Gene therapy in Parkinson's disease consists of the creation of new cells that produce a specific neurotransmitter (dopamine),
protect the neural system, or the modification of genes that are
related to the disease. Then these cells are transplanted to a patient
with the disease. There are different kinds of treatments that focus on
reducing the symptoms of the disease but currently there is no cure.
Current treatments
Parkinson's disease
(PD) is a progressive neurological condition that is the result of the
death of the cell that contains and produces dopamine in substantia nigra.
People with PD may develop disturbance in their motor activities. Some
activities can be tremor or shaking, rigidity and slow movements (bradykinesia). Patients may eventually present certain psychiatric problems like depression and dementia.
Current pharmacological intervention consist on the administration of
L-dopa, a dopamine precursor. The L-dopa therapy increases dopamine
production of the remaining nigral neurons. Other therapy is the deep brain electrical stimulation to modulate the overactivity of the subthalamic nucleus to the loss of dopamine signaling in the stratum. However, with this treatment, the number of substantia nigra neurons decrease so it becomes less efficient.
These treatments try to reduce the symptoms of the patient
focusing on increasing the production of dopamine but they do not cure
the disease. The new treatments for PD are in clinical trials and most
of them are centered on gene therapy. With this, researchers expect to compensate the loss of dopamine or to protect the dopamine neurons from degeneration.
The pharmacological and surgical therapies for PD focus on
compensating the ganglia dysfunction caused by the degeneration of the
dopaminergic neuron from substantia nigra.
Gene therapy background
There
are many new PD treatments in clinical trials and several of those are
focusing on gene therapeutic approaches that compensate the loss of
dopamine or protect the nervous system dopamine neurons from
degeneration. There are some important reasons for focusing on gene
therapy as a treatment for PD. First of all, currently there is no cure
for this disease. Secondly, some genes have been identified which can
modulate the neuron phenotype or act as neuroprotective agents. Also,
the environment of the brain cannot afford repeated injections into the
region where the substantia nigra meets the striatum, the nigrostriatum.
Therefore, gene therapy could be a single treatment appealing, viral
vectors used in the therapy are diffusible and capable to do
transduction of the striatum.
Gene therapy bases
The
main idea of the gene therapy is to create new generations of cells
that produce particular neurotransmitter (dopamine) and then transplant
these cells to the patients with PD.
This is because the neurons cannot proliferate nor be renewed; and
replacing lost neurons it is a process that is currently going under
investigation. Also, the use of embryonic dopaminergic cells cannot be used because these cells are difficult to obtain and modifications of cell can only be made on somatic cells, not germline. With the modifications of the transplanted cell, there can be a change in the expression of the genes or normalize them.
Types of gene therapy
There are several types of gene therapy. There are therapies for symptomatic approaches like the production of ectopic L-dopa, the full ectopic dopamine synthesis, the ectopic L-dopa conversion or the use of glutamic acid descarboxylase (GAD). Also there are disease modifying therapies like NTN or GNDF (glial cell line-derived neurotrophic factor),
the regulation of the α-synuclein and Parkin gene expression. Currently
the main studies are using AAV2 as a vector platform, making it the
standard vector for this disease although a lentevirus has also been
used.
In the different types of the gene therapy, the investigations are
encoding enzymes that are necessary for dopamine synthesis, such as tyrosine hydroxylase, GTP cyclohydrolase 1 and AADC.
Symptomatic approaches
A
symptomatic approach is a treatment focused on the symptoms of the
patients. The first one, consists in the ectopic dopamine synthesis.
Here, the production of ectopic L-dopa in the striatum is another
alternative gene therapy. This therapy consists on transferring the TH
and GTP cyclohydrolase 1 genes into the MSNs because the endogenous AADC
activity is able to convert the L-dopa into dopamine.
In an experiment in 2005, using tyrosine hydroxylase (TH) and GCH1
altogether with vectors, they could provide normal levels of L-dopa to
rats. The results of this experiment showed reduced dyskinesias by 85%
as well as, the reversion view of abnormal projections in the strium
using the TH-GCH1 gene transfer.
Dopamine synthesis can be fully ectopic. In this case, the enzyme
AADC it is in charge of converting the levodopa to dopamine. In
Parkinson disease, the loss of neurons from the nigrostriatum leads to
the inability to convert levodopa to dopamine. The goal of AAV2-hAADC is
to restore normal levels of AADC in the striatum so there could be more
conversion of levodopa, and therefore reducing levodopa- induced
dyskinesia. Using the gene therapy, in 2012, an experiment was accomplish with primates testing tyrosine hydroxylase (TH) transgene
in primate astrocytes. Gene therapy was made with the transfer of a TH
full-length cDNA using rat TH. The results showed behavioural
improvement in the monkeys that received the plasmid, unlike the control
monkey.
Another type is the ectopic L-dopa conversion in which they use a
gene enzyme replacement therapy that can be used to increase the
efficacy of the pharmacological L-dopa therapy by using AAV vectors.
This AAV vectors have been designed to send the AADC coding sequence to
the MSN (medium spiny neurons) in the striatum to be able to convert
administered L-dopa into dopamine.
Other kind of gene therapy as a symptomatic approach is the use
of glutamic acid decarboxylase (GAD) expression in the subthalamic
nucleus. This is a gene enzyme replacement therapy that can be used to
increase the efficacy of the pharmacological L-dopa therapy by using AAV
vectors. This AAV vectors have been designed to send the AADC coding
sequence to the MSN in the striatum to be able to convert administered
L-dopa into dopamine. A phase 2 study, published in the journal Lancet Neurology Parkinson,
says that a gene therapy called NLX-P101 dramatically reduces movement
damage. In this study, they used glutamic acid decarboxylase (GAD).
They introduced genetic material in the brain related to motor
functions. The symptoms included tremor, stiffness and difficulty in
movements; and were improved in half of the group in gene therapy, while
in the control group, 14% improved them.
Disease modifying
There
are therapies in development based in the modification of the disease.
The first one is the neurotrophic factors gene delivery. In this
therapy, GNDF or NTN are used to protect the system. GNDF is a factor of
the TGFß superfamily, is secreted by astrocytes (glia cells that are in charge of the survival of the midbrain dopaminergic neurons)
and is homologous to NTN, persephin and artemin. Preclinical studies of
the nigrostriatal dopaminergic in relation to Parkinson disease system
have shown that GNDF and NTN are very potential neuroprotective agents.
Another type in the disease’s modification technique is the synuclein
silencing. Some cases of PD were related to polymorphisms in the
α-synuclein promoter and also in the multiplication of the locus that
carries the α-synuclein gene. Therefore, trying to down-regulate the
α-synuclein expression could impact the development of the disease.
There have been explored several viral vector-based gene delivery system
that interfere with α- synuclein expression, and they depend on the
interference of the RNA (destabilizing the α-synuclein RNAm) and/or the
block the protein translation (using short hairpin RNA or micro RNA
directed against the α-synuclein RNAm sequence).
The discovery of the Parkin gene is another type of modification
of PD. The Parkin gene is linked with mutations associated with
autosomal recessive juvenile parkinsonism (previous state of Parkinson
with the typical symptoms and pathology but with a slow progression).
The mutations in the Parkin gene are responsible for the development of
the autosomal recessive juvenile parkinsonism.
New projects and investigations
More
gene therapy trials have been conducted for PD (with the
adeno-associated virus 2 gene), the objectives and strategies used on
the actual researches are clear, the research tries to translate the
experience obtained during the trials and try to improve the development
of new technology for the gene therapy of PD.
An electron micrograph of bacteriophages attached to a bacterial cell. These viruses are the size and shape of coliphage T1.
Phage therapy or viral phage therapy is the therapeutic use of bacteriophages to treat pathogenicbacterial infections. Bacteriophages, known as phages, are a form of viruses. Phages attach to bacterial cells, and inject a viral genome into the cell. The viral genome effectively replaces the bacterial genome, halting the bacterial infection. The bacterial cell causing the infection is unable to reproduce, and instead produces additional phages. Phages are very selective in the strains of bacteria they are effective against. Advantages include reduced side-effects and reduced risk of the bacterial developing resistance. Disadvantages include the difficulty of finding an effective phage for a particular infection.
Phages are often compared to antibiotics. Phages tend to be more successful than antibiotics where there is a biofilm covered by a polysaccharide layer, which antibiotics typically cannot penetrate. Bacteriophages are much more specific than antibiotics. They are typically harmless not only to the host organism but also to other beneficial bacteria, such as the gut flora, reducing the chances of opportunistic infections. They have a high therapeutic index, that is, phage therapy would be expected to give rise to few side effects, even at higher-than therapeutic levels. Because phages replicate in vivo (in cells of living organism), a smaller effective dose can be used.
This specificity is also a disadvantage: a phage will kill a bacterium only if it matches the specific strain. Consequently, phage mixtures ("cocktails") are often used to improve the chances of success.
Alternatively, samples taken from recovering patients sometimes
contain appropriate phages that can be grown to cure other patients
infected with the same strain.
Phages are currently being used therapeutically to treat
bacterial infections that do not respond to conventional antibiotics,
particularly in Russia and Georgia. There is also a phage therapy unit in Wrocław, Poland, established 2005, the only such centre in a European Union country. Phages are the subject of renewed clinical attention in western countries, such as the United States. In 2019, the United States Food and Drug Administration approved the first US clinical trial for intravenous phage therapy.
Phage therapy has many potential applications in human medicine as well as dentistry, veterinary science, and agriculture. If the target host of a phage therapy treatment is not an animal, the term "biocontrol" (as in phage-mediated biocontrol of bacteria) is usually employed, rather than "phage therapy".
The discovery of bacteriophages was reported by the Englishman Frederick Twort in 1915 and the French-Canadian Felix d'Hérelle in 1917. D'Hérelle said that the phages always appeared in the stools of Shigella dysentery patients shortly before they began to recover.
He "quickly learned that bacteriophages are found wherever bacteria
thrive: in sewers, in rivers that catch waste runoff from pipes, and in
the stools of convalescent patients".
Phage therapy was immediately recognized by many to be a key way
forward for the eradication of pathogenic bacterial infections. A
Georgian, George Eliava, was making similar discoveries. He travelled to the Pasteur Institute in Paris where he met d'Hérelle, and in 1923 he founded the Eliava Institute in Tbilisi, Georgia, devoted to the development of phage therapy. Phage therapy is used in Russia, Georgia and Poland.
In Russia, extensive research and development soon began in this
field. In the United States during the 1940s commercialization of phage
therapy was undertaken by Eli Lilly and Company.
While knowledge was being accumulated regarding the biology of
phages and how to use phage cocktails correctly, early uses of phage
therapy were often unreliable. Since the early 20th century, research into the development of viable therapeutic antibiotics had also been underway, and by 1942 the antibiotic penicillin G
had been successfully purified and saw use during the Second World War.
The drug proved to be extraordinarily effective in the treatment of
injured Allied soldiers whose wounds had become infected. By 1944,
large-scale production of Penicillin had been made possible, and in 1945
it became publicly available in pharmacies. Due to the drug's success,
it was marketed widely in the U.S. and Europe, leading Western
scientists to mostly lose interest in further use and study of phage
therapy for some time.
Isolated from Western advances in antibiotic production in the
1940s, Russian scientists continued to develop already successful phage
therapy to treat the wounds of soldiers in field hospitals. During World War II,
the Soviet Union used bacteriophages to treat many soldiers infected
with various bacterial diseases e.g. dysentery and gangrene. Russian
researchers continued to develop and to refine their treatments and to
publish their research and results. However, due to the scientific
barriers of the Cold War, this knowledge was not translated and did not proliferate across the world.
A summary of these publications was published in English in 2009 in "A
Literature Review of the Practical Application of Bacteriophage
Research".
There is an extensive library and research center at the George Eliava Institute in Tbilisi, Georgia. Phage therapy is today a widespread form of treatment in that region.
As a result of the development of antibiotic resistance
since the 1950s and an advancement of scientific knowledge, there has
been renewed interest worldwide in the ability of phage therapy to
eradicate bacterial infections and chronic polymicrobial biofilm (including in industrial situations).
Phages have been investigated as a potential means to eliminate pathogens like Campylobacter in raw food and Listeria in fresh food or to reduce food spoilage bacteria. In agricultural practice phages were used to fight pathogens like Campylobacter, Escherichia and Salmonella in farm animals, Lactococcus and Vibrio pathogens in fish from aquaculture and Erwinia and Xanthomonas
in plants of agricultural importance. The oldest use was, however, in
human medicine. Phages have been used against diarrheal diseases caused
by E. coli, Shigella or Vibrio and against wound infections caused by facultative pathogens of the skin like staphylococci and streptococci.
Recently the phage therapy approach has been applied to systemic and
even intracellular infections and the addition of non-replicating phage
and isolated phage enzymes like lysins to the antimicrobial arsenal. However, actual proof for the efficacy of these phage approaches in the field or the hospital is not available.
Some of the interest in the West can be traced back to 1994, when
Soothill demonstrated (in an animal model) that the use of phages could
improve the success of skin grafts by reducing the underlying Pseudomonas aeruginosa infection. Recent studies have provided additional support for these findings in the model system.
Although not "phage therapy" in the original sense, the use of
phages as delivery mechanisms for traditional antibiotics constitutes
another possible therapeutic use. The use of phages to deliver antitumor agents has also been described in preliminary in vitro experiments for cells in tissue culture.
In June 2015 the European Medicines Agency hosted a one-day workshop on the therapeutic use of bacteriophages
and in July 2015 the National Institutes of Health (USA) hosted a
two-day workshop "Bacteriophage Therapy: An Alternative Strategy to
Combat Drug Resistance".
Phage
therapy is the use of bacteriophages to treat bacterial infections.
This could be used as an alternative to antibiotics when bacteria
develop resistance. Superbugs that are immune to multiple types of drugs
are becoming a concern with the more frequent use of antibiotics.
Phages can target these dangerous microbes without harming human cells
due to how specific they are.
Bacteriophage treatment offers a possible alternative to conventional antibiotic treatments for bacterial infection.
It is conceivable that, although bacteria can develop resistance to
phage, the resistance might be easier to overcome than resistance to
antibiotics. Just as bacteria can evolve resistance, viruses can evolve to overcome resistance.
Bacteriophages are very specific, targeting only one or a few strains of bacteria. Traditional antibiotics have a more wide-ranging effect, killing both harmful bacteria and useful bacteria such as those facilitating food digestion.
The species and strain specificity of bacteriophages makes it unlikely
that harmless or useful bacteria will be killed when fighting an
infection.
A few research groups in the West are engineering a broader spectrum phage, and also a variety of forms of MRSA treatments, including impregnated wound dressings, preventative treatment for burn victims, phage-impregnated sutures. Enzybiotics
are a new development at Rockefeller University that create enzymes
from phage. Purified recombinant phage enzymes can be used as separate
antibacterial agents in their own right.
Phage Therapy also has the potential of preventing or treating infectious diseases of corals. This could assist with decline of coral around the world.
Application
Collection
The
simplest method of phage treatment involves collecting local samples of
water likely to contain high quantities of bacteria and bacteriophages,
for example effluent outlets, sewage and other sources. The samples are taken and applied to the bacteria that are to be destroyed which have been cultured on growth medium.
If the bacteria die, as usually happens, the mixture is
centrifuged; the phages collect on the top of the mixture and can be
drawn off.
The phage solutions are then tested to see which ones show growth
suppression effects (lysogeny) or destruction (lysis) of the target
bacteria. The phage showing lysis is then amplified on cultures of the
target bacteria, passed through a filter to remove all but the phages,
then distributed.
Treatment
Phages
are "bacterium-specific" and it is, therefore, necessary in many cases
to take a swab from the patient and culture it prior to treatment.
Occasionally, isolation of therapeutic phages can require a few months
to complete, but clinics generally keep supplies of phage cocktails for
the most common bacterial strains in a geographical area.
Phage cocktails are sold in pharmacies in eastern countries.
The composition of bacteriophagic cocktails has been periodically
modified to add phages effective against emerging pathogenic strains.
Phages in practice are applied orally, topically on infected
wounds or spread onto surfaces, or used during surgical procedures.
Injection is rarely used, avoiding any risks of trace chemical
contaminants that may be present from the bacteria amplification stage,
and recognizing that the immune system naturally fights against viruses
introduced into the bloodstream or lymphatic system.
Individualised phage therapy was successfully used by Robert T. Schooley and others to treat a case of multi-drug-resistant Acinetobacter baumannii in the U.S. in 2015.
Reviews of phage therapy indicate that more clinical and microbiological research is needed to meet current standards.
Clinical trials
Funding
for phage therapy research and clinical trials is generally
insufficient and difficult to obtain, since it is a lengthy and complex
process to patent bacteriophage products. Scientists comment that 'the
biggest hurdle is regulatory', whereas an official view is that
individual phages would need proof individually because it would be too
complicated to do as a combination, with many variables. Due to the
specificity of phages, phage therapy would be most effective with a
cocktail injection, which is generally rejected by the U.S. Food and Drug Administration
(FDA). Researchers and observers predict that for phage therapy to be
successful the FDA must change its regulatory stance on combination drug
cocktails.
Public awareness and education about phage therapy are generally
limited to scientific or independent research rather than mainstream
media.
In 2007 a Phase 1/2 clinical trial was completed at the Royal National Throat, Nose and Ear Hospital, London, for Pseudomonas aeruginosa infections (otitis). Documentation of the Phase-1/Phase-2 study was published in August 2009 in the journal Clinical Otolaryngology.
Phase 1 clinical trials have now been completed in the Southwest
Regional Wound Care Center, Lubbock, Texas for an approved cocktail of
phages against bacteria, including P. aeruginosa, Staphylococcus aureus and Escherichia coli (E. coli). The cocktail of phages for the clinical trials was developed and supplied by Intralytix. PhagoBurn, a phase 1/2 trial of phage therapy against P. aeruginosa wound infection in France and Belgium in 2015–17, was terminated early because the phage therapy was not effective.
Locus Biosciences created a cocktail of three CRISPR modified phages. The study in 2019 of 30 patients will look at the reduction of E. coli in their urinary tracts. Twenty patients will get a phage cocktail, and 10 will get a placebo.
In February 2019, the FDA approved the first clinical trial of intravenously administered phage therapy in the United States.
Administration
Phages can usually be freeze-dried and turned into pills without materially reducing efficiency. Temperature stability up to 55 °C and shelf lives of 14 months have been shown for some types of phages in pill form.
Application in liquid form is possible, stored preferably in refrigerated vials.
Oral administration works better when an antacid is included, as this increases the number of phages surviving passage through the stomach.
Topical administration often involves application to gauzes that are laid on the area to be treated.
In 2019, a Brownsville, MN man with a long-standing bacterial infection in his knee received a phage treatment at the Mayo Clinic which successfully killed the bacteria and avoided planned amputation of his lower leg.
Obstacles
The
high bacterial strain specificity of phage therapy may make it
necessary for clinics to make different cocktails for treatment of the
same infection or disease because the bacterial components of such
diseases may differ from region to region or even person to person. In
addition, this means that 'banks' containing many different phages must
be kept and regularly updated with new phages.
Further, bacteria can evolve different receptors either before or
during treatment. This can prevent phages from completely eradicating
bacteria.
The need for banks of phages makes regulatory testing for safety
harder and more expensive under current rules in most countries. Such a
process would make difficult the large-scale use of phage therapy.
Additionally, patent
issues (specifically on living organisms) may complicate distribution
for pharmaceutical companies wishing to have exclusive rights over their
"invention", which would discourage a commercial corporation from
investing capital in this.
The negative public perception of viruses may also play a role in the reluctance to embrace phage therapy.
Legislation
Approval
of phage therapy for use in humans has not been given in Western
countries with a few exceptions. In the United States, Washington and
Oregon law allows naturopathic physicians to use any therapy that is legal any place in the world on an experimental basis,
and in Texas phages are considered natural substances and can be used
in addition to (but not as a replacement for) traditional therapy (they
have been used routinely in a wound care clinic in Lubbock, TX, since
2006).
In 2013 "the 20th biennial Evergreen International Phage Meeting
... conference drew 170 participants from 35 countries, including
leaders of companies and institutes involved with human phage therapies
from France, Australia, Georgia, Poland and the United States."
Safety
Much of
the difficulty in obtaining regulatory approval is proving to be the
risks of using a self-replicating entity which has the capability to
evolve.
As with antibiotic therapy and other methods of countering bacterial infections, endotoxins are released by the bacteria as they are destroyed within the patient (Herxheimer reaction). This can cause symptoms of fever; in extreme cases toxic shock (a problem also seen with antibiotics) is possible. Janakiraman Ramachandran argues that this complication can be avoided in those types of infection where this reaction is likely to occur by using genetically engineered
bacteriophages which have had their gene responsible for producing
endolysin removed. Without this gene, the host bacterium still dies but
remains intact because the lysis is disabled. On the other hand, this
modification stops the exponential growth of phages, so one administered
phage means one dead bacterial cell. Eventually these dead cells are consumed by the normal house-cleaning duties of the phagocytes, which utilize enzymes to break down the whole bacterium and its contents into harmless proteins, polysaccharides and lipids.
Temperate (or Lysogenic)
bacteriophages are not generally used therapeutically, as this group
can act as a way for bacteria to exchange DNA; this can help spread antibiotic resistance or even, theoretically, make the bacteria pathogenic (see Cholera). Carl Merril claimed that harmless strains of corynebacterium may have been converted into C. diphtheriae that "probably killed a third of all Europeans who came to North America in the seventeenth century". Fortunately, many phages seem to be lytic only with negligible probability of becoming lysogenic.
The 1925 novel and 1926 Pulitzer prize winner Arrowsmith used phage therapy as a plot point.
Greg Bear's 2002 novel Vitals features phage therapy, based on Soviet research, used to transfer genetic material.
The 2012 collection of military history essays about the changing
role of women in warfare, "Women in War – from home front to front
line" includes a chapter featuring phage therapy: "Chapter 17: Women who
thawed the Cold War".
Steffanie A. Strathdee's 2019 book The Perfect Predator: An Epidemiologist’s Journey to Save Her Husband from a Deadly Superbug,
co-written with her husband Thomas Patterson, was published by Hachette
Book Group in 2019. It describes Dr Strathdee's ultimately successful
attempt to introduce phage therapy as a life-saving treatment for her
husband, critically ill with a completely antibiotic-resistant Acinetobacter baumannii infection following severe pancreatitis.
Treatment and therapy are generally considered synonyms. However, in the context of mental health, the term therapy may refer specifically to psychotherapy.
Semantic field
The words care, therapy, treatment, and intervention overlap in a semantic field, and thus they can be synonymous depending on context. Moving rightward through that order, the connotative level of holism decreases and the level of specificity (to concrete instances) increases. Thus, in health care contexts (where its senses are always noncount), the word care tends to imply a broad idea of everything done to protect or improve someone's health (for example, as in the terms preventive care and primary care, which connote ongoing action), although it sometimes implies a narrower idea (for example, in the simplest cases of wound care or postanesthesia care,
a few particular steps are sufficient, and the patient's interaction
with that provider is soon finished). In contrast, the word intervention tends to be specific and concrete, and thus the word is often countable; for example, one instance of cardiac catheterization is one intervention performed, and coronary care
(noncount) can require a series of interventions (count). At the
extreme, the piling on of such countable interventions amounts to interventionism, a flawed model of care lacking holistic circumspection—merely treating discrete problems (in billable increments) rather than maintaining health. Therapy and treatment, in the middle of the semantic field, can connote either the holism of care or the discreteness of intervention, with context conveying the intent in each use. Accordingly, they can be used in both noncount and count senses (for example, therapy for chronic kidney disease can involve several dialysis treatments per week).
The words aceology and iamatology are obscure and obsolete synonyms referring to the study of therapies.
The English word therapy comes via Latin therapīa from Greek: θεραπεία and literally means "curing" or "healing".
Types of therapies
By chronology, priority, or intensity
Levels of care
Levels of care classify health care into categories of chronology, priority, or intensity, as follows:
Emergency care handles medical emergencies
and is a first point of contact or intake for less serious problems,
which can be referred to other levels of care as appropriate.
Intensive care, also called critical care,
is care for extremely ill or injured patients. It thus requires high
resource intensity, knowledge, and skill, as well as quick decision making.
Ambulatory care is care provided on an outpatient
basis. Typically patients can walk into and out of the clinic under
their own power (hence "ambulatory"), usually on the same day.
Home care is care at home, including care from providers (such as physicians, nurses, and home health aides) making house calls, care from caregivers such as family members, and patient self-care.
Primary care is meant to be the main kind of care in general, and ideally a medical home that unifies care across referred providers.
Secondary care
is care provided by medical specialists and other health professionals
who generally do not have first contact with patients, for example,
cardiologists, urologists and dermatologists. A patient reaches
secondary care as a next step from primary care, typically by provider
referral although sometimes by patient self-initiative.
Tertiary care is specialized consultative care, usually for inpatients
and on referral from a primary or secondary health professional, in a
facility that has personnel and facilities for advanced medical
investigation and treatment, such as a tertiary referral hospital.
Follow-up care is additional care during or after convalescence. Aftercare is generally synonymous with follow-up care.
End-of-life care is care near the end of one's life. It often includes the following:
Hospice care is palliative care very near the end of life when cure is very unlikely. Its main goal is comfort, both physical and mental.
Lines of therapy
Treatment decisions often follow formal or informal algorithmic guidelines. Treatment options can often be ranked or prioritized into lines of therapy: first-line therapy, second-line therapy, third-line therapy, and so on. First-line therapy (sometimes called induction therapy, primary therapy, or front-line therapy)
is the first therapy that will be tried. Its priority over other
options is usually either: (1) formally recommended on the basis of clinical trial
evidence for its best-available combination of efficacy, safety, and
tolerability or (2) chosen based on the clinical experience of the
physician. If a first-line therapy either fails to resolve the issue or
produces intolerable side effects,
additional (second-line) therapies may be substituted or added to the
treatment regimen, followed by third-line therapies, and so on.
An example of a context in which the formalization of treatment
algorithms and the ranking of lines of therapy is very extensive is chemotherapy regimens. Because of the great difficulty in successfully treating some forms of cancer, one line after another may be tried. In oncology the count of therapy lines may reach 10 or even 20.
Often multiple therapies may be tried simultaneously (combination therapy or polytherapy). Thus combination chemotherapy is also called polychemotherapy, whereas chemotherapy with one agent at a time is called single-agent therapy or monotherapy.
Adjuvant therapy
is therapy given in addition to the primary, main, or initial
treatment, but simultaneously (as opposed to second-line therapy). Neoadjuvant therapy
is therapy that is begun before the main therapy. Thus one can consider
surgical excision of a tumor as the first-line therapy for a certain
type and stage of cancer even though radiotherapy is used before it; the
radiotherapy is neoadjuvant (chronologically first but not primary in
the sense of the main event). Premedication
is conceptually not far from this, but the words are not
interchangeable; cytotoxic drugs to put a tumor "on the ropes" before
surgery delivers the "knockout punch" are called neoadjuvant
chemotherapy, not premedication, whereas things like anesthetics or
prophylactic antibiotics before dental surgery are called premedication.
Step therapy or stepladder therapy is a specific type of prioritization by lines of therapy. It is controversial in American health care because unlike conventional decision-making
about what constitutes first-line, second-line, and third-line therapy,
which in the U.S. reflects safety and efficacy first and cost only
according to the patient's wishes, step therapy attempts to mix cost
containment by someone other than the patient (third-party payers) into
the algorithm. Therapy freedom and the negotiation between individual and group rights are involved.
By intent
Therapy type
Description
abortive therapy
A therapy that is intended to stop a medical condition from
progressing any further. A medication taken at the earliest signs of a
disease, such as an analgesic taken at the very first symptoms of a migraine headache to prevent it from getting worse, is an abortive therapy. Compare abortifacients, which abort a pregnancy.
A therapy that figuratively provides a bridge to another step or phase, crossing over some immediate chasm (challenge), in contrast with destination therapy, which is the final therapy in cases where clinically appropriate.
consolidation therapy
A therapy given to consolidate the gains from induction therapy. In cancer, this means chasing after any malignant cells that may be left.
curative therapy
A therapy with curative intent, that is, one that seeks to cure the root cause of a disorder. (also called etiotropic therapy)
definitive therapy
A therapy that may be final, superior to others, curative, or all of those.
A therapy that is the final destination rather than a bridge to another therapy. Usually refers to ventricular assist devices to keep the existing heart going, not just until a heart transplant can occur, but for the rest of the patient's life expectancy.
A therapy given on an empiric basis; that is, one given according to
a clinician's educated guess despite uncertainty about the illness's
causative factors. For example, empiric antibiotic therapy administers a
broad-spectrum antibiotic
immediately on the basis of a good chance (given the history, physical
examination findings, and risk factors present) that the illness is
bacterial and will respond to that drug (even though the bacterial
species or variant is not yet known).
An experimental therapy. Use of experimental therapies must be ethically justified, because by definition they raise the question of standard of care. Physicians have autonomy to provide empirical care (such as off-label care) according to their experience and clinical judgment, but the autonomy has limits that preclude quackery. Thus it may be necessary to design a clinical trial around the new therapy and to use the therapy only per a formal protocol.
Sometimes shorthand phrases such as "treated on protocol" imply not
just "treated according to a plan" but specifically "treated with
investigational therapy".
A therapy that is intended to prevent a medical condition from occurring (also called prophylaxis). For example, many vaccines prevent infectious diseases.
A therapy tried after others have failed; it may be a "last-line" therapy.
stepdown therapy
Therapy that tapers the dosage gradually rather than abruptly
cutting it off. For example, a switch from intravenous to oral
antibiotics as an infection is brought under control steps down the
intensity of therapy.
supportive therapy
A therapy that does not treat or improve the underlying condition, but instead increases the patient's comfort.[3] For example, supportive care for flu, colds, or gastrointestinal upset can include rest, fluids, and over the counter pain relievers; those things don't treat the cause, but they do treat the symptoms and thus provide relief. Supportive therapy may be palliative therapy (palliative care). The two terms are sometimes synonymous, but palliative care often connotes serious illness and end-of-life care, whereas supportive care
is always connotatively neutral (it may be as simple as mere bedrest
for the common cold). Therapy may be categorized as having curative intent (when it is possible to eliminate the disease) or palliative intent (when eliminating the disease is impossible and the focus shifts to minimizing the distress that it causes). The two are often contradistinguished (mutually exclusive) in some contexts (such as the management of some cancers), but they are not inherently mutually exclusive; often a therapy can be both curative and palliative simultaneously. Supportive psychotherapy aims to support the patient by alleviating the worst of the symptoms, with the expectation that definitive therapy can follow later if possible.
systemic therapy
A therapy that is systemic. In the physiological sense, this means affecting the whole body (rather than being local or locoregional), whether via systemic administration, systemic effect, or both. Systemic therapy in the psychotherapeutic sense
seeks to address people not only on the individual level but also as
people in relationships, dealing with the interactions of groups.
Primary Health Care, or PHC refers to "essential health care" that is based on scientifically sound and socially acceptable methods and technology. This makes universal health care
accessible to all individuals and families in a community. It is
through their full participation and at a cost that the community and
the country can afford to maintain at every stage of their development
in the spirit of self-reliance and self-determination. In other words, PHC is an approach to health beyond the traditional health care system that focuses on health equity-producing social policy. PHC includes all areas that play a role in health, such as access to health services, environment and lifestyle.
Thus, primary healthcare and public health measures, taken together,
may be considered as the cornerstones of universal health systems. The World Health Organization, or WHO,
elaborates on the goals of PHC as defined by three major categories,
"empowering people and communities, multisectoral policy and action; and
primary care and essential public health functions as the core of
integrated health service." Based on these definitions,
PHC can not only help an individual after being diagnosed with a disease
or disorder, but actively prevent such issues by understanding the
individual as a whole.
This ideal model of healthcare was adopted in the declaration of the International Conference on Primary Health Care held in Alma Ata, Kazakhstan in 1978 (known as the "Alma Ata Declaration"), and became a core concept of the World Health Organization's goal of Health for all.
The Alma-Ata Conference mobilized a "Primary Health Care movement" of
professionals and institutions, governments and civil society
organizations, researchers and grassroots organizations that undertook
to tackle the "politically, socially and economically unacceptable" health inequalities in all countries. There were many factors that inspired PHC; a prominent example is the Barefoot Doctors of China.
Goals and principles
A primary health care worker in Saudi Arabia, 2008
The ultimate goal of primary healthcare is the attainment of better health services for all. It is for this reason that the World Health Organization (WHO), has identified five key elements to achieving this goal:
reducing exclusion and social disparities in health (universal coverage reforms);
organizing health services around people's needs and expectations (service delivery reforms);
integrating health into all sectors (public policy reforms);
pursuing collaborative models of policy dialogue (leadership reforms); and
increasing stakeholder participation.
Behind these elements lies a series of basic principles identified in the Alma Ata Declaration
that should be formulated in national policies in order to launch and
sustain PHC as part of a comprehensive health system and in coordination
with other sectors:
Equitable distribution of health care – according to this principle, primary care
and other services to meet the main health problems in a community must
be provided equally to all individuals irrespective of their gender,
age, caste, color, urban/rural location and social class.
Community participation – in order to make the fullest use of local,
national and other available resources. Community participation was
considered sustainable due to its grass roots nature and emphasis on
self-sufficiency, as opposed to targeted (or vertical) approaches
dependent on international development assistance.
Use of appropriate technology –
medical technology should be provided that is accessible, affordable,
feasible and culturally acceptable to the community. Examples of
appropriate technology include refrigerators for cold vaccine
storage. Less appropriate examples of medical technology could include,
in many settings, body scanners or heart-lung machines, which benefit
only a small minority concentrated in urban areas. They are generally
not accessible to the poor, but draw a large share of resources.
Multi-sectional approach – recognition that health cannot be
improved by intervention within just the formal health sector; other
sectors are equally important in promoting the health and self-reliance
of communities. These sectors include, at least: agriculture (e.g. food
security); education; communication (e.g. concerning prevailing health
problems and the methods of preventing and controlling them); housing;
public works (e.g. ensuring an adequate supply of safe water and basic
sanitation); rural development; industry; community organizations
(including Panchayats or local governments, voluntary organizations, etc.).
In sum, PHC recognizes that healthcare is not a short-lived
intervention, but an ongoing process of improving people's lives and
alleviating the underlying socioeconomic conditions that contribute to
poor health. The principles link health, development, and advocating
political interventions rather than passive acceptance of economic
conditions.
Approaches
The hospital ship USNS Mercy(T-AH-19) in Manado, Indonesia, during Pacific Partnership 2012.
The primary health care approach has seen significant gains in health
where applied even when adverse economic and political conditions
prevail.
Although the declaration made at the Alma-Ata conference deemed
to be convincing and plausible in specifying goals to PHC and achieving
more effective strategies, it generated numerous criticisms and
reactions worldwide. Many argued the declaration did not have clear
targets, was too broad, and was not attainable because of the costs and
aid needed. As a result, PHC approaches have evolved in different
contexts to account for disparities in resources and local priority
health problems; this is alternatively called the Selective Primary
Health Care (SPHC) approach.
Selective Primary Health Care
After
the year 1978 Alma Ata Conference, the Rockefeller Foundation held a
conference in 1979 at its Bellagio conference center in Italy to address
several concerns. Here, the idea of Selective Primary Health Care was
introduced as a strategy to complement comprehensive PHC. It was based
on a paper by Julia Walsh and Kenneth S. Warren entitled “Selective
Primary Health Care, an Interim Strategy for Disease Control in
Developing Countries”.
This new framework advocated a more economically feasible approach to
PHC by only targeting specific areas of health, and choosing the most
effective treatment plan in terms of cost and effectiveness. One of the
foremost examples of SPHC is "GOBI" (growth monitoring, oral
rehydration, breastfeeding, and immunization), focusing on combating the main diseases in developing nations.
GOBI and GOBI-FFF
GOBI
is a strategy consisting of (and an acronym for) four low-cost, high
impact, knowledge mediated measures introduced as key to halving child mortality by James P. Grant at UNICEF in 1983. The measure are:
Growth monitoring: the monitoring of how much infants grow
within a period, with the goal to understand needs for better early
nutrition.
Three additional measure were introduced to the strategy later
(though food supplementation had been used by UNICEF since it#'s
inception in 1946), leading to the acronym GOBI-FFF.
Food supplementation: for example, iron and folic acid fortification/supplementation to prevent deficiencies in pregnant women.
These strategies focus on severe population health problems in
certain developing countries, where a few diseases are responsible for
high rates of infant
and child mortality. Health care planning is used to see which
diseases require most attention and, subsequently, which intervention
can be most effectively applied as part of primary care in a least-cost
method. The targets and effects of selective PHC are specific and
measurable. The approach aims to prevent most health and nutrition problems before they begin.
PHC and population aging
Given
global demographic trends, with the numbers of people age 60 and over
expected to double by 2025, PHC approaches have taken into account the
need for countries to address the consequences of population ageing.
In particular, in the future the majority of older people will be
living in developing countries that are often the least prepared to
confront the challenges of rapidly ageing societies, including high risk
of having at least one chronic non-communicable disease, such as diabetes and osteoporosis. According to WHO, dealing with this increasing burden requires health promotion and disease prevention intervention at the community level as well as disease management strategies within health care systems.
PHC and mental health
Some
jurisdictions apply PHC principles in planning and managing their
healthcare services for the detection, diagnosis and treatment of common
mental health
conditions at local clinics, and organizing the referral of more
complicated mental health problems to more appropriate levels of mental
health care.
The Ministerial Conference, which took place in Alma Ata, made the
decision that measures should be taken to support mental health in
regard to primary health care. However, there was no such documentation
of this event in the Alma Ata Declaration. These discrepancies caused an
inability for proper funding and although was worthy of being a part of
the declaration, changing it would call for another conference.
Individuals with severe mental health disorders are found to live
much shorter lives than those without, anywhere from ten to
twenty-five-year reduction in life expectancy when compared to those
without. Cardiovascular diseases
in particular are one of the leading deaths with individuals already
suffering from severe mental health disorders. General health services
such as PHC is one approach to integrating an improved access to such
health services that could help treat already existing mental health
disorders as well as prevent other disorders that could arise
simultaneously as the pre-existing condition.
Background and controversies
Barefoot Doctors
The
"Barefoot Doctors" of China were an important inspiration for PHC
because they illustrated the effectiveness of having a healthcare
professional at the community level with community ties. Barefoot
Doctors were a diverse array of village health workers who lived in
rural areas and received basic healthcare training. They stressed rural
rather than urban healthcare, and preventive rather than curative
services. They also provided a combination of western and traditional
medicines. The Barefoot Doctors had close community ties, were
relatively low-cost, and perhaps most importantly they encouraged
self-reliance through advocating prevention and hygiene practices.
The program experienced a massive expansion of rural medical services
in China, with the number of Barefoot Doctors increasing dramatically
between the early 1960s and the Cultural Revolution (1964-1976).
Criticisms
Although
many countries were keen on the idea of primary healthcare after the
Alma Ata conference, the Declaration itself was criticized for being too
“idealistic” and “having an unrealistic time table”.
More specific approaches to prevent and control diseases - based on
evidence of prevalence, morbidity, mortality and feasibility of control
(cost-effectiveness) - were subsequently proposed. The best known model
was the Selective PHC approach (described above). Selective PHC favoured
short-term goals and targeted health investment, but it did not address
the social causes of disease. As such, the SPHC approach has been
criticized as not following Alma Ata's core principle of everyone's
entitlement to healthcare and health system development.
In Africa, the PHC system has been extended into isolated rural
areas through construction of health posts and centers that offer basic
maternal-child health, immunization, nutrition, first aid, and referral
services. Implementation of PHC is said to be affected after the introduction of structural adjustment programs by the World Bank.
_June_6,_2012,_in_Manado,_Indonesia,_during_Pacific_Partnership_2012_120606-N-CW427-402.jpg)
