Right ventricular function in pulmonary (arterial) hypertension.

The right ventricle (RV) is the main determinant of prognosis in pulmonary hypertension. Adaptation and maladaptation of the RV are of crucial importance. In the course of disease, RV contractility increases through changes in muscle properties and muscle hypertrophy. At a certain point, the point of "uncoupling," the afterload exceeds contractility, and maladaptation as well as dilation occurs to maintain stroke volume (SV). To understand the adaptational processes and to further develop targeted medication directly affecting load-independent contractility, an accurate and precise assessment of contractility and RV-pulmonary artery (PA) coupling should be performed. In this review, we shed light on existing methods to assess RV function, including the gold standard measurement of contractility and RV-PA coupling, and we evaluate existing surrogates of RV-PA coupling.

[Update pulmonary arterial hypertension : Definitions, diagnosis, therapy]. / Update pulmonalarterielle Hypertonie : Definitionen, Diagnose, Therapie.

The term pulmonary arterial hypertension comprises a group of pulmonary vascular diseases of different etiologies that are characterized by similar precapillary vascular remodeling processes and result in exertional dyspnea and right heart insufficiency. The specific pharmacological treatment approach considers the risk of mortality and phenotypical properties and includes treatment with phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostanoids, as well as with more novel substances, such as a soluble guanylyl cyclase stimulator and an oral prostacyclin receptor agonist. The prognosis of the disease is mainly determined by the right heart insufficiency for which there is currently no specific pharmacological treatment. Lung transplantation may be offered as a last option. This review provides an overview of the current European guidelines from 2015 and the recommendations of the Cologne Consensus Conference for pulmonary hypertension from 2016.

Abdominoplasty and simultaneous laparoscopic ventral hernia repair. Clinical study about 45 patients.

INTRODUCTION: Abdominoplasty procedures sometimes reveal the presence of ventral hernias (umbilical or trocar-site hernias). Our objective is then to deal with the excess abdominal skin and fat tissue at the same time as the ventral hernia. This can be done with a single surgical procedure combining abdominoplasty with umbilical transposition and laparoscopic ventral hernia repair (LVHR) with mesh. The main objective of our study is to assess the outcome of the combined procedure of abdominoplasty and LVHR with mesh, compared to abdominoplasty alone. MATERIALS AND METHODS: A retrospective single-centre cohort study was conducted, including patients operated on with the combined method (ABDO-LVHR group) and patients who underwent abdominoplasty alone (ABDO group). We noted major and minor complications, with infection issues as our main concern. RESULTS: We included 15 patients in the ABDO-LVHR group and 30 in the ABDO group. The results show no statistically significant difference for infectious complications in the ABDO-LVHR group compared to the ABDO group (20% vs 3.3%; P=0.100). There was no instance of complete umbilical necrosis. Other major and minor complications occurred at the rates typically described in the literature without difference between the two groups. CONCLUSION: There was no significant difference between our two groups in terms of infectious complications. LVHR carried out at the same time as abdominoplasty with umbilical transposition is a positive combination of procedures. Further studies are necessary to confirm that the risk in terms of infectious complications is no higher than for abdominoplasty alone. LEVEL OF EVIDENCE: III.

[Pulmonary hypertension : What is new in therapy?]. / Pulmonale Hypertonie : Was ist neu in der Therapie?

Pulmonary hypertension (PH) comprises a group of pulmonary vascular diseases that are characterized by progressive exertional dyspnea and right heart insufficiency ultimately resulting in right heart decompensation. The classification is into five clinical subgroups that form the absolutely essential basis for decisions on the indications for different pharmacological and non-pharmacological forms of treatment. The guidelines were updated in 2015 and in addition to the hitherto existing pharmacological treatment options of phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostacyclins, the soluble guanylate cyclase stimulator riociguat has now been incorporated for treatment of certain forms of PH. This article provides an overview of the new treatment recommendations in the current guidelines, e. g. for PH patients who are in intensive care units due to surgical interventions or progressive right heart insufficiency.

[On the Differential Diagnosis of Intractable Psychogenic Chronic Cough: Neuropathic Larynx Irritable - Gabapentin's Antitussive Action]. / Zur Differenzialdiagnose des quälenden psychogenen chronischen Hustens: neuropathischer Larynx irritable - Gabapentin als Antitussivum.

We present the case of a 76 year old female inpatient who suffered from a chronic intractable cough which arose simultaneously to a severe major depression and was secondary to an exorbitant psychological distress. Chronic cough had never been experienced before and was initially considered to have a mere psychogenic origin since a comprehensive and guideline-based diagnostic screening did not reveal any underlying somatic cause. However, several factors cast doubt on the solitary psychic genesis of the chronic cough: i) occurrence immediately after a penetrant cold, ii) embedding in other complaints of laryngeal hyperreagibility (larynx irritable), such as persistent globus pharyngeus sensation, throat clearing and episodic dysphonia, iii) first occurrence on old life, iv) erupting from sleep as well, v) persistence despite remission of the major depression, and v) no sustaining benefit from specific psychotherapy and speech therapy. Therefore, diagnostics were extended to apparative tools for objective evaluation of swallowing by using fiberoptic videoendoscopic (FEES) and videofluoroscopic (VFS) techniques, which revealed signs of laryngeal neuropathy but without evidence of penetration or aspiration. A co-existing small goiter and an impaired glucose tolerance along with a putative intracellular vitamin B12 or folate deficiency (as indirectly derived from an apparent hyperhomocysteinemia) were assumed to be responsible for the neuropathy and underwent specific treatments. The impaired glucose tolerance and putative vitamin deficit were compatible with a distal symmetric sensorimotoric, even subclinical polyneuropathy of the lower extremities. The larynx irritable improved under gabapentin being confirmed by drug removals several times, and finally calmed down almost completely under gabapentin, which was in line with the scant literature of this topic. Re-examination of the larynx per FEES nine months later showed no deficits any more under the well-tolerated treatment (gabapentin, levothyroxine, vitamin B12 and folic acid substitution, weight reduction and physical training). All in all, the larynx irritable as well as the chronic cough were most probably induced by a laryngeal neuropathy and were not solely of psychic origin. Due to good treatment options a larynx irritable should be regularly taken into consideration of the investigation of intractable chronic cough. Therefore, an apparative evaluation of deglutition is recommended in the diagnostic toolbox of chronic cough - even if embedded in a psychiatric disorder or distress - before diagnosing a sole psychic origin. An hypothetical scheme of the development of a larynx irritable caused by neuropathic and non-neuropathic ("nociceptive") conditions is proposed.

[Dyspnoea in Patients with Pulmonary Hypertension (PH) - a Survey in Spezialized German PH Centres]. / Dyspnoe bei Patienten mit Pulmonaler Hypertonie (PH) - Ergebnisse einer Befragung in deutschen PH-Zentren.

Dyspnoea is the predominant symptom in patients with pulmonary hypertension (PH) at diagnosis. However, since dyspnoea is nonspecific and often occurs in a number of common diseases, the presence of PH can easily be underdiagnosed.In addition, this symptom underlies a high variability in the subjective perception, therefore further diagnostic procedures are often delayed by the patients.A survey of the incidence and severity of dyspnoea in 372 patients with PAH was conducted by questionnaire in German centres. Age, sex distribution and the range of comorbidities corresponded to the findings of national and international registries.Approximately 99 % of patients reported the presence of dyspnoea on exertion, even at low loads.Remarkably, in 13 % of patients dyspnoea occurs as a paroxysmal symptom, which may lead to the differential diagnosis of bronchial asthma. In addition, the patients who were being followed in specialized PH centres reported an increase in dyspnoea during the last year.The results of the survey on the incidence of dyspnoea in patients with PAH are consistent with the findings of international studies.

[Medical treatment of pulmonary hypertension: what's new?]. / Medikamentöse Therapie der pulmonalen Hypertonie: Was ist neu?

Pulmonary hypertension (PH) is a chronic progressive disease of the pulmonary circulation of multifactorial causes. The current diagnostic classification of PH distinguishes five main groups, which have as a common feature an increased pulmonary arterial pressure and pulmonary resistance. The classification differentiates pulmonary arterial hypertension (PAH), PH due to left heart disease, PH in lung diseases and/or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH), and PH with unclear/multifactorial mechanisms. Recent advances in basic research with the approval of new drugs and the establishment of therapeutic strategies, mainly in PAH and CTEPH, require a differentiated view of the disease, a careful diagnosis and initiation of therapy, and regular follow-ups. In this article, we provide an overview of the complex drug therapy currently available for PAH patients.

[Education, advanced and further training in the field "psychology in rehabilitation"]. / Aus-, Fort- und Weiterbildung "Psychologie in der Rehabilitation"

The commission for vocational training, training and further education of the German Society of Rehabilitation Science tends to discuss and to give recommendations for various professions in rehabilitation. The working group, which is led by J. Bengel/Freiburg and M. Morfeld/Magdeburg-Stendal created an inventory of Rehabilitation Psychology. The training programs for Rehabilitation Psychology at universities and universities of applied science in Germany are based on a job profile of psychologists in medical and vocational rehabilitation. The different universities have diverse priorities focusing on Rehabilitation Psychology. The offer changes because of the adaption of requirements and implementation of Bologna Reform. The training and further education offers are specific and available for large indication areas. Finally outstanding issues and problems are pointed out.

Long-term outcome with intravenous iloprost in pulmonary arterial hypertension.

There is limited data on the long-term efficacy of intravenous iloprost in patients with pulmonary arterial hypertension (PAH). This retrospective multicentre analysis evaluated the clinical course of patients with PAH treated with i.v. iloprost, in most cases after having received inhaled iloprost as first-line therapy. Between 1997 and 2001, 79 PAH patients were treated with i.v. iloprost and followed until 2007. These patients had advanced and progressive disease as indicated by a mean pulmonary vascular resistance of 1,533 dyn x s x cm(-5) at the time of diagnosis and of 1,858 dyn x s x cm(-5) at the onset of i.v. iloprost therapy. Introduction of i.v. iloprost therapy resulted in initial haemodynamic and clinical improvement. At the end of the observation period, however, 50 (61%) patients had died and 21 (26%) required lung transplantation. Transplantation-free survival rates at 1, 3, and 5 yrs were 86%, 59% and 45%, respectively, after the diagnosis of PAH, and 54%, 31% and 15%, respectively, after the introduction of i.v. iloprost therapy. Predictors of an adverse outcome at baseline were a low 6-min walk distance and a low mixed venous oxygen saturation. In conclusion, despite initial haemodynamic and clinical improvement, overall long-term survival with i.v. iloprost therapy was limited.

[Therapy of pulmonary arterial hypertension]. / Therapie der pulmonalarteriellen Hypertonie.

Current international guidelines on the treatment of pulmonary arterial hypertension (PAH) are compiled by the European Society of Cardiology and the American College of Chest Physicians. The classification of pulmonary hypertension and guidelines on diagnosis and therapy were last adopted at the 4th World Congress of PAH in Dana Point (California) in the year 2008. Based on these guidelines this article presents an overview of the current therapy recommendations for patients with PAH corresponding to group 1 of the diagnostic WHO classification of pulmonary hypertension. Here it is recommended that diagnostic and therapy should be carried out in an expert centre. The therapy forms for PAH can be classified into basic therapy (e. g. oral anticoagulants, diuretics and oxygen therapy) and specific therapy (e. g. phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostanoids). Finally, some new substances will be presented which have already progressed relatively far in the clinical development.

Treatment with low-dose tacrolimus inhibits bleeding complications in a patient with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) can be found in patients suffering from a loss-of-function mutation of the gene encoding for the activin receptor-like kinase 1 (ALK-1), a bone morphogenetic protein (BMP) type 1 receptor. Interestingly, ALK-1 mutations also lead to hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant disease characterized by arteriovenous malformations (AVMs) leading to potentially life-threatening bleeding complications such as epistaxis. Current therapeutic options for both diseases are limited and often only temporary or accompanied by severe side effects. Here, we report of a patient with a mutation of the ALK-1 gene suffering from both HHT and PAH. Recently, it was shown that tacrolimus increased ALK-1 signaling and had beneficial effects in selected end-stage PAH patients. We thus hypothesized that treatment with tacrolimus may prevent disease progression in this patient. Surprisingly, treatment with low-dose tacrolimus dramatically improved his HHT-associated epistaxis but did not attenuate progression of PAH.

Phase I and pharmacokinetic study of 5-aza-2'-deoxycytidine (NSC 127716) in cancer patients.

A phase I trial and pharmacokinetic study of 5-aza-2'-deoxycytidine (5-aza-dCyd) were conducted in 21 patients with advanced solid tumors. The drug was given as three 1-h infusions, separated by intervals of 7 h. Treatment was repeated every 3-6 weeks. Forty-six cycles of 5-aza-dCyd were administered at 7 dose levels ranging from 25 to 100 mg/m2 in three infusions. The dose-limiting toxicity was myelosuppression, with a delayed white blood cell nadir, occurring at Day 22. Other toxicities included a mild, reversible elevation of serum creatinine in three patients, minimal nausea and vomiting in six patients, and transient fatigue in three patients. In this study one partial response in a patient with an undifferentiated carcinoma of the ethmoid sinus was observed. Plasma and urinary concentrations of 5-aza-dCyd were measured using a bioassay based on growth inhibition of L1210 leukemia cells in vitro. For 75 and 100 mg/m2 given as 1-h infusions, mean peak plasma concentrations of 0.93 and 2.01 microM, respectively, were attained. In seven of nine courses at doses of 25-60 mg/m2, plasma 5-aza-dCyd concentration was less than 0.01 microM. In one case at 30 mg/m2 and another at 60 mg/m2, peak plasma drug concentrations were determined to be 0.244 and 0.409 microM, respectively. Following cessation of the infusion rapid disappearance of drug from plasma was observed with a t1/2 alpha and t1/2 beta of 7 and 35 min, respectively. High clearance values and a total urinary excretion of less than 1% of the administered dose suggest that 5-aza-dCyd is eliminated rapidly and largely by metabolic processes. For the present schedule studied, a dose of 75 mg/m2 in three infusions, every 5 weeks, is recommended for phase II trials in solid tumors.

Delayed-type hypersensitivity reactions to tumor-associated antigens in colon carcinoma patients immunized with an autologous tumor cell/Bacillus Calmette-Guérin vaccine.

Five different colon tumor-associated antigens (CTAA) were tested for their ability to induce an immune response in vivo and in vitro in ten colon carcinoma patients immunized with an irradiated autologous tumor cell/Bacillus Calmette-Guérin vaccine (active specific immunization) after resection of the primary tumor. The CTAA were defined by two different human monoclonal antibodies (MCA 1688 and MCA 28A32) derived by immortalization of peripheral blood B-lymphocytes from an active specific immunization patient. Delayed-type cutaneous hypersensitivity responses against a mixture of CTAA 28A32-50K and -32K were positive in seven of ten patients tested. In vitro T-cell responses upon stimulation with CTAA 28A32-32K were found to be positive in seven of ten patients and correlated with delayed-type cutaneous hypersensitivity responses to the antigen mixture. These data suggest that CTAA 28A32-32K might contain an important tumor-related T-cell epitope. Moreover, this method is suitable to define potential future candidates for antitumor vaccine development.

Phase I and pharmacokinetic studies of high-dose uridine intended for rescue from 5-fluorouracil toxicity.

The clinical effects and pharmacokinetics of high-dose uridine were determined in seven patients with advanced-stage cancer and in one healthy volunteer. Uridine was also examined for its effect on 5-fluorouracil toxicity in two patients. Uridine was administered as a 1-hr i.v. infusion at doses of 1 to 12 g/sq m. Plasma and urine samples were analyzed for uridine and uracil using high-pressure liquid chromatography. In 23 courses of uridine alone, the only toxicity observed was transient shivering after one of two courses at 12 g/sq m. This side effect was also seen after administration of uridine (10 g/sq m) during combination with 5-fluorouracil. The pretreatment plasma uridine concentration was elevated from low micromolar to millimolar levels with uridine administration at doses up to 12 g/sq m. Maximal areas under the concentration-time curve were about 5 mmol/liter/hr. Both peak plasma level and area under the curve for uridine increased linearly with dose. Uridine plasma decay curves were biphasic with a terminal half-life of 118 min. Half-life, volume of distribution (634 ml/kg), and total clearance (4.98 ml/kg/min) appeared to be independent of dose. Plasma uracil concentration increased gradually after administration of uridine to plateau levels. Maximal plasma uracil concentrations were about one-tenth that of peak uridine concentrations. The plasma uracil level declined with a half-life of about 40 min after uridine levels decreased to 300 microM. Total urinary excretion of uridine was 24% of the dose, while the amount of uracil recovered in urine was 3.4%. In two patients, uridine rescue was attempted during 5-fluorouracil dose escalation. Uridine at 5 to 6 g/sq m given on 1 or on 2 days after 5-fluorouracil did not prevent myelosuppression and gastrointestinal toxicity associated with increasing plasma concentrations of 5-fluorouracil. These data show that uridine administered as a 1-hr infusion at doses which provide peak plasma uridine concentrations in the millimolar range is well tolerated. Rapid elimination of uridine primarily due to catabolism results in modest exposure to substantially elevated plasma uridine concentrations. Preliminary findings suggest that prolonged treatment with uridine may be required to test its potential to rescue patients from 5-fluorouracil toxicity.

Phase I study of ethylenediamine platinum(II) malonate (NSC 146 068), a second generation platinum analogue.

Ethylenediamine platinum(II) malonate [JM-40 (NSC 146 068)] has been selected for clinical studies because of its favorable preclinical toxicity profile as a "second generation" platinum analogue. When compared to cisplatin, JM-40 was less emetic in the ferret and less nephrotoxic in the dog, while its antitumor activity approached that of cisplatin. Twenty-nine patients received 86 courses of JM-40 as a single dose every 3-4 wk. After 13 dose escalation steps the maximum tolerable dose was reached at 1200 mg/m2. The dose limiting toxicities were nausea, vomiting, and nephrotoxicity. The renal damage seemed reversible up to a dose level of 1000 mg/m2 and consisted of a glomerular and tubular dysfunction. JM-40 did not cause any other dose related side effect or myelo-suppression. Pharmacokinetic studies at a dose of 1000 mg/m2 revealed mean terminal half-lives of 5.0 and 1.9 days for platinum in plasma and plasma ultrafiltrate, respectively. The mean cumulative excretion of platinum in urine accounted for 57% of the dose up to day 5. Two partial responses were observed in a patient with a large cell carcinoma of the lung and in one with a carcinoma of the lacrimal gland. Limited evaluation of JM-40 in phase II studies is warranted. The recommended dose is 1000 mg/m2 every 4 wk and 800 mg/m2 for patients pretreated with platinum analogues.

[Risk stratification and follow-up assessment of patients with pulmonary arterial hypertension: Recommendations of the Cologne Consensus Conference 2016]. / Risikostratifizierung und Verlaufskontrollen bei PAH-Patienten: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed information about the diagnosis of pulmonary hypertension, and furthermore provide novel recommendations for risk stratification and follow-up assessments. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to risk stratification and follow-up assessment of patients with PAH. This manuscript summarizes the results and recommendations of this working group.

[Decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension]. / Dekompensierte Rechtsherzinsuffizienz, Intensiv- und Perioperativ-Management bei Patienten mit pulmonaler Hypertonie: Empfehlungen der Kölner Konsensus Konferenz 2016.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed recommendations for the targeted treatment of pulmonary arterial hypertension (PAH). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the management of decompensated right heart failure, intensive care management and perioperative management in patients with pulmonary hypertension. This article summarizes the results and recommendations of the working group on decompensated right heart failure, intensive care and perioperative management in patients with pulmonary hypertension.

Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans.

Pharmacokinetics of doxorubicin (DOX), epidoxorubicin (EPI), and their metabolites in plasma have been performed in eight patients receiving 40 to 56 mg/m2 of both anthracyclines as a bolus injection in two sequential cycles. Terminal half-life and volume of distribution appeared to be smaller in case of EPI, whereas plasma clearance and cumulative urinary excretion was larger in comparison to DOX. The major metabolite of DOX was doxorubicinol (Aol) followed by 7-deoxy-doxorubicinol (7d-Aolon). Metabolism to glucuronides was found in case of EPI only. The area under the curves (AUC) of the metabolites of EPI decreased in the order of the glucoronides E-glu greater than Eol-glu, 7d-Aolon greater than epirubicinol (Eol). The AUC of Eol was half of the value in its counterpart Aol. In the case of EPI, the AUC of 7d-Aolon was twice the level of that of the corresponding metabolite of DOX. The terminal half-lives of the cytostatic metabolites Aol and Eol were similar, but longer than the corresponding values of their parent drugs. Half-lives of the glucuronides (E-glu, Eol-glu) were similar to the half-life of their parent drug. 7d-Aolon had a somewhat shorter half-life in comparison to both DOX and EPI. Approximately 6.2% of EPI and 5.9% of DOX were excreted by the kidney during the initial 48 hours. Aol was found in the urine of patients treated with DOX, whereas Eol, E-glu, and Eol-glu were detected in urine of patients treated with EPI. The cumulative urinary excretion appeared to be 10.5% for EPI and its metabolites, and 6.9% for DOX and its metabolite. The plasma concentration v time curves of (7d)-aglycones showed a second peak between two and 12 hours after injection, suggesting an enterohepatic circulation for metabolites lacking the daunosamine sugar moiety. The plasma concentrations of the glucuronides were maximal at 1.2 hours for E-glu and 1.9 hours for Eol-glu. All other compounds reached their maximum plasma concentration during the first minutes after the administration of DOX and EPI. Deviating plasma kinetics were observed in one patient, probably due to prior drug administration.

Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors.

PURPOSE: To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. PATIENTS AND METHODS: Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter. RESULTS: Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m(2). The MTD was initially found at 45 mg/m(2), with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m(2), which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 micromol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU. CONCLUSION: The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m(2) bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2) bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.

Pharmacokinetics and pharmacodynamics of lobaplatin (D-19466) in patients with advanced solid tumors, including patients with impaired renal of liver function.

The purpose of this study was to determine the influence of impaired renal and liver function on the pharmacokinetics and pharmacodynamics of lobaplatin in cancer patients. A total of 25 patients with advanced solid tumors not amenable for standard treatment entered the study. Patients had normal organ function or an impaired liver or renal function (two levels). The starting dose of lobaplatin was 50 mg/m2 i.v. given every 3 weeks. The blood and urine of all patients were sampled for the determination of (ultrafilterable) platinum, intact lobaplatin, creatinine, and blood cell counts. No objective responses were recorded. Five patients experienced no change and received 4-10 cycles (median, 6 cycles) of lobaplatin. The extent and duration of hematological toxicity were worse in patients with impaired renal function. Thrombocytopenia was most prominent; grade 4 toxicity was observed in 15 patients in the first two cycles of treatment. The concentration-time curves of ultrafilterable platinum and intact lobaplatin revealed almost identical patterns. The elimination of ultrafilterable platinum [final half-life (t1/2 final) = 131+/-15 min; clearance (Cl) = 125+/-14 ml/min/1.73 m2] was much faster than that of total platinum (t1/2 final = 6.8+/-4.3 days, CI = 34+/-11 ml/min/1.73 m2). No pharmacokinetic differences were observed between patients with normal organ function and those with an impaired liver function within the investigated range. An impaired renal function resulted in an increase of the t1/2 final due to a decrease of the total body Cl that resulted in a higher exposure of the body to the drug. The calculated creatinine Cl was linearly correlated with the total body clearance of ultrafilterable platinum (r = 0.91), which resulted in the dosage formula D = AUCinfinity (1.1 Cl(CrU) + 16), in which D represents dose, AUC represents area concentration-time curve, and Cl(CrU) represents creatinine Cl. The thrombocyte surviving fraction correlated well with the AUC value of ultrafilterable platinum (r = 0.72). It can be concluded that the hematological toxicity and the pharmacokinetics of lobaplatin are strongly affected by renal function. The total body Cl of ultrafilterable platinum correlated well with the creatinine Cl and the thrombocyte surviving fraction. In patients with renal function, represented by a creatinine clearance > or =30 ml/min/1.73 m2, the derived dosage formula will enable us to calculate the dose that is expected to lead to an acceptable extent of thrombocytopenia in a patient with a given renal function. Prospective studies with larger groups of patients are needed to prove the value of this dosage formula.