Choice of starting dose and escalation for phase I studies of antitumor agents

Summary The standard approaches to initial dose selection and dose escalation in phase I trials may be inappropriately conservative. These approaches mandate accrual of large numbers of patients, most of whom are treated at low and potentially ineffective doses. We compared the clinically determined maximum tolerable dose (MTD) with the starting dose of 45 drugs that had undergone phase I studies during the period 1977–1989. We also examined the number of dose-escalation steps required to achieve the MTD in relation to nonhematologic and hematologic dose-limiting toxicity. The median ratio of MTD to starting dose for all drugs was 20 (range, <1–433) and the median number of dose levels studied to reach the MTD was 8 (range, 0–23). For drugs with nonhematologic dose-limiting toxicity, the median ratio of MTD to starting dose was 30 (range, 3–385) as compared with 12.8 (range, <1–433) for those with hematologic dose-limiting toxicity (P=0.023). The median number of dose-escalation steps required to reach the MTD was 9 (range, 2–18) for drugs with nonhematologic dose-limiting toxicity as compared with 5.5 (range, 0–23) for those with hematologic dose-limiting toxicity (P=0.038). We also examined the response rate for 1,110 patients treated with 21 phase-I-study drugs for which response information was available. Responses were reported for 29 patients (2.6%). Among the 476 patients treated at the 3 highest dose steps, 17 responded (3.6%), which is double the response rate obtained at the lower doses (P=0.08). It is suggested that although the usual methods for choosing starting doses and dose-escalation schemes for phase I studies are safe, they are overly conservative and delay opportunities for therapeutic benefit in phase I and subsequent phase II trials.This research was supported in part by NCI grant 2P30-CA-14236-16     

Reversible reorganisation of the motor cortical representation of the hand in cervical dystonia.

Previous work has suggested that there may be a widespread disturbance of motor control mechanisms in patients with cervical dystonia. In the present study, we used transcranial magnetic stimulation to investigate the topography of the corticomotor projection to the abductor pollicis brevis (APB) muscle in 10 subjects with idiopathic torticollis. Threshold-adjusted stimuli were delivered at multiple scalp sites during a low-level voluntary contraction of the APB, and maps were generated of motor evoked potential amplitude versus scalp site. The cortical maps for the APB on the side opposite to the direction of head rotation were displaced laterally or posteriorly in all subjects and reverted to a more normal position after botulinum toxin injection of the cervical muscles in 5 subjects. The findings point to a reversible reorganisation of the corticomotor representation of the hand on the same side as the sternocleidomastoid (SCM) muscle that is involved in producing the dystonia. These results provide further evidence for the involvement of cortical centres and for a more widespread abnormality of motor control mechanisms in focal dystonia. The findings also support the notion that head turning is chiefly mediated by the hemisphere ipsilateral to the direction of the head rotation by means of a corticomotor projection to the contralateral SCM.     

The effects of pulse configuration on magnetic stimulation.

A study is presented in which the authors have examined the effects of pulse configuration, stimulation intensity, and coil current direction during magnetic stimulation. Using figure-8 and circular coils, the median nerve was stimulated at the cubital fossa and at the wrist of 10 healthy volunteers, and the response amplitude and site of stimulation were determined. The key findings of this study are in agreement with other researchers' findings and confirm that biphasic stimulating pulses produce significantly higher M-wave amplitudes than monophasic stimulating pulses for the same stimulus intensity. Mean response amplitudes for biphasic stimuli applied by both coils at the elbow and wrist are consistently higher for the normal current direction. Mean response amplitudes for monophasic pulses are almost always higher for reversed currents. The site for effective stimulation (the position of the virtual cathode) cannot be defined within a fixed distance from the center of the coil (3 to 4 cm), as has been suggested by other researchers, but was found to vary depending on the coil current amplitude and direction as well as the degree of inhomogeneity of the tissues surrounding the nerve. There is a statistically significant relationship between virtual cathode shift and stimulus intensity for biphasic and monophasic pulses. Reversing the coil current direction has no statistically significant effect on the virtual cathode position. Virtual cathode shifts can be measured for biphasic and monophasic stimulations using a figure-8 coil at the wrist and the elbow. However, such a shift is difficult to determine with a circular coil.     

Otolaryngologic aspects of lyme disease

Lyme disease is a systemic illness caused by the spirochete Borrelia burgdorferi and transmitted by the bite of a tick in the Iocodes ricinus complex. While the illness is often associated with a characteristic rash, erythema migrans, patients may also present with a variety of complaints in the absence of the rash. The otolaryngologist may be called upon to see both groups of patients, with any number of signs and symptoms referable to the head and neck, including headache, neck pain, odynophagia, cranial nerve palsy, head and neck dysesthesia, otalgia, tinnitus, hearing loss, vertigo, temporomandibular pain, lymphad-enopathy, and dysgeusia. We review our institutional experience with 266 patients with Lyme disease, 75% of whom experienced head and neck symptoms. We also summarize the diagnostic and treatment modalities for this illness.     

Prostate Development in Prune Belly Syndrome (PBS) and Posterior Urethral Valves (PUV): Etiology of PBS-Lower Urinary Tract Obstruction or Primary Mesenchymal Defect?

Prune belly syndrome (PBS) has been recognized since 1950 as the triad of absent abdominal wall musculature, undescended testes, and urinary tract anomalies. The etiology, however, remains uncertain. Theories of mesenchymal maldevelopment, obstruction, and genetic origin have been proposed. To evaluate the role of lower urinary tract obstruction as it relates to prostatic development and PBS, we studied the lower urinary tract of 15 cases of PBS, 8 cases of posterior urethral values (PUV), and 34 age-matched controls. It is generally accepted that prostatic growth and development are dependent on mesenchymal-epithelial interactions. We evaluated the mesenchymal and epithelial differentiation and relationships, and found distinctly different and consistent abnormalities between PBS and PUV as compared with one another and controls. The findings suggest that in PBS, prostatic growth and development are hindered because of destruction or absence of the appropriate primitive mesenchyme. Our studies could not definitely exclude very early obstruction as a cause of the findings because of lack of appropriate fetal material.     

Regional preferences of AMPA receptor modulators determined through agonist binding autoradiography

Autoradiographic techniques were used to test if positive modulators of AMPA-type glutamate receptors have regionally differentiated effects on ligand binding. Cyclothiazide, a drug with ten fold greater effects on `flip' than `flop' splice variants of the receptors, had unequal effects across the subdivisions of hippocampus; i.e., it reduced [³H]AMPA binding in field CA3 with an EC₅₀ of 24 μM and in field CA1 and dentate gyrus with EC₅₀s between 60 and 100 μM. The EC₅₀ for the drug's influence on binding was also significantly lower in the superficial than in the deeper layers of the neocortex, though these differences were not as pronounced as those in the hippocampus. The ampakine CX614, a compound with a modest preference for flop variants, had a slightly lower EC₅₀ for its effects on [³H]AMPA binding in CA1 than in CA3. This result was confirmed with [³H]fluorowillardiine binding. The effects of the ampakine in neocortex tended to be greater in the deeper than superficial layers but this did not reach statistical significance. These results indicate that differential effects of modulators on AMPA receptor subunits are reflected in their relative potency across brain subdivisions. This raises the possibility that subclasses of positive modulators will exhibit a measurable degree of selectivity in their physiological and behavioral influences.