Month: May 2015

Factors Contributing to Drug-Induced Diseases

May 28, 2015 Adverse Drug Reactions, Pharmacoeconomics, Pharmacogenetics, Pharmacokinetics, Pharmacology No comments , ,

470px-Emblem_of_the_United_NationsPharmacokinetic and pharmacodynamic factors

Toxic or exaggerated responses to normal drug doses can lead to drug-induced diseases and other adverse events for two reasons. First, excessively high concentrations of unbound drug or metabolite at the site of action may occur as a result of unusual pharmacokinetics (absorption, distribution, metabolism, excretion) of the drug or metabolites. Second, response to a given concentration of unbound drug or metabolite at the site of action (pharmacodynamics) may be exaggerated or unusual because of many factors, including changes in the number and/or binding affinity of target receptors as well as alternations in signal-transduction pathways. The pharmacokinetic and pharmacodynamic behaviours of drug may be influenced by factors related to concurrent diseases, physiologic status, concomitantly administered drugs or food, lifestyle, and genetic variability.

Concurrent Diseases

The effects of disease on pharmacokinetics have been extensively reviewed. For drugs or drug metabolites that are highly dependent on the kidney or liver for elimination, usual does produce higher-than-normal serum drug concentrations in patients with kidney or liver disease respectively. This results in an exaggerated response, particularly for drugs with narrow therapeutic index.

Cardiovascular diseases, such as acute myocardial infarction or heart failure, may reduce hepatic and/or renal blood flow and decrease the elimination of drugs that are normally highly extracted by the liver. Serum concentrations and response are increased if such drugs are administered intravenously.

Hypothyroidism may be associated with a decrease in both hepatic and renal drug clearances.

Many diseases can also decrease the serum protein binding of drugs. For example, kidney and liver diseases have been associated with decreased albumin binding of some drugs. These changes generally do not result in an altered clinical response, however, because the concentration of unbound drug is unaffected. Nevertheless, misinterpretation of total serum drug concentrations of highly protein-bound drugs that are routinely monitored may lead a clinician to inappropriately increase the dose, thus resulting in toxicity.

Concurrent diseases may also be associated with enhanced pharmacodynamic responses to drugs for a variety of reasons. For example, the incidence of skin rashes and serious dermatologic adverse effects such as Stevens-Johnson syndrome is increased in patients with human immunodeficiency virus (HIV) infection who are taking trimethoprim-sulfamethoxazole. Patients with cytomegalovirus infection who are taking ampicillin are also at increased risk for skin rashes. Although the precise mechanisms are unkown, desensitisation procedures generally reduce the severity of the adverse effect if rechallenge with the drug is necessary.

Physiologic Conditions

The pharmacokinetics of a drug may be affect by age, pregnancy, and sex. In general, the rate of elimination of a drug is impaired in premature newborns, increases in early childhood to more efficient rates than those in adults, and then progressively declines with advancing age. In addition, early patients may also suffer from decreased mental status or diminished physical function. When these physiologic conditions are compounded by decreased elimination of some drugs, the patient is more susceptible to drug-induced falls or physical injury (i.e., benzodiazepines). A variety of physiologic changes during pregnancy may affect the pharmacokinetics of drugs, but no consistent patterns have been identified. The higher serum concentrations of digoxin reported in pregnant patients may be caused by increased bioavailability resulting from decreased gastric emptying time. Women have a higher risk of drug-induced adverse events as compared with men, which has been attributed to the fact that they take more drugs than men, have lower activity of drug-metabolising enzymes, and have estrogen-related effects on drug receptors, as in the case of drug-induced torsades de pointes.

DDIs

Drug-drug interactions may cause altered pharmacokinetics (bioavailability, distribution, clearance) or altered pharmacodynamics by additive or antagonistic effects. Such interactions have been extensively reviewed and are more often a predictable and preventable cause of morbidity and mortality. By far the most frequent contributing factors to drug-induced disease resulting from drug interactions are those that affect bioavailability and drug elimination. A large number of important interactions occur in the liver and gastrointestinal tract because of decreases in the rate of a drug’s metabolism or transport caused by other drugs that are inhibitors of these system.

P-glycoprotein, a transporter protein expressed on the luminal surfaces of intestinal epithelial cells, biliary hepatocytes, and renal tubular cells, transports drug from within the cell to the intestine, bile, or urine, respectively. Inhibition of P-glycoprotein can therefore increase the bioavailability and decrease renal and biliary excretion of affected drugs, thus increasing their serum concentrations. Other interaction mechanisms that may result in reduced renal excretion include reduction of the glomerular filtration rate and increased reabsorption of drug into blood from the renal tubule.

Drugs that displace other drugs from serum protein-binding sites without affecting their metabolism cause only transient increases in unbound drug concentration, and hence do not generally result in adverse effects. Displacement of drugs such as warfarin (long half-life, small volume of distribution, and narrow therapeutic range) can be clinical important, however, and necessitate a temporary reduction in the dose of the affected drug.

Serious drug-drug interactions may also occur when drugs produce additive effects through different mechanisms. Examples include: 1.the combined blood-pressure-lowering effects of calcium channel-blockers and β-blockers; 2.the increased risk of gastrointestinal bleeding resulting from non steroidal anti-inflammatory drug (NSAID)-omdiced gastric erosion in patients taking warfarin; and 3.exaggerated cyclic guanine monophosphate (cGMP)-mediated smooth-muscle relaxation caused by the combination of sildenafil (which inhibits cGMP degradation) and nitrates (which increase GMP production), leading to potentially serious hypotension. An example of a drug-drug interaction involving active or toxic metabolites is the potentiation of acetaminophen hepatotoxicity in patients receiving enzyme inducer such as rifampin, presumably by increasing the formation of toxic acetaminophen metabolites.

Drug-Food Interactions

Drug-food interactions have been extensively reviewed. One of the most serious drug-food interactions occurs with first generation nonselective monoamine oxidase inhibitors and tyramine, an amino acid found in aged or fermented foods and beverages. The suppressed metabolism of large amounts of tyramine may result in hypertensive-crisis, the so-called cheese reaction (tyramine, dopamine, norepinephrine and epinephrine are all monoamines). A large dietary intake of tyramine (or a dietary intake of tyramine while taking MAO inhibitors) can cause the tyramine pressor response, which is defined as an increase in systolic blood pressure of 30 mmHg or more. The displacement of norepinephrine (noradrenaline) from neuronal storage vesicles by acute tyramine ingestion is thought to cause the vasoconstrictionand increased heart rate and blood pressure of the pressor response. In severe cases, adrenergic crisis can occur (from wiki at http://en.wikipedia.org/wiki/Tyramine).

Components of grapefruit juice are known to suppress the presystemic elimination of certain drugs that are either metabolised in the intestinal wall by the cytochrome P-450 isozyme CYP3A4, are substrates for P-glycoprotein, or both, resulting in increased bioavailability. Drugs for which bioavailability increases dramatically when taken with grapefruit juice include lovastatin, simvastatin, buspirone, and amiodarone.

In general, an increase in drug bioavailability caused by food intake is not a problem if doses throughout the course of treatment are taken consistently at a fixed time relative to a meal. However, a clinically important drug-food interaction was reported for a particular once-daily theophylline product, which has since been reformulated. When taken with high-fat meals, a sudden, rapid release of a large amount of theophylline occurred, leading to excessively hight serum theophylline concentrations.

The salt, protein, or vitamin content of the diet also may affect the renal excretion of drugs. For example, a patient taking lithium who initiates a low-salt diet for treatment of hypertension or heart failure excretes less lithium, resulting in higher serum lithium concentrations and potential toxicity, given this drug’s narrow therapeutic range. A low-protein diet is associated with decreased renal clearance of oxypurinol, apparently through enhanced reabsorption efficiency by the uric acid transporter system.

Lifestyle Factors

Alcohol and caffeine consumption can affect both the pharmacokinetics and the pharmacodynamics of other drugs, leading to serious drug-induced diseases. There are many examples of alcohol exaggerating the central nervous system depressant effects of drugs, including benzodiazepines, phenothiazines, tricyclic antidepressants, opiates, and anthistamines. Caffeine has an additive and potentially dangerous stimulant effect when taken with ephedrine in herbal weight-loss and athletic performance-enhancing supplements.

Genetic Variability

As a result of the rapidly evolving field of pharmacogenomics, interindividual differences in drug related toxicity and therapeutic response are not always considered to be “idiosyncratic” responses. Rther, it is widely recognized that genetic makeup is responsible for a significant portion of drug-induced diseases. Many genes that encode metabolic enzymes or drug transporters are polymorphic, meaning that some groups of patients with certain gene variants have relatively inactive enzymes or transporters, while others have unusually active forms. In addition, the proportion of patients with active or inactive forms may differ among racial groups.

Polymorphisms in metabolising enzymes have been extensively reviewed. Patients with low N-acetyltransferase activities, known as “slow acetylators,” are more likely to suffer from peripheral nerve damage when administered standard isoniazid doses as compared with fast acetylators. Likewise, slow acetylators of hydrazine are more likely to suffer from hydaralazine-induced lupus erythematosus. At least four of the major cytochrome P-450 isozymes (CYP2A6, CYP2C9, CYP2C19, CYP2D6) responsible for oxidative drug metabolism are polymorphic in nature. Patients with gene variants that produce low-activity enzymes for the metabolism of warfarin experience a higher risk of serious bleeding events. Severe and potentially fatal hematologic toxicity occurs in the small percentage of patients receiving azathioprine or mercaptopurine who have a genetic deficiency in the thiopurine methyltransferase enzyme.

Polymorphisms in receptors, ion channels, or other proteins involved in drug response also occur. These result in widely variable pharmacodynamic responses among patients despite similar concentrations of the drug at the site of action. Examples include the polymorphisms in: 1.dopamine receptors, which affect the risk of drug induced tardive dyskinesia; 2.skeletal-muscle ryanodine receptors, which affect the risk of anesthesia-induced malignant hyperthermia; 3.potassium or sodium channels, which affect the risk of potentially fatal tornadoes de points when certain antiarrhythmic drugs are administered; 4.glucose-6-phosphate dehydrogenase, which if deficient, leads to red-cell homeless in patients who take drugs with a high redox potential, such as aspirin, nitrofurantoin, sulfonamides, and quinidine; and 5.the major histocompatibility complex, which mediates hypersensitivity reactions to drugs such as abacavir and nevirapine.


Adherence To Prescribed Therapy

Noncompliance implies that the patient is intentionally or willfully not following directions for medication use, which may or may not be the case. For this reason, some prefer the term non adherence, because it places no blame on either the patient or the health care professional. Common causes of non adherence are listed in Table 1. Regardless of the cause, non adherence can lead to drug-induced disease. Patients may take more or less drug than prescribed or recommended, modify medications in an inappropriate fashion (e.g., crush a sustained-release tablet), or continue to take a prescribed drug even though the underlying medical condition for which the drug was originally prescribed has resolved. Any of these actions can put patients at increased risk for drug-induced disease.

Screen Shot 2015-05-28 at 5.01.13 PMIt is estimated that the prevalence of medication non adherence is 40% to 70%. McDonnell and Jacobs analyzed the cause for hospital admissions from preventable adverse drug reactions. Of 158 drug-related hospital admissions over an 1-month period, patient non adherence with a prescribed medication regimen was the identified cause of 33% of these admissions. Unfortunately, health care providers typically are unable to identify patients at risk for non adherence. Patient age, sex, race, intelligence, and educational background have not been shown to be predictive of adherence or non adherence to a prescribed drug regimen.

Until the most effective strategy or strategies to improve adherence can be identified, it is recommended that healthcare professionals keep drug regimens simple, provide clear and complete instructions, encourage medication adherence by scheduling regular appointments, respond clearly and promptly to patients’ questions and concerns, and reinforce adherence with the prescribed regimen at every opportunity.


Medication Errors

Medication errors contribute significantly to the problem of drug-induced disease. These errors can include a variety of problems involving any step in the drug-use process. In an study, 67% of hospital admissions caused by adverse drug reactions were attributed to inadequate patient monitoring (e.g., failure to order appropriate laboratory tests to monitor drug response or failure to respond appropriately to abnormal laboratory-test results) and 51% were caused by inappropriate drug doses.

Fortunately, not all medication errors result in clinically significant problems. In one study of hospitalized patients, only 7 to 100 medication errors were thought to be serious enough to cause harm (all adverse effects are harm and might not be preventable, whereas all medication errors are preventable and do not necessarily cause harm). However, in a view of the overall frequency of medication errors that occur each year, a 7% proportion of serious medication errors may result in many affected lives.

Medication errors and drug-induced diseases may result from the limitations of an individual practitioner, from problems latent in the system or setting in which the practitioner operates, or from a combination of the above. In most cases, medication errors are caused by system-related problems including the absence of redundancies and system defenses needed to detect and counter an error in an individual’s judgment before the medication reaches the patient.

 

The Way Chemotherapy Impacts Cancer

May 13, 2015 Uncategorized No comments , , , , , ,

720px-US-DeptOfHHS-LogoUnderstand how to be effective?

Comparing drug targets in the treatment of bacterial and viral diseases to the treatment of cancer helps to frame the issue of drug targets in cancer. Bacteria possess numerous enzymes that are either unique to, or sufficiently different from, the host such that we have numerous classes of drugs with wide therapeutic index/indices. Viral genomes code for a limited number of genes, and they rely heavily on the host to provide basic metabolic functions. Nevertheless, the enzymatic differences in viral genes or unique viral gene products have allowed for the development of active drugs.

In the case of cancer, the situation is much different. For the most part, cancer cells use the same biochemical machinery as normal cells. Thus, for the majority of cancers, no “optimal” drug target of a vital enzyme is unique to the cancer cell. The biochemical targets of many chemotherapeutic agents are well characterized, but these targets are often identical in normal and cancer cells.

According to the similar or most partially same biochemical machinery as normal cells, chemotherapeutic agents could make a same degree of significant damage to normal cells as to cancers. In fact, however, many chemotherapy regimens have significant activity against cancers with acceptable toxicity to normal tissues. Therefore, the question is raised as to how these agents act if they do not target unique enzymes.

How the Chemotherapeutic agents act on cancer cells?

What is secret for chemotherapeutic agent being effective for cancer cells meanwhile acceptable toxicity to normal cell also being guaranteed? The answer is that different cell signal status between cancer cells and normal cells. For a cell to become malignant, it may acquire an increase in the activity of positively acting growth signals (activation of protooncogenes), a decrease in the activity of negatively acting growth signals (loss of tumor suppressor gene function), and a decrease in the activity of some of the pathways leading to programmed cell death. For any given cancer, numerous alterations are required, and specific alterations are necessary to occur in specific types of tumors. Thus, what makes a cancer cell different from normal cells is that normal signals that regulate proliferation and cell death are out of balance in such a way to produce the malignant phenotype. This regulatory imbalance, however, also means that normal mechanisms that protect cells from metabolic and genomic insults are missing in cancer cells, and, thus, the state of dysregulation itself becomes the target of chemotherapy.

The concept of programmed cell death, apoptosis, is also central to the understanding of chemotherapy action. Recent work has demonstrated that most, if not all, chemotherapy drugs currently in use induce apoptosis in susceptible cells. Current models of apoptosis divide the process into initiation and execution phases.

The apoptotic program can be initiated by numerous stimuli. These include specific extracellular signals, like the Fas ligand interacting with the Fas receptor to eliminate auto-reactive T Cells, the loss of trophic stimuli (removal of growth factors in vitro), and perturbations in the cell cycle (e.g., forced expression of MYC in normal quiescent cells leads to apoptosis). DNA damage where agents and approaches exert their cytotoxic effect is also a potent inducer of apoptosis.

The execution phase of apoptosis is more generalized and begins with the activation of a group of proteases known as capsizes. These enzymes cleave a wide range of cellular proteins, inactivating some and activating others, leading to dismantling of the cell structure, inhibition of transcription and DNA synthesis, and degradation of the genome.

Exceptions

There are a number of examples of protein expressed in tumors that may be unique to malignant cells and play a role in the malignant phenotype. These unique proteins could be the “optimal” targets because normal cells do not have these proteins.

A direct role for viral gene products in carcinogenesis may exist for several human tumors. Because the viral gene products that are important for cellular transformation are unique to virally infected cells, they represent potential drug targets. However, the use of target viral proteins may be limited by the fact that the viral proteins may no longer be necessary once the malignant phenotype is fully realized.

Genetic mutations that give rise to altered polypeptides represent another target that is unique to the cancer cells. These mutations can either be point mutations or translocations that give rise to novel fusion proteins, which do not exist in normal cells.

Telomerase is another example. It is a ribonucleoprotein complex that is normally only expressed in germ cells and is responsible for maintaining the length of the telomere repeats in germ cells and transformed cells. In somatic cells, progressive shortening of theorems occur with each cell division, and this shortening process is believed to contribute to senescence. In cancers, telomerase is reactivated and involved with the immortalization of cells by maintaining telomere length.

Type of Observational Clinical Studies

May 10, 2015 Clinical Research, Clinical Trials No comments , , , , ,

327px-Phs.svgThere are several different schemes for classifying study designs. We have adopted one that divides studies into those in which the subjects were merely observed, sometimes called observational studies, and those in which some intervention was performed, generally called experiments.


Observational Studies

Observational studies are of four main types: case-series, case-control, cross-sectional, and cohort studies. When certain characteristics of a group (or series) of patients (or cases) are described in a published report, the result is called a case-series study; it is the simplest design in which the author describes some interesting or intriguing observations that occurred for a small number of patients.

Case-control, cross-sectional, and cohort studies are defined by the period of time the study covers and by the direction or focus of the research question. Cohort and case-control studies generally involve an extended period of time defined by the point when the study begins and the point when it ends; some process occurs, and a certain amount of time is required to assess it. For this reason, both cohort and case-control studies are sometimes also called longitudinal studies. The major difference between them is the direction of the inquiry or the focus of the research question: Cohort studies are forward-looking, from a risk factor to an outcome, whereas case-control studies are backward-looking, from an outcome to risk factors. The cross-sectional study analyzes data collected on a group of subjects at one time.

  • Case-Series Studies

A case-series report is a simple descriptive account of interesting characteristics observed in a group of patients. Case-series reports generally involve patients seen over a relatively short time. Generally case-series studies do not include control subject, persons who do not have the disease or condition being described. Generally investigators would not include case-series in a list of types of studies because they are generally not planned studies and do not involve any research hypotheses.

  • Case-Control Studies

Figure 1 Case-Control Stuides

Screen Shot 2015-05-10 at 1.51.02 PMCase-control studies begin with the absence or presence of an outcome and then look backward in time to try to detect possible causes or risk factors that may have been suggested in a case-series report. The cases in case-control studies are individuals selected on the basis of some disease or outcome; the controls are individuals without the disease or outcome. The history or previous events of both cases and controls are analyzed in an attempt to identify a characteristic or risk factor present in the cases’ histories but not in the controls’ histories. The Figure 1 on the left illustrates that subjects in the study are chosen at the onset of the study after they are known to be either cases with the disease or outcome (square) or controls without the disease or outcome (diamond). The histories of cases and controls are examined over a previous period to detect the presence (shaded areas) or absence (unshaded areas) of predisposing characteristics or risk factors, or, if the disease is infectious, whether the subject has been exposed to the presumed infectious agent. In case-control designs, the nature of the inquiry is backward in time, as indicated by the arrow pointing backward in figure 1 to illustrate the backward, or retrospective, nature of the research process. We can characterize case-control studies as studies that ask “what happened?” In fact, they are sometimes called retrospective studies because of the direction of inquiry. Case-control studies are longitudinal as well because the inquiry covers a period of time.

Investigators sometimes use matching to associate controls with cases on characteristics such as age and sex. If an investigator feels that such characteristics are so important that an imbalance between the two groups of patients would affect any conclusions, he or she should employ matching. This process ensures that both groups will be similar with respect to important characteristics that may otherwise cloud or confound the conclusions.

  • Cross-Sectional Studies

Cross-sectional studies also are known as surveys, epidemiological studies, and prevalence studies. Cross-sectional studies analyse data collected on a group of subjects at one time rather than over a period of time. Cross-sectional studies are designed to determine “What is happening?” right now. Subjects are selected and information is obtained in a short period of time.

Figure 2 Cross-Sectional Studies

Screen Shot 2015-05-10 at 2.19.52 PM

  • Cohort Studies

A cohort is a group of people who have something in common and who remain part of a group over an extended time. In medicine, the subjects in cohort studies are selected by some defining characteristic (or characteristics) suspected of being a precursor to or risk factor for a disease or health effect. Cohort studies ask the question “What will happen?” and thus, the direction in cohort studies is forward in time. For cohort studies, researcher select subjects at the onset of the study and then determine whether they have the risk factor or have been exposed. All subjects are followed over a certain period of time to observe the effect of the risk factor or exposure. Because the events of interest transpire after the study is begun, these studies are sometimes called prospective studies.

Many cohort studies are prospective; that is, they begin at a specific time, the presence or absence of the risk factor is determined, and then information about the outcome of interest is collected at some future time. However, one also can undertake a cohort study by using information collected in the past and kept in records or files, which we call it historical cohort studies. This approach to a study is possible if the records on follow-up are complete and adequately detailed and if the investigators can ascertain the current status of the patients.

Some investigators also call this type of study a retrospective cohort study because historical information is used; that is the events being evaluated actually occurred before the onset of the study. The direction of the inquiry is till forward in time.

Figure 3 Cohort Studies

Screen Shot 2015-05-10 at 2.38.07 PM

The Plan to Future (ongoing updating)

May 7, 2015 Pharmacy Education No comments , ,

552519_10150623880396074_321083388_nThe good news is that I got the offer to the master degree program of clinical pharmacy in China Pharmaceutical University. The university is a pharmacy university as a whole. In China there are lots of Medical Universities but only two the pharmacy universities exist in China – China Pharmaceutical University and Shenyang Pharmaceutical University. It is apparent that the China Pharmaceutical University is one of the most top pharmacy schools in China. The master degree of clinical pharmacy just began in two or three of years ago, which is a professional degree program. Within the program of Master Degree of Clinical Pharmacy two direction are there, including direction of Hospital Pharmacy and direction of Clinical Trial. I was so lucky that I was distributed to the direction of Hospital Pharmacy, the last one person (29th). OK, you must know that I quitted my job to participate the Graduate School Admission Exam 2015. Therefore if I failed the exam, I both lost my job and the chance to graduate school.

Now I tell myself that the affair to get the offer to graduate school has ended and I must have a plan for next three years. So now I sit in front of my hackintosh to think the future plans. The nearest plan in my brain is that I should get the TOEFL done with a score as enough as NABP (National Association of Boards of Pharamcy) requires. NABP requires the TOEFL should be as minimal as 93 in total to meet the preretirement of foreign pharmacist license certification. Yes, as what I just said it’s obvious that I am interested in U.S. Pharmacist license and I want to become a U.S. licensed pharmacist. The detail schedule for TOEFL has not been determined but I think I should get it done during the three years of study. I wrote a letter to NABP to consult for the license program for foreign pharmacists and I am wait for their reply. I remembered that I shipped the mail on about April 20th 2015. It would take about 20 days to reach NABP.

So in summary my primer plan til now is that I should get the TOEFL down with a minimal score as enough as NABP requires. I will update this thread in future while the future plan gets more detail in my mind.

Update on 11:18pm May 7th 2015

Just a minute ago I notice that the “phonics” is a good way to improve my oral English. Therefore during the last time before the September I should master the way of phonics to improve my English.

Update on 10:57pm May 22nd 2015

There are so many textbooks to read but the time is not very enough for me. So I shall focus on my major disciplines that include critical care, infectious diseases, and hematology. Time is limited, so efficacy of learning is important.

Update on 5:38pm May 24th 2015

I just took Nancy and Van’s suggestion to improve oral English by watching TED videos. That’s go great, though most of the time I must watch the subtle. However, it is a good start. I think great improvement needs a period of time to accumulate. I will keep on.

The Outcomes of Inflammation (Acute Inflammation)

May 3, 2015 Infectious Diseases, Physiology and Pathophysiology No comments , , ,

Although, as might be expected, many variables may modify the basic process of inflammation, including the nature and intensity of the injury, the site and tissue affected, and the responsiveness of the host, all acute inflammatory reactions typically have one of three outcomes.

  • Complete Resolution

In a perfect world, all inflammatory reactions, once they have succeeded in eliminating the offending agent, should end with restoration of the site of acute inflammation to normal. This is called resolution and is the usual outcome when the injury is limited or short-lived or when there has been little tissue destruction and the damaged parenchymal cells can regenerate. Resolution involves removal of cellular debris and microbes by macrophages, and resorption of deem fluid by lymphatics.

  • Healing by Connective Tissue Replacement

Also known as scarring, or fibrosis, which occurs after substantial tissue destruction, when the inflammatory injury involves tissues that are incapable of regeneration, or when there is abundant fibrin exudation in tissue or in serous cavities (pleura, peritoneum) that cannot be adequately cleared. In all these situations, connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue, a process also called organization.

  • Progression of the Response to Chronic Inflammation

Acute to chronic transition occurs when the acute inflammatory response cannot be resolved (like the stimulators of acute inflammation could not be eliminated adequately, etc.), as a result of either the persistence of the injurious agent or some interference with the normal process of healing.