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. 2023 Jan 19;12(2):158. doi: 10.3390/biology12020158

Table 1.

Characteristics of clinical studies of natural products suggested as adjunct therapeutics for pancreatic adenocarcinoma and type 2 diabetes.

Author Study Design, Duration, Quality Participants
(Sample Size, Diagnosis)		 Intervention Preparation Used Outcome Measures Results Adverse Events
Curcuma longa L./Curcumin
Dhillon et al., 2008
[60]		 Open-label
non-randomized phase II clinical trial
8 weeks, up to 18 months
Jadad score: 4		 N = 25
Patients with pancreatic adenocarcinoma
M = 13; F = 12;
Median age: 65 years (range 43–77)
Prior therapy: surgery, radiotherapy, gemcitabine -/+ other chemotherapy, erlotinib, no therapy
Healthy volunteers
N = 48–62 (depending on the cytokine being measured)		 Curcumin (1 capsule—1000 mg/1 g of curcuminoids: 900 mg curcumin, 80 mg desmethoxycurcumin, 20 mg bisdesmethoxycurcumin)
  • –

    Dose: 8 g daily p.o.

 Cytokine levels: IL-6,-8,-10,
IL-1RA/receptor antagonist
Nuclear factor-κB/NF-kB (p65)
Cyclo-oxygenase 2/ COX-2
Phosphorylated signal transducer and activator of transcription 3 (PSTAT3)		 ∙ Patients
  • –

    Cytokines: elevated levels (IL-6,8,10) at baseline→ variable level changes after the treatment ↓↑

  • –

    Mean ± SD baseline and post-treatment (↓↓/↑↑ p < 0.05, significant difference):

  • –

    NF-kB ↓ 74.50 ± 10.00→65.80 ± 14.20 (p = 0.131)

  • –

    COX-2 ↓↓ 60.80 ± 12.53→44.7 ± 17.37 (p = 0.029)

  • –

    PSTAT3 ↓↓ 40.20 ± 15.76→ 21.10 ± 13.30 (p = 0.009)

  • –

    Tumor regression, cytokines levels ↓ in few patients

  • –

    Stable disease for over 18 months, ↓ tumor lesions: one patient

  • –

    73% reduction in tumor for a month, CA125 level ↓: one 1 patient

  • –

    Stable weight and wellbeing for 8 months, but progression in non-target lesions: one patient

∙ Volunteers IL-6, IL-8, IL-10 → undetectable serum levels IL-1RA→detectable serum levels NF-kB, pSTAT3 → not activated		 No serious side effects reported
Epelbaum et al., 2010
[61]		 Open-label
non-randomized phase II clinical trial
1 week to 12 months
Jadad score: 3		 N = 17
Patients with pancreatic adenocarcinoma (locally advanced or metastatic)
M = 10; F = 7;
Median age: 69 years (range 54–78)		 Curcumin (1 capsule—500 mg of curcuminoids: curcumin 450 mg, desmethoxycurcumin
40 mg, bisdesmethoxycurcumin 10 mg)
  • –

    Dose: 4000 mg of curcumin b.i.d. p.o. (overall 8000 mg) + Gemcitabine—1000 mg/m2 IV weekly for 3 of 4 weeks (two cycles)

 Overall survival (OS)
Tumor response rate
Clinical benefit rate (CBR)
Time to tumor progression (TTP)
CA 19-9 serum levels
Toxicity profile
  • –

    Early discontinuation of the overall treatment due to toxicity: five patients

  • –

    Sudden death: one patient

  • –

    CBR: achieved in four patients

  • –

    Local control/response rate 45.5% (2–12 months):

  • –

    Partial response rate: one patient for 7 months;

  • –

    Stable disease: four patients for 2, 3, 6, 12 months, respectively;

  • –

    ↓ CA19-9: three patients baseline vs. post-treatment: 90,830→63,130, 714→96, 214→42

  • –

    CA19-9 normal levels: two patients

  • –

    TTP—median 2 ½ months (range = 1–12 months): six patients

  • –

    OS—median 5 months (range = 1–24 months)
  • –

    Gastrointestinal toxicity (grade 3): fullness, upper abdominal pain => curcumin dose reduced (two patients) or discontinued (five patients)

  • –

    Toxicity specific to curcumin did not affect gemcitabine dosing

  • –

    Hematological toxicity (grade 1): neutropenia, thrombocytopenia (four patients)
Pastorelli et al., 2018
[62]		 Single arm prospective phase II clinical trial
9 cycles +, cycle—every 28 days
Jadad score: 4		 N = 44
Patients with pancreatic adenocarcinoma (locally advanced or metastatic)
M = 29; F = 15;
Median age: 66 years (range 42–87)
Prior treatment: dexamethasone 8 mg or metoclopramide 10 mg, i.v.		 Curcumin (Meriva®—phytosome/phospholipids complex of curcumin, one capsule—500 mg)
  • –

    Dose: 2000 mg/day p.o. + Gemcitabine—10 mg/m2/min, infused over 100 min. and diluted in 500 mL normal saline—a dose-intense infusion on 1, 8, 15 days; two–14 cycles

 Tumor response rate
Progression-free survival (PFS)
Overall survival (OS)
Quality of life assessment
Inflammation markers (CRP; sCD40L; cytokines IL-8,-6, MIP-1; adhesion molecules)
Full blood counts
CA19-9 serum levels
Toxicity profile
  • –

    Partial response: 27.3% patients

  • –

    Stable disease: 34.1% patients

  • –

    Progression disease: 38.6% patients

  • –

    Disease control rate: 61.4%

  • –

    Median OS at follow-up time of 26 months: 10.2 months (95% CI, 8.8–11.7)

  • –

    Median PFS: 8.4 months (95% CI, 5.0–11.8)

  • –

    Median OS (locally advanced pancreatic cancer): 16 months

  • –

    Median OS (metastatic disease): 8.5 months

  • –

    MIP-1α serum levels ↓

  • –

    Patients non-responsive to treatment/high baseline levels of IL-6, sCD40L, CRP → poor response, worse OS, ↑ sCD40L after first cycle of chemotherapy

  • –

    Patients responding to treatment → no significant variations of biomarkers between baseline and first/third cycles of the treatment

  • –

    A slight increase in quality of life
  • –

    Hematological toxicities grade 3–4 due to dose-intense schedule of Gemcitabine

  • –

    Neutropenia (grade 3–4, 38.6%)

  • –

    Anemia (grade 3–4, 6.8%)

  • –

    Thrombocytopenia (grade 3–4, 6.8%)

  • –

    Fatigue (grade 1–2, 29.5%)

  • –

    Nausea and vomiting (grade 1–2, 2%)

  • –

    Oral mucositis (grade 1–2, 6.8%)

  • –

    Diarrhea (grade 1–2, 9%; grade 3–4 2.2%)

Kanai et al., 2011
[63]		 Open-label phase I–II clinical trial (2 centers)
>6 months Jadad score: 4		 N = 21
Patients with pancreatic adenocarcinoma
M = 13; F = 8;
Median age: 67 (range 44–79)
Prior treatment: surgery, radiotherapy, chemotherapy (Gemcitabine/S-1, Gemcitabine alone)		 Curcumin (complex of curcuminoids: curcumin 73%, demethoxycurcumin 22%, bisdemethoxycurcumin 4%)
  • –

    Dose: 8 g daily p.o. + Gemcitabine/S-1

Combination (19 patients); Gemcitabine monotherapy (two patients)
  • –

    Dose: 1.000 mg/m2 of gemcitabine i.v. on days 1, 8, 60 mg/m2 of S-1 p.o. for 14 consecutive days every 3 weeks

 phase I:
Safety, Treatment completion rate (TCR)
phase II:
Tumor response rate
Overall survival (OS)
Compliance rate of curcumin
Blood cell count
CEA (carcinoembryonic antigen), CA19-9
Toxicity profile
Plasma curcumin levels
  • –

    TCR: 100% (95% CI 84–100%; p < 0.001)

  • –

    Compliance rate: 90% (95% CI 70–99%)

  • –

    Median OS: 161 days (95% CI 109–223 days)

  • –

    1-year survival rate: 19% (95% CI 4.4–41.4%)

  • –

    No partial or complete response

  • –

    Stable disease: 28% based on RECIST

  • –

    Plasma curcumin levels—from 29 to 91 ng/mL

 Hematological toxicity:
  • –

    Leucopenia (grade 4, 33%)

  • –

    Neutropenia (grade 3–4, 38%)

  • –

    Thrombocytopenia (grade 3–4, 10%);

  • –

    ↓ Hemoglobin (grade 3–4, 19%)

  • –

    Non-hematological toxicity

  • –

    Fatigue, drowsiness, anorexia

  • –

    Obstruction of the GIT, edema

  • –

    Stomatitis, nausea/vomiting, diarrhea, skin rash, fever due to infection

=> Reduced dose of curcumin to 6 g/day or chemotherapy and curcumin suspended until recovery
Adibian et al., 2019
[68]		 Randomized, double-blind, placebo controlled clinical trial
10 days
Jadad score: 7		 N = 44
Patients with type 2 diabetes
Curcumin group N = 21
M = 13; F = 8; Mean ± SD age 58±
Control group N = 23
M = 9; F = 14; Mean ± SD age: 60 ± 7		 Curcumin (1 capsule 500 mg of curcuminoids: curcumin 347 mg, demethoxycurcumin 84 mg, bisdemethoxycurcumin 9 mg, turmeric oil 38 mg)
  • –

    Dose: 500 mg t.d.s. p.o.

    Placebo (one capsule, 444 mg of rice flour)

 Lipid profile (triglyceride) total, HDL, LDL, cholesterol
high-sensitivity C-reactive protein (HS-CRP),
adiponectin (anti-inflammatory cytokine)
Anthropometric parameters:
weight, height, waist, hip circumferences, BMI		 Mean change ± SD in curcumin group and placebo group, respectively (↓↓/↑↑ p < 0.05 in the intervention group, significant difference):
  • –

    Serum triglycerides ↓↓ (−14.2 ± 30.6 vs. −5.2 ± 36.6)

  • –

    LDL ↓ (−3.7 ± 21.4 vs. −7.6 ± 34.7)

  • –

    HDL ↑ (0.3 ± 2.2 vs. 2.8 ± 5.3)

  • –

    hs-CRP ↓↓ (−2.5 ± 4.3 vs. 0.8 ± 3.2)

  • –

    Adiponectin ↑↑ (12.1 ± 7.7 vs. 7 ± 7.1)

  • –

    mean weight ↓ vs. control

  • –

    Fasting blood glucose ↓ in curcumin group vs. baseline

  • –

    Insulin levels ↓ vs. control

  • –

    HBA1c ↓ vs. control

  • –

    BMI ↓ in curcumin group, ↑ in control group

 Not provided
Rahimi et al., 2016
[69]		 Randomized double-blind placebo controlled clinical trial
3 months
Jadad score: 6		 N = 70
Patients with type 2 diabetes
Curcumin group N = 35
M = 17; F = 18; Mean ± SD age: 56.34 ± 11.17
Control group N = 35
M = 14; F = 21; Mean ± SD age: 60.95 ± 10.77		 Curcumin (Nano-curcumin/SinaCurcumin®—80 mg of curcumin in the form of nano-micelle)
  • –

    Dose: 80 mg/daily p.o.

    Placebo (N/A)

 Fasting blood glucose (FBG)
Glycated hemoglobin (HbA1C)
Estimated average glucose (eAG)
Lipid profile (total cholesterol (TC), HDL, LDL cholesterol, triglyceride (TG)
BMI		 Mean baseline and post-treatment in Curcumin group and placebo group, respectively (↓↓/↑↑ p < 0.05 in the intervention group, significant difference):
  • –

    FBG (mg/dL) ↓↓ (135.5→120.29 vs. 148.30→176.0)

  • –

    HbA1C (%) ↓↓ (7.59→7.31 vs. 7.49→9.00)

  • –

    eAG ↓↓ (171.2→167.00 vs. 168.4→211.6)

  • –

    TC (mg/dL) ↓ (163.4→158.62 vs. 162.4→149.00)

  • –

    LDL (mg/dL) ↓↓ (96.57→91.04 vs. 99.78→84.00)

  • –

    HDL (mg/dL) ↑↑ (54.30→60.95 vs. 60.35→55.00)

  • –

    TG (mg/dL) ↑↑ (109→131 vs. 142→113)

  • –

    BMI (kg/m2) ↓↓ (26.92→25.57 vs. 27.27→27.50)

 Not provided
Panahi et al., 2018
[70]		 Randomized double-blind placebo controlled clinical trial
3 months
Jadad score: 5		 N = 100
Patients with type 2 diabetes
Curcumin group N = 50
M = 25; F = 25; Mean ± SD age: 43 ± 8
Control group N = 50
M = 26; F = 24; Mean ± SD age: 41 ± 7		 Curcumin (Curcumin C3 Complex ®, curcuminoids: curcumin, demethoxycurcumin, bisdemethoxycurcumin + Bioperine ®)
  • –

    Dose: one capsule/500 mg of curcumin, and 5 mg of piperine daily p.o.

    Placebo (capsule with unknown content with added 5 mg of piperine)

 Fasting insulin (FI)
Fasting glucose (FG)
Glycated hemoglobin (HbA1c)
High-sensitivity C-reactive protein (hs-CRP)
Aspartate aminotransferase (AST)
Alanine aminotransferase
(ALT)
Homeostatic model assessments of insulin resistance (HOMA-IR) and
beta-cell function (HOMA-β)
BMI, weight		 Mean change ± SD in curcumin and placebo group, respectively (↓↓/↑↑ p < 0.05 in the intervention group, significant difference):
  • –

    FI (mIU/L) ↓ (−0.9 ± 3 vs. −0.7 ± 2)

  • –

    HbA1c (%) ↓↓ (−0.9 ± 1.1 vs. −0.2 ± 0.5)

  • –

    HOMA-IR index ↓ (−0.2 ± 0.4 vs. −0.1 ± 0.3)

  • –

    HOMA-β ↑ (2.7 ± 16.2 vs. −4.4 ± 16.1)

  • –

    FG (mg/dL) ↓ (−9 ± 16 vs. −3 ± 11)

  • –

    hs-CRP ↓↓ (−0.6 ± 0.8 vs. 0.02 ± 0.6)

  • –

    Creatinine (mg/dL) ↓ (−0.2 ± 0.3 vs. −0.1 ± 0.3)

  • –

    ALT (U/L) ↓ (−2 ± 6 vs. −1 ± 5)

  • –

    AST (U/L) ↓ (−3 ± 5 vs. −0.3 ± 4)

  • –

    BMI (kg/m2) ↓↓ (−0.5 ± 0.5 vs. 0.2 ± 0.7)

  • –

    Weight (kg) ↓↓ (−1.4 ± 1 vs. 0.7 ± 2)

 No side effects reported
Hodaei et al., 2019
[71]		 Randomized double-blind placebo controlled clinical trial
10 weeks
Jadad score: 7		 N = 44
Patients with type 2 diabetes
Curcumin group N = 21
M = 13; F = 8; Mean ± SD age: 58 ± 8
Control group N = 23
M = 9; F = 14; Mean ± SD age: 60 ± 7		 Curcumin (1 capsule 440 mg of curcuminoids:347 mg curcumin, 84 mg desmethoxycurcumin, 9 mg bisdesmethoxycurcumin; and 38 mg of turmeric oil)
  • –

    Dose: 500 mg t.d.s. p.o. (total 1500 mg)

    Placebo (one capsule 444 mg of cooked rice flour)

  • –

    Dose 1 capsule t.d.s. p.o.

 Fasting blood glucose (FBG)
Total antioxidant capacity (TAC)
Malondialdehyde (MDA)
Fasting insulin (FI)
HbA1c
HOMA-β
HOMA-IR
Weight, BMI		 Mean change ± SD in curcumin and placebo group, respectively (↓↓/↑↑ p < 0.05 in the intervention group, significant difference):
  • –

    FBG (mg/dL) ↓↓ (−7 ± 2 vs. 3 ± 0.2)

  • –

    FI (mU/L) ↑ (0.2 ± 3 vs. 1.4 ± 1.3)

  • –

    HbA1c (%) ↓ (−0.3 ± 0.4 vs. 0.1 ± 0.5)

  • –

    HOMA-IR ↑ (0.4 ± 21 vs. 12 ± 4)

  • –

    HOMA-B ↑ (3 ± 21 vs. 12 ± 37)

  • –

    TAC ↓ (−0.01 ± 0.01 vs. 0.1 ± 0)

  • –

    MDA (μmol/L) ↑ (0.5 ± 0.1 vs. 0.5 ± 0.1)

  • –

    Mean weight (kg) ↓↓ (−0.64 ± 0.22 vs. 0.19 ± 0.37)

  • –

    BMI (kg/m2) ↓ (−0.3 ± 0.03 vs. −0.1 ± 0)

 No serious side effects reported
Nigella sativa L./Thymoquinone
Al-Amri et al., 2009
[64]		 Open-label non-randomized phase I clinical study
Median 3.71 weeks (range 1–20 weeks)
Jadad score: 2		 N = 21
Patients with various types of cancer, including pancreatic adenocarcinoma N = 2
(Others: non-small cell lung carcinoma, prostatic, colonic, gastric, renal cell, hepatocellular carcinoma, leiomyosarcoma, diffuse large B-cells lymphoma
M = 11; F = 10;
Median age: 56 (range 23–92)		 Thymoquinone—dose: 1 mg/kg/day, 6 mg/kg/day, 10 mg/kg/day, p.o.
Dose increased up to 2600 mg/day
Thymoquinone dose in patients with pancreatic cancer: 85 mg/day, 500 mg/ day		 Toxicity profile
Complete blood count (CBC)
Renal function (RFT)
Liver function (LFT)
Random blood glucose (RBS)
Lipid profile
Erythrocyte sedimentation rate
Tumor markers (CEA, CA125, CA19-9, CA153, BHCG, AFP, PSA, LDH)
Prothrombin time (PT)
Partial thromboplastin time (PTT)
  • –

    Overall improvement in patient’s general condition: four patients

  • –

    Increased weight gain of 2 kg: four patients

  • –

    Reduction of tumor markers, but not by more than 25% of baseline levels (measured values not provided)

  • –

    CBC, RFT, LFT, RBS, lipid profile, ESR: no significant changes from baseline (measured values not provided)

 No side effects reported
Hadi et al., 2018 [72] Randomized double-blind placebo controlled clinical trial
8 weeks
Jadad score: 6		 N = 43
Patients with type 2 diabetes
Nigella sativa group N = 23
M = 10; F = 13; Mean ± SD age: 51.4 ± 9.2
Control group N = 20
M = 10; F = 10; Mean ± SD age: 56 ± 3.4		 Nigella sativa (one capsule 500 mg of N.sativa oil extract)
  • –

    Dose: 500 mg b.i.d. p.o.

    Placebo

  • –

    Dose: 500 mg capsule b.i.d. p.o. (content of capsule not provided)

 Fasting blood glucose (FBG)
Pro-inflammatory cytokines:
Tumor necrosis factor-α (TNFα)
Interleukin 1β (IL-1β)
Pro-oxidant biomarkers:
Nitric oxide (NO)
Malondialdehyde (MDA)
Antioxidant biomarkers:
Superoxide dismutase (SOD)
Catalase (CAT)		 Mean change ± SD in Nigella sativa and placebo group, respectively (↓↓/↑↑ p < 0.05 in the intervention group, significant difference):
  • –

    FBG (mg/dL) ↓↓ (−23 ± 39.1 vs. 8.5 ± 2.2)

  • –

    TNFα (pg/mL) ↓ (−1.3 ± 4.2 vs. 0.45 ± 3.4)

  • –

    IL-1β (pg/mL) ↓ (−0.37 ± 3.4 vs. 1.38 ± 1.9)

  • –

    SOD (U/mL) ↑↑ (7.5 ± 16.9 vs. −7.1 ± 16.7)

  • –

    CAT (U/mL) ↑ (1.8 ± 27.6 vs. −0.86 ± 4.2)

  • –

    MDA (nmol/L) ↓↓ (−0.7 ± 1.3 vs. 0.98 ± 2.6)

  • –

    NO (nmol/L) ↓ (−0.6 ± 1.5 vs. −0.16 ± 1.6)

 No severe side effects reported
Hosseini et al., 2013
[73]		 Randomized double-blind placebo controlled clinical trial
3 months
Jadad score: 6.5		 N = 70
Patients with type 2 diabetes
Nigella sativa group N = 35
M = 14; F = 21; Mean ± SD age: 48.74 ± 7.33
Control group N = 35
M = 16; F = 19; Mean ± SD age: 50.72 ± 5.69		 Nigella sativa
  • –

    Dose: 2.5 mL b.i.d. p.o. after meals (5 mL of oil daily; cold press N. sativa oil)

    Placebo

  • –

    Dose: 2.5 mL of mineral oil t.d.s. p.o.

  • –

    0.1 mL of the mixture of chlorophyl and red chili extract was added to placebo and N. sativa oil to achieve similar appearance and flavor

 Fasting blood glucose (FBG)
2h-postprandial blood glucose (2hppBG)
Glycated hemoglobin (HbA1c)
Lipid profile (total cholesterol/TC, LDL, HDL, triglyceride)
Aspartate transaminase (AST)
Alanine transaminase (ALT)
Alkaline phosphatase (ALP)
Creatinine levels, BMI
  • –

    Mean change in Nigella sativa and placebo group, respectively (↓↓/↑↑ p < 0.05 in the intervention group, significant difference):

  • –

    FBG (mg/dL) ↓↓ (−10.15 vs. 3.61)

  • –

    PBG (mg/dL) ↓↓ (−8.25 vs. 1.32)

  • –

    HbA1c (%) ↓↓ (−3.40 vs. −1.02)

  • –

    BMI (kg/m2) ↓↓ (−4.18 vs. 0.64)

  • –

    TC (mg/dL) ↓ (−3.16 vs. 2.75)

  • –

    Triglyceride (mg/dL) ↓ (−4.43 vs. 6.00)

  • –

    HDL (mg/dL) ↑ (1.03 vs. 3.90)

  • –

    LDL (mg/dL) ↓ (−1.8 vs. 2.96)

  • –

    Creatinine (mg/dL) ↓ (−4.39 vs. 4.34)

  • –

    AST (U/L) ↓ (−1.45 vs. −3.02)

  • –

    ALT (U/L) ↓ (−2.92 vs. −1.31)

  • –

    ALP (IU/L) ↑ (1.80 vs. 3.20)

 No serious side effects reported
  • –

    Mild transient nausea: four patients

  • –

    No liver enzyme and kidney functional adverse effects observed
Kaatabi et al., 2015
[74]		 Participant-blinded placebo controlled clinical trial
1 year
Jadad score: 5.5		 N = 114
∙Patients with type 2 diabetes
(on standard hypoglycemic medication: sulfonylureas, metformin)
Nigella sativa group N = 57
M = 33; F = 24; Mean ± SE age: 46.82 ± 1.14
Control group N = 57
M = 30; F = 27; Mean ± SE age: 46.12 ± 0.85		 Nigella sativa (1 capsule 500 mg of N.sativa seed powder)
  • –

    Dose: 1 g (two capsules) b.i.d. p.o. (overall 2 g/day)

    Placebo

  • –

    Dose: 260 mg of charcoal capsules

 Fasting blood glucose (FBG)
Glycated hemoglobin (HbA1c)
C-peptide
Total antioxidant capacity (TAC)
Superoxide dismutase (SOD)
Catalase (CAT)
Glutathione thiobarbituric acid-reactive substances (TBARS)
Insulin resistance
β-cell function		 Mean baseline and 12-month treatment in Nigella sativa and placebo group, respectively (↓↓/↑↑ p < 0.05 in the intervention group, significant difference):
  • –

    FBG (mg/dL) ↓↓ (195→172 vs. 180→180)

  • –

    HbA1c (%) ↓↓ (8.6→8.2 vs. 8.2→8.5)

  • –

    C-peptide (ng/mL) ↓ (2.9→2.8 vs. 2.9→2.8)

  • –

    Insulin resistance ↓↓ (3.0→2.5 vs. 2.5→2.5)

  • –

    Β-cell function (%) ↑↑ (45.8→58.6 vs. 59.4→56.6)

  • –

    TBARS (μM) ↓↓ (54.1→41.9 vs. 48.3→52.9)

  • –

    TAC (mM) ↑↑ (2.1→2.9 vs. 2.5→2.3)

  • –

    CAT (nmol/min/mL) ↑↑ (55.0→71.7 vs. 66.6→65.3)

  • –

    SOD (U/mL) ↑↑ (1.7→2.0 vs. 2.3→2.3)

  • –

    Glutathione (μM) ↑↑ (3.6→4.3 vs. 3.3→3.0)

 No side effects reported
Glycine max (L.)/Genistein/Soy isoflavones
Lohr et al., 2016
[65]		 Open-label phase Ib clinical trial
13.2 months
Jadad score: 4		 N = 16
Patients with pancreatic carcinoma (metastatic or locally advanced, no prior treatment)
M = 12; F = 4;
Median age: 61 years (range 35–73)		 Genistein/AXP107-11 (multi-component crystalline form of genisteine)
  • –

    Escalating dose: 200 mg (three patients), 400 mg (three patients), 600 mg (three patients), 800 mg (seven patients) b.i.d. p.o.

  • –

    Monotherapy for the first 2 weeks + Gemcitabine—1000 mg/m2/w during the first 7 of 8 weeks, then maximum of 4 × 4-week treatment cycles with dose given on days 1, 8, 15.

Combined treatment for max. 6 months, then AXP107-11 monotherapy (0.4–7.2 months)		 Pharmacokinetics (PK)
Toxicity profile
Maximum tolerated dose (MTD)
Efficacy of AXP107-11 and Gemcitabine combination Response
Time to progression (TTP)
Progression-free survival (PFS)
Overall survival (OS)
CA19-9
  • –

    MTD not reached in the study. No more toxic events on lower or higher doses. Due to administration burden of large capsules, dose was stopped at 1600 mg/day = 16 capsules

  • –

    PK: t-max 1.5 and 3 h; mean Cmax (800 mg AXP107-11) 1.1 μM; stable plasma concentrations, around 0.1 μM AXP107-11 (mean 0.07–0.14 μM) maintained 5–12 h post-dose

  • –

    CA 19-9 ↓ of >50%: eight patients

  • –

    Quality of life ↓ (70 vs. baseline 80–100, after average of 12 weeks (range 2–57))

  • –

    Stable disease (44%): seven patients

  • –

    Partial responses (13%): two patients

  • –

    Response duration 7.1 months: one patient

  • –

    Progressive disease at first evaluation with short TTP: seven patients

  • –

    >6-month survival: seven patients

  • –

    1-year survival: three patients (19%)

  • –

    Median PFS 2.6 months (range 0.7–13.2)

  • –

    Median OS 4.9 months (range 1.5–19.5 months)

 No toxic adverse effects during AXP107-11 monotherapy (1st 2 weeks)
  • –

    AXP107-11 did not increase toxicity in combination with Gemcitabine

  • –

    Hematologic toxicities:

  • –

    Grade 3 thrombocytopenia and platelet count, grade 4 neutropenia: one patient

  • –

    Grade 3 neutropenia: three patients

  • –

    Grade 3 non-hematological toxicities: four patients

  • –

    Grade 3 white blood cell count: two patients

  • –

    Non-hematologic toxicities:

  • –

    Grade 3 fatigue, nausea: 1 patient

  • –

    Grade 3 vomiting: one patient

  • –

    Grade 3 infection: one patient

  • –

    Grade 3 pancreatitis: one patient
El-Rayes et al., 2011
[66]		 Open-label phase II clinical trial
23 months
Jadad score: 4		 N = 20
Patients with pancreatic adenocarcinoma (locally advanced unresectable or metastatic, no prior chemo-/radiotherapy)
M = 12; F = 8;
Median age: 58 years (range 39–75)		 Soy isoflavones (Novasoy®: genistin, daidzin, glycitin in 1.3:1.0:0.3 ratio)
  • –

    Dose: 531 mg (177 mg, three tablets) b.i.d. p.o. on day 7 until the end of study + Gemcitabine—dose 1000 mg/m2 i.v. on days 1, 8, 15 of each cycle + Erlotinib—150 mg s.d. p.o. on day 1–28 Cycles repeated every 28 days

 Tumor response rate
Progression-free survival (PFS)
Overall survival (OS)
Toxicity profile
Immunohistochemistry for Akt and NF-κB
  • –

    Median OS: 5.2 months (95% CI, 4.6-N/A months)

  • –

    Median PFS: 2 months (95% CI, 2.0–9.0 months)

  • –

    6-month survival rate: 50% (95% CI, 32–78%)

  • –

    Partial response: one patient/5%

  • –

    Stable disease: six patients/30% (95% CI, 12–54%)

  • –

    Phosphorylated Akt, NF-kB grade 0–3 → grade 3—PFS: 4–14 weeks (however, no correlation proved to the best response, PFS)

  • –

    No survival improvement by adding soy isoflavones to gemcitabine and erlotinib
  • –

    No toxicities due to soy isoflavones

  • –

    Gemcitabine/Erlotinib related grade 3–4 toxicities:

  • –

    Neutropenia: four patients

  • –

    Thrombocytopenia: one patient

  • –

    Nausea: one patient

  • –

    Fatigue: five patients

  • –

    Vomiting: three patients

  • –

    Infection: one patient

  • –

    Dehydration: one patient

  • –

    Diarrhea: one patient

  • –

    Grade 2 skin rash: 10 patients

  • –

    Grade 3 cellulitis: one patient

  • –

    DVT/pulmonary embolism: three patients
Sharma et al., 2019
[75]		 Randomized placebo controlled clinical trial
60 days
Jadad score: 3.5		 N = 20
Patients with type 2 diabetes
Glycine max group N = 10
Control group N = 10
Age range: 40–60 years		 Glycine max leaves
  • –

    Dose: 10 g of powder daily (incorporated in biscuits)

    Placebo: regular biscuits

 Fasting blood glucose (FBG)
Postprandial blood glucose (PBG)
Glycated hemoglobin (HbA1c)
Lipid profile: total cholesterol (TC), LDL, HDL, VLDL
cholesterol, triglyceride		 Mean change in Glycine max and placebo group, respectively (↓↓/↑↑ p < 0.05 in the intervention group, significant difference):
  • –

    FBG (mg/dL) ↓↓ (−6.1 vs. 1.88)

  • –

    PBG (mg/dL) ↓↓ (−9.23 vs. 0.76)

  • –

    HbA1c (mg/dL) ↓↓ (−1.28 vs. 0)

  • –

    TC (mg/dL) ↓↓ (−4.63 vs. 1.7)

  • –

    triglyceride (mg/dL) ↓↓ (−8.8 vs. 2.2)

  • –

    HDL (mg/dL) ↑ (0.95 vs. −0.57)

  • –

    LDL (mg/dL) ↓↓ (−3.8 vs. 3.2)

  • –

    VLDL (mg/dL) ↓↓ (−1.76 vs. 6.1)

 No adverse effects reported
Choi et al., 2014
[76]		 Randomized, double-blind placebo controlled clinical trial
12 weeks
Jadad score: 6		 N = 45
Patients with pre-type 2 diabetes

Glycine max group N = 15
M = 7; F = 8; Mean ± SE age 49.71 ± 3.48
Control group N = 15
M = 9; F = 6;
Mean ± SE age: 49.33 ± 4.15
Lagerstroemia speciosa (Banaba) group N = 15
M = 6; F = 9;
Mean ± SE age: 47.00 ± 4.01		 Glycine max (70% ethanol leaf extract, concentrated in vacuo and lyophilized to powder)
  • –

    Dose: 1 g b.i.d. p.o. (2 g/day in total)

    Placebo (four capsules containing starch)

  • –

    Dose: 2 g per day

 Fasting blood glucose (FBG)
Glycated hemoglobin (HbA1c)
HOMA-IR (insulin resistance)
Transaminase levels (AST, ALT)
Total cholesterol (TC), LDL, HDL cholesterol
Triglyceride
Atherogenic Index (AI)
Systolic, diastolic blood pressure (BP)		 Mean baseline and post-treatment in Glycine max and placebo group, respectively (↓↓/↑↑ p < 0.05 in the intervention group, significant difference):
  • –

    FBG (mg/dL) ↓↓ (112.00→102.50 vs. 119.43→124.57)

  • –

    HbA1c (%) ↓↓ (6.35→6.14 vs. 6.191→6.73)

  • –

    Plasma insulin (μL/U/mL) ↓ (3.92→3.62 vs. 3.70→3.89)

  • –

    HOMA-IR ↓ (1.08→0.92 vs. 1.07→1.18)

  • –

    Triglyceride (mg/dL) ↓ (262.88→217.13 vs. 269.83→269.93)

  • –

    TC (mg/dL) ↓ (188.64→174.50 vs. 185.62→174.41)

  • –

    HDL (mg/dL) ↑ (18.87→21.77 vs. 18.32→17.34)

  • –

    LDL (mg/dL) ↓ (117.19→109.31 vs. 113.33→103.07)

  • –

    AI ↓ (9.38→7.18 vs. 9.77→9.74)

  • –

    ALT (U/L) ↓↓ (17.31→13.39 vs. 10.19→11.68)

  • –

    AST (U/L) ↓↓ (25.15→23.55 vs. 17.92→21.06)

  • –

    Systolic BP (mmHg) ↓ (129→124 vs. 128→125)

  • –

    Diastolic BP (mmHg) ↑ (75.2→75.3 vs. 75.7→78.8)

 No serious adverse effects reported
Ginkgo biloba L.
Hauns et al., 1999
[67]		 Open-label prospective phase II clinical trial
Duration of evaluation—until progression
Jadad score: 3.5		 N = 32
Patients with pancreatic carcinoma (locally advanced or metastatic; prior treatment: surgery, chemo-/radio-/immunotherapy, none, other)
M = 18; F = 14; Mean ± SD age: 58.2 ± 8.4		 Ginkgo biloba (parenteral GBE 761 ONC/Ginkgo biloba leaves special extract EGb 761; one capsule 175 mg: 42 mg ginkgo flavone glycosides, 10.5 mg terpene lactones (ginkgolides, bilobalide)
  • –

    Dose: 350 mg of GBE-761-ONC in 250 mL physiologic saline solution as 30 min infusion on days 1–6 + 5-fluorouracil

  • –

    Dose: 500 mg/m2/day in 250 mL physiologic saline solution as 30 min. infusion on days 2–6

  • –

    Treatment cycle: every 3 weeks until progression

 Tumor response rate
Overall survival (OS)
Efficacy
Tolerability
Toxicity profile
Quality of life
  • –

    Progressive disease: 22 patients (68.8%)

  • –

    Partial response: three patients (after four cycles) (9.4%)

  • –

    Stable disease: seven patients (after four cycles) (21.9%)

  • –

    Complete response: zero patients

  • –

    Median OS: 5.6 months (range 2.6–7.3 months)

  • –

    Disease duration > 15 months: one patients(3.1%)

  • –

    Ginkgo + 5-FU combination—improvement of the treatment tolerability and overall quality of life

  • –

    Quality of life—constant during the treatment period:

  • –

    deterioration after first cycle: 10 patients; second cycle: 14 patients, third cycle: four patients;

  • –

    Improvement after first cycle: 10 patients; second cycle: three patients; third cycle: seven patients; fourth cycle: three patients

 All adverse events related to 5-FU, disease progression, other medication
  • –

    Grade 3 leukopenia: three patients

  • –

    Grade 3 thrombocytopenia, hemoglobin-related: two patients

  • –

    Non-hematological toxicities: ↑ alkaline phosphatase, bilirubinemia (of grade 4): one patient

  • –

    Gastrointestinal symptoms

Kudolo, 2001
[77]		 Open-label follow-up controlled clinical trial
3 months
Jadad score: 2.5		 N = 20
Patients with type 2 diabetes

Hyperinsulinemia group N = 12
  • –

    Diet-controlled N = 6 (M/F = 3/3; Mean ± SD age: 52 ± 6)

  • –

    Hypoglycemic medication (metformin, glipizide, or glyburide) N = 6 (M/F = 4/2; mean ± SD age: 57 ± 6)

Pancreatic exhaustion group N = 8 (M/F = 4/4; Mean ± SD age: 51 ± 9) on hypoglycemic medication (metformin, glipizide, glyburide, or troglitazone)		 Ginkgo biloba (EGb 761—50:1 standardized Ginkgo biloba extract: 24% Ginkgo flavone glycosides, 6% terpenes)
  • –

    Dose: 120 mg daily (administered to all participants)

 Pancreatic β-cell function
Fasting insulin (FI)
Fasting C-peptide
Fasting blood glucose (FBG)
Fibrinogen
Coagulation: Prothrombin time (PT), Partial thromboplastin time (PTT)
Lipid profile (total cholesterol (TC), LDL, HDL cholesterol, triglyceride)
Liver function (AST, ALT)
Lactate dehydrogenase (LDH)		 Mean baseline and post-treatment in hyperinsulinemic group of diet controlled and on medication and pancreatic exhaustion group, respectively (↓↓/↑↑ p < 0.05, significant difference):
  • –

    FBG (mg/dL) 117→118 ↑ vs. 143→139 ↓ vs. 152→157 ↑

  • –

    FI (μU/mL) 29→26 ↓ vs. 46→39 ↓ vs. 16→20 ↑

  • –

    Fasting C-peptide (ng/mL) 3.8→3.7 ↓ vs. 5.2→4.4 ↓ vs. 2.5→3.3 ↑

  • –

    Fibrinogen (mg/dL) 286→287 ↑ vs. 345→343 ↓ vs. 307→336 ↑

  • –

    PT (s) 11.4→11.4 ø vs. 11.4→11.7 ↑ vs. 11.3→11.1 ↓

  • –

    PTT (s) 24.6→24.4 ↓ vs. 24.0→24.3 ↑ vs. 24.7→23.1 ↓

  • –

    TC (mg/dL) 194→186 ↓ vs. 176→159 ↓ vs. 181→183 ↑

  • –

    Triglycerides (mg/dL) 170→157 ↓ vs. 184→174 ↓ vs. 196→181 ↓

  • –

    HDL (mg/dL) 39→38 ↓ vs. 35→34 ↓ vs. 37→40 ↑

  • –

    LDL (mg/dL) 121→117 ↓ vs. 102→91 ↓ vs. 105→111 ↑

  • –

    AST (U/L) 23→23 ø vs. 30→30 ø vs. 23→22 ↓

  • –

    ALT (U/L) 28→29 ↑ vs. 31→31 ø vs. 30→23 ↓

  • –

    LDH (U/L) 173→153 ↓ vs. 184→163 ↓ vs. 105→152 ↑↑

  • –

    Response to glucose loading during a standard 75 g oral glucose

  • –

    tolerance test:

  • –

    Glucose area (mg/dL/h) 424→410 ↓ vs. 418→479 ↑↑ vs. 481→551 ↑

  • –

    Insulin area (μU/mL/h) 193→182 ↓ vs. 199→142 ↓↓ vs. 51→86 ↑↑

  • –

    C-peptide area (ng/mL/h) 14.3→15.9↑ vs. 15.6→15.1↓ vs. 7.2→13.7↑↑

 No adverse effects reported
  • –

    In contrast, effects reported by Ginkgo biloba use:

  • –

    Increased wellbeing

  • –

    Maintaining better mental focus

  • –

    Increased sensation in the feet in patients with numbness
Aziz et al., 2018
[78]		 Randomized double-blind placebo controlled clinical trial (multicenter)
90 days
Jadad score: 6		 N = 47
Patients with type 2 diabetes
(Prior/current treatment: Metformin 500 or 850 mg)
Ginkgo biloba group N = 27
M = 1; F = 26; Mean ± SD age 48.7 ± 9.6
Control group N = 20
M = 1; F = 19; Mean ± SD age 48.2 ± 10.3		 Ginkgo biloba (extract as the standard powder (EGb761))
  • –

    Dose: 120 mg (capsule)/day + metformin 1.36 ± 0.45 g s.d. p.o. Placebo (starch)

  • –

    Dose: 120 mg (capsule)/day + metformin 1.24 ± 0.67 g s.d. p.o

.		 Blood glycated hemoglobin (HbA1c)
Fasting serum glucose (FSG)
Serum insulin (SI)
Body mass index (BMI)
Insulin resistance (IR)
Visceral adiposity index (VAI)
Liver enzymes activity (AST, ALT, ALP)
Urea
Creatinine
Hematocrit (Hct), Hemoglobin (Hb)
Red/white blood cells
Platelets 		Mean baseline and post-treatment in Ginkgo biloba and placebo group, respectively, (↓↓/↑↑ p < 0.05 in the intervention group, significant difference):
  • –

    HbA1c (%) ↓↓ (8.6→7.7 vs. 8.8→8.4)

  • –

    FSG (mg/dL) ↓↓ (194.4→154.7 vs. 166.7→173.8)

  • –

    SI (μU/mL) ↓↓ (18.5→13.4 vs. 17.5→15.8)

  • –

    IR ↓↓ (9.0→N/A) vs. (9.4→N/A)

  • –

    BMI kg/m2 ↓↓ (34.0→31.6 vs. no change (value N/A)

  • –

    VAI ↓↓ (192.0→158.9 vs. 196.5→208.2)

  • –

    AST (U/L) ↑ (18.4→18.8 vs. 22.2→18.1)

  • –

    ALT (U/L) ↓ 17.8→17.5 vs. 19.2→17.0)

  • –

    ALP (U/L) ↓↓ (93.8→86.1 vs. 97.6→82.1)

  • –

    Urea (mg/dL) ↓↓ (28.1→24.5 vs. 25.6→27.1)

  • –

    Creatinine (mg/dL) ↓↓ (0.69→0.60 vs. 0.67→0.73)

  • –

    Hct (%) ↑↑ (37.1→41.0 vs. 38.3→40.9)

  • –

    Hb (g/dL) ↑↑ (12.6→13.4 vs. 12.9→13.5)

  • –

    RBC (×109 cells/L) ↑↑ (4.8→5.2 vs. 4.6→4.8)

  • –

    WBC (×106 cells/L) ↓ (8.6→8.1 vs. 8.9→8.5)

  • –

    Platelet (×109 cells/L) ↑ (233→242 vs. 252→206 ↓↓)

 No serious adverse effects observed

↓/↑ decrease/increase of parameters; ↓↓/↑↑ significant decrease/increase