The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. The first published report on grapefruit drug interactions was in 1991 in the Lancet entitled "Interactions of Citrus Juices with Felodipine and Nifedipine," and was the first reported food-drug interaction clinically. However, the effect only became well-publicized after being responsible for a number of bad interactions with medication.

Some fruit juices and fruits can interact with numerous drugs, in many cases causing adverse effects. The effect was first discovered by accident, when a test of drug interactions with alcohol used grapefruit juice to hide the taste of the ethanol.

It is still best-studied with grapefruit and grapefruit juice, but similar effects have more recently been seen with some (not all) other citrus fruits. One medical review advises patients to avoid all citrus juices until further research clarifies the risks. The interacting chemicals are found in many plants, and so many other foods may be affected; effects have been observed with apple juice, but their clinical significance is not yet known.

Normal amounts of food and drink, such as one whole grapefruit or a small glass () of grapefruit juice, can cause drug overdose toxicity. Fruit consumed three days before the medicine can still have an effect. The relative risks of different types of citrus fruit have not been systematically studied. Affected drugs typically have an auxiliary label saying “Do not take with grapefruit” on the container, and the interaction is elaborated on in the package insert. People are also advised to ask their physician or pharmacist about drug interactions.

The effects are caused by furanocoumarins (and, to a lesser extent, flavonoids). These chemicals inhibit key drug metabolizing enzymes, such as cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells. As a result, many drugs are affected. Inhibition of enzymes can have two different effects, depending on whether the drug is either

1. metabolized by the enzyme to an inactive metabolite, "or"

2. activated by the enzyme to an active metabolite.

If the active drug is metabolized by the inhibited enzyme, then the fruit will stop the drug being metabolized, leaving elevated concentrations of the medication in the body, which can cause adverse effects. Conversely, if the medication is a prodrug, it needs to be metabolised to be converted to the active drug. Compromising its metabolism lowers concentrations of the active drug, reducing its therapeutic effect, and risking therapeutic failure.

Low drug concentrations can also be caused when the fruit suppresses drug absorption from the intestine.

6-Pyruvoyltetrahydropterin synthase deficiency is an autosomal recessive disorder that causes malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency.

It belongs to the rare diseases. It is a recessive disorder that is accompanied by hyperphenylalaninemia. Commonly reported symptoms are initial truncal hypotonia, subsequent appendicular hypertonia, bradykinesia, cogwheel rigidity, generalized dystonia, and marked diurnal fluctuation. Other reported clinical features include difficulty in swallowing, oculogyric crises, somnolence, irritability, hyperthermia, and seizures. Chorea, athetosis, hypersalivation, rash with eczema, and sudden death have also been reported. Patients with mild phenotypes may deteriorate if given folate antagonists such as methotrexate, which can interfere with a salvage pathway through which dihydrobiopterin is converted into tetrahydrobiopterin via dihydrofolate reductase. Treatment options include substitution with neurotransmitter precursors (levodopa, 5-hydroxytryptophan), monoamine oxidase inhibitors, and tetrahydrobiopterin. Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).

ADT tachyphylaxis specifically occurs in depressed patients using SSRIs and MAOIs. Currently, SSRIs are the preferred treatment for depression among clinicians, as MAOIs require the patient to avoid certain foods and other medications due to the potential for interactions capable of inducing dangerous side effects. Provided is a list of medications known to be subject to Poop-out.

Following a declination or total extinction in response to a previously therapeutic dose of an antidepressant, the issue is clinically addressed as stemming from tolerance development. Several strategies are available, such as exploring drug options from a different drug class used to treat depression. The patient can also choose to switch to another SSRI (or MAOI, if applicable) while maintaining proportionate dose. If tolerance develops in a drug from the same class, the clinician may recommend a regular cycle consisting of all effective treatments within the SSRI or MAOI classes, in order to minimize transitional side effects while maximizing therapeutic efficacy.

Other options include increasing dose of the same medication, or supplementation with another antidepressant. Dual reuptake inhibitors, also known as tricyclic antidepressants have been shown to have lower rates of tachyphylaxis.

Drug-induced angioedema is a known complication of the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists (ARBs), and Angiotensin-Neprilysin Inhibitor LCZ969. The angioedema appears to be dose dependent as it may resolve with decreased dose.

Some common ACE Inhibitors are:

- Benazepril (Lotensin)

- Captopril (Capoten)

- Enalapril (Vasotec)

- Lisinopril (Prinivil, Zestril)

- Ramipril (Altace)

Some common ARBs are:

- Candesartan (Atacand)

- Losartan (Cozaar)

- Olmesartan (Benicar)

- Valsartan (Diovan)

Angioedema presents itself as an abrupt onset of non-pitting, non-itchy swelling that involves the mucosal layers. Some common locations of angioedema are the face, particularly the lips and around the eyes, hands and feet, and genitalia. A rare, yet serious complication is one inside the abdomen, the symptom usually being severe stomach upset, which is much less obvious than the other locations.

The chance of drug-induced angioedema is extremely uncommon, however, as studies show incidence of less than 1%. The reason this adverse effect may occur is due to the build-up of bradykinin, a vasodilator. This causes blood vessels to dilate and allow for fluid buildup in the mucosal surfaces.

The cause of PPE is unknown. Existing hypotheses are based on the fact that only the hands and feet are involved and posit the role of temperature differences, vascular anatomy, differences in the types of cells (rapidly dividing epidermal cells and eccrine glands).

In the case of PPE caused by PLD, the following mechanism has been demonstrated: sweat deposits and spreads the drug on the skin surface; then the drug penetrates into the stratum corneum like an external agent; palms and soles have high density of sweat glands, and their stratum corneum is approximately 10 times thicker than the rest of the body, and becomes an efficient long-term reservoir for the penetrating PLD, which was deposited on the skin before.

Acral erythema is a common adverse reaction to cytotoxic chemotherapy drugs, particularly cabozantinib, cytarabine, doxorubicin, and fluorouracil and its prodrug capecitabine.

Targeted cancer therapies, especially the tyrosine kinase inhibitors sorafenib and sunitinib, have also been associated with a high incidence of acral erythema. However, acral erythema due to tyrosine kinase inhibitors seems to differ somewhat from acral erythema due to classic chemotherapy drugs.

Apitoxins are under preliminary research for their potential biological effects, such as in cancer.

CML accounts for 8% of all leukaemias in the UK, and around 680 people were diagnosed with the disease in 2011.

Antidepressants, including SSRIs, can cross the placenta and have the potential to affect the fetus and newborns, presenting a dilemma whether pregnant women should take antidepressants at all, and if they do, whether tapering them near the end of pregnancy could have a protective effect for the newborn.

Postnatal adaptation syndrome (PNAS) (originally called “neonatal behavioral syndrome”, “poor neonatal adaptation syndrome”, or "neonatal withdrawal syndrome") was first noticed in 1973 in newborns of mothers taking antidepressants; symptoms in the infant include irritability, rapid breathing, hypothermia, and blood sugar problems. The symptoms usually develop from birth to days after delivery and usually resolve within days or weeks of delivery.

The mechanisms of antidepressant withdrawal syndrome have not yet been conclusively identified. The leading hypothesis is that after the antidepressant is discontinued, there is a temporary deficiency in the brain of one or more essential neurotransmitters that regulate mood, such as serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid, and since neurotransmitters are an interrelated system, dysregulation of one affects the others.

The main component is melittin amounting to 52% of venom peptides.

- Apamin increases cortisol production in the adrenal gland

- Adolapin, contributing 2–5% of the peptides

- Phospholipase A2 amounts to 10–12% of peptides. Phospholipase A2 activates arachidonic acid which is metabolized in the cyclooxygenase-cycle to form prostaglandins

- Hyaluronidase contributes 1–3% of peptides

- Histamine contributing 0.5–2% and is involved in the allergic response

- Dopamine and noradrenaline which contribute 1–2%

- Protease-inhibitors contribute 2%

- Tertiapin

M2 is a subtype of AML (Acute Myeloid Leukemia).

It is also known as "Acute Myeloblastic Leukemia with Maturation".

Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.

On the other hand, there is evidence that HIV-1 infection on its own contributes to the development of the lipodystrophic phenotype by interfering with some key genes of adipocyte differentiation and mitochondrial function on patients which have not received antiretroviral treatment.

The American Cancer Society estimates that in 2014, about 5,980 new cases of chronic myelogenous leukemia were diagnosed, and about 810 people died of the disease. This means that a little over 10% of all newly diagnosed leukemia cases will be chronic myelogenous leukemia. The average risk of a person getting this disease is 1 in 588. The disease is more common in men than women, and more common in whites than African-Americans. The average age at diagnosis is 64 years, and this disease is rarely seen in children.

Clostridial necrotizing enteritis (CNE), also called enteritis necroticans and pigbel, is an often fatal type of food poisoning caused by a β-toxin of "Clostridium perfringens", Type C. It occurs in some developing countries, but was also documented in Germany following World War II. The toxin is normally inactivated by certain proteolytic enzymes and by normal cooking, but when these protections are impeded, the disease emerges.

The exact mechanism of HIV-associated lipodystrophy is not fully elucidated. There is evidence indicating both that it can be caused by anti-retroviral medications and that it can be caused by HIV infection in the absence of anti-retroviral medication.

Patients with hematological disease related to the cited "FLT3" fusion genes present with either a myeloid or lymphoid neoplasm plus eosinophilia. Four of 6 patients with "ETV6-FLT3"-related disease, a patient with "GOLGB1-FLT3"-related disease, and a patient with "TRIP11-FLT3"-related disease presented with findings similar to T-cell lymphoma while a patient with "SPTBN1-FLT3"-related disease had findings of chronic myelogenous leukemia. Two patients with "ETV6-FLT3"-related disease experienced complete hematologic remissions when treated with a multi-kinase inhibitor, sunitinib, that has inhibitory activity against FLT3 protein. However, these remissions were short-lived. A third patient with "ETV6-FLT3"-related disease was treated with a similarly active kinase inhibitor, sorafenib. This patient achieved a complete hematological response and was then given a hematopoietic stem cell transplantation. The latter treatment regimen, FLT3 inhibitor followed by hematopoietic stem cell transplantation, may be the best approach currently available for treating "FLT3"-releated hematological disease.

Clonal hypereosinophilia, also termed Primary hypereosinophelia or clonal eosinophilia, is a grouping of hematological disorder characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell, in the bone marrow, blood, and/or other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

The clone of eosinophils bear a mutation in any one of several genes that code for proteins that regulate cell growth. The mutations cause these proteins to be continuously active and thereby to stimulate growth in an uncontrolled and continuous manner. The expanding population of eosinophils, initially formed in the bone marrow may spread to the blood and then enter into and injure various tissues and organs.

Clinically, clonal eosinophilia resembles various types of chronic or acute leukemias, lymphomas, or myeloproliferative hematological malignancies. However, many of the clonal hypereosinophilias are distinguished from these other hematological malignancies by the genetic mutations which underlie their development and, more importantly, by their susceptibility to specific treatment regiments. That is, many types of these disorders are remarkably susceptible to relatively non-toxic drugs.

As one route to reducing TAMs CSF1R inhibitors have been developed as a possible cancer therapy and many are in early clinical trials. CSF1R inhibitors in clinical trials include : Pexidartinib, PLX7486, ARRY-382, JNJ-40346527, BLZ945, Emactuzumab, AMG820, IMC-CS4. (MCS110 is a CSF1 inhibitor)

Another CSF1R inhibitor that targets/depletes TAMs is Cabiralizumab (cabira; FPA-008) which is a monoclonal antibody and is in early clinical trials for metastatic pancreatic cancer.

Acute myeloid leukemia (AML) is a type of cancer affecting blood cells that eventually develop into non-lymphocyte white blood cells. The disease originates from the bone marrow, the soft inner portion of select bones where blood stem cells develop into either lymphocyte or in this particular condition, myeloid cells. This acute disease prevents bone marrow cells from properly maturing, thus causing an accumulation of immature myeloblast cells in the bone marrow.

Acute myeloid leukemia is more lethal than chronic myeloid leukemia, a disease that affects the same myeloid cells, but at a different pace. Many of the immature blast cells in acute myeloid leukemia have a higher loss of function and thus, a higher inability to carry out normal functions than those more developed immature myeloblast cells in chronic myeloid leukemia (O’Donnell et al. 2012). Acute in acute myeloid leukemia means that the amounts of blast cells are increasing at a very high rate. Myeloid refers to the type of white blood cells that are affected by the condition.

Acute myeloid leukemia is the most common acute leukemia that is affecting the adult population. The 5-year survival rate for the cancer stands at around 26% (ACS, 2016).

M2 acute myeloblastic leukemia with maturation refers to the subtype of acute myeloid leukemia characterized by the maturation stages of the myeloid cell development and the location of the AML1 gene. One of the hallmarks of M2 subtype acute myeloid leukemia is the formation of a fusion protein, AML1-ETO or RUNX1-RUNX1T1, due to a translocation of chromosome 8 to chromosome 21 or t(8;21) (Miyoshi et al., 1991, Andrieu et al., 1996). This cytogenetic abnormality has been found in 90% of M2 acute myeloblastic leukemia; while the other 10% constitutes a mix of M1 and M4 acute myeloid leukemia (GFHC, 1990).

Another translocation between chromosome 6p23 and chromosome 9q34 is also associated with the M2 subtype. The t(6;9) causes the formation of a fusion oncogene made of DEK (6p23) and CAN/NUP214 (9q34). This rare translocation has a poor prognosis compared to the t(8;21) because 70% of t(6;9) acute myeloid leukemia patients have the FLT3-ITD mutation (Schwartz et al., 1983, Kottaridis, 2001). The FLT-ITD mutation is one of the most lethal mutations in acute myeloid leukemia (Chi et al., 2008).

M2 acute myeloblastic leukemia with maturation, as classified by the FAB system, constitutes 25% of adult AML (Wiki Main article: AML).

Tumor-associated macrophages (TAMs) are the multifarious group of cells that originate mainly from the peritumoral tissue or bone marrow and can be divided into two main types: M1 and M2. Among them are the infiltrating M1 tumor-associated macrophages present in the early stages of tumorigenesis, which can secrete proinflammatory cytokines and turn in inhibit tumor growth. On the contrary, M2 tumor-associated macrophages are predominant in the late stage of tumor formation. Type II cytokines, which are secreted by them, can promote anti-inflammatory reaction and thus promote tumor growth. However, it remains unclear when M1 tumor-associated macrophages are transformed to M2 tumor-associated macrophages, but tumor hypoxia is currently thought to be associated with such a shift. M2 tumor-associated macrophages secrete many proteases such as cathepsin, cytokines, and an epidermal growth factor. The presence of M2 TAMs make the tumor prone to growth and angiogenesis, which in turn damages other tissues.

Clinically, in 128 patients in the first or second stage of breast cancer it was found that more patients with M2 tumor-associated macrophages had a higher degree of histology, more angiogenesis, and worse overall survival. Patients with more M1 tumor-associated macrophages displayed the opposite effect. .

Macrophages are the most common cells in breast tumors. They have a profound effect on the immune status of tumor tissues. Macrophages act as professional phagocytes in the body, specifically killing and eliminating cells or microbes that are perceived to be a threat. They represent the first line of defence and the bridge of connecting the innate and adaptive arms of the immune system. However, the large number of tumor cells and the derived factors present within the tumour microenvironment (TME) act to attenuate the tumoricidal activity function of macrophages. The TME consists of hypoxic conditions, growth factors and immunosuppressive cytokines that convert trophic macrophages to tumor-associated macrophages (TAM). These features promote tissue growth and repair and are an integral part of development so that macrophages within breast tumors are inadvertently authorized to promote tumor growth and metastasis.

Frontal Fibrosing Alopecia has been most often reported in post-menopausal women with higher levels of affluence and a negative smoking history. Autoimmune disease is found in 30% of patients.