Incorporating Natural Products, Pharmaceutical Drugs, Self-Care and Digital/Mobile Health Technologies into Molecular-Behavioral Combination Therapies for Chronic Diseases

Abstract

Merging pharmaceutical and digital (mobile health, mHealth) ingredients to create new therapies for chronic diseases offers unique opportunities for natural products such as omega-3 polyunsaturated fatty acids (n-3 PUFA), curcumin, resveratrol, theanine, or α-lipoic acid. These compounds, when combined with pharmaceutical drugs, show improved efficacy and safety in preclinical and clinical studies of epilepsy, neuropathic pain, osteoarthritis, depression, schizophrenia, diabetes and cancer. Their additional clinical benefits include reducing levels of TNFα and other inflammatory cytokines. We describe how pleiotropic natural products can be developed as bioactive incentives within the network pharmacology together with pharmaceutical drugs and self-care interventions. Since approximately 50% of chronically-ill patients do not take pharmaceutical drugs as prescribed, psychobehavioral incentives may appeal to patients at risk for medication non-adherence. For epilepsy, the incentive-based network therapy comprises anticonvulsant drugs, antiseizure natural products (n-3 PUFA, curcumin or/and resveratrol) coupled with disease-specific behavioral interventions delivered by mobile medical apps. The add-on combination of antiseizure natural products and mHealth supports patient empowerment and intrinsic motivation by having a choice in self-care behaviors. The incentivized therapies offer opportunities: (1) to improve clinical efficacy and safety of existing drugs, (2) to catalyze patient-centered, disease self-management and behavior-changing habits, also improving health-related quality-of-life after reaching remission, and (3) merging copyrighted mHealth software with natural products, thus establishing an intellectual property protection of medical treatments comprising the natural products existing in public domain and currently promoted as dietary supplements. Taken together, clinical research on synergies between existing drugs and pleiotropic natural products, and their integration with self-care, music and mHealth, expands precision/personalized medicine strategies for chronic diseases via pharmacological-behavioral combination therapies.

Fig. (1)

Structures of selected pleiotropic natural products (A), and their multiple functions within the network pharmacology (B). Pleiotropic natural products exert pharmacological properties via specific molecular targets and signaling pathways, while also delivering anti-inflammatory activities. Additional benefits of pleiotropic natural products may include antidepressant, cardiovascular, metabolic, neuroprotective, cognitive, antioxidant, or anticancer activities [11-15, 41].

Fig. (2)

Medication adherence rates for selected chronic disorders and clinical consequences of non-adherence. Medication adherence values were obtained from medication-possession ratio (MPR) reported in retrospective studies [114-121]. For CVD, a meta-analysis value was used. Adherence data vary significantly in values depending on a population, type of study (prospective or retrospective) and methods used to measure adherence.

Fig. (3)

A psychobehavioral basis of integrating pleiotropic natural product into the network pharmacology in which the compound becomes both an incentive and an active ingredient of the combination therapy. (A) - External incentives are tested to support medication adherence [134]. (B) – A new concept of combining a pharmaceutical drug with a specific natural product which becomes pharmacologically-active incentive. (C) Having a choice as a psychobehavioral incentive targeting an intrinsic motivation of a patient. Shared-decision making and daily self-administration of natural product support self-care.

Fig. (4)

Molecular-behavioral combination therapy for epilepsy patients. (A) Three components of the molecular-behavioral combination therapy are antiseizure pharmaceutical drug, n-3 PUFA as pharmacologically-active incentives, and mobile app delivering antiseizure music and epilepsy self-management content [3]. Given high prevalence of depression as comorbidity for chronic disorders, the add-on therapy (in shaded area) can be specifically prescribed for patients with refractory epilepsy and experiencing symptoms of depression. Mobile apps and software for treating depression and anxiety show promise in clinical trials [211-213]. In addition to n-3 PUFA, curcumin also can be developed as psychobehavioral incentives due to its antiseizure and antidepressant activities. (B) An example of a parallel study design to test the molecular-behavioral combination therapy in form of a drug-device combination product. Patients with refractory epilepsy are usually given two or more antiseizure drugs (Rx group). To establish efficacy of all possible combinations, such four-arm study can last 6-12 months, and can further include crossover, as was previously used to establish efficacy of n-3 PUFA in patients with refractory epilepsy [60], or/and a delayed start/prerandomization to reduce placebo responses [214]. Determining pharmacokinetic interactions between natural products and antiseizure drugs are important to ensure the safety of the drug-drug combination study (2^nd and 4^th arm), even though natural products may have prescription medicine status (e.g. n-3 PUFA as Lovaza^® or Vascepa^®).

Fig. (5)

Roles of self-care and the reward system in the incentivized therapies. Due to the long duration of chronic medical conditions, healthy habits and self-care can slow down progression of the chronic disease, improve the therapy outcomes and the health-related quality of life after reaching remission. (A) Self-care consists of disease self-management (patient behaviors related to management and prevention of disease symptoms), self-efficacy and empowerment (perceived abilities to cope with, control and manage disease symptoms). Digital technologies become effective means to deliver empowerment and disease self-management content [148, 150]. (B) Patients activate the habit-forming mechanism by a self-administration of an incentive. The habit-forming loop scheme is adapted from “The Power of Habit” by Charles Duhigg. (C) Integration of incentive-based nonpharmacological interventions with pharmacotherapies can lead to decreasing the dose of pharmaceutical drugs, an opportunity instantly applicable in the treatment of chronic, neuropathic pain with opioids, or arthritis with NSAIDs and other anti-inflammatory drugs. Randomized clinical trials will determine if this strategy also applies to epilepsy patients or those with depression to decrease dosing or number of medications.