Table 4 Clinical trials of the traditional plants used for skin problems in Turkey

Alkanna tinctoria

N = 60

Inclusion: Wounds after removal of the skin graft.

Exclusion: Hypersensiti- vity reaction to the topical formulation, diabetes, renal failure, liver failure, malnourish- ment, cancer and hypoalbumi- nemia (serum albumin < 4 g/dl), as well as elderly (age > 60 years) and pregnant patients

RCT, SB, PBO- controlled

Groups:

A.tinctoria: dressing with its root extract ointment 20%

PBO: standard dressing (dressing with standart ointments)

Follow-up at 4 weeks

Primary: Wound healing

Secondary: The percentage change in wound surface area, complete healing, adverse effects

Wound scores (Bates- Jensen wound assessment tool):

A.tinctoria:

Day 0: 25.07 ± 7.24 (p = 0.08)

Day 14: 9.97 ± 1.30 (p = 0.001)

Day 28: 9.03 ± 0.18 (p = 0.001)

PBO:

Day 0: 25.17 ± 7.42 (p = 0.08)

Day 14: 20.63 ± 6.64 (p = 0.001)

Day 28: 11.83 ± 2.77 (p = 0.001)

Complete wound healing (Patients with Wound score < 10, n (%))

A.tinctoria:

Day 14: 15 (50%) (p = 0.001) Day 28: 29 (96.66%) (p = 0.001)

PBO:

Day 14: 0 (0%)

Day 28: 7 (23.3%) (p = 0.001)

Statistically significant difference was found between the wound scores of treatment and placebo groups.

No side-effects were noted during the study

[35]

Allium cepa

N = 90

Inclusion: Surgical wounds at least 2.5 cm, Asians over 18 years age

Exclusion: Wound infections, taking agents that would affect wound healing, comorbidities such as diabetes, contractive skin disorders

RCT

Groups:

A.cepa extract 10% (Contractu-bex®)- 30 persons (twice daily)

Silicone gel 10% (Kelo-cort®)- 30 persons (twice daily)

No treatment group- 30 persons

Follow-up at 12 weeks

Primary: Objective scar assessment

Secondary: Subjective scar assessment, subject- reported compliance, adverse effects

A.cepa/ Silicone gel/ No treatment

Objective scar assessment (results)

Vancouver Scar Scale: 3.8 ± 1.4/ 3.9 ± 1.1/5.4 ± 1.1 (first and second group difference p = 0.492 Not significant)

Image Panel Scale: 5.2 ± 1.7/ 5.4 ± 1.1/6.2 ± 1.3 (first and second group difference p = 0.331 Not significant)

Subjective scar assessment

Body Image Scale:16.8 ± 3.8/ 16.3 ± 2.3/14.9 ± 1.9 (first and second group difference p = 0.175 Not significant)

Cosmetic Scale: 15.9 ± 3.6/ 15.7 ± 4.2/13.7 ± 3.0 (first and second group difference p = 0.847 Not significant)

Vancouver Scar Scale (p = 0.003), Image Panel Scale (p = 0.017), Body Image Scale (p = 0.004), and Cosmetic Scala (p = 0.035) scores were significantly different between two groups and no treatment group. The method of the study is not blinded.

Patient compliance with the gel:

A.cepa/ Silicone gel

Excellent: 20(67%), 21(70%)

Good: 8(27%),8(27%)

Poor: 1(3%), 2(7%)

Adverse events with the gel

Irritation: 2(7%), 1 (3%)

Itching: 1(3%), 0

Erythema and Burning sense: 0

[36]

Allium cepa

N = 24

Inclusion: New surgical wounds at least 4 cm

Exclusion:-

RCT, DB, split-scar

Each scar was divided into two equal portions, and each half was assigned treatment with either onion extract gel or petrolatum.

Each product was applied three times daily

Treatment up to 8 weeks and evaluation up to 12 weeks

Outcomes: Scar healing

A.cepa extract/ Petrolatum

Week 2:

Redness: 2.45 ± 0.50/ 2.50 ± 0.44 (p = 0.9414)

Itchiness: 1.58 ± 0.53/ 1.09 ± 0.38 (p = 0.2841)

Burning: 0.77 ± 0.34/ 0.85 ± 0.35 (p = 0.8483)

Pain: 0.68 ± 0.29/ 0.68 ± 0.29 (p = 4259)

Cosmetic appearance: Same changes 11(%46)- Better 5(21%)/ Better 8(33%)(p = 3654)

Week 12:

Redness: 0.29 ± 0.11/0.29 ± 0.13 (p = 0.9142)

Itchiness: 0.86 ± 0.047/0.57 ± 0.027 (p = 0.4533)

Burning: 0.043 ± 0.02 0.043 ± 0.02 (p = 1.0000)

Pain: 0.043 ± 0.02/ 0.043 ± 0.02 (p = 1.0000)

Cosmetic appearance: Same changes 12(%86)- Better 1(7%)/ Better 1(7%)

Not significant difference was seen in any value for 12 weeks

No side-effects were noted during the study

[37]

Allium sativum, H. perforatum, Calendula officinalis

N = 25

Inclusion: Venous ulcers

Exclusion: Ulceration greater than 10 cm2, clinical signs of infection thrombophlebitis; hyperglycemia; kidney disease, or malignancy.

Non-RCT, Pilot

Treatment: Herbadermal® (Dry water extract of Allii sativi bulbus (2.7% allicin),

Dry ethanol extract of Hyperici herba (total flavonoid 3.1%,; hypericin 0.1%),

Oil extract of Calendulae flos (1:5; total flavonoids 0.02%) and vaseline)

Ointment was applied topically 5 times a day over a period of 7 weeks.

Follow-up at 7 weeks

Outcomes: Venous ulcers healing

Ulcer area and healing parameters:

Persons: 1–5 / 6–10 / 11–15 / 16–20 / 21–25

Before and after the study:

Pre-treatment: 4.23 / 7.54 / 7.22 / 6.32 / 6.98

Week 1: 3.80/ 7.45/ 7.0 / 6.14 /6.9

Week 3: 3.12/ 6.91/ 6.3/ 5.75/ 5.6

Week 5: 2.76/ 5.76/ 5.8/ 4.0/ 4.1

Week 7: 0.0(%100), 4.7(%37.66), 5.2(%31.03), 2.8(%62.86), 1.8(%76.12)

Epithelialization:

Average score/ İmprovement %

Week 0: 7.43/−

Week 1: 4.56/38.56

Week 3: 1.46/80.26

Week 5: 0.46/93.72

Week 7: 0.25/99.10

Ulcer surroundings:

Week 0: 7.23/−

Week 1: 5.10/ 29.49

Week 3: 3.33/ 53.91

Week 5: 2.93/ 59.44

Week 7: 2.13/ 70.50

Number of patients with isolated bacteria

Week 0/1/3/5/7

S.aureus / P. aeruginosa: 5/−/5/−/−

S.aureus:15/10/10/20/15

P.aeruginosa: 5/15/10/5/10

Especially, epithelialization results are significant. But, the method of the study is limited.

No side-effects were noted during the study

[38]

Borago officinalis

N = 32

Inclusion: Children with atopic dermatitis

Exclusion: The patients with severe symptoms

RCT, DB, PBO- controlled

Treatment: Undershirts coated with borage oil (including 498 mg of gamma linolenik asit per 100 g of cotton)

PBO: Non-coated undershirts

Follow-up at 2

weeks

Outcomes: Changes of clinical symptoms

Changes of scores of the clinical symptoms

Treatment group:

Week 0:

Itch: 1.44 ± 0.51

Erythema: 0.81 ± 0.83

Transepidermal water loss: 10

Week 2:

Itch: 0.94 ± 0.57 (p = 0.033)

Erythema: 0.31 ± 0.48 (p = 0.033)

Transepidermal water loss: 7–7.5 (p = 0.0480)

While itching and erythema revealed statistically significant differences, papules, erosion, scaling and lichenification revealed in the treatment group. Transepidermal water loss from the back was decreased.

PBO group: There were no statistically significant differences in the placebo group for all clinical symptoms.

Overall assessments of response by children’s parents

Treatment group: Improved (75%)

PBO: Improved (56.2%)

Undershirts coated with borage oil showed better therapeutic response than the non-coated undershirt

No side-effects were noted during the study

[39]

Calendula officinalis

N = 41

Inclusion: Patients with diabetic foot ulcers, adequate glycemic control, neuropathic ulcers(0.5–45 cm2), age 18–90 years

Exclusion: Active Charcot foot, Cellulitis, osteomyelitis, gangrene, or deep tissue infection, pregnant women, allergy, receiving systemic corticosteroids

Prospective, descriptive

Treatment: Hydroglyco-lic 4% flowers extract of C.officinalis for twice daily

Follow-up at 30 weeks

Outcomes: Ulcers healing

Ulcer area reduction and healing rate:

Ulcer area (cm²):

Baseline: 8.68 ± 8.55

Week 30: 0.57 ± 1.68

Healing rate (week 30):

Complete healing: 32 (78%)

The remaining 9 (22%) achieved an overall reduction in the wound area of 75%.

Ulcer types:

Baseline- Week 30

Wagner I: 34 (82.9%)- 9 (21.9%)

Wagner II 7 (17.1%)- 0 (0.0%)

Ulcer microbiology:

Baseline- Week 30

Colonized diabetic foot ulcers: 26.8%- 14.6%

Infected diabetic foot ulcers: 48.8% 2.4%

Ulcer duration (weeks)- Median (range)

Baseline: 65.0

Week 30: -

Complete healing was seen for 78% of patients at the end of study and this rate is high. But, the method of the study is limited.

No side-effects were noted during the study

[40]

Calendula officinalis

N = 51

Inclusion: Diagnosed with head and neck cancer and taken radiotherapy, aged over 18 years

Exclusion: Tumor wounds in the head and neck, previous history of radiotherapy in the same treatment field, allergy

RCT, DB

Treatment: 4% Calendula oil, 1% vitamin A and liquid vaseline.

Control: Essential fatty acid - sunflower oil, 1% vitamin A, 0.2% vitamin E and 5% caprylic acid

Primary outcomes: Develop- ment of radioderma- titis,

Radiation Therapy Oncology Group

Acute Skin Toxicity Grades

Development of radiodermatitis

10th session of radiotherapy:

Essential fatty acid(n = 27)- Calendula(n = 24)

10th session:

Grade 0: 24(88.89%)- 22(91.67%)

Grade 1: 3(11.11%)-2(8.33%)

35th session:

Grade 0: 0(0%)- 2(22.22%)

Grade 1: 4(57.14%)- 5(55.56%)

Grade 2: 1(14.29%)-0(0%)

Grade 3: 2(28.57%)- 2(22.22%)

Last session:

Grade 0: 1(7.69%)- 3(21.43%)

Grade 1: 6(46.15%)- 8(57.14%)

Grade 2: 3((23.08%)- 1(7.14%)

Grade 3: 3(23.08%)- 2(14.29%)

30 days after the treatment period

Grade 0: 9(90%)- 11(91.67%)

Grade 1: 0 (0%)- 1(8.33%)

Grade 2: 1(10%)- 0(0%)

Calendula showed better therapeutic response than the essential fatty acid, as the proportion of radiodermatitis Grade 2 in the essential fatty acid group is higher than Calendula group.

No side-effects were noted during the study

[41]

Calendula officinalis

N = 254

Inclusion: The women, 18 to 75 years of age, with a nonmetastatic breast adenocarcino-ma treated by either lumpectomy or mastectomy with or without adjuvant postoperative chemotherapy or hormonal treatment

Exclusion: Women with bilateral or in situ breast cancer, allergy, pregnant women

Phase III, RCT

Treatment: C.officinalis((Pommade au Calendula par Digestion)

Control: Trolamine

Primary: Prevention of skin toxicity of Radiation Therapy Oncology Group grade 2 or higher

Secondary: Assessment of pain, allergy, dermatitis, patient satisfaction, the quantity of the agent used.

Skin Toxicity in breast cancer patients treated with postoperative radiotherapy

Skin toxicity (grade):

Calendula/ Trolamine

Breast

0–1: 78(79%)- 75(71%)

2–3: 21(21%)-30(%29) (p = 0.21)

Submammary fold

0–1: 65(66%)- 52(50%)

2–3: 34(34%)- 53(50%) (p = 0.02)

Armpit and tangential area

0–1: 70(72%)- 53(52%)

2–3: 27(28%)- 48(48%) (p = 0.004)

Chest wall

0–1:24(89%)- 17(79%)

2–3: 3(11%)- 6(26%) (p = 0.17)

Supraclavicular nodes

0–1: 55(72%)- 29(37%)

2–3: 21(28%)- 49(63%) (p < 0.001)

Internal mammary nodes

0–1: 53(86%)- 50(74%)

2–3: 9(14%)- 18(26%) (p = 0.09)

Overall

0–1: 74(59%)- 47(37%)

2–3: 52(41%)- 81(63%) (p < 0.001)

Calendula is statistically effective for the prevention of acute dermatitis of grade 2 or higher.

No side-effects were noted during the study

[42]

Cydonia oblonga (Quince)

N = 50

Inclusion: Skin ulcer caused by punch biopsy

Exclusion: History of hypersensitivi-ty to phenytoin, immune suppression (cancer, HIV), autoimmune disorders, malignancy, pregnancy.

Exclusion:-

RCT, DB

Treatment: 5% Quince seed cream

Control: 1% phenytoin cream

All creams were used to twice a day for 2 weeks

Primary: Healing of ulcers

Secondary: Adverse effects

The Mean of Ulcer Size Before and After the Treatments:

Phenytoin/ C.oblonga

Before: 0.525 ± 0.060/ 0.533 ± 0.090 (p = 0.740)

Day 3: 0.306 ± 0.041/ 0.170 ± 0.109 (p = 0.001)

Day 7: 0.161 ± 0.172/ 0.043 ± 0.029 (p = 0.003) Day 14: 0.033 ± 0.026/ 0.004 ± 0.005 (p = 0.001)

Complete healing percentage:

Day 3: 0/0

Day 7: 0/%13.6

Day 14: %21.7/ %86.4

Complete healing rate and changes of ulcer size in the treatment group was seen statistically superior to the control group.

Adverse effects

Phenytoin/ C.oblonga:

Burning: 26.1%/ 9.1%

Pain: 13%/ 0%

Itching: 8.7%/ 13.6%

Contact dermatitis: 4.3%/ 0%

No complica- ted: 39.1%/ 77.3%

[43]

Euphorbia peplus

N = 36

Inclusion: Patients with basal cell carcinoma, intraepidermal carcinoma or squamous cell carcinomas

Phase I/II

Treatment:100–300 uL of E. peplus sap once daily for 3 days

Outcomes: Treatment of Non- melanoma skin cancer

Number of lesions showing complete clinical response, partial clinical response and stable disease (S at 1 month

Basal cell carcinoma (no:28): 23(%82)/5(18%)/0

İntraepidermal carcinoma(16): 15(94%)/0/1(6%)

Squamous cell carcinomas(4): 3(75%)/0/1(25%)

Complete response at last follow-up:

Basal cell carcinoma: 16(57%)

İntraepidermal carcinoma: 12(75%)

Squamous cell carcinoma:2(50%)

Biopsy histology (no.negative/no. tested)

Basal cell carcinoma:18/20

İntraepidermal carcinoma: 7/8

Squamous cell carcinoma:1/2

Complete healing was seen for the most of the patients

No side-effects were noted during the study

[2]

Ficus carica

N = 59

Inclusion: Children with atopic dermatitis

Exclusion: Severe atopic dermatitis (Scoring atopic dermatitis index> 50), secondary skin infection, another skin disease, immünodefi- ciency disorder

RCT, DB, PBO

Treatment: Fig fruit extract 8% (Melfi cream)

Control: Hydrocor- tisone 1%

Pbo: Base cream

The patients were instructed to apply their allocated creams twice a day for two weeks.

Primary: Reduction of main symptoms (intensity and pruritus)

Secondary: Complete healing, adverse effects

Scoring atopic dermatitis

Before/ After

Treatment: 33.84 ± 10.05/14.85 ± 8.83 (p < 0.0001)

Control: 29.53 ± 13.58/ 16.73 ± 9.44 (p < 0.001)

Pbo: 28.48 ± 10.34/ 34.30 ± 12.61 (Placebo results are failed)

Intensity

Treatment: 6.75 ± 2.81/ 3.06 ± 1.80 (p < 0.0001)

Control: 6.28 ± 2.84/ 3.28 ± 1.77 (p < 0.001)

Pbo: 5.60 ± 2.22/ 6.93 ± 2.89

(Placebo results are failed)

Pruritus

Treatment: 5.31 ± 2.70/1.93 ± 1.91 (p < 0.0001)

Control:3.50 ± 2.76/ 2.35 ± 1.98 (p < 0.004)

Pbo: 5.0 ± 2.80/5.66 ± 2.92 (Placebo results are failed)

Treatment with fig extract had significant efficacy in terms of reducing the Scoring atopic dermatitis index, pruritus and intensity scores in comparison with Hydrocortisone 1.0% (p < 0.05).

No side-effects were noted during the study

[44]

Foeniculum vulgare

N = 38

Inclusion: Female patients with idiopathic hirsutism localized to the face

Exclusion:-

RCT, DB, PBO

Treatment: F. vulgare (fennel) seed extract 1%, 2%

PBO: Vehicle cream

The creams were applied twice daily for 12 weeks

Outcomes: Reduction of hair diameters in patients

Baseline characteristics of three study groups

Average hair diameter

Fennel 1%: 67.5

Fennel 2%: 59.9

Pbo: 55.8

The mean value of reduction of hair diameter

Fennel 1%: 7.8% (SD = 3.7)

Fennel 2%: 18.3% (SD = 8.3)

Pbo: − 0.5% (SD = 2.1)

The efficacy of treatment with the fennel extracts is more potent in comparison with the placebo.

No side-effects were noted during the study

[45]

Foeniculum vulgare

N = 22

Inclusion: Patients with mild to moderate idiopathic hirsutism limited to face

Exclusion: Severe hirsutism, increased serum androgen level.

RCT, DB, PBO

Treatment: F.vulgare (Fennel) gel 3%

PBO: Vehicle cream

Follow-up at 24 weeks

Primary: Changes in hair thickness

Secondary: Adverse effects

Degree of hirsutism

Treatment/PBO

Mild:2(9%)/8(40%)

Moderate: 20(9%)/ 12(60%)

Hair thickness

Before/ After

Treatment: 97.9 ± 31.5/ 75.6 ± 26.7 (p < 0.001)

PBO: 92.1 ± 29.5/97.0 ± 29.6 (Not significant)

The efficacy of treatment with the fennel extracts is more potent in comparison with the placebo.

No side-effects were noted during the study

[46]

Hypericum perforatum

N = 21

Inclusion: Patients with subacute atopic dermatitis (Scoring atopic dermatitis index< 80)

Exclusion: İnfectious disease, Severe underlying clinical disease

RCT, DB, PBO

Treatment: H. perforatum extract cream (20–25:1;

hyperforin content of 1.5%)

PBO: Vehicle cream

The patients were treated twice daily over a period of four weeks

Primary:The clinical intensity of the skin lesions

Secondary: Bacterial colonisation of skin lesions, skin tolerance and cosmetic acceptability of the study medications

The half-side comparison of skin lesion intensities (Scoring atopic dermatitis index)

Change from baseline:

Mean ± SD/ Median [min.; max.]/ 95% CI/ p-value

Day 7:

Treatment: − 3.0 ± 3.1/ –3.0 [− 10.0; 5.0] / [− 5.0; − 2.0]/ (p = 0.002)

Placebo: − 0.6 ± 1.2/ –0.5 [− 2.0; 2.0]/ [− 2.0; 0.0]/ (p = 0.002)

Day 14:

Treatment: − 4.7 ± 3.3/ –6.0 [− 10.0; 2.0] / [− 7.0; 3.0]/ (p = 0.016)

Placebo: − 2.1 ± 3.0/ –2.0 [− 10.0; 4.0]/ [− 4.0; 0.0]/ (p = 0.016)

Day 28:

Treatment: − 5.4 ± 4.9/ –6.5 [− 12.0; 5.0] /[− 9.0; − 4.0]/ (p = 0.022)

Placebo: − 2.3 ± 3.3/ –2.5 [− 8.0; 5.0]/ [− 4.0; − 1.0]/ (p = 0.022)

Number of CFUs of bacteria in general and of Staphylococcus aureus in particular

Day 0

Treatment/ PBO

0: 1(5.6%)/ 1(5.6%)

1–10: 4(22.2)/ 7(38.9)

11–20: 4(22.2%)/ 1(5.6%)

> 20: 9(50%)/ 9(50%)

Day 28:

0: 2(11.1%)/1(5.6%)

1–10: 8(44.4%)/ 5(27.8%)

11–20: 4(22.2%)/ 1(5.6%)

> 20: 4(22.2%)/ 11(61.1%)

The hypericum-cream was significantly superior to the vehicle according to the scoring atopic dermatitis index (p < 0.05).

In total, 4 adverse events were recorded in 3 patients. None of the adverse events was classified as serious. In all cases, there was an acute episode of atopic dermatitis leading to withdrawal from the study. One patient additionally developed contact eczema; in this instance a relationship with the study medication (hypericum-free vehicle) was considered probable.

[47]

Achillea millefolium, H. perforatum

N = 134

Inclusion: Primiparous women with episiotomy wounds, being nulliparous; gestational age of 37–42 weeks; having a single fetus; no use of particular medications

Exclusion: mismatch between the fetus head and the mother’s pelvis in pelvic examination; disorder in the labor progress; manual placenta removal; third and fourth degree perineal rupture

RCT, PBO, DB

Treatment groups:

1- H. perforatum ointment (Group 1)

2- A. millefolium ointment (Group 2)

3- Placebo ointments (PBO)

4- Non-inter- vention (NI)

The patients were treated twice a day for 10 days

Outcomes: Healing of wounds

Group 1(Min/Max/Median/IQR)- Group 2 (Min/Max/Median/IQR)- Placebo (Min/ Max/Median/ IQR)- No intervention (Min/Max/Median/IQR)

Pain level

2th Day Group 1: 3/10/9/2.5- Group 2: 6/10/9/ 2- PBO: 3/10/9/2.- NI: 6/10/9/2 (p = 0.226)

7th Day Group 1: 0/7/4/2.5- Group 2: 3/8/6/2- PBO: 1/9/6.5/3- NI: 4/9/7/1 (p < 0.001)

10th Day Group 1: 0/5/2/2.5- Group 2: 0/6/4/2 - PBO: 0/8/5.5/1.2- /NI: 2/8/6/2 (p < 0.001)

14th Day Group 1: 0/3/0/1- Group 2: 0/5/0/2- PBO: 0/7/3/4.25- NI: 0/7/4/3 (p < 0.001)

Redness

7th Day Group 1: 0/8/3/5 Group 2: 0/15/5/6- PBO: 0/15/7/3.5- NI: 5/15/8/4 (p < 0.001)

10th Day Group 1: 0/5/0/0- Group 2: 0/8/0/2.5- PBO: 0/12/4/5- NI: 0/12/5/ 2 (p < 0.001)

14th Day Group 1: 0/0/0/0- Group 2: 0/5/0/0- PBO: 0/10/0/0.5 - NI: 0/10/04 (p < 0.001)

Ecchymosis

7th Day Group 1: 0/3/0/0- Group 2: 0/3/0/0 - PBO: 0/6/0/5- NI: 0/7/0/5 (p < 0.001)

10th Day Group 1: 0/0/0/0- Group 2: 0/0/0/0- PBO: 0/4/0/0- NI: 0/4/0/0 (p < 0.041)

Edema

7th Day Group 1: 0/5/0/4.5- Group 2: 0/10/0/5- PBO: 0/15/5/5.5- NI: 0/15/5/3 (p < 0.001)

10th Day Group 1: 0/0/0/0- Group 2: 0/5/0/0- PBO:0/8/0/1- NI: 0/10/0/5 (p < 0.001)

14th Day Group 1:0/0/0/0- Group 2: 0// 0/0- PBO: 0/4/0/0- NI: 0/5/0/0 (p = 0.322)

Frequency of wound dehiscence and wound discharge in patients in subject groups

Dehiscence

7th Day Group 1: 5(31.3%)- Group 2: 3(18.8%)- PBO:3(18.8%)- NI:5(31.3%) (p = 0.807)

10th Day Group 1: 2(50%)- Group 2: 0(0%)- PBO:0 (0%)- NI: 2(50%) (p = 0.306)

Discharge

7th Day Group 1: 3(14.3%)- Group 2: 5(23.8%) PBO: 6(28.6%)- NI: 7(33.3%) (p = 0.655)

10th Day Group 1: 1(20%)- Group 2: 0(0%)- PBO: 2(40%)- NI: 2(40%) (p = 0.755)

Almost all results of H. perforatum and A. millefolium showed significant difference in comparison with placebo and non-intervention except for discharge and dehiscence incidence.

No side-effects were noted during the study

[48]

H. perforatum, Calendula arvensis

N = 24

Inclusion: Surgical wounds from childbirth with caesarean section

Exclusion:-

Non-RCT

Treatment: A mixture of oily extracts of H.perfora- tum 70% and C. arvensis 30%

Control: Wheat germ oil (320:1000)

The two groups were treated twice daily for 16 consecutive days

Outcomes: Healing of surgical wounds, Surface Perimeter Area assessment

Area of surgical wounds before and after treatment with the Hypericum–Calendula oily extract (treated group)

Surface Perimeter Area (before-after)/ % wound reduction

Mean: 13.58 ± 2.71–8.16 ± 1.40 (%37.6 ± 9.9)

Extension of the wound before and after treatment with wheat germ oil (control group)

Surface Perimeter Area (before-after)/ % wound reduction

Mean: 15.75 ± 2.13 / 12.66 ± 2.49 (%15.83 ± 4.64)

The Hypericum– Calendula mixture was found superior to the control treatment in terms of healing of surgical wounds.

No side-effects were noted during the study

[49]

H. perforatum

N = 10

Inclusion: Symmetrical plaque-type psoriasis

Exclusion:-

Single-blind, PBO, Pilot study

Treatment: H. perforatum (5% wt/wt), vaseline (84% wt/wt), propylene glycol (10% wt/wt) and avicel (1% wt/wt)

PBO: Vehicle cream

-The hypericum ointment was applied to one side of each patient’s body and the vehicle to the opposite side twice daily for 4 weeks

Outcomes: Healing of erythema

Mean erythema scores, scaling scores, and thickness scores

Before/ After

Treatment:

Erythema: 2.6 (2.6 ± 0.5)/ 1.1 (1.1 ± 0.74)*

Scaling: 2.5 (2.5 ± 0.85)/ 0.7 (0.7 ± 0.48)*

Thickness: 2.4 (2.4 ± 0.52)/ 1.1 (1.1 ± 0.74)*

PBO:

Erythema: 2.6 (2.6 ± 0.7)/ 1.9 (1.9 ± 0.74)*

Scaling: 2.4 (2.4 ± 0.52)/ 2.1 (2.1 ± 0.57)*

Thickness: 2.1 (2.1 ± 7.4)/ 1.8 (1.8 ± 0.42)*

*A statistically significant difference was found between the scores after treatment in placebo and formulated active ointment (P = 0.01, P = 0.004, P = 0.04). But the method of study is limited.

No side-effects were noted during the study

[50]

H. perforatum

N = 125

Inclusion: Women with first surgical childbirth, age range 17–35 years

Exclusion: Scars from prior abdominal surgery, history of medical and obstetrical problems

RCT, DB

Treatment: Oily extract of H. perforatum

PBO: Vehicle ointment

Control: No intervention

The two groups were treated three times daily for 16 consecutive days

Outcomes: Healing of wounds

Assessment of the Wound Healing by the REEDA Scale on the 10th Day Postpartum

Treatment (n = 47)/ Placebo (n = 42)/ Control (n = 34)

Redness: 0.11(0.31)/ 0.36(0.49)/ 0.35(0.49) [χ² = 9.56, p < 0.008]

Edema: 0.06(0.25)/ 0.05(0.21)/ 0.21 (0.41) [χ² = 6.53, p < 0.04]

Ecchymosis: 0.02(0.14)/0.00 (0.00)/ 0.00 (0.00) [χ² = 1.66, p = 0.44]

Discharge: 0.00(0.00)/ 0.20(0.59)/ 0.21(0.54) [χ² = 7.22, p < 0.03]

Approximation: 0.00 (0.00)/ 0.16(0.37)/ 0.03(0.17) [χ² = 10.45, p < 0.005]

REEDA: 0.19(0.50)/ 0.75(1.08)/ 0.79(1.17) [χ² = 10.51, p < 0.005]

Assessment of the Hypertrophic Scar by the Vancouver scar scale on the 40th Day Postpartum

Treatment (n = 44)/ Placebo (n = 40)/ Control (n = 32)

Pigmentation: 1.91(1.05)/ 2.58(0.68)/ 2.62(0.71) [χ² = 15.72, p < 0.0001]

Height: 0.41(0.50)/ 0.73(0.55)/ 0.84(0.37) [χ² = 15.21, p < 0.0001]

Pliability: 0.98(0.63)/ 1.60(0.59)/ 1.84(0.63) [χ² = 30.03, p < 0.0001]

Vascularity: 0.02(0.15)/ 0.15(0.36) 0.16 (0.37) [χ² = 4.95, p = 0.08]

Vancouver: 3.32(1.54)/5.03(1.29)/ 5.50(0.92) [χ² = 43.23, p < 0.0001]

There were significant differences in wound healing and scar formation between treatment with placebo and control groups.

No side-effects were noted during the study

[51]

Lavandula stoechas

N = 120

Inclusion: Primiparous women underwent episiotomy

Exclusion: Allergy

RCT

Treatment: Essential Lavender oil

Control: Povidone-iodine

The two groups were treated twice daily for 10 consecutive days.

Outcomes: Healing of episiotomy

Comparison of episiotomy healing evaluation in treatment and control groups

Control/ Treatment

Pain:

No pain: 17(28.3%)/ 25(41.7%)

Moderate: 25(41.7%)/

27(45%)

Severe: 18(30%)/ 8(13.3%) [p = 0.063]

Edema:

No edema: 36(60%)/ 30(50%)

1–2(cm): 19(15%)/ 16(26.7%)

2>: 7(1.7%)/ 0(0%) [p = 0.320]

Leaved suture:

No: 27(45%)/ 24(40%)

1–3:18(30%)/ 16(26.7%)

4–6: 15(25%)/ 20(33.3%) [p = 0.62]

Redness:

No: 13(21.7%)/ 31(51.7%)

1–3: 8(13.3%)/ 6(10%)

4–7: 11(18.3%)/ (15 25%)

7>: 28(46.7%)/ 8(13.3%) [p = 0.001]

Dehiscence:

Yes: 26(43.3%)/ 19(31.7%)

No: 34(56.7%)/ 41(68.3%) [p = 0.129]

There was no significant difference between two groups in surgery site complications. However, redness in the lavender group was significantly less than controls (p < 0.001).

No side-effects were noted during the study

[52]

Melissa officinalis

N = 120

Inclusion: History of recurrent herpes labialis (at least 4 episodes per year), experiences in noticing the typical prodromes (itching, tingling, burning, tautness)

Exclusion: -

RCT, DB, PBO

Treatment:

1% Lo-701 - dried extract from lemon balm leaves (70:1)

PBO: Vehicle cream

The two groups were treated four times daily for 5 days

Outcomes: Healing of Herpes labialis

Daily score of herpetic symptoms on day 2 of therapy

Treatment: 4.03 ± 0.33

PBO: 4.94 ± 0.40 (p = 0.042)

Total score of symptoms in both treatment groups over 5 days

Treatment: 13.3 ± 0.96

PBO: 14.9 ± 1.24 (p = 0.16)

Significant difference was seen on day 2 of therapy but the difference on day 5 wasn’t statistically significant.

No side-effects were noted during the study

[53]

Myrtus communis (myrtle)

N = 20

Inclusion: Women with acne skin

Exclusion: Atopy, chronic skin disease, having another acne treatment, taken a medicine which may affect the hormonal system

Non-ran- domized

controlled

Treatment: Foam cleanser, toner, emulsion, and cream pack including myrtle essential oil

Control: Foam cleanser, toner, emulsion, and cream pack without myrtle

The two groups were treated twice daily for 6 weeks

Outcomes: Healing of acne skin

The comparison of erythema in groups

weekly

Treatment/ Control

Week 0: 392.5 ± 62.5/ 378.3 ± 47.9

Week 3: 379.5 ± 57.9/ 387.5 ± 68.3

Week 6: 365 ± 48.4/ 386 ± 68.2 (p = 0.083)

The comparison of sebum in groups weekly

Week 0: 7.6 ± 2.7/ 8.7 ± 5.4

Week 3: 6.7 ± 2.4/ 9.5 ± 5.4

Week 6: 5.2 ± 2.7/ 9.2 ± 4.3 (p = 0.033)

The comparison of desquamation in groups weekly

Week 0: 245.2 ± 95.2/ 232.5 ± 101.5

Week 3: 241.9 ± 97.8/ 252.4 ± 97.5

Week 6: 146.3 ± 75.4/ 268.1 ± 96.1 (p = 0.000)

The comparison of skin microorganism in groups weekly

Week 0: 8343.9 ± 3486.6/ 7883.3 ± 2192.8

Week 3: 6436.2 ± 2710.4/ 7555.7 ± 2252.9

Week 6: 5009.4 ± 1863.3/ 7548.1 ± 2426 (p = 0.009)

The comparison in weekly average of outstanding pores, large pores, and blackheads

Myrtle(weeks 0:3:6)/ Control (weeks 0, 3,6)

Outstanding pores: 1271.9 ± 677.3: 1080.8 ± 586.7: 907.5 ± 484.6/ 1127.7 ± 905.9: 1132.5(± 799.9): 1146.9(± 853.8)

(p = 0.000)

Large pores: 38.8 ± 46.4: 35.1 ± 44.5: 34.5 ± 43.4 / 30.9 ± 54: 31.2 ± 53.5: 31.9 ± 54 (p = 0.005)

Blackheads: 649.2 ± 468.2: 508.5 ± 342.4: 287.2 ± 229.8/ 569.5 ± 630.1: 569.5 ± 630.1: 619.1 ± 647.1 (p = 0.000)

The comparison in the group Korean acne grading scale (0,1,2,3,4): (Mean ± SD)

Treatment/ Control

Week 0: 1.8 ± 1.0/ 1.6 ± 0.8

Week 6: 0.9 ± 0.9/ 1.5 ± 0.7 (p = 0.006)

Statistically significant differences were seen between the groups for almost all results. But, the method of study is limited.

No side-effects were noted during the study

[54]

Olea europaea

N = 34

Inclusion: Patients with diabetic foot ulcer (grade1,2), age of 30–65 years, body mass index of 18 to 35

Exclusion: Foot gangrene, osteomyelit

RCT, DB

Treatment: Olive oil

Control: Routine care

The two groups were treated once daily for 4 weeks

Outcomes: Healing of diabetic foot ulcer

Comparison of ulcer parameters and total ulcer status scores at the baseline and during follow up visits in each group

Treatment/ Control

Degree:

Baseline: 69.0 ± 11.83/ 61.0 ± 17.54 (p = 0.154)

After 1 week: 79.33 ± 10.15/ 69.33 ± 17.30 (p = 0.064)

After 2 weeks: 87.33 ± 9.79/ 74.33 ± 17.20 (p = 0.017)

After 3 weeks: 92.33 ± 9.79/ 80.0 ± 16.47 (p = 0.019)

After 4 weeks: 96.66 ± 6.17/ 82.66 ± 15.56

(p = 0.03)

Color:

Baseline: 66.0 ± 9.10/ 65.33 ± 12.45 (p = 0.868)

After 1 week: 84.0 ± 9.85 / 69.0 ± 11.68 (p = 0.001)

After 2 weeks: 90.0 ± 10.1/ 78.66 ± 14.57 (p = 0.019)

After 3 weeks 94.66 ± 6.39/ 86.0 ± 11.83 (p = 0.019)

After 4 weeks 97.33 ± 4.57/ 86.66 ± 12.34 (p = 0.04)

Surrounding tissues

Baseline: 67.0 ± 15.32/ 69.0 ± 11.68 (p = 0.691)

After 1 week: 81.33 ± 12.31/ 73.33 ± 8.16 (p = 0.045)

After 2 weeks: 90.33 ± 9.72/ 79.33 ± 12.22 (p = 0.011)

After 3 weeks: 94.66 ± 6.11/ 83.00 ± 13.33 (p = 0.005)

After 4 weeks: 97.33 ± 4.57/ 83.0 ± 13.33 (p < 0.001)

Drainages

Baseline: 86.0 ± 14.54/ 84.0 ± 16.81 (p = 0.730)

After 1 week: 93.33 ± 9.75/ 87.33 ± 15.33 (p = 0.212)

After 2 weeks: 97.33 ± 7.03/ 92.66 ± 13.34 (p = 0.241)

After 3 weeks: 98.86 ± 5.16/ 94.00 ± 10.55 (p = 0.135)

After 4 weeks 100 ± 00.00/ 96.00 ± 8.28 (p = 0.072)

Total ulcer status

Baseline: 288.00 ± 40.52/ 277.33 ± 35.55 (p = 0.450)

After 1 week: 342.00 ± 33.63/301.67 ± 35.89 (p = 0.004)

After 2 weeks: 365.00 ± 29.82/ 325.00 ± 43.91 (p = 0.007)

After 3 weeks: 373.67 ± 37.48 / 43.00 ± 26.20 (p = 0.056)

After 4 weeks:391.33 ± 15.05/ 348.00 ± 43.08 (p = 0.001)

At the end of the study:

Complete healing: 73.33%/ 13.3% (p = 0.003)

Partial healing: 26.7%/ 73.3%

Lack of healing: 0%/ 13.3%

Statistically significant differences were seen between the groups for the rate of complete ulcer healing at the end of study. Only, in terms of the results of ulcer drainages were not seen differences between the groups.

No side-effects were noted during the study

[55]

Olea europaea, Helianthus annuus (Sunflower)

N = 19

Inclusion: Volunteers with and without a history of atopic dermatitis

Exclusion: Volunteers who were pregnant, breast- feeding, or using prescription immunomodulatory medication in the last 6 months

RCT, SB, Forearm- controlled, cohort study

Group 1: Olive oil (olive oil to the designated one forearm and opposite forearm acted as an untreated control)

Group 2: Sunflower seed oil and olive oil (olive oil to one forearm and Sunflower seed oil to the other forearm)

The two groups were treated twice daily for 5 weeks

Outcomes: Effect of Olive and Sunflower Seed Oil on the Adult Skin Barrier

Cohort 1(7 volunteers with a self- reported previous history of atopic dermatitis (no symptoms for 6 months))

Cohort 2 (12 volunteers, 6 with no history of skin disease and 6 with a self-reported previous history of atopic dermatitis (no symptoms for 6 months)

Biophysical properties of test sites before and after 4 weeks of treatment

Sunflower seed oil (grouped/healthy/ atopic dermatitis): Olive oil (grouped/healthy/atopic dermatitis)

Hydration (capacitance):

Difference(%): Sunflower: 115 ± 5.8 (p = 0.04) / 112 ± 9.7 (p = 0.39)/ 118 ± 7.1 (p = 0.045): Olive: 110 ± 4.7(p = 0.07)/112 ± 6.1(p = 0.15)/ 109 ± 7.8(p = 0.33)

Skin surface-pH

Difference(%): Sunflower: 0.01 ± 0.09(p = 0.89)/ 0.26 ± 0.08(p = 0.02)/ -0.23 ± 0.09(p = 0.06)/ Olive:-0.01 ± 0.09 (p = 0.88)/ 0.06 ± 0.13(p = 0.66)/− 0.09 ± 0.12(p = 0.51)

Erythema

Difference(%): Sunflower: 100 ± 6.2(p = 0.76)/ 98 ± 10.7(p = 0.67)/103 ± 7.3(p = 0.70)/ Olive: 114 ± 8.1(p = 0.08)/116 ± 10.5(p = 0.17)/ 112 ± 13.3(p = 0.38)

In contrast to sunflower seed oil, topical treatment with olive oil can damage the skin barrier for patients with atopic dermatitis. Sunflower seed oil, when used in the same way, preserved stratum corneum integrity, did not cause erythema, and improved skin hydration by 12% to 18% in the same volunteers.

Olive oil applied twice daily for 4 weeks (less than a tablespoon- ful) caused a significant reduction in stratum corneum integrity and thickness, failed to impart a significant effect on stratum corneum hydration, and induced mild erythema in volunteers with and without a history of atopic dermatitis.

[56]

Pistacia terebinthus

N = 15

Inclusion: Metastatic colorectal patients who developed skin toxicity while receiving first-line cetuximab in combination with chemotherapy

Exclusion:-

Non-ran- domized

Treatment:P. terebinthus soap

The group was treated twice daily for 1 week

Outcomes: Healing of skin toxicity

The features of patients, skin toxicity and response to soap treatment after the 1st week

Skin toxicity grades (before-after)

Numbers (15 persons):

1: Grade 3 to Grade 1

2: Grade 3 to Grade 1

3: Grade 2 to complete response (CR)

4: Grade 2 to CR

5: Grade 3 to Grade 1

6: Grade 3 to CR

7: Grade 2 to CR

8: Grade 3 to Grade 1

9:Grade 2 to CR

10: Grade 3 to CR

11: Grade 3 to Grade 1

12: Grade 3 to CR

13: Grade 3 to Grade 1

14: Grade 2 to CR

15: Grade 2 to CR

Complete response rates in patients with Grade 2 and Grade 3 skin toxicities were 100 and 33%, respectively. In the remaining patients with Grade 3 toxicity the skin toxicity regressed to Grade 1. Significant difference was seen for patients with Grade 2 skin toxicities.

No side-effects were noted during the study

[57]

Rosmarinus officinalis, Calendula officinalis

N = 20

Inclusion: Volunteers with healthy skin

Exclusion: Severe internal diseases, pregnancy, lactation, and uncertain contraception, dermatological diseases, immunosupp- ressive therapy

RCT, PBO, SB

Treatment groups: 1-Rosemary extract dyed 5%

2-Rosemary extract undyed 5%

3-Marigold extract dyed 5%

4-Marigold extract undyed 5%

5-Faradiol myristic acid ester 5%

6-Faradiol palmitic acid ester 5%

7-Faradiol ester -enriched fraction 5%

8-Hydrocor-tisone 0.25%

9-Base cream DAC

((Deutscher Arzneimittel- Codex)

- Ten minutes after application of the irritant, 9 test areas received treatment (parallel treatment).

Outcomes: Protective effects in healthy volunteers with experimen- tally induced Sodium- Lauryl-Sulfate Irritant contact dermatitis

Values of the visual score at days 1, 2, 3 and 5

Rosemary-undyed: 0/0.25/0.56/0.69 *** Cortisone: 0/0.44/0.69/0.69 *** Rosemary-dyed: 0/0.38/0.7/ 0.81 *** Marigold-dyed: 0/0.38/0.75/0.81 *** Marigold-undyed: 0/0.38/0.75/0.88 ** FDE-enriched: 0/0.44/0.56/0.88 ** FD palmitic acid: 0/0.5/0.75/0.94 ** FD myristic acid: 0/ 0.5/0.81/1.31 * DAC (vehicle): 0/0.56/0.69/1.06 ** Control (untreated): 0/0.88/1.44/1.75

Values of the Chromametry at days 2, 3 and 5

Marigold-undyed: 3.07/5.9971.19 ** FDE-enriched: 4.07/6.73/1.23 *** Cortisone: 3.79/ 6.17/1.73 *** Rosemary-dyed: 4.40/7.63/2.01 *** Marigold-dyed: 4.14/5.90/2.11 *** FD palmitic acid: 4.30/6.34/2.17 ** FD myristic acid: 3.88/6.61/2.31 ** Rosemary-undyed: 4.61/6.22/2.43 ***

DAC (vehicle): 3.44/6.34/2.58 *** Control (untreated): 5.07/7.30/3.37

Values of the Tewametry at days 2, 3 and 5

Rosemary-dyed: 7.48/11.68/17.13 *** Rosemary-undyed: 6.05/10.76/17.54 ** Marigold-dyed: 7.29/12.53/18.55 ** Cortisone: 7.33/12.44/19.42 * FDE-enriched: 6.40/11.53/19.58 ** FD palmitic acid: 6.94/11.99/21.18 * Marigold-undyed: 7.79/14.49/22.02 * FD myristic acid: 7.68/14.72/22.60 * DAC (vehicle): 6.33/14.11/20.60 * Control (untreated): 10.86/20.89/31.58

(* p < 0.05; ** p < 0.01; *** p < 0.001

Statistically significant difference was seen between the scores treatment and placebo groups for these results)

No side-effects were noted during the study

[58]

Vitis vinifera, Urtica dioica, Glycyrrhiza glabra, Alpinia officinarum, Thymus vulgaris

N = 49

Inclusion: Patients with anterior epistaxis

Exclusion: Pregnant, epistaxis after the nasal operation, systemic disease, posterior epistaxis

RCT, Nonblinded

Treatment: Ankaferd Blood stopper®[V.vinifera(0.08 mg/ml), U.dioica(0.06 mg/ml), G.glabra(0.07 mg/ml), A.officinarum(0. 07 mg/ml), T.vulgaris(0.05 mg/ml)]

Control: Phenyl- ephrine

Ankaferd blood stopper and Phenyl- ephrine tampons were applied when bleeding times.

Outcomes: Hemostatic efficacy

Success rate of ankaferd blood stopper and phenylephrine applications (Number of applications and success rates):

1: Treatment: 15(62.5%), Control:7(28%)

2: Treatment: 4(16.7%), Control: 9(36.0%)

No: Treatment: 5(20.8), Control: 9(36.0) (p < 0.05)

Success rate of ankaferd blood stopper and phenylephrine compared against bleeding intensity

(Bleeding intensity(1,2,3): group (application numbers) and success rates):

1: Treatment (1): 5(100%), Treatment (2): 0(0%), Treatment (unsu): 0(0%), Control(1): 6(85.7%), Control(2): 1(14.3%), Control (unsu): 0(0%)

2: Treatment(1): 5(100%), Treatment(2): 0(0%), Treatment (unsu): 0(0%), Control(1): 1(12.5%), Control(2): 6(75%), Control (unsu): 1(12.5%)

3: Treatment(1):5(35.7%), Treatment(2): 4(28.6%), Treatment (No): 5(35.7%), Control(1): (0%), Control(2): 2(20%), Control (unsu): 8(80%)

Treatment (unsu) and Control (unsu) values indicated unsuccessful rates.

Ankaferd blood stopper was seen more effective than phenylephrine at control of

anterior epistaxis (79.2 vs. 64%, p < 0.05).

No side-effects were noted during the study

[59]

Vitis vinifera, Urtica dioica, Glycyrrhiza glabra, Alpinia officinarum, Thymus vulgaris

N = 47

Inclusion: Pediatric patients undergoing tonsillectomy

Exclusion: Patients with bleeding disorders

Nonrando- mized, Nonblinded

Treatment: Ankaferd Blood stopper®

Control: Knot-tie technique

Outcomes: Blood loss, surgical time and complica- tions

Assessment of hemostasis time, blood loss and number of knot-tie

Right tonsil (Treatment)/Left tonsil (Knot-Tie):

Operation time (min): 3.19 0.74 / 7.29 2.33

Blood loss (ml): 1.57 2.26/ 14.04 7.23

Knot tie number: 0.006 0.32/ 1.97 1.22 (p = 0.001)

Statistically significant difference was seen for all results.

No side-effects were noted during the study

No complica- tions were seen after the study

[60]

Vitis vinifera, Urtica dioica, Glycyrrhiza glabra, Alpinia officinarum, Thymus vulgaris

N = 630

Inclusion: Patients undergoing transradial catheterization

Exclusion: Sheath diameter different form 6F, age < 18 years, abnormal Barbeau’s test before puncture.

RCT, PBO

Groups:

1-Ankaferd Blood stopper®

2-Conven- tional Sterile Gauze

3- TR band

Primary: Hemostatic efficacy

Secondary: Radial artery occlusion

Treatment/ Conventional sterile gauze/ TR band

Radial artery occlusion at the end of hemostasis: 0(0)/ 1(0.49)/ 1(048) (p = 0.36)

Radial artery occlusion at 24 h follow-up 0(0)/ 1(0.49)/ 1(0.48) (p = 0.63)

Radial artery occlusion at 30-day follow-up: 0(0)/ 0(0)/ 0(0) (p = 1.00)

Hematoma: 4(1.98)/ 3(1.47)/ 2(0.97) (p = 0.70)

Bleeding after device removal: 19(9.40) / 55(26.96)/ 56(27.31) (p < 0.001)

Statistically significant difference was found for the bleeding results.

No side-effects were noted during the study

[61]