Evaluation of rodent-only toxicology for early clinical trials with novel cancer therapeutics.

Preclinical toxicology studies are performed prior to phase I trials with novel cancer therapeutics to identify a safe clinical starting dose and potential human toxicities. The primary aim of this study was to evaluate the ability of rodent-only toxicology studies to identify a safe phase I trial starting dose. In addition, the ability of murine studies to predict the quantitative and qualitative human toxicology of cancer therapeutics was studied. Data for 25 cancer drugs were collated for which the preclinical and clinical routes and schedules of administration were either the same (22/25), or closely matched. The maximum tolerated dose/dose lethal to 10% of mice (MTD/LD10) was identified for 24 drugs, and in patients the maximum administered dose (MAD) was associated with dose-limiting toxicity (DLT) in initial clinical trials with 20 compounds. In addition, for 13 agents, the toxicity of the drug at one-tenth the mouse MTD/LD10 was also investigated in rats, following repeated administration (20 doses). A phase I trial starting dose of one-tenth the mouse MTD/LD10 (mg m(-2)) was, or would have been, safe for all 25 compounds. With the exception of nausea and vomiting, which cannot be assessed in rodents, other common DLTs were accurately predicted by the murine studies (i.e. 7/7 haematological and 3/3 neurological DLTs). For two of the 13 drugs studied in rats, repeated administration of one-tenth the mouse MTD/LD10 was toxic, leading to a reduction in the phase I trial starting dose; however, one-tenth the mouse MTD/LD10 was subsequently tolerated in patients. For the 20 drugs where clinical DLT was reached, the median ratio of the human MAD to the mouse MTD/LD10 was 2.6 (range 0.2-16) and the median ratio of the clinical starting dose to the MAD was 35 (range 2.3-160). In contrast, in 13 subsequent phase I trials with 11 of the initial 25 drugs, the median ratio of the clinical starting dose to the MAD was 2.8 (range 1.6-56), emphasizing the value of early clinical data in rapidly defining the dose range for therapeutic studies. For all 25 drugs studied, rodent-only toxicology provided a safe and rapid means of identifying the phase I trial starting dose and predicting commonly encountered DLTs. This study has shown that the routine use of a non-rodent species in preclinical toxicology studies prior to initial clinical trials with cancer therapeutics is not necessary.     

Anaplastic large cell lymphoma: a clinicopathologic analysis

The clinicopathologic features of anaplastic large cell lymphoma (ALCL) are reviewed. ALCL is a heterogeneous group of tumours, and histologic examination alone is not adequate in providing useful prognostic information. However, using a combination of clinical, phenotypic, and genotypic features, several distinct clinicopathologic entities have been identified. A subset of ALCL as presently defined is characterized by a balanced translocation, t(2;5)(p23;q35), resulting in a novel fusion protein (NPM-ALK) that can be readily detected by immunohistochemical methods using antibodies against the ALK protein. Detection of ALK protein, along with other methods for demonstrating the t(2;5), has assisted in identifying a distinct biologic entity within the heterogeneous group of ALCL with significant prognostic implications. It is important to separate these from cases of ALK-negative ALCL, which have a poorer prognosis, and cases of primary cutaneous ALCL, which have an excellent prognosis.     

Statistical properties of thermodynamic quantities for cyclodextrin complex formation

Literature values of DeltaG degrees (change in Gibbs free energy), DeltaH degrees (change in enthalpy), and TDeltaS degrees (temperature times change in entropy) for 1:1 complex formation by alpha-, beta-, and gamma-cyclodextrins constitute normally distributed populations with the following statistical parameters (all energy quantities in kcal mol(-1); n is the number of data points; mu is the population mean; sigma is the standard deviation): for alpha-cyclodextrin, n = 512, micro(DeltaG) = -2.85, sigma(DeltaG) = 1.23, micro(DeltaH) = -4.77, sigma(DeltaH) = 2.98, micro(TDeltaS) = -1.96, and sigma(TDeltaS) = 2.72; for beta-cyclodextrin, n = 415, micro(DeltaG) = -3.67, sigma(DeltaG) = 1. 37, micro(DeltaH) = -4.24, sigma(DeltaH) = 2.89, micro(DeltaS) = -0. 56, and sigma(TDeltaS) = 2.63; for gamma-cyclodextrin, n = 42, micro(DeltaG) = -3.71, sigma(DeltaG) = 1.19, micro(DeltaH) = -3.10, sigma(DeltaH) = 3.39, micro(TDeltaS) = +0.69, and sigma(TDeltaS) = 3. 29. The temperature is 298.15 K. The mean DeltaG degrees values correspond to binding constants of 123, 490, and 525 M(-1) for alpha-, beta-, and gamma-cyclodextrins, respectively.     

Hypo-hyperparathyroidism: evidence for a defective parathyroid hormone.

Biochemical evidence for hypoparathyroidism and roentgenographic evidence for hyperparathyroidism were present in a 7-year-old girl with seizures and tetany. She was hypocalcemic (4.7 mg/dl), hyperphosphatemic (11 mg/dl), and normomagnesemic, with elevated parathyroid hormone level (2,603 pg/dl and 3,693 pg/dl in immunoassays utilizing two different antisera). Somatic features of pseudohypoparathyroidism were absent. Increased serum alkaline phosphatase activity (335 IU/liter) with evidence of subperiosteal bone resorption suggested parathyroid hormone activity on bone. Intramuscular administration of parathyroid extract caused a rise in serum calcium level (9.6 mg/dl) and a fall in serum phosphorus level (7.9 mg/dl). The serum calcium, phosphorus, and alkaline phosphatase activity became normal during vitamin D therapy. Parathyroid hormone values and bone roentgenograms became normal. With serum calcium and phosphorus levels normal, ethylenediaminetetraacetic acid infusion was followed by an increase in plasma parathyroid hormone level but not in urinary cyclic adenosine monophosphate (AMP) or phosphaturia; in contrast, parathyroid extract induced cyclic AMP excretion and phosphaturia. These results suggest that endogenous parathyroid hormone in this patient affects bone resorption but not renal handling of phosphate. We infer that this represents a defective endogenous parathyroid hormone.     

Respiratory function after repair of congenital diaphragmatic hernia

Respiratory function studies were carried out in 22 infants who had successful repair of diaphragmatic herniae of the Bochdalek type. Thoracic gas volume was initially reduced in only 3 of these, but subsequent studies showed that improvement occurred. There were no consistent abnormalities in either dynamic compliance or mean pulmonary conductance. This is evidence that there is rapid adaptation which compensates for any alteration in the parenchymatous tissue in the lungs or abnormalities in the bronchial tree in infants soon after the repair of congenital diaphragmetic herniae. Further studies are necessary to determine the changes in these lungs with growth.     

Cure of ommaya reservoir associated staphylococcus epidermidis ventriculitis with a simple regimen of vancomycin and rifampin without reservoir removal

Staphylococcus epidermidis ventriculitis developed in a patient undergoing treatment for meningeal lymphoblastic lymphoma via Ommaya subcutaneous reservoir. Treatment with a regimen of intravenous and intraventricular vancomycin and oral rifampin resulted in prompt cure of the infection without removal of the reservoir. The antiobiotic therapy, guided by CSF bacteriocidal levels, was convenient to administer, nontoxic, and well tolerated. No interruption of lymphoma treatment was necessary.     

常咯啉在实验性心律失常狗的药代动力学-药效动力学分析

用Harris冠脉结扎法诱发的心律失常狗研究常咯啉药代动力学-药效动力学。7只狗按83.33μg·kg^-1·min^-1静脉滴注60min,在给药期间和停药后不同时间记录ECG及测定血药浓度。C-T数据用药代程序计算药代参数;药效数据用药代-药效同步分析模型计算药效动力学参数,K₁₀, T_1/2,Vd,Cl分别为0.0087min^-1,78.03min,40.55ml·kg^-1和0.421ml·kg^-1·min^-1;K_eO和Ce(50)分别为0.0048min^-1和2.01μg·ml^-1.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN

• 1 Autoradiographic binding studies have shown that the AT₁ receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT₁ receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord.
• 2 While there are differences between species, AT₂ receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.
• 3 Circulating AngII acts on AT₁ receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.
• 4 Centrally administered AngII may act on AT₁ receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.
• 5 Recent evidence shows that centrally administered AT₁ antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.
• 6 Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT₁ receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.

     

抗胆碱药3-(2-苯基-2-环戊基-2-羟基-乙氧基)奎宁环烷的立体化学和构效关系

研究了强效抗胆碱药dl-3-(2-苯基-2-环戊基-2-羟基-乙氧基)-奎宁环烷的四个光学异构体的两种不对称合成方法,用HPLC检测了异构体含量,讨论了构效关系。