C. Tesseromatis

The role of the protein-binding on the mode of drug action as well the interactions with other drugs.

SummaryDrug transport and disposition are influenced by a non-specific and reversible drug binding to plasma and tissues proteins. Albumin and al acid glycoprotein are the most important transport proteins of the blood. Albumin possesses specific sites for acidic and basic drug binding and can interact with them in the plasma since a third site is trapped only by digoxin. Diseases and stress conditions induce conformational changes either in plasma or in tissue proteins by the synthesis of endogenous substances which can strong interfere with the amount of the free pharmacological effective drug ratio. This may affect the binding of drugs in target molecules inducing significant pharmacokinetic alterations. Stress conditions are associated with FFA increase in serum playing an antagonistic role with other acidic molecules (e.g. ampicillin) to the same binding site. The bounded drug is displaced and freer ratio is available to interact with various organ receptors leading to pharmacological effect enhancement and therefore to side effects manifestation such as seizures. Furthermore conjunctive tissues diseases, ageing, prolonged bleeding, starvation or diseases affecting protein profile, characterized by reduced total plasma proteins, followed by albumin decrease and lessen binding sites lead to more free drug availability enhancing its pharmacological effect. Increased a1-acid glycoprotein the acute phase protein as by heart infraction or liver morbidities (e.g CCl4 intoxication) mainly occupied from basic substances, in the case of cationic drug treatment resulted to the enhancement of the and consequently to pronounced effectiveness. In addition, renal failure reduced free fractions of many acidic drugs. It may be concluded that by narrowed therapeutic index of a medicine, and when drug/drug or drug/disease interactions are anticipated, drug monitoring seems to be necessary for its dosage adjustment.

Morphological Changes of Gingiva in Streptozotocin Diabetic Rats

Gingivitis and periodontitis are chronic bacterial diseases of the underlying and surrounding tooth tissues. Diabetes mellitus is responsible for tooth deprivation both by decay and periodontal disease. The streptozotocin-induced diabetes results in a diabetic status in experimental animals similar to that observed in diabetes patients. The aim of the study was to investigate the relationship between the gingival lesions and the microangiopathy changes in streptozotocin-induced diabetes mellitus. Forty male Wistar rats were divided into two groups (control and experimental). Diabetes mellitus was induced by 45 mg/kg IV streptozotocin. The histological investigation of the marginal gingival and the relevant gingival papilla showed inflammation of the lamina propria and the squamous epithelium as well as marked thickness of the arteriole in the diabetic group, but no changes were observed in the control group. The results suggested a probable application of a routine gingival histological investigation in diabetic patients in order to control the progress of disease complications. It may be concluded that histological gingival investigation can be used as a routine assay for the control of the diabetic disease and prevention of its complications.

Does stress influence ampicillin concentration in serum and tissues

SummaryExercise produces changes of drug levels in plasma and increases the concentration of free fatty acids (FFAs), which may interfere with drug-protein binding. FFAs seem to play an antagonistic role to drugs since they have a strong binding capacity to serum albumin. The aim of this study was to evaluate the influence of the consecutive exercise-induced stress in ampicillin levels. Two groups of Wistar rats were used. Group A consisted of six subgroups that were subjected to cold swimming (4°C) for 5, 10, 15, 20, 25, 30 days respectively. Group B was the control group. The animals were injected im. with ampicillin (1 g/Kg/8h in 5 doses). Results showed that exercise enhanced stress parameters (FFAs, adrenal weight, Ht%) and led to an ampicillin increase in all experimental groups comparatively to controls.

H3 propranolol serum levels following lidocaine administration in rats with CCL4 - induced liver damage

SummaryLiver disease alters the pharmacokinetic and pharmacodynamic properties of hepatically eliminated drugs. The main factors influenced are plasma albumin levels, enzyme balance (induction & inhibition) and drug binding to tissue proteins.The influence of lidocaine on serum, heart and liver propranolol levels in Wistar rats after liver injury induced by carbon tetrachloride CCl4 0.4 ml/kg × 2/wkl, was investigated.40 male Wistar rats were divided into four groups (I, II, III, IV; n=10), Group I animals received only propranolol (labelled + cold substance) 40 mg/kg/12 h p.o., group II propranolol plus lidocaine in a single dose of 4mg/kg s.c, group III was treated with CCl4 for 6 weeks and received propranolol ×2 at the same dosage as group I, while group VI was treated with CCl4 and the same drug dosage as group II. The simultaneous administration of H3-propranolol and lidocaine increased propranolol levels in the serum and tissues. The liver in damaged animals showed an increase of propranolol level under lidocaine co-administration, probably due to CCl4 — induced liver enzyme activity, resulting in a rapid propranolol metabolism or to competition between both drug protein binding sites. The increased propranolol levels in the heart after lidocaine administration were probably due to attributed to its high affinity for heart tissue. Consequently, as regards the therapeutic approach for patients with liver disease receiving propranolol their propranolol dosage should be reduced when lidocaine is co-administered.

Alterations in cefalosporin levels in the serum and mandible of hyperlipaedemic rats after co-administration of ibuprofen

SummarySeveral interactions between antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) have been described in the literature, and it has been reported that hyperlipidaemia induces significant changes in cefalosporin levels. The aim of this study was to determine the changes in the levels of several cefalosporins in the serum and mandible after ibuprofen co-administration in hyperlipaedemic rats. One hundred and forty male Wistar rats were used and divided in 4 groups (A−D), each of which was further divided into 5 subgroups (1–5), either with placebo or with various treatment regimes. The co-administration of NSAIDs led to increased cefalosporin levels in both control and hyperlipidaemic animals. Hyperlipidaemia was also found to augment cefalosporin levels. These observed increases might be due to the displacement of the cephalosporins from their binding sites in serum albumin and tissue proteins in the presence of ibuprofen. NSAIDs showed a greater binding affinity for tissue proteins compared to the cephalosporins, and probably play an antagonistic role in protein binding, resulting in higher concentrations of anbtibiotics.

Stress-induced lidocaine modification in serum and tissues

SummaryThe aim of this study is to examine the influence of acute (trauma) and chronic (cold swimming and adjuvant rheumatoid arthritis) stress on lidocaine concentrations in plasma. Forty male Wistar rats were used. The animals were divided into four groups. Group A served as control. Group B underwent mandible osteotomy. Group C was submitted to swimming stress in cold water 4°C for ten minutes daily for 15 minutes, while group D underwent experimental arthritis with Freud’s adjuvant. All groups received lidocaine i.m (2.5 mg/kg). Blood samples were collected and FFA (free fatty acid), unbound-lidocaine, albumin and a1-acid glycoprotein concentrations were estimated. Furthermore, the adrenals, heart and liver were isolated. The adrenals’ relative weight (adrenal weight/body weight) was assessed, while lidocaine concentrations in the heart and the liver incubation medium were measured by intertechnic a-counter.Lidocaine and FFA levels in serum as well as the adrenal weights demonstrated a significant elevation in stress-groups as compared to the control group. Furthermore, in the stress-groups, lidocaine concentrations in heart tissue were significantly increased, whereas in the liver they were significantly reduced as compared to the control group. Our results indicate that stress can alter lidocaine levels in plasma and tissues, suggesting that stress should be considered an important factor when determining the dosage of lidocaine in clinical application.

Ketamine-induced changes in metabolic and endocrine parameters of normal and 2-kidney 1-clip rats.

Background and objective: The aim of this study was to investigate the effect of ketamine on the endocrine and lipid metabolic status of the renal‐banded animals. Methods: Forty male rats were randomly divided into four groups. Group A served as control, Group B animals received ketamine intraperitoneally at a dose of 100 mg kg−1, Group C was submitted to 2‐kidney 1‐clip experimental hypertension and Group D received ketamine as above, as well as being submitted to renal artery clipping. Atrial natriuretic peptide, angiotensin II and free fatty acid concentrations were measured in serum. In addition, adipose tissue lipoprotein lipase activity and angiotensin II content were determined, while the left ventricular weight relative to body weight was used as a cardiac hypertrophy index. Results: In renal‐banded rats (Groups C and D) serum atrial natriuretic peptide, free fatty acid and angiotensin II concentrations as well as ventricular weight were increased, while adipose tissue lipoprotein lipase activity was lower than in control animals (Groups A and B). Ketamine administration did not influence angiotensin II concentrations either in normal (Group B) or banded rats (Group D). Ketamine increased serum atrial natriuretic peptide and free fatty acid concentrations only in normal animals (Group B). It had no influence on adipose tissue lipoprotein lipase activity either in normal (Group B) or banded animals (Group D). Adipose angiotensin II content did not differ between the four groups. Conclusion: Ketamine increased the atrial natriuretic peptide and free fatty acid concentration in normal rats. In 2‐kidney 1‐clip animals, ketamine did not elicit an additional response of serum atrial natriuretic peptide or free fatty acids levels. Its contribution to these factors was not significant.

Adjuvant arthritis-induced changes on ampicillin binding in serum and tissues under the influence of non-steroidal anti-inflammatory drugs in rats.

SummaryAdjuvant arthritis, as a model for investigating rheumatoid arthritis (RA), is characterized by reduced plasma albumin levels and interferes with drug binding in the plasma and tissues (liver and bone). Ampicillin interacts with non-steroidal anti-inflammatory drugs (NSAIDs) due to the acidic pka.The aim of this study was to investigate in vitro the concentrations of ampicillin in the serum, femur, mandible and liver proteins following the co-administration of ketoprofen, flurbiprofen, ibuprofen, oxyphenbutazone and ASA in adjuvant arthritis versus healthy control rats. Ampicillin binding was found to be reduced in the serum of arthritic rats, and ampicillin binding to serum proteins was also reduced under the influence of NSAIDs in the control animals. Differences in ampicillin binding were observed in the various tissues due to the effect of adjuvant arthritis as well as that due to the co-administration of NSAIDs.In conclusion, this in vitro study may provide a plausible explanation for the ampicillin-NSAIDs interaction and such a finding may be of therapeutic significance in the treatment of painful arthritic disease such as RA.

Stress can affect drug pharmacokinetics via serum/tissues protein binding and blood flow rate alterations

Binding of drugs to plasma and tissue proteins is critically involved in their pharmacokinetics and pharmacodynamics. Stress affects drugs’ protein binding via alterations in plasma proteins’ levels and excessive increase of free fatty acids due to cortisol-induced fat mobilisation. Free fatty acids play a crucial antagonistic role to drugs for the binding sites on albumin, the major binding plasma protein, resulting in subtherapeutic or toxic levels of many medications’ pharmacological classes (oral anticoagulants, beta-lactames, fluoroquinolones, local anaesthetics). Upon stress, changes in blood flow rate and vascular function are also important parameters that can alter drug distribution and pharmacokinetics. Many cases are reported where stress-induced pharmacokinetic alterations led to serious clinical consequences. However, the stress affected drug activity do not always deteriorate the clinical outcome, due to the adaptive and defensive mechanisms of healthy organism. Sensitive population as patients with serious underlying diseases or after trauma or surgery should be given special attention. Clinicians should be alert and monitor cases where stress-induced drugs’ pharmacokinetic modifications can have negative impact on the clinical outcome.

Lipid kinetics in obese patients undergoing laparoscopy. the impact of cortisol inhibition by etomidate

SummaryThe aim of this study was to investigate the response of cortisol, insulin and lipid parameters [serum Lipoprotein Lipase activity, choleseryl-ester transfer protein, triglycerides, total Cholesterol, High Density Lipoprotein, Free Fatty Acids] during the perioperative period in obese patients undergoing laparoscopic cholecystectomy.Twenty obese patients were included and divided in two groups. In group A (n=10) patients were anaesthetized with propofol and group B (n=10) with etomidate. Blood samples were collected before induction in anaesthesia, just after the end of the operation and at one, two and three hours postoperatively.According to our results, in both groups serum LPL activity showed a significant decrease whereas serum Free Fatty Acids a potent increase over time. Likewise, both groups did not demonstrate significant changes over time in choleseryl-ester transfer protein activity, total cholesterol, triglycerides, High Density Lipoprotein or insulin concentrations in serum. Furthermore, Cortisol release was significantly inhibited in the etomidate group while substantially enhanced in propofol group. Additionally, apart of triglycerides, no difference was found between the two groups in all the lipid parameters and insulin concentrations. In conclusion, serum Free Fatty Acids levels and Lipoprotein Lipase activity demonstrated significant alterations in obese patients underwent laparoscopic cholecystectomy and this result did not seem to be related with the anaesthetic agent used for induction in anaesthesia.