Ginkgo Extract Is Safe in Patients with Hepatocellular Carcinoma and Does Not Affect Tumor Response, but It May Increase Survival

Hepatocellular carcinoma (HCC) is a type of liver cancer and is the third greatest cause of cancer-related death worldwide. When diagnosed in the advanced stage, it is associated with a poor prognosis and death after a median of 6 months if untreated. A common therapy is a sorafenib, which is an oral multikinase inhibitor that increases median survival times by 2-3 months. HCC involves many signaling pathways, so researchers are looking at combining sorafenib with other therapies to increase the benefits. Many in vitro studies have shown that ginkgo (Ginkgo biloba, Ginkgoaceae) leaf extract (GBE) has activities against a variety of cancer cells, and it is reported to inhibit the development of HCC in a rat model. Hence, the purpose of this prospective, open-label, non-randomized study was to evaluate the efficacy and safety of a combination of GBE and sorafenib in treating patients with advanced HCC.

Patients (n = 27 in Phase 1 and n = 32 in Phase 2, aged ≥ 20 years) diagnosed with HCC by histological examination or typical diagnostic images participated in this study conducted at Tianjin First Center Hospital; Tianjin, China. Study dates were not given. Included patients had no indication for surgical resection or any other local therapy (e.g., ablation, chemoembolization, radiation therapy); had had no systemic chemotherapy; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) of ≥ 1 untreated target lesion and ECOG (Eastern Cooperative Oncology Group) performance status 0-1; had neutrophil count ≥ 1500/μL, hemoglobin ≥ 9.0 g/dL, platelets ≥ 50,000/μL, total bilirubin < 3.0 mg/dL, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 5x the upper limit of normal (ULN), albumin ≥ 2.8 g/dL, serum creatinine ≤ ULN, prothrombin time ≥ 40%, and Child-Pugh score A; were able to take food and drugs orally; and had life expectancy of ≥ 12 weeks. Patients were excluded if they had received previous therapy for HCC, an albumin preparation or blood transfusion, or any major surgery ≤ 30 days before study entry; had any surgery ≤ 15 days before study entry; had portal vein tumor thrombus in the primary trunk; had uncontrollable hypertension; had clinically significant pleural effusion, ascites, or pericardial fluid; had symptomatic hepatic encephalopathy, bone metastasis, brain lesions, or any central nervous system tumor; had active infection other than hepatitis B virus and hepatitis C virus (HCV) infection; had serious gastrointestinal bleeding ≤ 30 days before study entry; had gastroesophageal variances requiring treatment; were pregnant, lactating, or did not agree to use contraception during study treatment; or had a second primary cancer, except for in situ carcinoma or a cancer treated > 5 years ago without recurrence.

The first phase was to determine the maximum tolerated dose of GBE. A dosing scheme common to cancer trials was employed. Dosing was increased until a dose-limiting toxicity (DLT) occurred. DLTs included non-hematologic grade 3 or grade 4 toxicities that required treatment interruption for ≥ 7 days or that took ≥ 7 days to resolve to ≤ grade 1 despite treatment (excluding a list of common chemotherapy side effects, such as alopecia, hypertension, hypercholesterolemia, hand-foot skin reaction, and vomiting); hematologic toxicities of grade 4 or of grade 3 with specified complications or needing dose interruptions for > 7 days; increase in bilirubin or creatinine to ≥ 2x ULN; and hepatitis B reactivation or HCV flare. All patients received 400 mg sorafenib 2x/day. The first dose of GBE (obtained from Xi’an Honson Biotechnology Co.; Xi’an, China) was 60 mg/day (Cohort 1, n = 6). The second dose was 120 mg/day (Cohort 2, n = 8). The third dose was 240 mg/day (Cohort 3, n = 10). The fourth dose was 360 mg/day (Cohort 4, n = 3). The enrollment schedule was planned to minimize exposure of more patients than necessary to a dose that proved to be toxic. Patients remained on treatment until disease progression or toxicity. In the second phase, which enrolled 32 patients, the efficacy, and safety of the optimal GBE dose were evaluated. All patients were followed for 1 year for survival. Physical examination, vital signs, height and weight, ECOG performance status, and laboratory parameters were assessed. Best overall response rate (efficacy) was evaluated by RECIST with tumors assessed by standard computed tomography/magnetic resonance imaging of the abdomen at baseline and at 8-week intervals until the end of treatment. Blood was collected for pharmacokinetic assessment.

In Phase 1, no patient in Cohort 1 or 2 had a DLT. In Cohort 3, 1 patient had a DLT (grade 4 AST/ALT elevation). In Cohort 4, 2 of 3 patients had a DLT (grade 3 hand-foot skin reaction [Note: The paper elsewhere suggested that such reactions were not enumerated among DLTs.] and grade 3 gastrointestinal bleeding). Due to the high rate of DLTs in Cohort 4, it was decided that the dose used in Cohort 3 (240 mg/day GBE plus 400 mg 2x/day sorafenib) would be the maximum tolerated dose and the dose used in Phase 2.

In Phase 2, 2 patients (6%) stopped treatment because of adverse effects (AEs). Treatment-related AEs included hyperbilirubinemia (94% of patients), AST elevation (94%), thrombocytopenia (84%), anemia (72%), ALT elevation (66%), hand-foot skin reaction (59%), and fatigue (53%). The most common grade 3/4 AEs were AST elevation (28%), thrombocytopenia (19%), neutropenia (19%), hyperbilirubinemia (13%), and ALT elevation (13%). This toxicity profile was comparable to the expected toxicity of sorafenib monotherapy, except that the frequency of elevated liver enzymes was higher than that expected from either sorafenib or GBE monotherapy.

Regarding efficacy, 3 patients (9.4%) had a partial response, 21 patients (65.6%) had stable disease, and 8 patients (25%) had progressive disease. Mean overall survival was 11.6 months. Time to disease progression was a median of 2.5 months, which is similar to sorafenib monotherapy, and the tumor response rate and disease control rate did not significantly differ from those reported in a previous study of sorafenib monotherapy. However, median survival time was 11.6 months, which represented a “slightly” improved overall survival compared with the prior cohort treated with sorafenib alone. In terms of pharmacokinetics, the increase in the maximum concentration of unspecified compounds with increasing dose was usually proportional to the dose, whereas the increase in minimum concentration was more than dose-proportional.

The authors conclude that since treatment-related toxicity was similar to that observed with sorafenib monotherapy, the combination was safe and tolerable. Since the addition of GBE to sorafenib did not appear to improve tumor response, yet might have modestly improved median survival by some other mechanism, the authors suggest that further research is warranted. Limitations of the study include the small sample size and those only Chinese patients were included. The results could differ in other populations. The authors state no conflict of interest.

Resource:

Cai Z, Wang C, Liu P, Shen P, Han Y, Liu N. Ginkgo biloba extract in combination with sorafenib is clinically safe and tolerable in advanced hepatocellular carcinoma patients. Phytomedicine. November 15, 2016;23(12):1295-1300.

Food as Medicine: Watermelon (Citrullus lanatus, Cucurbitaceae)

History and Traditional Use


Range and Habitat

The watermelon is the largest edible fruit grown in the United States: an annual trailing plant with fruits that can grow from 5-50 pounds and vines that can reach up to 20’ in length. Each fruit forms from a yellow flower, and the spherical or ovoid fruit is typically smooth and green or green with lighter banded stripes. The watermelon is native to the Kalahari Desert in Africa, and it thrives in well-draining, sandy soil. Currently, watermelons are cultivated all over the world, with Asia producing 60% of watermelons globally. The United States ranks fifth in global watermelon production. Forty-four states grow watermelons, including Texas, Florida, Georgia, and California, which collectively produce 2/3 of all the watermelons domestically.

Phytochemicals and Constituents

Watermelon contains an array of important vitamins and minerals including vitamin A, vitamin C, vitamin B-6, potassium, and beta-carotene. Watermelon also contains the important bioactive compounds citrulline and lycopene. Vitamin C acts as an antioxidant and anti-cancer agent. Watermelon’s vitamin C content may be linked to reducing blood pressure, as does its smaller amounts of vitamins B6 and E. The human body converts beta-carotene into vitamin A, which promotes healthy eyes, a strong immune system, and healthy skin. Vine fruits like watermelon are a good source of potassium, a crucial electrolyte for nerve and muscle function. Potassium is an essential nutrient as the body ages, as it decreases high blood pressure and reduces the risk of kidney stones, stroke, and bone density loss.

Citrulline is a precursor to the amino acid arginine and is involved in the process of removing nitrogen from the blood and eliminating it through urine. Arginine is a precursor for the synthesis of nitric oxide in the body, which is a vasodilator (blood vessel-widening agent). Conditions that benefit from vasodilation, such as cardiovascular diseases, erectile dysfunction, and headaches may benefit from increased arginine intake. Arginine also helps the body make protein, which boosts muscle growth, enhances wound healing, combats fat accumulation, and stimulates the immune system.

Though the tomato (Solanum lycopersicum) is more well-known as a source for lycopene (and in fact, its name is derived from lycopersicum), lycopene is a carotenoid found in many red foods, including watermelon, papaya (Carica papaya), pink grapefruit (Citrus x paradisi), and red carrots (Daucus carota subsp. sativus). A powerful antioxidant, lycopene may help prevent heart disease and has shown a potent ability to protect the body from “free radicals,” which may play a role in the development of heart disease, Alzheimer’s disease, and many cancers. Lycopene may also boost sperm counts and lower the risk of prostate cancer.

Historical and Commercial Uses

Though native to the African Kalahari desert, where the watermelon gourd was often used as a canteen, the cultivation of watermelon spread quickly, and other cultures adopted it as a beneficial, healing food. Ancient Egyptians used watermelon to treat reproductive problems such as erectile dysfunction and prostate inflammation. The peoples of Russia and Central Asia used watermelon as a diuretic and to cleanse the blood. In Traditional Chinese Medicine, watermelon is considered cooling and moistening, producing a diuretic effect, and commonly is used to treat thirst, edema, and inflammation of the kidney and urinary tracts.18 Because watermelon is 92% water, many traditional uses of watermelon overlap with current uses, including hydration, cleansing, and eliminating impurities. Since watermelon is digested relatively quickly, the folk traditions of the Papua New Guinea aborigines known as Onabasulu advised against eating watermelon and other juicy fruits after a heavy meal or if suffering from a stomachache.

African cuisine treats the watermelon as a vegetable and uses the entire fruit: seeds, rinds, and flesh. The seeds are eaten as snacks added to dishes or ground into flour for use in baked goods. The rind can be stir-fried, stewed, candied, pickled, or grilled. The flesh is eaten or juiced, but it can also be fermented into alcohol; in the southern part of Russia, the juice is combined with hops to make beer.

Modern Research

The traditional uses for watermelon as a medicine are beginning to gain scientific confirmation, particularly in regards to its applications against erectile dysfunction, dehydration, kidney disease, and anti-aging concerns. Watermelon’s antioxidant and nutrient content defend against many different conditions.

Current research shows that citrulline in watermelons has beneficial effects on the heart, dilating the blood vessels and improving blood flow. In one clinical study, obese participants with pre-high blood pressure or stage-one high blood pressure significantly reduced their ankle and brachial systolic blood pressure, diastolic blood pressure, mean arterial pressure, and carotid wave reflection with ingestion of citrulline from watermelons. A review of consumption of citrulline from watermelon demonstrated improvements in glycemic control and circulatory problems in diabetics, a reduction in cardiovascular risk factors, and increased levels of arginine, an essential amino acid. Because arginine is involved in maintaining the health of the reproductive, pulmonary, renal, gastrointestinal, hepatic, and immune systems, citrulline is of increasing interest in the realm of scientific study. Studies show that citrulline is more bioavailable in the body than arginine, making it a better candidate for arginine deficiency diseases such as renal carcinoma, chronic inflammatory diseases, or blood cell diseases like sickle cell anemia and malaria. Citrulline research also has shown promising results of becoming a biomarker for bowel problems of the small intestine as well as kidney failure.13

Lycopene’s powerful antioxidant properties have been shown to reduce the risks of prostate, lung, gastric, and colorectal cancers. However, due to its antioxidant effect, it seems to interfere with chemo and radiation therapy. In addition to being an antioxidant, lycopene has been shown to be heart-protective and lowers LDL cholesterol. In one study, lycopene ingestion showed a reduction in the risk of stroke, especially ischemic strokes in men. Finally, lycopene has been linked to a reduction in cardiovascular risks.

Nutrient Profile


Macronutrient Profile
(Per 1 cup diced watermelon [approx. 152 g]):

46 calories
1 g protein
11.5 g carbohydrate
0.2 g fat

Secondary Metabolites (Per 1 cup diced watermelon [approx. 152 g]):

Excellent source of:

Vitamin C: 12.3 mg (20.5% DV)
Vitamin A: 865 IU (17.3% DV)

Very good source of:

Potassium: 170 mg (4.9% DV)

Also provides:

Magnesium: 15 mg (3.8% DV)
Vitamin B-6: 0.07 mg (3.5% DV)
Thiamin: 0.05 mg (3.3% DV)
Vitamin E: 0.08 mg (3% DV)
Manganese: 0.06 mg (3% DV)
Dietary Fiber: 0.6 g (2.4% DV)
Iron: 0.4 mg (2.2% DV)
Phosphorus: 17 mg (1.7% DV)
Folate: 5 mcg (1.3% DV)
Calcium: 11 mg (1.1% DV)

DV = Daily Value as established by the US Food and Drug Administration, based on a 2,000 calorie diet.


Recipe: Pickled Watermelon Rinds

Adapted from Bon Appétit


For an equally delicious condiment without the wait, use these ingredients to make watermelon rind chutney: increase sugar to 1 ½ cups, water to 1 cup, and finely mince the ginger. Bring all ingredients to a boil in a large pan, then simmer for 45-60 minutes until the rind is translucent and tender and the liquid reduces and thickens. Remove whole spices before serving.

Ingredients:

  • 4 lbs of watermelon
  • 1 serrano chili, thinly sliced, seeds removed if desired
  • 1-inch piece of fresh ginger, peeled and thinly sliced
  • 2-star anise pods
  • 1 tablespoon kosher salt
  • 1 teaspoon black peppercorns
  • 1 cup sugar
  • 1 cup apple cider vinegar

Directions:

  1. Using a vegetable peeler, remove the tough green outer rind from watermelon; discard.
  2. Slice watermelon into 1”-thick slices. Cut away all but 1/4” of flesh from each slice; reserve flesh for another use. Cut rind into 1” pieces for roughly 4 cups of the rind.
  3. Bring chili, ginger, star anise, salt, peppercorns, sugar, vinegar, and 1/2 cup of water to a boil in a large, non-reactive saucepan, stirring to dissolve sugar and salt.
  4. Add watermelon rind. Reduce heat and simmer until just tender, about 5 minutes. Remove from heat and let cool to room temperature, setting a small lid or plate directly on top of rind to keep submerged in brine, if needed.
  5. Transfer rind and liquid to an airtight container; cover and chill at least 12 hours.

Doctors Should Discuss Herbal Medication Use with Heart Disease Patients

Physicians should be well-versed in the herbal medications heart disease patients may take to be able to effectively discuss their clinical implications, potential benefits, and side effects – despite a lack of scientific evidence to support their use, according to a review paper published in the Journal of the American College of Cardiology.

Herbal medications do not require clinical studies before being marketed to consumers or formal approval from regulatory agencies, so their efficacy and safety are rarely proven. In the U.S., herbal medications can only be found unsafe by the Food and Drug Administration after they have caused harm. Still, they remain popular among heart disease patients for their potential cardiovascular benefits. A recent survey said 1 in every 5 people will take an herbal or dietary supplement in their lifetime.

Researchers in this review paper looked at 42 herbal medications that have a possible indication for treating one or more cardiovascular condition, including hypertension, heart failure, coronary artery disease, dyslipidemia, thromboembolic disorders or peripheral artery disease. They then selected 10 of the most commonly used in cardiovascular medicine to discuss possible indications, biological and clinical data, and safety concerns.

The researchers said that despite all the clinical evidence on these herbal medications, there is an overall lack of evidence available, and it is not always possible to clearly establish a cause-effect link between exposure to herbal medications and potential side effects.

They concluded that because of the popularity of these medications and the potential for drug interactions or other safety concerns, physicians should start a conversation around herbal medication use to effectively counsel their patients. Many patients don’t volunteer information on their herbal medication use to their doctor because they do not perceive them as drugs. Physicians are also unlikely to regularly gather correct information on their use. However, herbal medication use has been associated with poor adherence to conventional medications, which is a serious concern.

“Communicating with the patient is a crucial component of the process,” said Graziano Onder, MD, Ph.D., senior author of the review paper and an assistant professor in the department of geriatrics, neurosciences, and orthopedics of the Università Cattolica del Sacro Cuore in Rome. “The pros and cons of specifics herbal medications should be explained and their risk-benefit profile properly discussed.”

Researchers said physician education is an important consideration as well since the study of alternative medicine is not part of medical school curriculums in the U.S. Obtaining the necessary knowledge to provide better care for patients around the use of herbal medications is solely up to the physician.

“Physicians should improve their knowledge of herbal medications in order to adequately weigh the clinical implications related to their use,” Onder said.

Living with A-fib: Tips and Outlook

Atrial fibrillation, commonly known as A-fib, is an irregular heartbeat. It can lead to the heart not pumping enough oxygen-rich blood to the rest of the body.

With proper medical treatment, people with A-fib can lead a full, healthy life. There are also several changes that people can make to improve their quality of life and help reduce the severity of symptoms.

Lifestyle changes

Though living with A-fib can be challenging, there are several steps a person can take to deal with the condition besides receiving regular medical care. These include:

Older people exercising in the park
Beginning or increasing an exercise routine is a recommended lifestyle change for people with A-fib.
  • Quitting smoking can improve living with A-fib and reduce further heart and lung risks.
  • Increasing and continuing exercise is important for people with A-fib. As with any exercise routine, a person should consult their doctor to ensure it is safe for them.
  • Eating a heart-healthy diet can impact on overall health and fitness and people with A-fib should eat less trans fat and sugar while increasing their green leafy vegetables, lean proteins, and fiber intake.
  • Maintaining a healthy weight, through both diet and exercise, can help.
  • Reducing alcohol consumption as alcohol intake can have a negative impact on the heart. Some people with A-fib need to avoid alcohol altogether, so everyone with the condition should consult their doctor before drinking.
  • Managing stress as this can complicate A-fib. People with A-fib can take steps to reduce their stress levels through exercise, meditation, or other methods.

People with A-fib should also maintain follow-up care with their doctor to ensure proper treatment is continued.

What does A-fib do to the body

A-fib can have a number of potential impacts on the body ranging from mild to severe. Some of these include:

  • Blood clots: When the heart is not pumping hard enough, blood can pool and form a clot within it. If a clot escapes it can cause issues elsewhere in the body.
  • Heart problems: Over time, the irregular beating can cause the heart to weaken.
  • Shortness of breath: Irregular pumping of the blood to the lungs can result in fluid building up, which can then lead to shortness of breath and fatigue.

A-fib may also lead to a buildup of fluid in the legs, ankles, and feet. Other problems can include weight gain, light-headedness, and a general sense of being unwell. Additionally, people may experience irritability and tiredness during previously routine activities.

A-fib itself is generally not life-threatening but the condition can lead to severe complications, which include stroke and heart failure.

A stroke may occur after a blood clot has formed in the heart and moved towards the brain, blocking an artery. A doctor will often be most concerned about a person’s risk of a stroke when they are diagnosed with A-fib. Symptoms of stroke should not be ignored, including a headache and slurred speech.

Heart failure can be a long-term effect of unmanaged A-fib. The condition weakens the heart over time, making a person more likely to suffer from new or worsening heart failure. The threat of heart failure can be reduced greatly by medical supervision of A-fib.

Treatment

Electrical cardioversion for A-fib
Electrical cardioversion may be used to treat A-fib by shocking the heart to stop it so that it may restart with a regular beat.

Doctors treating A-fib typically look at treatments to reset the rhythm of the heart, control the rate it is beating, and reduce the risks of blood clots.

The way a doctor treats A-fib depends on a number of factors, including whether the person has other heart problems, other medications they are taking, their response to previous treatments, and the severity of their A-fib.

Cardioversion

Cardioversion is used to reset the heart rhythm. It can be electrical or carried out with drugs.

Electrical cardioversion involves shocking the heart to temporarily stop it with the aim that when restarted, it will resume with regular beats. Typically, this procedure is done under sedation.

Cardioversion can also be delivered through medication, called antiarrhythmics, which are delivered into the vein, or by mouth. Very often, the initial treatment is conducted in a hospital. However, a doctor may prescribe similar medications to be taken regularly to prevent further episodes.

A doctor will likely prescribe blood thinners to be taken for several weeks to prevent clots before cardioversion treatment. A test for blood clots may also be done before cardioversion.

Preventive medication

Several types of medication can control heart rhythm and heart rate.

After a cardioversion, a doctor may prescribe anti-arrhythmic medications to prevent further problems with heart rhythm including dofetilide, flecainide, propafenone, amiodarone, and sotalol.

To control heart rate, a doctor may prescribe medications that include digoxin, calcium channel blockers, and beta-blockers.

Catheter and surgical procedures

In cases where medication is not effective, additional procedures should be taken. These include:

  • Catheter ablation: Long, thin tubes are inserted into the groin and guided through blood vessels to the heart. Electrodes at the tips can destroy the areas causing A-fib, scarring the tissue so that the erratic electrical signals return to normal.
  • Surgical maze procedure: Using a scalpel, a doctor creates a pattern of scar tissue in the upper chambers of the heart. The scar tissue can’t carry electricity, so the scars interfere with stray electrical impulses that cause A-fib. The procedure involves open heart surgery.
  • Atrioventricular (AV) node ablation: The tissue pathway connecting the upper chambers and lower chambers of the heart (AV node) is destroyed with a catheter. In this procedure, a pacemaker is then implanted to control the responsibilities of the AV node. People who have this procedure may still need to take blood-thinning medications to prevent clots from forming.

Preventing blood clots

warfarin tablets
Warfarin may be prescribed to help prevent blood clots.

As blood clots are a major concern for people with A-fib, a doctor is likely to prescribe medication that helps prevent these. This is particularly true if a person has issues with heart disease.

The two types of medication typically prescribed are warfarin and newer anticoagulants. Warfarin medications need to be used with care under direct supervision of a doctor, as they can cause dangerous bleeding.

Newer anticoagulants do not require such frequent monitoring as warfarin.

Coping and outlook

A-fib is a commonly diagnosed condition. As a result, there are many treatment options and therapies that can greatly reduce the symptoms or correct A-fib.

Treating A-fib can allow a person to live a normal life. Left untreated, a person could experience further complications such as stroke or worsening heart disease.

Recognizing the signs, being proactive in making lifestyle changes, and treating A-fib are the best ways to help prevent complications.

A-fib and Exercise: Health Benefits and Risks

Atrial fibrillation is an irregular heartbeat caused by faulty electrical signals in the upper chambers of the heart. In people with atrial fibrillation, the heart beats irregularly and often too quickly.

Atrial fibrillation (A-fib) can result in the heart not pumping enough oxygen-rich blood to the rest of the body, which may cause symptoms like heart fluttering, weakness, and dizziness. It may eventually lead to serious complications including stroke and new or worsening heart failure.

Is it safe to exercise with A-fib?

[woman looking at heart monitor while exercising]
Wearing a heart monitor during exercise enables people with A-fib to check their heart rate easily and reduce the risk of symptoms.

A-fib may reduce a person’s ability to exercise. It is generally recommended that people with A-fib do some exercise. However, people with A-fib should consult with their doctor and take proper precautions before starting any exercise program.

In some cases, a heart specialist may not want a person to start or increase an exercise program before treatment for A-fib starts. In other cases, moderate exercise and increases in current routines may be encouraged.