PubMed Health⌕ Search

Biomedical subjects

S Zohar

Publications and source records attributed to S Zohar.

At least 19 recordsLinked to original sources
PubMed2006

A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia.

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m(-2) day(-1) was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m(-2) day(-1). Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m(-2) day(-1) for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m(-2), and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m(-2) day(-1). The mean half-life of ssHHT was 11.01+/-3.4 h, the volume of distribution at steady state was 2+/-1.4 l kg(-1) and the plasma clearance was 11.6+/-10.4 l h(-1). Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m(-2) day(-1).

Acute Disease↗
PubMed2006

Experimental designs for phase I and phase I/II dose-finding studies.

We review the rationale behind the statistical design of dose-finding studies as used in phase I and phase I/II clinical trials. We underline what the objectives of such dose-finding studies should be and why the widely used standard design fails to meet any of these objectives. The standard design is a "memoryless" design and we discuss how this impacts on practical behaviour. Designs introduced over the last two decades can be viewed as designs with memory and we discuss how these designs are superior to memoryless designs. By superior we mean that they require less patients overall, less patients to attain the maximum tolerated dose (MTD), and concentrate a higher percentage of patients at and near to the MTD. We reanalyse some recently published studies in order to provide support to our contention that markedly better results could have been achieved had a design with memory been used instead of a memoryless design.

Antineoplastic Agents↗
PubMed2006

The VAD chemotherapy regimen plus a G-CSF dose of 10 microg/kg is as effective and less toxic than high-dose cyclophosphamide plus a G-CSF dose of 5 microg/kg for progenitor cell mobilization: results from a monocentric study of 82 patients.

A study was conducted to compare the efficiency and toxicity of two peripheral blood stem cell (PBSC) mobilization procedures for newly diagnosed patients with multiple myeloma. Patients from group 1 (n=51) were treated by high-dose cyclophosphamide (HD-CY) plus G-CSF (5 microg/kg/day), and the second group (n=31) by VAD regimen plus G-CSF administration (10 microg/kg/day). Successful mobilization, defined by a minimal count of 2.5 x 10(6) CD34(+) cells/kg collected, was achieved in 96 and 90% of patients in groups 1 and 2, respectively (P=0.15). The mean peripheral blood CD34(+) cells concentration and the mean CD34(+) cells/kg collected were higher in group 2 than in the group 1 (P=0.05). The mean number of leukaphereses necessary to collect a count of 2.5 x 10(6) CD34(+) cells/kg was reduced in group 2 compared to group 1. Adverse events, blood products consumption and time spent in the hospital were significantly greater after HD-CY. In conclusion, VAD plus a G-CSF dose of 10 microg/kg administration seems preferential to HD-CY plus a G-CSF dose of 5 microg/kg for PBSC collection because of equivalent or better efficiency in stem cell mobilization, strong favorable toxicity profile and reduced cost.

Antigens, CD34↗
PubMed2005

Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method.

OBJECTIVE: Intravenous ibuprofen (IBU) has been found to be as effective as indomethacin for the treatment of patent ductus arteriosus (PDA) in preterm infants and has been associated with fewer adverse effects in comparative phase III studies. The dose regimen used (10-5-5 mg/kg/day) was based on limited pharmacokinetic data and no phase II study was available to determine the optimal dose of IBU for this indication. The present study was designed to determine the minimum effective dose regimen (MEDR) of IBU (one course) required to close ductus arteriosus in preterm infants. METHOD: A double-blind dose-finding study was conducted using the continual reassessment method, a Bayesian sequential design. Two distinct target closure rates were initially chosen according to postmenstrual age (PMA) at birth: 80% in infants with a PMA of 27-29 weeks, and 50% in infants with a PMA < 27 weeks. Forty neonates (20 in each PMA group) with PDA were treated between days 3 and 5 of life. Four different dose regimens were tested: loading doses of 5, 10, 15 or 20 mg/kg, followed by two doses (1/2 loading dose) at 24-h intervals. Efficacy was evaluated by echocardiography 24 h after the third infusion. RESULTS: In infants with a PMA of 27-29 weeks, the estimated MEDR was 10-5-5 mg/kg with a final estimated probability of success of 77% (95% credibility interval: 56-92%). The 15-7.5-7.5 mg/kg dose regimen had a better estimated probability of success (88%, 95% credibility interval: 68-97%), but resulted in more minor renal adverse effects. In contrast, in infants with a PMA < 27 weeks, the estimated MEDR was 20-10-10 mg/kg with an estimated probability of success of 54.8% (95% credibility interval: 22-84%), whereas the conventional dose regimen resulted in a low estimated probability of success (30.6%, 95% credibility interval: 13-56%). In these infants, compared with those with a PMA of 27-29 weeks, minor renal adverse effects were more frequent from the 10-5-5 mg/kg/day dose regimen and did not appear to be clearly dose related. CONCLUSION: This study confirms that the currently recommended dose regimen (10-5-5 mg/kg) of IBU is associated with a high closure rate (80%) and few adverse effects in premature infants with a PMA of 27-29 weeks. The failure rate was much higher below 27 weeks. A higher dose regimen (20-10-10 mg/kg) might achieve a higher closure rate. However, tolerability and safety of this dose regimen should be assessed in a larger population before considering the use of these doses for ductus arteriosus closure.

Bayes Theorem↗
PubMed2005

Minimum effective dose of midazolam for sedation of mechanically ventilated neonates.

OBJECTIVE: To determine the minimal effective dose (MED) of intravenous midazolam, required for appropriate sedation in 95% of patients, 1 h after drug administration. METHODS: A double-blind dose-finding study using the continual reassessment method, a Bayesian sequential design. Twenty-three newborn infants hospitalized in intensive care unit participated. Inclusion criteria were: (i) post-natal age <28 days, (ii) gestational age >33 weeks, (iii) intubation and ventilatory support required for respiratory distress syndrome, (iv) need for sedation (i.e. one of the six following criteria: agitation or grimacing or crying facial expression before tracheal suctioning, agitation or grimacing or crying facial expression during tracheal suctioning). Each neonate was allocated to a loading dose, ranging from 75 to 200 microg/kg, and a maintenance dose ranging from 37.5 to 100 microg/kg/h. RESULTS: The primary endpoint was the level of sedation 1 h after the onset of infusion. The sedation procedure was classified as a success if all the following clinical criteria were met: no agitation, no grimacing and no crying facial expression before as well as during tracheal suctioning. Based on the 23 patients, the final estimated probability of success was 76.9% (95% credibility interval: 56.6-91.4%) for the 200 microg/kg loading dose. no significant adverse effect was observed. CONCLUSIONS: Continual reassessment is a new approach, suitable for dose-finding study in neonates. this method overcomes some of the ethical, statistical and practical problems associated with this population. Using this method, the MED was estimated to be the 200 mug/kg loading dose of midazolam.

Dose-Response Relationship, Drug↗
PubMed2003

Pregnancy outcome after laparoscopy or laparotomy in pregnancy.

STUDY OBJECTIVE: To assess obstetric performance and fetal outcomes after laparoscopy or laparotomy performed during pregnancy. DESIGN: Nationwide, multicenter, retrospective chart review (Canadian Task Force classification II-2). SETTING: Seventeen hospitals throughout Israel: 12 university or university-affiliated hospitals and 5 general hospitals. PATIENTS: Three hundred eighty-nine pregnant women. INTERVENTION: Laparoscopy or laparotomy for various indications. MEASUREMENTS AND MAIN RESULTS: Of 192 laparoscopies performed, 141 were during the first, 46 during the second, and 5 during the third trimester; respective figures for 197 laparotomies were 63, 110, and 24. No intraoperative complications were reported for either procedure. Six and 25 women had complications after laparoscopy and laparotomy, respectively. There was no significant difference in abortion rates between groups. Mean gestational age at delivery and mean birthweight were comparable between groups. No significant difference was found in frequency of fetal anomalies between groups or when compared with the Israel register of anomalies. CONCLUSION: Operative laparoscopy seems to be as safe as laparotomy in pregnancy.

Adult↗
PubMed2001

The continual reassessment method: comparison of Bayesian stopping rules for dose-ranging studies.

The continual reassessment method (CRM) provides a Bayesian estimation of the maximum tolerated dose (MTD) in phase I clinical trials and is also used to estimate the minimal efficacy dose (MED) in phase II clinical trials. In this paper we propose Bayesian stopping rules for the CRM, based on either posterior or predictive probability distributions that can be applied sequentially during the trial. These rules aim at early detection of either the mis-choice of dose range or a prefixed gain in the point estimate or accuracy of estimated probability of response associated with the MTD (or MED). They were compared through a simulation study under six situations that could represent the underlying unknown dose-response (either toxicity or failure) relationship, in terms of sample size, probability of correct selection and bias of the response probability associated to the MTD (or MED). Our results show that the stopping rules act correctly, with early stopping by using the two first rules based on the posterior distribution when the actual underlying dose-response relationship is far from that initially supposed, while the rules based on predictive gain functions provide a discontinuation of inclusions whatever the actual dose-response curve after 20 patients on average, that is, depending mostly on the accumulated data. The stopping rules were then applied to a data set from a dose-ranging phase II clinical trial aiming at estimating the MED dose of midazolam in the sedation of infants during cardiac catheterization. All these findings suggest the early use of the two first rules to detect a mis-choice of dose range, while they confirm the requirement of including at least 20 patients at the same dose to reach an accurate estimate of MTD (MED). A two-stage design is under study.

Bayes Theorem↗
PubMed2001

Acute mastoiditis--the antibiotic era: a multicenter study.

OBJECTIVES: To evaluate the clinical course and identify the causative organisms of acute mastoiditis in a community where most of the patients who develop acute otitis media are treated with antibiotics. METHODS: A multicenter retrospective review of a series of 223 consecutive cases of acute mastoiditis. SETTING: Nine secondary or tertiary academic or non-academic referral centers. RESULTS: Prior to the diagnosis of acute mastoiditis, 121 of the patients (54.3%) had been receiving oral antibiotic treatment for acute otitis media for periods ranging from 1 to 21 days (mean 5.3 days). Samples for bacterial culture were obtained from 152 patients. Cultures were negative in 60 patients. The organisms isolated in the 92 positive cultures were: Streptococcus pneumoniae (15 patients), Streptococcus pyogenes (14 patients), Staphylococcus aureus (13 patients), Staphylococcus coagulase negative (three patients), Pseudomonas aeruginosa (eight patients), Haemophilus influenzae (four patients), Proteus mirabilis (two patients), Escherichia coli (two patients), Klebsiella pneumoniae (one patient), Enterobacter (one patient), Acinetobacter (one patient), anaerobic gram-negative bacilli (one patient), and fungi (two patients). Ten patients had mixed flora. Sixteen patients presented with complications (cerebellar abscess, perisinus empyema, subdural abscess or empyema, extradural abscess, cavernous sinus thrombosis, lateral sinus thrombosis, bacterial meningitis, labyrinthitis, petrositis, or facial nerve palsy). CONCLUSIONS: Antibiotic treatment cannot be considered an absolute safeguard against the development of acute mastoiditis. Early myringotomy for acute otitis media seems to decrease the incidence of complications. The distribution of causative organisms in acute mastoiditis differs from that in acute otitis media. Intracranial complications in acute mastoiditis are not rare. Because of the diversity of causative organisms in acute mastoiditis and the growing resistance of bacteria to the various antibiotics, all means to obtain a sample for culture prior to antibiotic treatment, including general anesthesia.

Acute Disease↗
PubMed1997

Sex differences in mortality of Japanese macaques: twenty-one years of data from the Arashiyama West population.

Theorists argue that mortality in male mammals should be higher than that of females, and many studies of primates followed across the life course have found this to be the case. This study examines mortality patterns in the rapidly expanding Arashiyama West (Texas) population of Japanese macaques (Macaca fuscata) and finds that males have a significantly lower median survival age (12.2 years) in comparison to females (20.5 years). Males and females are born in equal proportions, but by adulthood there are 2-5 females to every male. Males are at higher risk of falling victim to infectious diseases and human-related causes of death, and they are more likely to "disappear" from the population, which is inferred to result largely from emigration. There are no significant sex differences in the risks of dying from predation, non-infectious illnesses, neonatal defect, or social stress. Males become more susceptible to mortality than females once they reach sexual maturity, and they remain at greater risk than females until their old age. There is no evidence that one sex or the other is at greater risk of dying as infants, or as juveniles. Comparing males of different age classes, adolescent and adult males are more likely to die and to disappear than are juvenile males. These findings support the "high-risk, high-gain" hypothesis that males are mainly lost to the population because of their risk-taking behaviors after sexual maturity, rather than the "fragile male" hypothesis that males are more vulnerable to mortality during the period of growth and development.

Animals↗
PubMed1997

Hypnotic effect of i.v. thiopentone is enhanced by i.m. administration of either lignocaine or bupivacaine.

We have compared the hypnotic requirements for i.v. thiopentone alone and in combination with i.m. lignocaine or bupivacaine. Ninety women, ASA I-II, undergoing minor gynaecological surgery were allocated randomly to nine groups of 10 patients to receive thiopentone combined with i.m. lignocaine, bupivacaine or saline, respectively. Thiopentone was administered in bolus doses of 0.5 mg kg-1 every 30 s until loss of response to verbal command. Lignocaine and bupivacaine significantly enhanced the hypnotic effect of thiopentone in a dose-dependent manner. The maximum doses tested (lignocaine 3.0 mg kg-1 and bupivacaine 1.0 mg kg-1) reduced the hypnotic dose of thiopentone by 39% and 48%, respectively. We conclude that if lignocaine or bupivacaine are injected into soft tissue before induction of anaesthesia by thiopentone, the i.v. dose of the latter should be modified accordingly.

Adult↗
PubMed1996

CA-125 is elevated in viable pregnancies destined to be miscarried: a prospective longitudinal study.

OBJECTIVE: To assess the predictive value of E2, hCG, CA-125, and morphometric parameters in early pregnancies with demonstrable fetal heartbeat, complicated by bleeding. DESIGN: Prospective longitudinal follow-up. SETTING: The emergency service of the Department of Obstetrics and Gynecology, "Rebecca Sieff" Hospital, Safed, Israel. PATIENTS: Twenty-five consecutive patients with vaginal bleeding during weeks 7 to 12 of pregnancy who had demonstrable fetal heartbeat. Ten women with normal pregnancies, serving as controls. MAIN OUTCOME MEASURE: The serum levels and the morphometric parameters were related to the outcome of pregnancy as revealed by future hospitalization, delivery, or telephone questioning. RESULTS: In the five patients who eventually aborted, the values of CA-125 were > 125 U/mL, whereas none of the successful pregnancies had a value > 93 U/mL. The mean values were 133 +/- 4.85 versus 36.95 +/- 23.1 U/mL for miscarriages and successful pregnancies, respectively. In normal pregnancies the respective value was 32.3 +/- 4.3 U/mL. Although mean E2 levels were lower in the serum of women who eventually aborted, there was a significant overlap of values with the successful pregnancies. All the other parameters measured had no correlation to the outcome of these pregnancies. CONCLUSION: CA-125 may serve as an accurate predictor of the outcome in early pregnancies with demonstrable fetal heartbeat, which are complicated by bleeding.

Abortion, Spontaneous↗
PubMed1995

Fertility, miscarriage and pregnancy after vertical banded gastroplasty operation for morbid obesity.

Vertical banded gastroplasty (VBG) is today the most widely performed bariatric operation. The procedures used previously for the same purpose resulted in metabolic derangements and other pathologies during pregnancy. In a retrospective study we compared the reproductive performance of nine women prior to VBG and after it. Of eighteen pregnancies prior to the operation, seven ended with miscarriage, while only one of fourteen pregnancies conceived after the operation was aborted. The rate of spontaneous conception was greatly increased after the operation and there were fewer complications in the course of the pregnancies. From the obstetrician and gynecologist's point of view VBG seems to be a good treatment for morbid obesity.

Abortion, Spontaneous↗
PubMed1993

[Pregnancy and delivery in women with coarctation of the aorta].

We report 2 cases of aortic coarctation in women aged 18.5 and 24 years, respectively. In 1 the malformation was found during gestation, while the other became pregnant after the diagnosis was made. Both had uneventful pregnancies and delivered healthy babies. Coarctation of the aorta is found in approximately 7% of those with congenital heart disease. The clinical diagnosis is made from the absence of femoral artery pulsations and low arterial pressure in arteries originating distal to the coarctation and hypertension in those proximal to it. Since it occurs mainly in males and is usually corrected during infancy, its incidence in pregnancy is low. Maternal morbidity may be high, since pregnancy increases the risk of aortic rupture or dissection, as well as of cerebral hemorrhage from rupture of an aneurysm of the circle of Willis. Surgical repair before conception reduces the risk of aortic complications during pregnancy, and also decreases the incidence of fetal complications, such as IUGR or congenital heart disease. The outcome of pregnancy is also influenced by coexistence of other malformations, such as bicuspid aortic valve which leads to infective endocarditis. In uncomplicated coarctation, pregnancy and delivery are usually uneventful. Cesarean section is done mainly for obstetric indications.

Adult↗
PubMed1992

High density lipoprotein concentration is increased during the ovulatory phase of the menstrual cycle in healthy young women.

This study aimed to examine the relation between sex steroid hormone fluctuations during the menstrual cycle and serum lipoproteins and their constituents. Serum was obtained in the early follicular, preovulatory, and midluteal phases from 18 young women. Ovulation was confirmed by estrogen and progesterone assays. High density lipoprotein cholesterol (HDL-C) was found to increase by 16% in the preovulatory phase, in comparison to the early follicular phase. Serum apolipoprotein-AI (Apo-AI) was elevated in the preovulatory and mid-luteal phases (14% and 19%, respectively) in comparison to the early follicular phase. Total cholesterol, triglycerides, very low, and low density lipoprotein-cholesterol (VLDL-C and LDL-C) and apolipoprotein-B (Apo-B) serum levels did not change throughout the cycle. In the mid-luteal phase, the Apo-AI/HDL-C ratio was higher than in the other two phases, suggesting altered HDL composition during this phase. These results suggest that endogenous progesterone, unlike some synthetic progestogens, does not negate the beneficial effect of estrogen on serum lipoproteins.

Adult↗
PubMed1992

Axillary vein thrombosis during pregnancy: a case report.

A 32-year-old multiparous woman had progressive swelling of the right arm at 32 weeks' gestation, accompanied by cyanosis and a preserved radial pulse. Phlebography demonstrated a 5-cm thrombus in the axillary vein. No known etiologic factors were found. Intravenous heparin administration resulted in rapid resolution of the clinical findings. Subcutaneous heparin 10,000 U/day was administered for secondary prophylaxis until cesarean at 39 weeks, during which a full dose was administered without complications. Axillary vein thrombosis during pregnancy may be diagnosed by either phlebography or duplex scanning, and preferably should be treated by heparin. Thrombolytic therapy is justified mainly for life-threatening complications such as pulmonary embolism.

Adult↗
PubMed1990

Midazolam acts synergistically with fentanyl for induction of anaesthesia.

The induction dose-response of midazolam was compared with the dose-response of its combination with fentanyl and with that of fentanyl alone in three groups of 60 unpremedicated, ASA physical status I or II women undergoing minor gynaecological surgery. The end-point of induction of anaesthesia was inability to open eyes upon command. Dose-response curves were determined for each group with a probit procedure and compared with an isobolographic analysis. Midazolam was found to act in synergism with fentanyl for induction of anaesthesia. Twenty-five percent of the ED50 of fentanyl was required in combination with 23% of the ED50 for midazolam to achieve the ED50 of the combination. This degree of synergism may explain mutual potentiation between opioids and benzodiazepines reported previously.

Adult↗