Insulin structure activity relationship for quinolones

insulin structure activity relationship for quinolones

The anti-TB property mode of action and structure activity relationship studies of the some known quinolone derivatives are studied. Furthermore, the activity of. Although the bactericidal activities of the quinolones correlated well with their . The relationships between bactericidal activity, PAE and chemical structure. Agui H, Mitani T, Izawa A, Komatsu T, Nakagome T. Studies on quinoline derivatives and related compounds. 5. Synthesis and antimicrobial activity of novel.

Human Pharmacodynamics A large body of human pharmacokinetic data has been accumulated during studies of the various quinolones. A pharmacodynamic perspective on these kinetic data comes from attempts to correlate either microbiologic or clinical endpoints to these kinetic indices. However, because there are numerous difficulties in conducting adequately powered clinical pharmacodynamic analyses, there remains a high degree of uncertainty over the proper dosage of these drugs in patients.

MIC of ciprofloxacin in one study ranged from 6 to over A range of this magnitude may occur in any patient population due to variability in pharmacokinetics and organism susceptibility.

This partially explains why clinical studies that do not directly measure AUC: MIC or another measure of the interaction between pharmacokinetics and pharmacodynamics cannot possibly differentiate between two doses of the same antibiotic or between two different antibiotics.

The studies cited previously by Forrest, Preston and Ambrose remain the landmark investigations of fluoroquinolone pharmacodynamic parameters which relate to patient outcomes. These investigations demonstrate the contributions of both the peak: Efficacy against Gram-negative organisms was optimal when peak: For Gram-positive pathogens, a free AUC: More specifically, these agents target the action of topoisomerase II also called DNA gyrase and topoisomerase IV, which belong to a group of related enzymes known as DNA topoisomerases found in all organisms Since DNA gyrase maintains the chromosome in a supercoiled state and repairs small single-strand breaks in DNA that occur during replication, its inhibition provides a possible explanation for the bactericidal activity of these agents.

The role of topoisomerase IV in bacteria is to separate the daughter chromosomes following the replication process. Bacterial resistance to the fluoroquinolones is primarily chromosomally mediated.

Structure-activity relationships of the fluoroquinolones.

Fluoroquinolones have two primary targets with multiple subunits: Both are critical to the organism for active replication. Ciprofloxacin and levofloxacin preferentially bind to the C subunit of topoisomerase IV, while gatifloxacin and moxifloxacin show a greater affinity for the A subunit of DNA gyrase. Resistance which develops in Gram-positive organisms occurs in this step-wise manner.

In general, a mutation in topoisomerase IV will occur first, producing only a small-to-moderate increase in MIC. Mutants isolated from patients were found to have alterations in the serine residue. Resistance to quinolones can also result from changes in permeability. While some efflux systems preferentially act on select agents, several confer resistance to all fluoroquinolones and some provide cross resistance with other classes of antimicrobials.

The magnitude of increase in MIC resulting from hyperexpression of genes that express efflux pump proteins is dependent on the quinolones and the particular efflux system. The pharmacokinetic parameters of the newer fluoroquinolones have many similarities, although there are differences in half-life, degree of absorption, metabolism, and elimination.

In general, quinolones exhibit linear pharmacokinetics, with increases in serum concentrations directly proportional to dose size, and pharmacokinetic properties serum half-life, total body clearance, etc. Renal clearance mechanisms are the most important for removal of ofloxacin, levofloxacin, and gatifloxacin.

Renal excretion of these compounds occurs via both tubular secretion and glomerular filtration, with glomerular filtration as the major component.

Hepatic mechanisms of elimination are more important for removal of trovafloxacin, and multiple mechanisms of elimination contribute to norfloxacin, ciprofloxacin, moxifloxacin and gemifloxacin elimination. Fluoroquinolones are excreted across the bowel wall into the intestinal lumen, which also explains their efficacy in diarrheal diseases. Absorption The excellent bioavailability of the quinolones allows oral dosing in place of the more traditional parenteral administration.

With most of the new fluoroquinolones, oral absorption is sufficient to achieve adequate serum bactericidal activity for systemic infections 50,, Fluoroquinolones are absorbed primarily in the duodenum and the proximal jejunum. Absorption does not require acidity or an alkaline environment and fluoroquinolones are absorbed to a similar extent in a fasting state or with a meal, The absolute bioavailability of several of these compounds has not been characterized because intravenous dosage forms are not available for human studies.

The fluoroquinolones are rapidly absorbed after oral dosing, reaching peak serum concentrations in 1 to 2 h. For comparison purposes, all values were normalized to a mg oral dose, making the assumption that peak serum concentrations and AUC are proportional to dose. Levofloxacin, trovafloxacin and moxifloxacin reach the highest peak values; norfloxacin, gemifloxacin, and ciprofloxacin are lower 96 These latter compounds have larger steady-state volumes of distribution Table 2.

Elderly and critically ill individuals absorb the drugs normally, but peak concentrations in these individuals are generally delayed and are usually higher, since such patients frequently have a concomitant decrease in renal function.

Study of Antimicrobial Quinolones and Structure Activity Relationship of Anti-Tubercular Compounds

For comparison purposes, all values were normalized to a mg oral dose, assuming that peak serum concentrations and AUC are proportional to dose. In some studies, peak concentration or AUC changed out of proportion to dose; however, the deviations from linearity were not substantial.

The potential clinical significance of the large differences between compounds in peak serum concentrations and AUC will be addressed as these AUC values are integrated with relative antimicrobial potency.

Clearly, the apparent volume of distribution of all fluoroquinolones exceeds the 0. However, the derived values in the literature vary considerably, even for the same quinolone, presumably because few studies used intravenous forms of these drugs to determine precise volumes of distribution. The accuracy of the derived value depends upon knowing bioavailability accurately enough to factor it out.

For example, after intravenous administration of ciprofloxacin, the apparent volume of distribution was 2. If an oral dose were used to assess this parameter, it would appear to be higher in the range of 3. This effect deserves attention because most of the fluoroquinolones that appear to have incomplete distribution volumes actually have incomplete bioavailability.

All of the newer fluoroquinolones are widely distributed throughout the body. Concentrations significantly above those in serum are attained in the kidney, liver, and lung; levels in saliva, bronchial secretions, and prostatic fluid are lower than those in serum 96, Urine drug concentrations are high and remain above the MICs of common urinary pathogens.

In most instances, they exceed inhibitory levels for urinary pathogens for a full 24 h. The lowest concentrations of fluoroquinolones in urine are seen with trovafloxacin 41,and moxifloxacin The highest urinary concentrations are noted with gatifloxacin 96and levofloxacin 364370because these compounds are well absorbed and are excreted by the kidney completely unchanged.

Most fluoroquinolones continue to achieve adequate therapeutic concentrations in the urine, even when renal function is greatly reduced. Consistent with transintestinal elimination,the fecal levels of most quinolones are sufficient to inhibit most gastrointestinal bacterial pathogens.

insulin structure activity relationship for quinolones

The levels of ciprofloxacin and ofloxacin in human aqueous humor range from 3. Ciprofloxacin, ofloxacin, and other quinolones appear to penetrate into prostate tissue and seminal fluid reaching concentrations exceeding those achieved in serum. Ciprofloxacin penetrates well into pancreatic tissue. The penetration ratio in one study was 1. Biliary concentrations also exceed those in serum After a single mg intravenous dose, concentrations of ciprofloxacin in cortical bone and cancellous bone were 6.

Other quinolones also appear to penetrate bone. However, these values should be interpreted cautiously because tissue: Bone marrow tissue concentrations are excellent and in almost every case exceed MICs for infecting bacteria Quinolones also reach high concentrations inside many cells.

  • Structure-activity relationships of the fluoroquinolones.
  • Quinolones

An anionic transport mechanism removes the compounds from white blood cells 96, Tissue concentrations are generally higher in infected tissues than in uninfected tissues, because of WBC accumulation. There are more white blood cells in infected tissue, and these compounds are probably present intracellularly in concentrations higher than those in extracellular fluids, though the degree of antimicrobial activity of these drugs at intracellular sites has not been well studied.

Thus any compromise of antimicrobial activity by the presence of serum protein should be minimal. Some of the newer fluoroquinolones have higher protein binding: Routes of Elimination Metabolism Hepatic metabolism is essential for clearance of several fluoroquinolones.

In the case of fluoroquinolones such as norfloxacin and ciprofloxacin, most metabolism occurs at the piperazine substituent on ring position 7 Figure 1. In contrast to the pathway for the earlier quinolone compounds, metabolic alteration of the newer fluoroquinolones does not typically occur on the position 7 ring. And whereas the metabolic products of earlier quinolones had antimicrobial activity, glucuronides formed at position 3 are clearly inactive because this part of the molecule is essential for antimicrobial activity.

As with most oxoquinolone metabolites, the oxo- metabolite of ciprofloxacin is active, although less so than ciprofloxacin. In animal studies using 14C-Iabeled ciprofloxacin, all of the radiolabeled drug can be accounted for in the combined collections of urine and stool. The remainder was recovered in urine as unchanged drug and metabolites, Extensive data on the metabolism of many of the newest fluoroquinolones are not yet available.

However, gatifloxacin and gemifloxacin appear to undergo minimal metabolic conversion. To some extent, all fluoroquinolones are excreted in bile, unchanged and as metabolites. For reasons detailed above, hepatic disease in the presence of normal renal function does not produce major changes in the serum half-life of the renally excreted agents ciprofloxacin, ofloxacin, levofloxacin, and gatifloxacin Little is known about the disposition of the hepatically cleared fluoroquinolones such as trovafloxacin and moxifloxacin in patients with hepatic disease.

Dramatic changes in half-life, similar to those occurring for renally excreted fluoroquinolones in renal failure, would be anticipated for these agents. Quantitative studies in patients with severe renal and hepatic disease are rare.

Further studies should be conducted to characterize pharmacokinetic alterations in these patients. Renal Excretion Quinolones are eliminated by renal mechanisms, including glomerular filtration and tubular secretion, as well as by nonrenal routes, such as hepatic metabolism and transintestinal transport The terminal half-lives of the fluoroquinolones range from 3.

Since the elimination of the compounds is different, terminal half-lives increase to varying degrees, depending on the degree of elimination via renal and hepatic function. Fluoroquinolones excreted primarily by hepatic metabolism e.

Renal clearance usually exceeds the glomerular filtration rate, suggesting that tubular secretion plays a major role in the elimination of these drugs. The fact that most of these antibiotics interact with probenecid,is further evidence that these compounds undergo renal tubular secretion.

Probenecid also reduces the renal excretion rate of norfloxacin, gemifloxacin, levofloxacin, and gatifloxacin. Fluoroquinolone compounds are moderately affected by renal disease, with levofloxacin, ofloxacin, and gatifloxacin showing the greatest sensitivity Table 2 69, With the exception of moxifloxacin, the available fluoroquinolones require dosage reduction for patients with renal insufficiency Table 6.

Accordingly, patients undergoing hemodialysis should receive the same reduced doses that would normally be given to patients with end stage renal function, and supplemental doses are not needed between dialysis sessions in anuric patients Frequently, alternate pathways account for excretion of drugs in patients with renal failure 69 This is evidenced in the finding that for some compounds only modest dose reductions are required even for patients with severe renal dysfunction.

Quinolones- Infectious Disease and Antimicrobial Agents

Renal impairment does not markedly affect trovafloxacin and moxifloxacin, because these compounds are primarily eliminated by non-renal pathways. Conversely, half-lives of ofloxacin, levofloxacin, and gatifloxacin can increase up to fivefold in severe renal dysfunction 69 No data are presently available regarding the impact of renal dysfunction on the half-life of gemifloxacin. Hepatic Metabolism Compared to the other fluoroquinolones, drug metabolism occurs to the greatest extent for trovafloxacin 41, and moxifloxacin This comparison verifies a shift in the excretion pattern of these drugs in patients with renal failure, for more of the compound is metabolized or excreted in bile.

As with all drugs subject to excretion by combinations of renal and metabolic pathways, patients with multiple organ failure and resulting impairment of both pathways would show extreme prolongations of serum half-life. In this case, neither elimination pathway can compensate for failure of the other, and marked accumulation would occur. Severe hepatic disease also would be expected to prolong the serum half-lives of trovafloxacin, moxifloxacin and norfloxacin. In fact, ciprofloxacin and norfloxacin may accumulate in patients with hepatic failure 80particularly with concomitant renal impairment 75 Potential risk of bone and cartilage adverse effects has limited the use of fluoroquinolones for pediatric infections.

Dosage adjustment should be based on the degree of renal impairment, severity of the infection, susceptibility of the pathogenic organism, and expected serum concentrations of the agent.

Hepatic Failure Pharmacokinetic studies in hepatically impaired patients are limited. Higher peak plasma levels of certain quinolones may be observed; however, dose adjustments may not be necessary unless there is concomitant renal impairment. The adverse events associated with the quinolones are typically mild, self-limited, and only rarely require discontinuation of treatment.

Some adverse effects of quinolones e. GI symptoms and arthropathy do not appear to be related to specific structural modifications of the drug; whereas phototoxicity and CNS effects are linked to specific structure-activity relationships Each quinolone tends to produce a characteristic profile of adverse effects.

The frequency of these various effects has not been evaluated in head-to-head comparative studies, because the clinical trials conducted for registration purposes usually study comparators from other antibiotic classes.

Rare but severe adverse reactions resulted in market withdrawal of several fluoroquinolones in the s. Since then, lomefloxacin has been associated with CNS toxicity and phototoxicity, and tosufloxacin has been linked to severe thrombocytopenia and nephritis. Sparfloxacin was voluntarily removed from the US market in due to concerns of phototoxicity and QT interval prolongation. Inclinafloxacin development was stopped in light of safety concerns regarding liver toxicity, arrhythmias, and phototoxicity.

Also ingrepafloxacin was voluntarily withdrawn from the worldwide market after reports of a small number of cardiovascular events related to QT prolongation. The production of trovafloxacin was limited shortly after its launch, then was subsequently withdrawn, due to reports of rare but serious liver injury. In May ofthree months after receiving a new contraindication against use in patients with diabetes mellitus, the manufacture of gatifloxacin was stopped, following data demonstrating its relationship with altered glucose metabolism 3, Fortunately, for compounds which remain on the market, adverse effect profiles are generally mild and more predictable.

The most frequently reported symptoms included nausea 1. For the most commonly prescribed quinolones, levofloxacin, ciprofloxacin, and moxifloxacin, the overall profile and rate of adverse events is similar. However, quinolone therapy can be associated with potentially serious adverse reactions which must be considered when prescribing any agent of this class.

Connective Tissue Damage Several quinolones pefloxacin, ciprofloxacin, norfloxacin, levofloxacin have been linked to tendon injury in a number of case reports and retrospective surveillance studies.

The mechanism by which fluoroquinolones are thought to damage connective tissue has not been established, but it is hypothesized to be related to oxidative damage and vascular ischemia. In animal studies, effects were more pronounced in subjects fed a magnesium-deficient diet, suggesting that chelation of magnesium could lead to radical formation and subsequent tissue damage A review of published case reports revealed that the most common site of tendopathy is the Achilles tendon, and injury can present as tendonitis or tendon rupture.

The median duration of therapy prior to the onset of symptoms was six days, and renal dysfunction and corticosteroid use were implicated as possible risk factors. Patients who engage in sports or frequent exercise should use caution when receiving fluoroquinolones. Another manifestation of connective tissue toxicity of the quinolones is inhibition of the epiphyseal growth plate and cartilage in the developmental stage. Arthropathy has primarily been observed in studies of young experimental animals, especially beagle dogs.

Clinical experience with the quinolones in the human pediatric population is limited because routine use in this age group is discouraged. The lack of a reliable early marker for articular damage in pediatric patients and the uncertain causal relationship between the use of the newer fluoroquinolones as opposed to nalidixic acid may further complicate the question of risk-benefit. In carefully selected pediatric patients, the use of quinolones with close monitoring and limited ambulation may be justified for indications such as pulmonary infection in cystic fibrosis, salmonellosis, complicated urinary tract infection or after exposure to anthrax 8.

Renal Injury Animal studies suggest the possibility of interstitial inflammatory reactions associated with precipitation of quinolone complexes within the kidney's tubular walls. Animals with distinct crystalluria have subsequently developed obstructive uropathy. The dose producing nephropathy exceeds the dose that produced crystalluria, and doses for both of these events produce serum concentrations well above the human therapeutic range. Acute renal failure, interstitial nephritis, and nonspecific nephritis were each reported once in the ciprofloxacin recipients reviewed by Arcieri et al.

Additional case reports have subsequently linked both ciprofloxacin and levofloxacin 66with the development of interstitial nephritis. Severe neurotoxic side effects are rare; however, hallucinations, depression, and psychotic reactions have been reported during therapy with many quinolones. The mechanism of neurotoxic effects is not clear but appears to be related to one of two properties: It appears that a large C-7 side chain may minimize the degree of GABA inhibition, and overall lipophilicity of the molecule is important for penetration across the blood-brain barrier Figure 1.

CNS effects may also be potentiated by interactions with other medications such as theophylline 47 Many patients reporting CNS symptoms in the early studies of fluoroquinolones had received concomitant theophylline or caffeine. Enoxacin and also ciprofloxacin, pefloxacin, and grepafloxacin significantly increase peak and trough serum theophylline concentrations. In a study that was uncontrolled for theophylline administration, enoxacin mg twice daily was associated with a These results follow the rank order of potency of these fluoroquinolones in inhibiting the theophylline-metabolizing isozyme.

Photosensitivity Varying frequencies of photosensitization have been reported with the quinolones. Of the older quinolones, nalidixic acid is well known to cause occasional phototoxic skin reactions, and on the basis of previous reactions to this agent, the potential for phototoxicity with the newer fluoroquinolones was predicted.

This side effect is dose related and can be avoided or prevented by avoiding exposure to sunlight or ultraviolet radiation. The potential for phototoxicity associated with ciprofloxacin, ofloxacin, trovafloxacin, levofloxacin, gatifloxacin, moxifloxacin, and gemifloxacin appears similar and are lower than that of clinafloxacin, lomefloxacin, and nalidixic acid, compounds that are substituted with an additional chlorine or fluorine moiety at the C-8 position.

Figure 1 Fluoroquinolones with a naphthyridone base, such as enoxacin, have also been linked to phototoxicity 48 Figure 2 In clinical trials of gemifloxacin, which contains a naphthyridone base, photosensitivity reactions were rare 0. These phototoxic quinolones induce free radical formation causing tissue damage In an analysis by the Food and Drug Administration FDA of spontaneous reports, lomefloxacin phototoxicity occurred in 70 perprescriptions, compared with less than 0.

Patients given these more definitively phototoxic fluoroquinolones should be cautioned to avoid exposure to sunlight. Glucose Metabolism Some quinolones have been shown in animal studies to increase insulin release from pancreatic islet cells Reports of altered glucose metabolism with gatifloxacin led to its removal from the market; however, other quinolones have been infrequently associated with this complication In many reports, patients experiencing hypoglycemia had diabetes mellitus and were also being treated with a hypoglycemic medication.

Elderly patients with or without diabetes may also be at a higher risk for quinolone-associated alterations in glucose metabolism 16 In a retrospective study of over patients in a Veterans Administration health care system, Lodise et al.

insulin structure activity relationship for quinolones

Cardiovascular Toxicity A great deal of attention has been directed to cardiovascular toxicity induced by some quinolones. Several quinolones have been linked to QT prolongation and arrhythmias including torsades de pointes.

Extensive ECG testing was conducted during the development of moxifloxacin. Although individual quinolones alter cardiac action potential to varying degrees, cardiovascular toxicity appears to be a class effect.

Case reports and clinical studies show that moxifloxacin carries the greatest risk of QT prolongation from all available quinolones in clinical practice while ciprofloxacin appears to be associated with the lowest risk. As with the adverse events, there is no head-to-head comparative study, and the rank ordering is by inference on the basis of noncomparative reports and studies against the same or similar non-quinolone comparator antibiotics Some significant and potentially significant interactions are summarized below.

Anticoagulants Studies on the interactions between quinolones and warfarin demonstrate that norfloxacin prolongs the elimination half-life of R -warfarin, while not affecting S -warfarin. Because the R -enantiomer is five to eight times less active than the S - isomer, the overall norfloxacin-warfarin interaction should be of little clinical significance.

In clinical trials of newer agents, no significant interaction with warfarin was described. However, several anecdotal cases have implied interactions between warfarin and commonly-prescribed quinolones 1564, Any patient receiving a quinolone along with warfarin anticoagulation should have prothrombin time closely monitored. Divalent Cations Fluoroquinolones form chelates with divalent cations, particularly aluminum and magnesium and, to a lesser degree, iron, zinc, and calcium.

Iron preparations behave similarly to antacids, and adequate time should be allowed between doses. Multivitamin preparations that contain minerals should be avoided as well. Allowing a 4- to 6-h interval between the administration of antacids or sucralfate and fluoroquinolones will likely avoid the interaction, but this is not always a suitable alternative for patients on long-term antacid treatment. Histamine-2 antagonists do not affect the oral absorption of fluoroquinolones and can be used for acid control when the quinolones must be used in the presence of acid-reducing medications.

The expanded use of oral fluoroquinolones in hospitalized patients has lead to concern over the possibility of similar interactions with enteral nutrition formulations.

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insulin structure activity relationship for quinolones

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insulin structure activity relationship for quinolones

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