A first-in-human phase I and pharmacokinetic study of CP-4126 (CO-101), a nucleoside analogue, in patients with advanced solid tumours.

BACKGROUND: CP-4126 (gemcitabine elaidate, previously CO-101) is a lipid-drug conjugate of gemcitabine designed to circumvent human equilibrative nucleoside transporter1-related resistance to gemcitabine. The purpose of this study was to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of CP-4126, and to describe its pharmacokinetic profile. METHODS: Eligible patients with advanced refractory solid tumours, and adequate performance status, haematological, renal and hepatic function, were treated with one of escalating doses of CP-4126 administered by a 30-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Blood and urine samples were collected to determine the pharmacokinetics (PKs) of CP-4126. RESULTS: Forty-three patients, median age 59 years (range 18-76; male = 27, female = 16), received one of ten dose levels (30-1600 mg/m(2)). Dose-limiting toxicities included grade 3 anaemia, grade 3 fatigue and grade 3 elevation of transaminases. The MTD and RP2D were 1250 mg/m(2) on basis of the toxicity and PK data. CP-4126 followed dose-dependent kinetics and maximum plasma concentrations occurred at the end of CP-4126 infusion. Seven patients achieved stable disease sustained for ≥3 months, including two patients with pancreatic cancer who had progressed on or after gemcitabine exposure. CONCLUSIONS: CP-4126 was well tolerated with comparable toxicity profile to gemcitabine. Future studies are required to determine its anti-tumour efficacy, either alone or in combination with other cytotoxic chemotherapy regimens.

Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors.

CP-4126 is a gemcitabine (2',2'-difluorodeoxycytidine; dFdC) 5' elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step design: a non-randomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II that compared oral CP-4126 with dFdC i.v.. CP-4126 was given on days 1,8,15 in a 4-week schedule with increasing doses until the RD was established. 26 patients with different solid tumours were enrolled in step I at seven dose levels (100-3,000 mg/day). The most frequent drug-related AEs were fatigue and dysgeusia, the majority being grade 1-2. One patient experienced a dose limiting toxicity after one dose of CP-4126 at 1,300 mg/day (ASAT grade 3). PK of CP-4126 could not be determined. The metabolites dFdC and dFdU obeyed dose-dependent pharmacokinetics. Exposures to dFdC were about ten-fold lower compared to exposures after comparable doses of dFdC i.v.. Nine patients reached stable disease as best response, whereby in one patient with vaginal carcinoma a 25 % reduction of tumor volume was reached. This study demonstrates that CP-4126 can be safely administered orally to patients up to 3,000 mg/day in a d1,8,15 q4w schedule with a tolerable safety profile. CP-4126 acts as a prodrug for dFdC when given orally, but because of the poor absorption and the rapid pre-systemic metabolism the study was terminated early and no RD could be determined.

A phase I-II study of elacytarabine (CP-4055) in the treatment of patients with ovarian cancer resistant or refractory to platinum therapy.

PURPOSE: Treatment of patients with recurrent ovarian cancer remains a challenge, and there is a need for new and more effective agents. A phase I-II study was designed to determine the recommended dose (RD) and the anti-tumour effect of a prolonged administration of elacytarabine, the elaidic ester of cytarabine, in patients with refractory/resistant recurrent ovarian cancer. EXPERIMENTAL DESIGN: The primary objective of the dose escalation phase I part was to determine the RD for elacytarabine when given twice for five consecutive days in a 4-week schedule, D1-5 and D8(+2)-12(+2) q4w. Three to six patients were to be enrolled at each dose level. The start dose was elacytarabine 75 mg/m(2)/day. The phase II part was designed as a two-step study based on response. RESULTS: A total of 28 patients entered the study, 17 patients in the phase I part and 11(#) patients in phase II. Three dose levels were tested: 75 mg/m(2)/day in 3 patients, 100 mg/m(2)/day in 7 + 11(#) patients, and 125 mg/m(2)/day in 7 patients. Three (17.6%) patients in phase I experienced a dose limiting toxicity (DLT), all at the 125 mg/m(2)/day dose level, establishing the lower dose of 100 mg/m(2)/day as the RD. The DLTs were neutropenia grade 4 according to the Common Terminology Criteria for Adverse Events (CTCAE) and thrombocytopenia grade 4 (2 patients), and vomiting grade 2 with hospitalisation and hypokalaemia grade 3 (1 patient). The best response was a clinically meaningful stabilization observed in 3 patients. In two of them, the disease stabilization exceeded the previous platinum-free interval (PFI). CONCLUSIONS: The RD for elacytarabine was 100 mg/m(2)/day, D1-5 and D8-12 q4w. The safety profile was comparable to the safety profiles reported in previous clinical studies with elacytarabine in solid tumours. Despite some longer-lasting disease stabilisations, two of them exceeding the previous progression-free interval, further investigations of elacytarabine in the ovarian cancer indication are not warranted.

Influence of a nonionic, iso-osmolar contrast medium (iodixanol) versus an ionic, low-osmolar contrast medium (ioxaglate) on major adverse cardiac events in patients undergoing percutaneous transluminal coronary angioplasty: A multicenter, randomized, double-blind study. Visipaque in Percutaneous Transluminal Coronary Angioplasty [VIP] Trial Investigators.

BACKGROUND: The potential merits and disadvantages of the use of ionic or nonionic contrast media in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) have been the subjects of controversy. The present study was designed to evaluate the possible influence of both types of contrast media on major adverse cardiac events (MACE) in patients undergoing PTCA. METHODS AND RESULTS: In a randomized, parallel-group, double-blind study, 1411 patients received either iodixanol (a nonionic, iso-osmolar contrast medium) or ioxaglate (an ionic, low-osmolar contrast medium) during PTCA. A standardized anticoagulation regimen was followed. Patients were monitored in the hospital for 2 days and followed-up at 1 month. The primary end point, a composite of MACE (death, stroke, myocardial infarction, coronary artery bypass grafting, and re-PTCA) after 2 days, occurred in 4.3% of the total population, with no statistically significant difference between groups (iodixanol, 4.7%; ioxaglate, 3.9%; P=0.45). Further, between 2-day and 1-month follow-ups, no significant difference (P=0.27) existed between the groups in the rates of MACE. Hypersensitivity reactions (P=0.007) and adverse drug reactions (P=0.002) were significantly less frequent in the iodixanol group. The only significant predicting factors for the occurrence of MACE were dissection/abrupt closure and country. CONCLUSIONS: No significant differences were observed between the iodixanol and ioxaglate groups with regard to MACE, although hypersensitivity and adverse drug reactions were significantly less frequent in patients who received iodixanol.

Injection-associated pain in femoral arteriography: a European multicenter study comparing safety, tolerability, and efficacy of iodixanol and iopromide.

PURPOSE: To evaluate injection-associated pain, safety, and efficacy with the isotonic contrast medium iodixanol (Visipaque 270 mg I/ml) compared with iopromide (Ultravist 300 mg I/ml) in femoral arteriography. METHODS: A multicenter, double-blind, randomized, parallel-group clinical investigation was carried out in 54 hospitals in Europe. Of the patients evaluated, 1225 received iodixanol and 1227 iopromide in conventional and/or digital subtraction angiography. RESULTS: The iodixanol group reported statistically significantly less injection-associated pain (0.9%) than the iopromide group (9.5%) (p << 0.001). Further, 4.1% in the iodixanol group experienced pain and/or severe heat sensation vs 19. 8% in the iopromide group (p << 0.001). In the iodixanol group, 1.8% of the patients experienced contrast-related adverse events vs 2.4% in the iopromide group (p = NS). Overall diagnostic information was optimal for 94.1% in the iodixanol group and 95.3% in the iopromide group (p = NS). CONCLUSIONS: Iodixanol 270 mg I/ml causes significantly less injection-associated pain during femoral arteriography and is as safe and efficacious as iopromide 300 mg I/ml.

Vasomotor response of the human face: laser-Doppler measurements during mild hypo- and hyperthermia.

The skin of the face is reputed not to vasoconstrict in response to cold stress because the face skin temperature remains steady during hypothermia. The purpose of the present work was to measure the vasomotor response of the human face to whole-body hypothermia, and to compare it with hyperthermia. Six male subjects were immersed in cold and in warm water to obtain the two conditions. Skin blood flow, evaporation, and skin temperature (Tsk) were recorded in three loci of the face, the forehead, the infra orbital area, and the cheek. Tympanic (Tty) and oesophageal (Toes) temperatures were also recorded during the different thermal states. Normothermic measurements served as control. Blood flow was recorded with a laser-Doppler flowmeter, evaporation measured with an evaporimeter. Face Tsk remained stable between normo-, hypo-, and hyperthermia. Facial blood flow, however, did not follow the same pattern. The facial blood flow remained at minimal vasoconstricted level when the subjects' condition was changed from normo- to hypothermia. When the condition changed from hypo- to hyperthermia a 3 to 9-fold increase in the blood flow was recorded. From these results it was concluded that a vasoconstriction seems to be the general vasomotor state in the face during normothermia.

Selective brain cooling is affected by wearing headgear during exercise.

The purpose of this work is to relate the concept of selective brain cooling (SBC) during exercise to heat loss from the head while either bare or covered. During hyperthermia, SBC is considered to occur if tympanic temperature (Tty) is lower than esophageal temperature (Tes). In experiment I the head heat loss was measured with and without headgear. Each of four subjects took part in three sessions of exercise on a cycle ergometer. The face was cooled to simulate outdoor conditions. The first session (no headgear) served as control for the two following sessions in which a headband and a woolen cap were worn. Evaporative and radiative-convective heat loss were monitored from the head. Wearing a cap significantly reduced the heat loss from the head compared with the control condition. During the headband session the heat loss was not significantly lower than the control values. Tty, Tes, and head skin temperatures (T(sk)) were also recorded. Tty was significantly lower (-0.55 +/- 0.15 degrees C) than Tes at the end of exercise (150-W exercise load) when no headgear was worn. During headgear sessions, Tty was no longer significantly lower than Tes, either during the headband (-0.15 +/- 0.31 degrees C) or during the cap session (-0.30 +/- 0.13 degrees C). In experiment II the influence of wearing headgear on temperature regulation was studied. Hand skin blood flow, hand T(sk), and heat loss from the hand were recorded in addition to the variables monitored in experiment I. Wearing headgear elevated Tty and peripheral vasomotor responses, whereas Tes evolved in the opposite direction.(ABSTRACT TRUNCATED AT 250 WORDS)

Heat loss from the human head during exercise.

Evaporative and convective heat loss from head skin and expired air were measured in four male subjects at rest and during incremental exercise at 5, 15, and 25 degrees C ambient temperature (Ta) to verify whether the head can function as a heat sink for selective brain cooling. The heat losses were measured with an open-circuit method. At rest the heat loss from head skin and expired air decreased with increasing Ta from 69 +/- 5 and 37 +/- 18 (SE) W (5 degrees C) to 44 +/- 25 and 26 +/- 7 W (25 degrees C). At a work load of 150 W the heat loss tended to increase with increasing Ta: 119 +/- 21 (head skin) and 82 +/- 5 W (respiratory tract) at 5 degrees C Ta to 132 +/- 27 and 103 +/- 12 W at 25 degrees C Ta. Heat loss was always higher from the head surface than from the respiratory tract. The heat losses, separately and together (total), were highly correlated to the increasing esophageal temperature at 15 and 25 degrees C Ta. At 5 degrees C Ta on correlation occurred. The results showed that the heat loss from the head was larger than the heat brought to the brain by the arterial blood during hyperthermia, estimated to be 45 W per 1 degree C increase above normal temperature, plus the heat produced by the brain, estimated to be up to 20 W. The total heat to be lost is therefore approximately 65 W during a mild hyperthermia (+1 degrees C) if brain temperature is to remain constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced systolic blood pressure elevations during maximum exercise at simulated altitudes.

Ten healthy female subjects performed maximum exercise on a bicycle in an altitude chamber during normoxia and hypobaric hypoxia simulating altitudes of 2,450, 3,700 and 4,600 m. The increases in systolic blood pressure responses were reduced with the degree of hypobaric hypoxia, whereas heart rate and diastolic pressure responses were unchanged. The increases in blood levels of aldosterone, plasma renin activity, adrenaline, noradrenaline, neuropeptide-Y and vasoactive intestinal peptide were similar at the different simulated altitudes. Angiotensin-converting enzyme and vasoactive intestinal peptide levels were not affected by hypoxia or maximum exercise. The present results suggest that the decreases in systolic blood pressure responses during hypobaric hypoxia could not be explained by altered responses of the measured vasoactive substances from the renin-angiotensin, gastrointestinal, and autonomic nervous systems.

[Commitment prerequisites according to paragraph 64 of the German penal code]. / Die Unterbringungsvoraussetzungen nach section 64 StGB.

Article 64 of the Penal Code of the Federal Republic of Germany provides for the commitment of alcohol and drug addicts to special institutions if further severe offences are to be expected due to their addiction. The measure of correction cannot be applied if treatment endeavours are given no chance. As the lack of compliance very often only appears in the course of the treatment, an amendment was made which added a new article. According to the new legal regulations, the measure of correction can be annulled after one year of detainment if the addict shows no aptitude for the therapy. The new regulation implicates an intensification of the therapeuticts role conflict, which is based on the fact that coerced therapy was little chance to be successful. Before establishing the deficient therapeutical capability of a patient, it should be conscientiously verified how far a team conflict or an insufficient therapeutical offer determines the decision. It should be considered that possibly one only wants to get rid of a troublesome patient.

[Segregation of psychiatrically ill offenders in specialty clinics--the end of the deportation game?]. / Ausgrenzung der psychisch kranken Straftäter in Sonderkliniken--Ende des Abschiebespiels?

Forensic psychiatric institutions (mentally ill offenders) have not developed according to the recommendations of psychiatric experts as suggested in the 'Psychiatric Enquete'. Paragraph 65 StGB with its provisions was eliminated from the penal code on the 1. Jan. 1985, hence independent social-therapeutic institutions will not come into existence in the FRG. Taking the current institutional conditions into account the authors investigate the chances and possibilities of client-orientated treatment.

[Inclusion of psychiatric-psychologic diagnoses among the 4 psychiatric symptoms of irresponsibility in articles 20 and 21 of the West Germany criminal code]. / Die Zuordnung der psychiatrisch-psychologischen Diagnosen zu den vier psychischen Merkmalen der articles 20, 21 StGB.

The reform efforts in the Federal Republic of Germany after the end of the war have led to a reformation of the regulations concerning legal responsibiltiy. The new law enumerates in articles 20 and 21 as prerequisites of irresponsibility or diminished responsibility for concepts: pathological psychic disturbance which comprises all psychic diseases like schizophrenia and manic-depressive states as well as psychic alterations resulting from brain damage. The second term is feeble-mindedness. The third one is profound disturbance of consciousness which refers to states of strong mental agitation not caused by an illness. Finally the new law used the concept of sever other mental abnormalities. Rather unfortunately the law has introduced the German expression "Abartigkeit" which has a derogatory tinge, insinuating the idea of degeneration. The adjudgment of irresponsibility or diminished responsibility does not depend on the type of psychiatric diagnosis. The new regulations offer the chance to psychiatry to take on more therapeutic responsibilities for mentally disturbed offenders.

[Criminologic aspects in the treatment of sex offenders]. / Kriminologische Aspekte bei der Behandlung von Sexualdelinquenten.

The conditions determining statutory offences as represented by indictable sex offences, have been amended and revised by the 4th Penal Reform Law of the Federal German Penal Code, in 1973, under the heading "Indictable Offences against Sexual Self-Determination". This heading, which is meant to convey a programme, however, does not agree with the actual contents or core of various paragraphs. These new statutes have been violently criticised by opponents coming from quite different camps. The development of sexual delinquency shows a rather decreasing crime rate since the end of World War II, compared to the increase in other categories of crime. The most frequently recorded sexual offences concern the performance of sexual acts with children, rape and exhibitionism. It is in these groups of criminal offences that we are most likely to find delinquents in whom psychotherapy seems indicated. Criteria for indicating such treatment are the desire of the person in question to receive treatment, and the presence of a personality disturbance; it is not the deed by itself. The article then cites the paragraphs under German penal legislation which are important when arriving at a decision to refer a delinquent to psychotherapeutic treatment; these are Sections 56 c, 63, 64 German Penal Code, Section 10 Penal Code for Adolescents, and Section 9 of the Federal Law Enforcement Act.