamic N-acetylaspartate/creatine (NAA/cre) levels were assessed by magnetic resonance spectroscopy. Associations between thalamic volume and clinical measures, quantitative sensory testing and neuropathic phenotype were explored. RESULTS: In diabetes, reduced gray matter volume was identified including bilateral thalamus (all p≤0.001) in comparison to healthy participants. Thalamic volume estimates were positively associated to intra-thalamic NAA/cre (r=0.4; p=0.006), however not to diabetes duration (p=0.5), severity of DSPN (p=0.7), or presence of pain (p=0.3). Individuals with the lowest thalamic volume had greatest loss of protective sensation (light touch using von Frey-like filaments, p=0.037) and highest pain tolerance to electric stimulation (tetanic stimulation, p=0.008) compared to individuals with the highest thalamic volume. CONCLUSIONS: In this cohort with type 1 diabetes and severe DSPN, thalamic atrophy was present and associated with reduced NAA/cre, indicating thalamic structural loss and dysfunction. Thalamic atrophy was associated to reduced sensory function involving large fiber neuropathy and sensation to tetanic stimulation that may reflect synaptic transmission. This may ultimately contribute to the current understanding of the pathophysiology behind the perception changes evident in DSPN.

Ethiopian Medicinal Plants Traditionally Used for the Treatment of Cancer; Part 3: Selective Cytotoxic Activity of 22 Plants against Human Cancer Cell Lines.

Medicinal plants have been traditionally used to treat cancer in Ethiopia. However, very few studies have reported the in vitro anticancer activities of medicinal plants that are collected from different agro-ecological zones of Ethiopia. Hence, the main aim of this study was to screen the cytotoxic activities of 80% methanol extracts of 22 plants against human peripheral blood mononuclear cells (PBMCs), as well as human breast (MCF-7), lung (A427), bladder (RT-4), and cervical (SiSo) cancer cell lines. Active extracts were further screened against human large cell lung carcinoma (LCLC-103H), pancreatic cancer (DAN-G), ovarian cancer (A2780), and squamous cell carcinoma of the esophagus (KYSE-70) by using the crystal violet cell proliferation assay, while the vitality of the acute myeloid leukemia (HL-60) and histiocytic lymphoma (U-937) cell lines was monitored in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) microtiter assay. Euphorbia schimperiana, Acokanthera schimperi, Kniphofia foliosa, and Kalanchoe petitiana exhibited potent antiproliferative activity against A427, RT-4, MCF-7, and SiSo cell lines, with IC50 values ranging from 1.85 ± 0.44 to 17.8 ± 2.31 µg/mL. Furthermore, these four extracts also showed potent antiproliferative activities against LCLC-103H, DAN-G, A2780, KYSE-70, HL-60, and U-937 cell lines, with IC50 values ranging from 0.086 to 27.06 ± 10.8 µg/mL. Hence, further studies focusing on bio-assay-guided isolation and structural elucidation of active cytotoxic compounds from these plants are warranted.

Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year, Randomized, Double-Blind, Placebo-Controlled Trial.

AIM: To investigate the effect of normalizing vitamin B12 (B12) levels with oral B12 (methylcobalamin) 1000 µg/day for one year in patients with diabetic neuropathy (DN). PATIENTS AND METHODS: In this prospective, double-blind, placebo-controlled trial, 90 patients with type 2 diabetes on metformin for at least four years and both peripheral and autonomic DN were randomized to an active treatment group (n = 44) receiving B12 and a control group (n = 46) receiving a placebo. All patients had B12 levels less than 400 pmol/L. Subjects underwent measurements of sural nerve conduction velocity (SNCV), sural nerve action potential (amplitude) (SNAP), and vibration perception threshold (VPT), and they performed cardiovascular autonomic reflex tests (CARTs: mean circular resultant (MCR), Valsalva test, postural index, and orthostatic hypotension). Sudomotor function was assessed with the SUDOSCAN that measures electrochemical skin conductance in hands and feet (ESCH and ESCF, respectively). We also used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE, respectively) and questionnaires to evaluate quality of life (QoL) and level of pain (pain score). RESULTS: B12 levels increased from 232.0 ± 71.8 at baseline to 776.7 ± 242.3 pmol/L at follow-up, p < 0.0001, in the active group but not in the control group. VPT, MNSIQ, QoL, pain score, SNCV, SNAP, and ESCF significantly improved in the active group (p < 0.001, p = 0.002, p < 0.0001, p < 0.000, p < 0.0001, p < 0.0001, and p = 0.014, respectively), whereas CARTS and MNSIE improved but not significantly. MCR, MNSIQ, SNCV, SNAP, and pain score significantly deteriorated in the control group (p = 0.025, p = 0.017, p = 0.045, p < 0.0001, and p < 0.0001, respectively). CONCLUSIONS: The treatment of patients with DN with 1 mg of oral methylcobalamin for twelve months increased plasma B12 levels and improved all neurophysiological parameters, sudomotor function, pain score, and QoL, but it did not improve CARTS and MNSIE.

Ethiopian Medicinal Plants Traditionally Used for the Treatment of Cancer, Part 2: A Review on Cytotoxic, Antiproliferative, and Antitumor Phytochemicals, and Future Perspective.

This review provides an overview on the active phytochemical constituents of medicinal plants that are traditionally used to manage cancer in Ethiopia. A total of 119 articles published between 1968 and 2020 have been reviewed, using scientific search engines such as ScienceDirect, PubMed, and Google Scholar. Twenty-seven medicinal plant species that belong to eighteen families are documented along with their botanical sources, potential active constituents, and in vitro and in vivo activities against various cancer cells. The review is compiled and discusses the potential anticancer, antiproliferative, and cytotoxic agents based on the types of secondary metabolites, such as terpenoids, phenolic compounds, alkaloids, steroids, and lignans. Among the anticancer secondary metabolites reported in this review, only few have been isolated from plants that are originated and collected in Ethiopia, and the majority of compounds are reported from plants belonging to different areas of the world. Thus, based on the available bioactivity reports, extensive and more elaborate ethnopharmacology-based bioassay-guided studies have to be conducted on selected traditionally claimed Ethiopian anticancer plants, which inherited from a unique and diverse landscape, with the aim of opening a way forward to conduct anticancer drug discovery program.

Diabetic Polyneuropathy - Advances in Diagnosis and Intervention Strategies.

Over half of people with diabetes mellitus develop diabetic polyneuropathy (DPN), which is a major cause of reduced quality of life due to disabling neuropathic pain, sensory loss, gait instability, fall-related injury, and foot ulceration and amputation. The latter represents a major health and economic burden, with lower limb amputation rates related to diabetes increasing in the UK. There is a need for early diagnosis of DPN so that early management strategies may be instigated, such as achieving tight glucose control and management of cardiovascular risk factors, in an attempt to slow its progression. To this end, a one-stop microvascular assessment involving a combined eye, foot and renal screening clinic has proven feasible in the UK. Unfortunately, there are currently no approved disease-modifying therapies for DPN. Some disease-modifying agents have demonstrated efficacy, but further large trials using appropriate clinical endpoints are required before these treatments can be routinely recommended. There has been emerging evidence highlighting a reduction in vitamin D levels in cases of painful DPN and the potential for vitamin D supplementation in deficient individuals to improve neuropathic pain; however, this needs to be proved in randomised clinical trials. The use of established agents for neuropathic pain in DPN is limited by poor efficacy and adverse effects, but patient stratification using methods such as pain phenotyping are being tested to determine whether this improves the outcomes of such agents in clinical studies. In addition, innovative approaches such as the topical 8% capsaicin patch, new methods of electrical stimulation and novel therapeutic targets such as NaV1.7 offer promise for the future. This article aims to discuss the challenges of diagnosing and managing DPN and to review current and emerging lifestyle interventions and therapeutic options.

Ethnobotanical Study of Medicinal Plants Used by Traditional Healers to Treat Cancer-Like Symptoms in Eleven Districts, Ethiopia.

There is no ethnobotanical study conducted specifically on medicinal plants traditionally used to treat cancer in Ethiopia. Yet, traditional herbalists in different parts of the country claim that they have been treating cancer-like symptoms using herbal remedies. The objective of this study was to document medicinal plants traditionally used to treat cancer-like symptoms in eleven districts, Ethiopia. Traditional herbalists were interviewed using semistructured questionnaires, and field visits were also carried out to collect claimed plants for identification purpose. Seventy-four traditional herbalists, who claimed that they knew about and/or had used medicinal plants to treat cancer-like symptoms, were selected using the snowball method and interviewed. Herbalists used their intuition and relied on the chronicity, growth of external mass, and spreading of the disease to other parts of the body, as a means to characterize cancer symptoms. Furthermore, in some of the study districts, herbalists reported that they treat patients who had already been diagnosed in modern healthcare institutions prior to seeking help from them. The inventory of medicinal plants is summarized in a synoptic table, which contains the scientific and vernacular names of the plants, their geographical location, the parts of the plants, and the methods used to prepare the remedies. A total of 53 traditionally used anticancer plants, belonging to 30 families, were identified during the survey. The most frequently reported anticancer plants were Acmella caulirhiza Del (Asteraceae), Clematis simensis Fresen. (Ranunculaceae), Croton macrostachyus Del. (Euphorbiaceae), and Dorstenia barnimiana Schweinf. (Moraceae). Organizing traditional healers, documenting their indigenous knowledge, and scientifically validating it for the development of better cancer therapeutic agents constitute an urgent and important task for policymakers and scientists.

Phytochemical analysis and evaluation of skin irritation, acute and sub-acute toxicity of Cymbopogon citratus essential oil in mice and rabbits.

Cymbopogon citratus has been used by the local people in Ankober district, northern Ethiopia, as traditional medicine to treat various ailments. Its essential oil has been shown to have antibacterial, antifungal, antiprotozoal, anti-carcinogenic, anti-inflammatory and antioxidant activities amongst others. This study was conducted to determine skin irritation, acute and subacute toxicity of C. citratus essential oil in mice and rabbits. The essential oil was analyzed using GC-MS. The essential oil at dose of 2000 mg/kg body weight was administered to mice for 21 consecutive days. The mice mortality, behavioral change, injury and other signs of illness were recorded once daily. Biochemical parameters were evaluated. Liver and kidney were taken after sacrifice for gross findings and histological analyses. 10 % ointment formulation of C. citratus oils was applied on the rabbit skin to determine skin irritation effects. The result revealed, the presence of citral (71.297%), myrcene (19.034%), 4, 5-epoxycarene (2.780%), linalool (1.713%), ((S)-cis-verbenol (1.110 %), linalool (1.713 %), ((S)-cis-verbenol (1.110 %) and undecan-2-one (1.001 %) in the C. citratus essential oil. There was no significant difference (p > 0.05) in the body weights, gross abnormalities of the organs and biochemical parameters compared to the control. No histopathological changes were detected in the organs tested. 10 % ointment formulation of C. citratus oils did not cause skin irritation. Analysis of results leads to the conclusion that Ethiopian C. citratus essential oil may be considered as relatively safe and non-toxic.

Evaluation of Skin Irritation and Acute and Subacute Oral Toxicity of Lavandula angustifolia Essential Oils in Rabbit and Mice.

Lavandula angustifolia is used in traditional and folk medicines of Ankober District, North Central Ethiopia, for the treatment of several livestock and human disorders. This toxicity study aimed to investigate L. angustifolia essential oil oral toxicity in mice and skin irritation in rabbit. L. angustifolia essential oil was analyzed using gas chromatography-mass spectrometry methods and showed predominance of Eucalyptol (52.36%), Camphor (11.91%), gamma-terpinene (8.775%) and endoborneol (7.585%). Limit test at 2000 mg/kg dose was used for L. angustifolia essential oil acute toxicity test and revealed LD50 value was higher than 2000 mg/kg. For subacute toxicity study 2000mg/kg was given orally to each mouse for 21 days. The result demonstrated no significant changes (p > 0.05) in the body weights, and biochemical parameters, gross abnormalities, water, and food intake were observed. No macroscopic changes were seen in the histopathology analysis of kidneys and livers. For skin irritation test shaved rabbit skin was treated with 10% ointment formulation. Ointment of L. angustifolia oil did not affect mice skin. Generally, this toxicity study demonstrated that L. angustifolia essential oil is nontoxic.

A regional comparison of distribution strategies and women's awareness, receipt, and use of misoprostol to prevent postpartum hemorrhage in rural Amhara and Oromiya regions of Ethiopia.

INTRODUCTION: In Ethiopia, postpartum hemorrhage is a leading cause of maternal death. The Maternal Health in Ethiopia Partnership (MaNHEP) project developed a community-based model of maternal and newborn health focusing on birth and early postpartum care. Implemented in the Amhara and Oromiya regions, the model included misoprostol to prevent postpartum hemorrhage. This article describes regional trends in women's use of misoprostol; their awareness, receipt, and use of misoprostol at project's endline; and factors associated with its use. METHODS: The authors assessed trends in use of misoprostol using monthly data from MaNHEP's quality improvement database; and awareness, receipt, use, and correct use of misoprostol using data from MaNHEP's endline survey of 1019 randomly sampled women who gave birth during the year prior to the survey. RESULTS: Misoprostol use increased rapidly and was relatively stable over 20 months, but regional differences were stark. At endline, significantly more women in Oromiya were aware of misoprostol compared with women who resided in Amhara (94% vs 59%); significantly more had received misoprostol (80% vs 35%); significantly more had received it during pregnancy (93% vs 48%); and significantly more had received it through varied sources. Most women who received misoprostol used it (> 95%) irrespective of age, parity, or education. Factors associated with use were Oromiya residence (odds ratio [OR] 9.48; 95% confidence interval [CI], 6.78-13.24), attending 2 or more Community Maternal and Newborn Health (CMNH) family meetings (OR 2.62; 95% CI, 1.89-3.63), receiving antenatal care (OR 1.67; 95% CI, 1.08-2.58) and being attended at birth by a skilled provider or trained health extension worker, community health development agent, or traditional birth attendant versus an untrained caregiver or no one. Correct use was associated with having attended 2 or more CMNH family meetings (OR 2.02; 95% CI, 1.35-3.03). DISCUSSION: Multiple distribution channels increase women's access to misoprostol. Most women who have access to misoprostol use it. Early distribution to pregnant women who are educated to use misoprostol appears to be safe and unrelated to choice of birthplace.

Duloxetine and pregabalin: high-dose monotherapy or their combination? The "COMBO-DN study"--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain.

This multicentre, double-blind, parallel-group study in diabetic peripheral neuropathic pain addressed whether, in patients not responding to standard doses of duloxetine or pregabalin, combining both medications is superior to increasing each drug to its maximum recommended dose. For initial 8-week therapy, either 60 mg/day duloxetine (groups 1, 2) or 300 mg/day pregabalin (groups 3, 4) was given. Thereafter, in the 8-week combination/high-dose therapy period, only nonresponders received 120 mg/day duloxetine (group 1), a combination of 60 mg/day duloxetine and 300 mg/day pregabalin (groups 2, 3), or 600 mg/day pregabalin (group 4). Primary outcome (Brief Pain Inventory Modified Short Form [BPI-MSF] 24-hour average pain change after combination/high-dose therapy) was analyzed comparing combination (groups 2, 3 pooled) with high-dose monotherapy (groups 1, 4 pooled). Secondary end points included response rates, BPI-MSF severity items, and comparison of duloxetine and pregabalin in BPI-MSF average pain. Eight hundred four patients were evaluated for initial therapy and 339 for combination/high-dose therapy. There were no significant differences between combination and high-dose monotherapy regarding BPI-MSF average pain (mean change: combination: -2.35; high-dose monotherapy: -2.16; P = 0.370) and most secondary end points, which, however, consistently favoured combination therapy. Fifty-percent response rates were 52.1% for combination and 39.3% for high-dose monotherapy (P = 0.068). In exploratory analyses of the initial 8-week therapy uncorrected for multiple comparisons, 60 mg/day duloxetine was found superior to 300 mg/day pregabalin (P < 0.001). Both drugs and their combination were well tolerated. Although not significantly superior to high-dose monotherapy, combination therapy was considered to be effective, safe, and well tolerated.

Central nervous system involvement in diabetic neuropathy.

Diabetic neuropathy is a chronic and often disabling condition that affects a significant number of individuals with diabetes. Long considered a disease of the peripheral nervous system, there is now increasing evidence of central nervous system involvement. Recent advances in neuroimaging methods detailed in this review have led to a better understanding and refinement of how diabetic neuropathy affects the central nervous system. Recognition that diabetic neuropathy is, in part, a disease that affects the whole nervous system is resulting in a critical rethinking of this disorder, opening a new direction for further research.

Microvascular perfusion abnormalities of the Thalamus in painful but not painless diabetic polyneuropathy: a clue to the pathogenesis of pain in type 1 diabetes.

OBJECTIVE: The pathogenesis of painful diabetic neuropathy (DN) remains undetermined, with both central and peripheral mechanisms implicated. This study investigates whether thalamic perfusion abnormalities occur in painful DN. RESEARCH DESIGN AND METHODS: Eighteen subjects with type 1 diabetes (no DN = 6, painful DN = 5, painless DN = 7) and six healthy volunteers (HV) were recruited. Microvascular perfusion characteristics (relative cerebral blood volume [rCBV], flow [rCBF], and transit time [tt(FM)]) of the thalamus and caudate nucleus were assessed using magnetic resonance perfusion imaging. The caudate nucleus was chosen to serve as an in vivo control region. RESULTS: Subjects with painful DN had significantly greater thalamic rCBV (means [SD]; painful DN, 228.7 [19.5]; no DN, 202.3 [25.8]; painless DN, 216.5 [65.5]; HV, 181.9 [51.7]; P = 0.04) and the longest tt(FM)(s) (painful DN, 38.4 [3.6]; no DN, 35.3 [13.2]; painless DN, 35.9 [13.7]; HV, 33.7 [14.9]; P = 0.07). There was no significant difference in markers of caudate nucleus perfusion. CONCLUSIONS: Painful DN is associated with increased thalamic vascularity. This may provide an important clue to the pathogenesis of pain in DN.

Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor.

OBJECTIVE: To assess the efficacy of Sativex, a cannabis-based medicinal extract, as adjuvant treatment in painful diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS: In this randomized controlled trial, 30 subjects with painful DPN received daily Sativex or placebo. The primary outcome measure was change in mean daily pain scores, and secondary outcome measures included quality-of-life assessments. RESULTS: There was significant improvement in pain scores in both groups, but mean change between groups was not significant. There were no significant differences in secondary outcome measures. Patients with depression had significantly greater baseline pain scores that improved regardless of intervention. CONCLUSIONS: This first-ever trial assessing the efficacy of cannabis has shown it to be no more efficacious than placebo in painful DPN. Depression was a major confounder and may have important implications for future trials on painful DPN.