Blood Level Monitoring Research Articles

Gentamicin Exposure and Sensorineural Hearing Loss in Preterm Infants.

ObjectiveTo evaluate the impact of gentamicin exposure on sensorineural hearing loss (SNHL) in very low birth weight (VLBW) infants.MethodsExposure to gentamicin was determined in infants born between 1993 and 2010 at a gestational age < 32 weeks and/or with a birthweight < 1500 g, who presented with SNHL during the first 5 years of life. For each case, we selected two controls matched for gender, gestational age, birthweight, and year of birth.ResultsWe identified 25 infants affected by SNHL, leading to an incidence of SNHL of 1.58% in our population of VLBW infants. The proportion of infants treated with gentamicin was 76% in the study group and 70% in controls (p = 0.78). The total cumulated dose of gentamicin administered did not differ between the study group (median 10.2 mg/kg, Q1-Q3 1.6–13.2) and the control group (median 7.9 mg/kg, Q1-Q3 0–12.8, p = 0.47). The median duration of gentamicin treatment was 3 days both in the study group and the control group (p = 0.58). Maximum predicted trough serum levels of gentamicin, cumulative area under the curve and gentamicin clearance were not different between cases and controls.ConclusionThe impact of gentamicin on SNHL can be minimized with treatments of short duration, monitoring of blood levels and dose adjustment.

Variation of trace element concentrations in patients undergoing hemodialysis in the north of Spain

Background: Trace elements are essential substances for the proper physiological and biochemical functioning of the organism. Hemodialysis patients are potentially at risk of deficiency or excess of these elements. The application of inductively coupled plasma mass spectrometry (ICP-MS) allows the simultaneous quantification of very small amounts of multiple trace elements. The aim was to measure the serum concentration of copper (Cu), zinc (Zn), selenium (Se), and nickel (Ni), and the whole blood concentration of arsenic (As), lead (Pb), and manganese (Mn), in patients undergoing hemodialysis as well as in controls.Methods: The study was carried out in 57 hemodialysis patients compared with 57 controls with normal renal function. Serum and whole blood samples from the dialysis group were collected before and after hemodialysis sessions and Cu, Zn, Se, Ni, As, Pb and Mn levels were determined using ICP-MS.Results: Hemodialysis patients showed significantly lower blood levels of Cu, Zn and Se than controls (p < 0.001) and higher concentrations of Ni, As and Pb (p < 0.0001). The levels of Mn were similar in both groups. After performing hemodialysis, Cu, Zn, Se and Ni concentrations were significantly higher than the pre-hemodialysis levels (p < 0.0001). However, the concentration of As decreased (p < 0.0001) and Pb and Mn levels were not significantly altered after the dialysis session.Conclusion: Hemodialysis patients are at increased risk of trace elements deficiency (especially for Zn and Se) or excess (Ni) in respect to healthy subjects. Monitoring of blood levels and supplementation of some trace elements may be indicated in patients undergoing hemodialysis.

Medication Safety

Medication Safety

Three-times-weekly, post-dialysis cefepime therapy in patients on maintenance hemodialysis: a retrospective study.

BackgroundIn hemodialysis patients, post-dialysis treatment with intravenous antibiotics permits even severe infections to be managed on an outpatient basis. Cefepime is a fourth-generation cephalosporin with a broad spectrum of action in monotherapy. We report on the pharmacokinetics of cefepime in post-dialysis therapy.MethodsSince June 2012, twelve infections were treated with post-dialysis cefepime in 9 patients on high-flux hemodialysis. The initial post-dialysis dose of cefepime was approximately 15 mg/kg. The following doses were adapted according to the trough serum levels obtained before the subsequent dialysis in order to be above the EUCAST breakpoints for susceptible organisms and above the MIC90. Residual plasma concentrations were determined before (n = 30) and after (n = 17) dialysis by liquid chromatography–mass spectrometry.ResultsOverall, the mean ± SD dose of cefepime was 920 ± 270 mg (14.5 ± 5.1 mg/kg), but it was significantly lower before the 48 h interval (775 ± 210 mg or 12.7 ± 4.5 mg/kg) compared to the 72 h interval (1125 ± 225 mg or 17.2 ± 4.9 mg/kg) (p < 0.05). The mean trough pre-dialysis concentrations were 10.7 ± 3.9 mg/l and 11.3 ± 5.6 mg/l at 48 and 72 h, respectively. These levels always largely exceeded the EUCAST susceptibility breakpoints for all the targeted bacteria (>1 mg/l) with the exception of Pseudomonas aeruginosa (>8 mg/l). Cefepime concentrations were higher in anuric patients compared to those with preserved diuresis (15.6 ± 3.5 vs 9.25 ± 3.6 mg/l; p < 0.001) and decreased on average by 81 % during dialysis (from 10.5 ± 3.7 to 1.96 ± 1.2 mg/l; p < 0.001). The clinical outcome of all patients was good.ConclusionsOutpatient treatment with cefepime administered post-dialysis three-times-weekly was effective and well-tolerated in our patients. According to our data, in patients infected by highly susceptible pathogens a fixed dose of cefepime of 1 g before every 48-h interval and of 1.5 g before every 72-h interval should be recommended, without need of routine monitoring of the cefepime blood levels. In patients having an infection with less susceptibles pathogens as P. aeruginosa, and particularly in those among them exhibiting residual renal function, higher initial doses are necessary (1.5 g before a 48-h interval and 2.0 g before a 72-h interval) with adaption according to the subsequent pre-dialysis trough serum levels.

Ribavirin: Past, present and future.

Before the advent of direct acting antiviral agents (DAAs) ribavirin, associated to pegylated-interferon played a crucial role in the treatment of chronic hepatitis C, preventing relapses and breakthroughs. In the present era of new potent DAAs, a place is still devoted to the drug. Ribavirin associated with sofosbuvir alone is efficient in the treatment of most cases of G2 infected patients. All options currently available for the last difficult-to-treat cirrhotic G3 patients contain ribavirin. Reducing treatment duration to 12 wk in G1 or G4 cirrhotic compensated patients is feasible thanks to ribavirin. Retreating patients with acquired anti NS5A resistance-associated variants using ribavirin-based strategies could be useful. The addition of ribavirin with DAAs combinations however, leads to more frequent but mild adverse events especially in cirrhotic patients. Preliminary data with interferon-free second generation DAAs combinations without ribavirin suggest that future of the drug is jeopardized even in difficult-to-treat patients: The optimization of ribavirin dosage according to an early monitoring of blood levels has been suggested to be relevant in double therapy with peginterferon or sofosbuvir but not with very potent combinations of more than two DAAs.

Therapeutic Drug Monitoring of Meropenem in Neonate with Necrotizing Enterocolitis: A Challenge.

Necrotizing enterocolitis (NEC) continues to be a major cause of neonatal morbidity and mortality. We describe the added value of therapeutic drug monitoring by presenting the case of a preterm infant with severe NEC treated with meropenem. Dosing strategy will achieve adequate patient outcome when treating pathogens with elevated MIC. As safe as meropenem is, there are not enough data for 40 mg/kg, every 8 h infused over 4 h; accordingly, strict monitoring of blood levels is mandatory. Based on our findings, a 4 h prolonged infusion of 40 mg/kg meropenem, every 8 h, will achieve an adequate patient outcome.

Bipolar Disorders and Carbamazepine: Pharmacokinetics, Pharmacodynamics, Therapeutic Effects and Indications of Carbamazepine: Review of Articles

Carbamazepine is a mood stabilizer which is approved for use in bipolar disorder with manic and mixed episodes. It is also approved for use for the treatment of trigeminal neuralgia, temporal lobe epilepsy (complex partial seizures) and generalized tonic-clonic seizure. It is metabolized in the liver, primarily by CYP450 3A4 and is an inducer of CYP450 3A4 enzyme. The specific mechanism of action of carbamazepine in stabilizing mood is unknown. It exerts effects by decreasing dopamine turn over, enhancement of brain γ-aminobutyric acid (GABA) levels via multiple actions of synthesis and degradation, and modulation of other neurotransmitters, voltage sensitive Na+ channels, extra hypothalamic neuropeptides, secondary messenger systems, and neuro protection. The most common side effects are nausea, vomiting, constipation, diarrhea, loss of appetite, sedation, dizziness and ataxia. Serious side effects may include skin rashes, decreased bone marrow function and confusion. It should not be used in those with a history of bone marrow problems. Routine blood level monitoring is necessary. There is an increased risk of fetal abnormalities if carbamaepine taken in pregnancy. Carbamaepine concentrations are known to be increased with concurrent use of antidepressants (such as fluexetine, fluovoxamine, nefazodone), omeperazole, efavirnaz, ratinovir, valproate, cemitidine and erythrpmycin. Its level decrease when administrated with Rifampin and Cisplatin.

Bipolar Disorders and Valproate: Pharmacokinetics,Pharmacodynamics, Therapeutic Effects and Indications of Valproate: Review of Articles

Valproate is a mood stabilizer which is approved for use in acute and maintenance mania. It is the first line drug for bipolar patients with presence rapid cycling, irritable mania, bipolar disorder with comorbid substance use disorders, severe mania with psychosis, mixed mania and secondary mania. The specific mechanism of action of valproate in stabilizing mood is unknown. It exerts effects by enhancement of brain γ-aminobutyric acid (GABA) levels via multiple actions of synthesis and degradation, and modulation of other neurotransmitters, voltage sensitive Na+ channels, extra hypothalamic neuropeptides, secondary messenger systems, and neuro protection. Common side effects include gastrointestinal (GI) distress, tremor, sedation, hair loss, increased appetite and weight gain. Hepatic failure, pancreatitis, and hyperammonemic encephalopathy are rare serious side effects associated with use of valproate. Routine blood level monitoring is not necessary. There is an increased risk of fetal abnormalities if valproateis taken in pregnancy. Valpraote concentrations are known to be increased with concurrent use of benzodiazepines, non-steroidal antiinflammatory drugs (NSAIDS) such as spirin, cemitidine and erythrpmycin. Its level decrease when administrated with phenobarbitone, phenytoin and carbamazepine.

The clinical pharmacist interventions to improve the immunosuppressive therapy management in a pediatric population: education, adherence, pharmacovigilance

To value and improve the adherence to the immunosuppressive therapy in a pediatric population and the pharmacovigilance activity. From January 2013 to October 2014, the pharmacist has developed an education program for 147 pediatric patients in the management of their home therapy. The methods used to evaluate the adherence were three: the measuring of trough blood concentration of immunosuppressive drugs, a questionnaire and the prescription refill rate. Our secondary goal was to create a family collaboration sensitizing patients and their parents to inform the physician or the pharmacist of any adverse drug reactions. During the education phase, the pharmacist answered patient/family's questions about therapy doubts and curiosities. In the trough blood level monitoring of immunosuppressive drugs, 9% of the patients had an average hematic concentration of immunosuppressive drug out of the expected range. Questionnaires showed that: 12.2% of the patients missed a dose of immunosuppressant drug in the previous month, 2% 2 doses and 1.3% 3 doses. 8.8% of the patients diverged once for about 2 hours the scheduled time in the previous month and 3.4% 2-3 times. 21% of the children/parents said they did not know the correct way of drugs intake in relation to meals. After the training, 45 children/parents followed pharmacist tips more. According the analysis of the prescription refill rate, 10.8% of the patients were late in withdrawing their medications. Through the combination of the three methods, 17.7% of the patients were non-adherent. We identified and reported 15 suspected ADR, of which 4 were serious. Children adherence is widely determined by the ability and role of their parents to manage home therapy. On the contrary, teenagers often want to manage their home therapy by themselves. Pharmacist has to talk to the patient to evaluate adherence obstacles and collaborate with the patient in order to overcome them. Parents can have an active role in reporting ADRs to the pharmacist.

The diagnostic and prognostic significance of monitoring blood levels of immature neutrophils in patients with systemic inflammation.

IntroductionIn this cohort study, we investigated whether monitoring blood levels of immature neutrophils (myelocytes, metamyelocytes and band cells) differentiated patients with sepsis from those with the non-infectious (N-I) systemic inflammatory response syndrome (SIRS). We also ascertained if the appearance of circulating immature neutrophils was related to adverse outcome.MethodsBlood samples were routinely taken from 136 critically ill patients within 48 hours of ICU entry and from 20 healthy control subjects. Clinical and laboratory staff were blinded to each other’s results, and patients were retrospectively characterised into those with SIRS (n = 122) and those without SIRS (n = 14). The patients with SIRS were further subdivided into categories of definite sepsis (n = 51), possible sepsis (n = 32) and N-I SIRS (n = 39). Two established criteria were used for monitoring immature white blood cells (WBCs): one where band cells >10% WBCs and the other where >10% of all forms of immature neutrophils were included but with a normal WBC count. Immature neutrophils in blood smears were identified according to nuclear morphology and cytoplasmic staining.ResultsWith the first criterion, band cells were present in most patients with SIRS (mean = 66%) when compared with no SIRS (mean = 29%; P <0.01) and with healthy subjects (0%). The prevalence of band cells was higher in definite sepsis (mean = 82%) than in patients with possible sepsis (mean = 63%; P <0.05) or with N-I SIRS (mean = 39%; P <0.001), and they had a sensitivity of 84% and a specificity of 71% for the detection of definite sepsis. With the second criterion (that is, patients with normal WBC counts), we noted that immature neutrophils did not differentiate any of the patient groups from one another. Patients who died within 1 week of blood sample provision had higher levels of myelocytes and metamyelocytes (median = 9%; P <0.05) than patients who died at 2 to 4 weeks (median =0.5%).ConclusionsRaised blood levels of band cells have diagnostic significance for sepsis, provided that measurements are not confined to patients with normal WBC counts, whereas an increased prevalence of myelocytes and metamyelocytes may have prognostic application.

Takotsubo syndrome and polymorphic ventricular tachycardia: The chicken or the egg

To the Editor, I read with great interest the study by Hojo et al. [1], published in the Journal, about a 74-year-old woman with bouts of polymorphic ventricular tachycardia (PVT) in the setting of Takotsubo syndrome (TTS) who was found to be hypokalemic and had prominent T-wave and J-wave electrical alternans, and mechanical alternans. The following are some thoughts and questions for the authors’ kind consideration: (1) It is conceivable that TTS came first, as the authors propose, followed by J-wave and T-wave alternans, and QTc interval prolongation, which led to PVT, with perhaps some further facilitation caused by the underlying hypokalemia. However, it is also possible that the patient had bouts of PVT precipitated by the underlying hypokalemia (although later hypokalemia was not associated with electrocardiographic repolarization changes), J-wave and T-wave alternans, and QTc interval prolongation, which in turn led to the physical stress that triggered the TTS. (2) Why did the patient’s hypokalemia take 56 h to control? Was there any reason that larger potassium infusions, of course under close potassium blood level monitoring, were not implemented? (3) The mechanical alternans could have been a phenomenon previously encountered in association with T-wave alternans and in the absence of heart failure, or could have been an epiphenomenon of the precipitated left ventricular failure due to TTS. (4) Although this patient’s hypokalemia was attributed to the hydrocortisone “she had taken for pituitary adrenal insufficiency after surgery for a pituitary tumor” [1], it is conceivable that hypokalemia was also further aggravated by the underlying circulating catecholamines (particularly epinephrine), and thus poorly responded to the potassium infusion. Both, TTS [2] and hypokalemia [3], [4] have been shown to be mediated by specific β2-adrenoreceptor stimulation.

Impact of pre-implant amiodarone exposure on outcomes in cardiac transplant recipients.

Amiodarone remains one of the preferred antiarrhythmic medications for patients with advanced heart failure awaiting cardiac transplant. However, the long half-life and rapid redistribution of this agent into donor myocardium expose heart transplant recipients to potential adverse outcomes. In reviewing the current body of literature, we found that pre-operative amiodarone exposure can increase the risk of bradycardia post-transplant; however, this is unlikely to require permanent pacemaker implant. Further, amiodarone has several serious drug-drug interactions with calcineurin inhibitors. Clinicians should therefore consider empiric reduction in initial dosing for tacrolimus or cyclosporine, and carefully monitor blood levels for at least 3months post-transplant. Although the evidence is conflicting, amiodarone exposure pre-operatively may increase the risk of early graft failure and mortality. Amiodarone use should be minimized whenever possible; if amiodarone cannot practically be discontinued in the pre-transplant phase, judicious monitoring for QTc prolongation and ventricular arrhythmia should be implemented after transplant. As most of the studies included in this review suffered from small sample sizes and limited follow-up, additional research in this area is warranted.

Clozapine toxicity due to a multiple drug interaction: a case report

IntroductionWe report the case of a multiple drug interaction involving clozapine, antifungals and oral contraceptives, which resulted in an increased clozapine plasma level, pericarditis with pericardial effusion and eosinophilia in a young Caucasian woman. These symptoms and signs disappeared a few days after discontinuation of clozapine. At present, we are not aware of reports of clozapine–antifungals interaction, whereas there is only one other case report on the interaction between oral contraceptives and clozapine. The purpose of this case report is to show the risk of potentially serious adverse effects stemming from drug interactions involving medications routinely used in clinical practice.Case presentationA 29-year-old Caucasian woman diagnosed with a schizoaffective disorder was admitted to a psychiatric unit for acute psychosis (hallucinations, delusions and catatonic behavior). She denied smoking tobacco products and was on long-term oral contraceptives. During the first month of hospitalization she was treated with antipsychotics and for 1 week she took simultaneously fluconazole and miconazole gel, after being diagnosed with oral candidiasis. On the last day of antifungals treatment, 29 days after admission, clozapine was started with resolution of psychotic symptoms. After 3 weeks, her clozapine plasma level had increased to 542ng/mL and eosinophilia was observed. She complained of nausea, vomiting and palpitations; echocardiography showed echocardiographic abnormalities and pericardial effusion. Oral contraceptives were discontinued and after 1 week clozapine was interrupted, with a complete resolution of side effects and pericardial effusion within 4 days.ConclusionsClozapine is metabolized by cytochrome P450. The use of inhibitors or other substrates of cytochrome P450, such as antifungals and oral contraceptives, can cause long-lasting interactions and clozapine toxicity. The Naranjo algorithm shows clozapine is a definite cause of pericarditis (score 9) and both clozapine–antifungals and clozapine–contraceptives interactions resulted probable (score 5) in Drug Interaction Probability Scale. A good knowledge on drugs that act as substrates, inhibitors or inducers of cytochrome P450 is mandatory. When those drugs are used in patients taking clozapine, blood level monitoring of clozapine should be recommended, since a lower dose of clozapine might be required to prevent clozapine toxicity.

Spectrophotometric analysis of lithium carbonate used for bipolar disorder

Lithium therapy is the gold standard of treatment for patients with Bipolar Disorder. However, despite its effectiveness, it is a potentially hazardous drug requiring regular monitoring of blood levels to ensure toxic levels are not reached. This paper describes the spectrophotometric analysis of Lithium carbonate in solution as a first step in developing a portable home monitoring device for blood lithium analysis.. Using a high-end spectrophotometer, solutions of lithium carbonate (Li2CO3) have been optically fingerprinted. Preliminary measurements indicate that the ultraviolet region shows a strong distinction between different lithium concentrations. Utilizing second derivative absorption curves, the region of 220 nm to 230 nm demonstrated the ability to differentiate between concentrations representing those found in patients. Furthermore, the method could determine to within a 1-6% accuracy whether an unknown solution of Li2CO3 is either inside or outside the high-end of the therapeutic limit.

Working out percentages: Weight loss and dosage

T topic of Calculations Skills this month is percentage calculations. Percentage is defined as a fraction or ratio where the denominator is 100 (per cent). Percentage statements may be used to indicate the concentration of a drug in solution; for example, sodium chloride 0.9% injection contains 0.9 g sodium chloride per 100 ml of solution. Percentages may also be used as part of drug dosage calculations, particularly for patients known to have factors that are likely to affect the pharmacokinetics of a drug; for example, impaired liver or renal function may lead to reduced drug clearance. Distribution may be affected in obese patients because of variable penetration of drugs into body fat stores. Diagnostic criteria may also include percentage statements. A significant and unintended reduction in body weight can be a non-specific indicator of diseases such as cancer or tuberculosis. A significant loss of weight is usually defined as more than 5% of body weight over 6–12 months. In 2013, the United Kingdom Medicines Information Pharmacists’ Group (UKMI, 2013) issued guidance on dosing of a range of antibiotics for obese patients. Aminoglycoside antibiotics are of particular concern because they have a narrow therapeutic index and tend to be prescribed in critically ill patients with serious infections. Too low a dose may lead to treatment failure, but too high a dose may lead to toxicity, including ototoxicity and nephrotoxicity. Although maintenance dosing is guided by therapeutic monitoring of blood levels, the initial adult dose is calculated based on body weight. In an obese patient, a dose calculated from total body weight (also known as actual body weight) may lead to a toxic blood level because aminoglycosides are highly water soluble and mainly confined to body water. The British National Formulary (Joint Formulary Committee, 2015). recommends that dosage is calculated using ideal weight for height in obese patients. As a rule of thumb, dosage adjustment is necessary for patients whose total body weight (TBW) exceeds ideal body weight (IBW) by 15% or more. Some manufacturers give guidance on dosage in obese patients. Obesity is defined by the National Institute for Health and Care Excellence (NICE) as a body mass index Alison Eggleton

Correlation Between Efficacy of Levetiracetam and Serum Levels Among Children With Refractory Epilepsy

BackgroundLevetiracetam is used as adjunctive therapy in various types of seizures. Studies evaluating the effect of levetiracetam on children with refractory epilepsy are scarce. The aim of this study was to evaluate the correlation between serum concentration of levetiracetam and either efficacy or tolerability in children with refractory epilepsy, and to determine the value of levetiracetam blood level monitoring. MethodsMedical records of 50 children with refractory epilepsy treated with levetiracetam and regularly followed at Assaf Harofeh Medical Center were retrospectively reviewed. Trough serum levetiracetam concentration was determined using high-performance liquid chromatography and correlated with the administered dose and clinical report. ResultsNo correlation between levetiracetam serum levels and clinical efficacy, tolerability or administered dosage was found. The average dose of levetiracetam was 43.7 ± 20.0 (range 14-100) mg/kg/day and the average serum concentration was 16.0 ± 9.5 (range 2.5-38.5) μg/mL. Forty-five patients (95%) had more than a 50% reduction of seizure frequency, with 22 (44%) patients becoming seizure-free for at least 6 months. Adverse events related to levetiracetam were reported in 15 (30%) patients. No correlation between serum concentrations and adverse events was found. These results were not affected by gender, age, type of seizure, and other drugs. ConclusionsDetermination of serum concentration is not needed in all children treated with levetiracetam. Serum concentrations may be valuable either in patients with refractory epilepsy for compliance evaluation or in patients with satisfactory control of seizures for determination of their therapeutic baseline.

The benefits of antiepileptic drug (AED) blood level monitoring to complement clinical management of people with epilepsy

IntroductionSome argue that there is no evidence to support the use of antiepileptic drug (AED) blood level monitoring when treating people with epilepsy (PWE). This paper identifies how AED monitoring can be invaluable in such treatment. Specific examples(i)Compliance: Antiepileptic drug blood levels often confirm noncompliance rather than adequate seizure control, confirming subtherapeutic levels in PWE attending hospitals due to seizures. Routine monitoring of AED levels may prevent breakthrough seizures by identifying noncompliance and instituting heightened compliance measures before experiencing breakthrough seizures without modifying dosages. For PWE attending hospitals due to seizures, loading with the AED shown to be subtherapeutic may be all that is required.(ii)Cluster seizures and status epilepticus: When using long-acting AEDs to complement benzodiazepines, blood level monitoring confirms that an adequate dosage was given and, if not, a further bolus can be administered with further monitoring. This is particularly useful when using rectal administration of AEDs.(iii)Polypharmacy: Polypharmacy provokes drug interactions in which case AED monitoring helps in differentiating adequate dosing, offending AED with toxicity and free level measuring benefits when total levels are unhelpful.(iv)Generic substitution: Generic AEDs can fluctuate considerably from a parent compound, and even a parent compound, sourced from an alternative supplier, may have altered bioavailability for which blood level monitoring is very useful. ConclusionsWhile therapeutic blood level monitoring is not a substitute for good clinical judgment, it offers a valuable adjunct to patient care.

Optical analysis of lithium carbonate: towards the development of a portable lithium blood level analyzer for bipolar disorder patients.

Lithium medication is the gold standard of treatment in Bipolar Disorder patients, preventing and reducing mood swings and suicidality. However, despite its effectiveness, it is a potentially hazardous drug requiring regular monitoring of blood levels to ensure toxic levels are not reached. This paper describes the first steps towards developing a new portable device that can be used by Bipolar Disorder patients to facilitate the analysis of lithium blood levels at home. Solutions of lithium carbonate have been optically fingerprinted using a high-end spectrophotometer. Preliminary measurements indicate that while the visible to near infrared region of the absorption spectra fall heavily within the water band, measurements in the Ultraviolet region show a strong distinction between different lithium concentrations. The optical spectra of Lithium in the 220 nm to 230 nm region demonstrated the ability to differentiate between concentrations representing those found in patients.

Efficiency of individual dosage of digoxin with calculated concentration.

BackgroundDigoxin is a frequently prescribed drug, particularly in the elderly population, in which there is an increased prevalence of atrial fibrillation and cardiac failure. With its complex pharmacokinetic profile and narrow therapeutic index, use of digoxin requires regular monitoring of blood levels. Recent evidence suggests that a lower concentration range (0.4–1.0 ng/mL) is preferable in patients with congestive heart failure and a higher range (0.8–2.0 ng/mL) is needed in patients with atrial tachyarrhythmia. The Konishi equation is widely used to predict the serum digoxin concentration (SDC) in Japan. This study assessed the correlation between SDC predicted by the Konishi equation and that actually measured in Chinese patients and investigated the impact of renal function on SDC.MethodsThe study subjects comprised 72 patients with cardiac failure or/and atrial tachyarrhythmia seen at our hospital from January 2012 to December 2013. The patients were divided into five groups according to Kidney Diseases Outcome Quality Initiative guidelines. SDCs were measured using the Abbott Architect i1000 immunology analyzer. The correlations between measured SDCs and calculated SDCs and between clearance of digoxin and creatinine clearance rate were assessed retrospectively.ResultsThe correlation between measured and predicted SDC calculated by the Konishi equation was significant (r=0.655, P<0.001) for the 72 patients overall; however, correlations within the different stages of renal function were nonsignificant, with a correlation found only in patients with stage 3 (30 mL per minute < creatinine clearance <60 mL per minute). With regard to the correlation between clearance of digoxin and creatinine clearance, our results show that although there was a significant correlation between clearance of digoxin and creatinine clearance in the group overall, correlations were not evident within the different stages of renal function.ConclusionThe results of this study indicate that clearance of digoxin and the creatinine clearance rate cannot be explained by renal function alone and that the validity of the Konishi equation for individualizing the digoxin dosage in Chinese patients is limited, being applicable only in stage 3 renal disease. Further research in larger numbers of patients across all stages of renal function will be required in the future to verify the original Konishi model.

Water channel in the binding site of a high affinity anti-methotrexate antibody.

In the present study, we report the structure of the free and drug-bound Fab fragment of a high affinity anti-methotrexate antibody and perform a thermodynamic analysis of the binding process. The anti-methotrexate Fab fragment features a remarkably rigid tunnel-like binding site that extends into a water channel serving as a specialized route to move solvent out and into the site upon ligand binding and dissociation. This new finding in antibody structure-function relationships directly relates to the fast association (1 × 10⁷ M⁻¹ s⁻¹) and slow dissociation (4 × 10⁻⁵ s⁻¹) rates determined for mAb ADD056, resulting in a very strong binding with a K(D) ~ 3.6 pM at 20 °C. As follows from the X-ray data analysis, the methotrexate-antibody complex is stabilized by an extended network of hydrogen bonds and stacking interactions. The analysis also shows structural involvement of the CDR H3 in formation of the water channel revealing another important role of this hypervariable region. This suggests a new direction in natural affinity maturation and opens a new possibility in antibody engineering. Methotrexate is a widely used therapeutic agent for many malignant diseases and inflammatory disorders. Unfortunately, it may also interfere with central aspects of metabolism and thereby cause inevitable side effects. Therefore, methotrexate therapy requires careful monitoring of drug blood levels, which is traditionally done by immunoassays. An understanding of the structure-function properties of antibodies selected for drug monitoring substantiates the performance and robustness of such tests.