Past and future of an IMI-PharmaTrain (IMI-PhT)-initiated multinational pharmaceutical medicine course at the Semmelweis University in Hungary.

The pharmaceutical medicine course at the Semmelweis University of Budapest, Hungary, was initiated as part of the Innovative Medicines Initiative (IMI is the main program, IMI-PharmaTrain is one of the IMI projects) Pharmaceutical Medicine Training Programs (16 IMI Call 2008/1/16). The aim was to extend training in the development of pharmaceutical medicine to those EU member states where no such education was present. The final program envisaged the development of a cooperative education supported by universities located in Central and Eastern Europe. It was considered to be the economically and scientifically most viable approach to combine the expertise from these countries to form a united teaching staff and provide education jointly for young professionals of the region. Semmelweis University was selected to manage this coordinated program. In this report, we describe the organization and functioning of this international university-based pharmaceutical medicine education project called the Cooperative European Medicines Development Course (CEMDC) and evaluate its successes and shortcomings. During the pandemic, the educational course was interrupted. The follow-on program is reorganized as a postgraduate MSc course named "Semmelweis Pharma MBA" and will be started in 2025. It will continue the established PharmaTrain educational tradition. However, it will deal in more detail with the transition from basic pharmacological to industrial research, as well as biopharmaceutical formulation and manufacturing and marketing aspects of medicines development.

Predictability of serious adverse reaction alerts for monoclonal antibodies.

OBJECTIVE: We analyzed the predictability of the United States Food and Drug Administration's Medwatch safety alerts on monoclonal antibodies with the aim of assessing the adequacy of their pre-approval safety evaluation. METHODS: An alert was considered observed when increased frequency, severity, or other new properties were reported for previously identified suspected adverse reactions. RESULTS: Up until January 2010, 36 safety alerts to mAbs were issued containing 61 alert terms. Just above a half (32) of the alert terms were assessed as observed. DISCUSSION: In addition to the observed reactions, a large proportion of unobserved reactions could have been predicted based on the mechanism of action and antibody target. Although retrospective assessment necessarily implies an element of subjectivity, there appears to be room for improvement in predicting adverse reactions to mAbs. CONCLUSIONS: Adverse reaction risk management and pharmaceutical care must focus on the observed reactions, but all effort should be made to extrapolate from the observed reactions to predict further safety issues. This should be taken into account by marketing authorization holders, prescribers, clinical trial sponsors, investigators and regulators.

[Oral idarubicin in treatment of advanced breast carcinoma]. / Idarubicin oral in der Behandlung des fortgeschrittenen Mammakarzinoms.

Idarubicin is the first anthracycline derivative which can be applied orally due to its high lipid solubility. The joint bioavailability of the parent compound and its active metabolite Idarubicinol is around 40%. The most frequently used administration schedule is 45 mg/m2, day 1 or 15 mg/m2, day 1-3 every third or forth week. The dosis for weekly administration is 15-20 mg/m2. The objective remission rate of the pooled data of 509 evaluable patients treated with the q3w schedule is 24% (CR 3%, PR 21%). The most important side effects are reversible leukopenia and moderate gastrointestinal toxicity. The cardiac toxicity and alopecia are significantly lower than that observed by doxorubicin or epirubicin treatment.

Clinical phase I and pharmacokinetic trial of vinorelbine administered as single intravenous bolus every 21 days in cancer patients.

We have performed a high-dose clinical and pharmacokinetic trial with vinorelbine administered as a bolus injection every 21 days. The aim was to evaluate a schedule with longer treatment intervals than one week and to determine the toxicity pattern of such a schedule. A total of 13 patients (pts) with solid tumors (non-small-cell lung [3 pts], unknown primary [3 pts], mesothelioma [2 pts], colon/rectum, sarcoma, thyroid, head/neck and cervix [1 pt each]) were entered [9 male, 4 female, median age: 56 years (range: 37-69)]. Dose levels were 35, 40 and 45 mg/m2 with a total of 26 cycles administered. At 40 mg/m2, 2/6 pts developed grade 4 granulocytopenia. 1/1 pt at 45 mg/m2 developed a grade 4 leuko- and granulocytopenia. Non-hematological toxicities were mild to moderate. Neurologic toxicity except for constipation was mild. Constipation occurred at 35 mg/m2 in 1/6 pts WHO grade 4, at 40 mg/m2 in 2/6 pts WHO grade 3 and at 45 mg/m2 in 1/1 pt WHO grade 4 and was due to neurotoxicity. No objective antitumor response was observed. Vinorelbine pharmacokinetics were analysed in whole blood and plasma and were similar to previously published studies using < or = 30 mg/m2. Our results confirm a high affinity of vinorelbine to corpuscular blood elements. We conclude that the MTD of vinorelbine administered once every 21 days as bolus injection is 40 mg/m2, the dose-limiting toxicities are constipation and granulocytopenia and the recommended dose for subsequent Phase II trials is 35 mg/m2.

Combination of daily 4-h infusion of 5-fluorouracil and cisplatin in the treatment of advanced head and neck squamous-cell carcinoma: a South-East European Oncology Group study.

Between April 1986 and May 1989 a multicentre study was conducted to evaluate the efficacy of a 4-h intravenous infusion of 1000 mg/m2 5-fluorouracil (5-FU) followed by a 1-h infusion of 25 mg/m2 cisplatin (CDDP) given for 4 consecutive days every 4 weeks to patients with advanced squamous-cell carcinoma of the head and neck. A total of 189 consecutive patients entered the study, including 106 who had previously undergone chemotherapy and 83 who were chemotherapy-naive. Of the 165 evaluable patients, 96 (58%) responded to treatment, including 22 (13%) who achieved a complete remission (CR). In the group of previously untreated patients an objective response (CR+PR) was seen in 78% (CR, 14%) whereas in pretreated patients the response rate (CR+PR) was 40% (CR, 13%). The median survival period was 10 months. No significant difference in the duration of survival or of remission was found between the two groups in relation to previous therapy, tumour localisation, disease stage or performance status. Almost half of the patients (49%) experienced leucopenia but it was severe in only 11% of cases. Anemia (mainly WHO grades 1-2) occurred in 38% of the patients. Nausea and vomiting were common (84%). Nephrotoxicity (23%) was mild and of short duration. Moderate hair loss was seen in 42% of the patients, and phlebitis occurred in 8%. A few cases of cardiotoxicity and neurotoxicity were observed. This regimen is well tolerated and can be given even on an outpatient basis. The resultant response rate and side effects appear to be similar to those previously reported for combination chemotherapy with CDDP and continuous 5-FU infusion.

Biochemical consequences of 5-fluorouracil gastrointestinal toxicity in rats; effect of high-dose uridine.

Selective protection of the normal host tissues from the toxic effects of anticancer agents would allow the use of higher, probably more effective, doses of the drugs. It has been demonstrated that delayed high-dose uridine administration after 5-fluorouracil decreases the extent of myelosuppression and causes faster regeneration of the bone marrow. We studied the biochemical consequences of the gastrointestinal toxicity caused by 5-fluorouracil and the potential of high-dose uridine treatment to influence these adverse effects. 5-Fluorouracil caused dose-related decreases in the biochemical parameters (thymidine kinase, sucrase, maltase, alkaline phosphatase) selected as early markers of the impaired metabolic activity of the intestinal mucosa. The nadir of the biochemical changes was reached between 24 h and 72 h after 5-fluorouracil treatment, and complete regeneration of the mucosa took 6-7 days. Delayed high-dose uridine administration failed to mitigate the severity of the gastrointestinal damage that ensued after 5-fluorouracil treatment, but caused significantly earlier regeneration of the mucosa.

[The role of ethical committees in drug trials performed according to "Good Clinical Practice"]. / Az etikai bizottságok szerepe a gyógyszerbevezetés jó klinikai gyakorlatának (good clinical practice, GCP) alkalmazásakor.

According to the author, the prerequisites for the more active participation of Hungary in the international clinical drug research are the introduction of GCP and the limitation of the time needed for study approval to 3-4 months. The scientific and ethical aspects of the approval should be separated at each phase of drug development for securing a rapid and clear administrative approach. The first task falls into the domain of the appropriate national agency. In Hungary it is performed by experts whose activity is coordinated by the National Institute of Pharmacy (OGYI). On the other hand, it is the primary and exclusive responsibility of the Ethical Committees to supervise the safety of the trial subjects. The sponsor has to apply for the scientific-governmental approval, while trial permission from the Ethical Committee must be requested by the investigator(s). The latter contacts should be also meticulously documented according the guidelines of GCP. It is recommended that, in line with well-established international principles, all ethical problems related to drug development should be dealt with at local, hospital-based Ethical Committees. Furthermore, the continuous medical-social supervision demanded by GCP can be realised only through the conscientious work of the local committees. Any additional "official loops" will lead only to the prolongation of the trial approval and would result in a confusing bureaucratic process blurring the responsibility of the participants. For the safe functioning of the drug approval process an auditing system based on the cooperation of the Drug Regulatory Agency and the Scientific Ethical Committee of the Ministry of Public Welfare should be put in place urgently.(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal effects of toremifene in breast cancer patients.

The effect of toremifene treatment on the serum levels of sex steroids (estradiol, progesterone, testosterone), FSH, LH, prolactin, TSH, T3, T4 and SHBG was investigated. Basal prolactin level and the "prolactin reserve capacity" of the hypophysis was also studied by the TRH functional test. Steroid hormone receptors were detected in the patients where a tumor biopsy could be obtained. In a randomized trial patients were treated by 60 and 300 mg of toremifene per os, daily. Hormone levels were assayed prior to treatment and at the 2nd, 6th, 8th and 12th week of tormifene therapy. The hormonal effects of toremifene were the most marked at the 2nd and at the 8th week. Estradiol decreased continuously, SHBG increased slightly and the high initial value of basal prolactin level decreased. The TRH-induced prolactin release was suppressed by tormifene after an 8-week period. No clinical response-related tendency was found.

Combined treatment of anaplastic astrocytoma (grade 3-4) with diacetyl-dianhydro-galactitol (DADAG).

Autoradiographic studies of labeled diacetyldianhydro-galactitol (DADAG) with tumor bearing animals revealed that the CNS accumulates high amounts of DADAG-derived radioactivity and the elimination from the brain seems to be relatively slow. This observation and the activity of DADAG against murine ependymoblastoma classified the drug as a promising agent for the treatment of malignant brain tumors. In a series of 30 evaluable consecutive patients who were operated on for anaplastic astrocytomas, DADAG has been applied during and subsequent to postoperative radiotherapy. No severe toxicity occurred. Survivals were compared with a group of patients who got irradiation alone. Statistical analysis did not show significantly better survivals in the DADAG treated group: median value was 46.5 weeks, p = 0.232.

The distribution of bromine content of dibromodulcitol in the central nervous system of patients with malignant gliomas.

The bromine content of human gliomas and white matter was determined by neutron activation analysis (NAA) following p.o. administration of a single dose of 400-500 mg/m2 dibromodulcitol (DBD). In another group of patients with brain gliomas, the bromine content was measured subsequent to application of a single dose of 334 mg/m2 of sodium bromide (equivalent dose regarding the bromine content of DBD). The bromine content of these two groups was compared to the values found in a third control group of untreated patients. The amount of bromine after DBD application was three to four times higher than in the untreated samples and the average accumulation ratio of 1.8 +/- 0.4 proved to be nearly identical both in tumour and white matter. The bromine values after NaBr treatment showed a different pattern of distribution. The accumulation was higher in the tumour tissue than in the normal white matter. These findings demonstrate that the pharmacokinetic properties of DBD- and NaBr-derived bromine are different, suggesting that the increase of bromine after DBD administration could be due to covalently bound bromine in DBD.

Phase II clinical evaluation of etoposide (VP-16-213, Vepesid) as a second-line treatment in ovarian cancer. Results of the South-East European Oncology Group (SEEOG) Study.

The objective of this trial was to define the antitumor activity and toxicity of etoposide for second-line treatment of patients with bulky ovarian carcinoma. Between February 1, 1986 and November 1, 1988 we recruited 82 patients. Out of them 77 (93.9%) were evaluable for toxicity and 71 (86.6%) for response. Patient characteristics are as follows: median age 57 years (range 15-75), median performance status: WHO 1, prior chemotherapy with more than 3 drugs 24 patients, with previous cisplatin 63 patients, with previous adriamycin 47 patients, with previous irradiation plus chemotherapy 17 patients. The following treatment schedule was applied: each patient started with 150 mg/m2 of etoposide administered i.v. on days 1-3. If this first cycle was well tolerated the dosage was escalated to 200 mg/m2 days 1-3. This higher dosage was then repeated at 4-week intervals. For evaluation of response the WHO criteria were used. One patient (1.4%) achieved complete remission and 5 (7.0%) partial remission. In 48 patients (67.6%) minor response or stabilisation of the disease were observed. Seventeen patients (24%) showed no response. The median duration of remission was 5.5 months (range 2-20). The median duration of stabilisation was 3 months (range 2-24). The median survival time was 10 months with a range of 2-30 months. The myelotoxic side-effects are as follows: WBC less than 2,000 was recorded in 6 patients and greater than 1,000 in 2 patients. Thrombocytopaenia with platelet count less than 50,000 occurred in 1 patient. 26 patients had anaemia WHO grades 2 and 3. Non-haematological toxicity consisted of nausea and vomiting (WHO grade 2:20 patients and grade 3:2 patients), alopecia (WHO grades 2-3:14 and 24 patients, respectively). Though the remission rate in this trial was low, the 10-month median survival with an acceptable quality of life can be taken as a fairly good salvage therapy result.

Evaluation of side effects of platinum complexes (CDDP, CBDCA, CHIP) on rat bone marrow.

The in vivo toxic actions of cis-dichloro-1, 1-cyclo-butane-dicarboxylate platinum (II): carboplatin (CBDCA), cis-diisopropyl-ammine-transdihydroxy-dichloro platinum (IV) and iproplatin (CHIP) were compared with those of cis-diamminedichloroplatinum (II): cisplatin (CDDP) on rat bone marrow. To elucidate the biochemical basis of side effects of platinum analogs, the protein and DNA content, thymidine kinase (TK) EC 2.7.1.21 activity and cellularity (MNC) were measured from the femoral bone marrow at 48 hours after i.v. single injection of these three compounds using equitoxic doses as fraction of LD50 (CDDP: 9, CHIP: 50, CBDCA: 80 mg/kg). Dose response studies showed that each drug depressed in dose dependent fashion the cellularity, DNA content and TK activity. As the I50 values indicated, the CHIP caused the most toxic effect in the bone marrow and the influence of CBDCA was the least. The nadir of biochemical alterations was observed 24-48 hours after drug administration. The recovery of bone marrow was completed 96 hours after the treatment.

Comparison of tumor growth inhibitory and toxic effects of a new fluorouracil--nitrosourea derivative (B-3839).

The toxic effect and anti-tumor activity of B-3839, a new molecular combination of pyrimidine antimetabolite 5-fluorouracil (5-FU) with the alkylating agent N-Chloroethyl-N-nitrosourea (BCNU), was compared to that of BCNU and 5-FU given alone and in physical combination. The tumor inhibitory effect of B-3839 was similar to that of BCNU given alone or combined with a low dose of 5-FU in the i.m. Walker tumor model. Furthermore, the bone marrow toxicity of BCNU was not significantly altered by either form of combination with 5-FU. The intestinal side effects, evaluated by measuring the decrease of marker enzyme (thymidine kinase, xanthine oxidase, alkaline phosphatase, sucrase, maltase) activities in isolated enterocytes, were dose-dependent and moderate. A significant, more than 30%, decrease occurred only if BCNU and 5-FU were given simultaneously or as B-3839. The molecular combination of the two drugs does not provide any additional advantage over their physical combination.

Acyclovir prevents dissemination of varicella in immunocompromised children.

Fifty immunocompromised children with varicella who exhibited no signs of dissemination were treated with intravenous acyclovir or placebo in a double-blind, randomized study. Twelve of 25 placebo recipients were withdrawn from treatment because of their deteriorating condition and were given open acyclovir therapy; only one of 25 recipients of acyclovir was similarly withdrawn (P less than .001). Among those patients who did not receive open treatment, acyclovir significantly reduced time to full crusting (P = .01). Overall, acyclovir, as judged by the physician, significantly improved the patients' condition.

Comparison of intestinal toxic effects of platinum complexes: cisplatin (CDDP), carboplatin (CBDCA), and iproplatin (CHIP).

The biochemical background of the intestinal side effects of cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) (CBDCA) and cis-diisopropylamine-trans-dihydroxy-dichloro platinum (IV) (CHIP) was compared with those of cis-diamminedichloroplatinum (II) (CDDP). Biochemical investigations were carried out on mucosal cells isolated by a combined chemical-mechanical method from the total length of the small intestine. After treatment with single, equitoxic doses of Pt analogues, the activities of thymidine kinase (TK) EC 2.7.1.21, sucrase (SUC) EC 3.2.1.26, maltase (MAL) EC 3.2.1.20, and protein content showed dose-dependent decreases, whereas the activity of alkaline phosphatase (AP) EC 3.2.1.20 increased slightly. The nadir of enzyme activity changes occurred 24-48 h after treatment. For the regeneration of the mucosa more than 96 h was necessary. Of the platinum analogues studied, CHIP proved to be the most toxic to the small intestine. While the highest doses of CDDP and CBDCA (0.66 x LD50) caused significant but less than 50% decreases in TK, SUC, MAL, and protein content (PROT), the CHIP doses needed for 50% reduction were between 0.44-0.66 x LD50.

The role of comparative pharmacokinetics in the planning of human dose escalation: the experience with diacetyldianhydrogalactitol.

The pharmacokinetics of diacetyldianhydrogalactitol (DADAG) was compared in mice, rats, and humans. The ratios of human therapeutic dose (ThD) to the LD10 were 8 and 5 in mice and rats, respectively. The ratios of the corresponding AUCs of DADAG were 20 and 17, whereas those of dianhydrogalactitol (DAG), the main, active metabolite of DADAG, were 8 in both species. The lower human-to-rodent ratio for DAG was due to the fact that twice as much DAG was formed in the animals. Other factors contributing to the larger AUC in man were the 3-5 times smaller distribution volume found in humans as well as the lower hexitol sensitivity of human bone marrow cells. We conclude that in addition to the distance between the AUCs of the LD10 and of the human starting dose, interspecies pharmacokinetic differences should also be considered in planning the rate of dose escalation.

Pharmacokinetics and toxicity of mitomycin C in rodents, given alone, in combination, or after induction of microsomal drug metabolism.

The pharmacokinetics of mitomycin (MMC) was studied in Wistar rats. Up to five half-lives, the plasma concentration-time curve was biphasic. The AUC changed linearly with increasing doses between 0.5 and 7.5 mg/kg, which corresponds to 0.2 and 3 times the LD50 value in rats. Most of the drug was metabolized, and only 1%-2% and 10%-15% of the dose was eliminated unchanged by biliary and urinary excretion, respectively. The AUC of MMC at the LD50 is slightly less than that reported for the human MTD. Inoculation of MMC together with 5-fluorouracil and doxorubicin did not change the terminal half-life of MMC but decreased the total body clearance and the volume of distribution. The lack of significant influence of phenobarbital and 3-methylcholanthrene pretreatment on the terminal elimination half-life suggests that microsomal drug-metabolizing enzymes inducible by these compounds do not play a decisive role in the in vivo biotransformation of MMC.