Prospective Design of Anti-Transferrin Receptor Bispecific Antibodies for Optimal Delivery into the Human Brain.

Anti-transferrin receptor (TfR)-based bispecific antibodies have shown promise for boosting antibody uptake in the brain. Nevertheless, there are limited data on the molecular properties, including affinity required for successful development of TfR-based therapeutics. A complex nonmonotonic relationship exists between affinity of the anti-TfR arm and brain uptake at therapeutically relevant doses. However, the quantitative nature of this relationship and its translatability to humans is heretofore unexplored. Therefore, we developed a mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model for bispecific anti-TfR/BACE1 antibodies that accounts for antibody-TfR interactions at the blood-brain barrier (BBB) as well as the pharmacodynamic (PD) effect of anti-BACE1 arm. The calibrated model correctly predicted the optimal anti-TfR affinity required to maximize brain exposure of therapeutic antibodies in the cynomolgus monkey and was scaled to predict the optimal affinity of anti-TfR bispecifics in humans. Thus, this model provides a framework for testing critical translational predictions for anti-TfR bispecific antibodies, including choice of candidate molecule for clinical development.

Effectiveness of t-PA in acute ischemic stroke: outcome relates to appropriateness.

OBJECTIVE: To examine whether the demonstrated efficacy of tissue-type plasminogen activator (t-PA) for acute ischemic stroke can be effective in a community setting. METHODS: Sixty-eight consecutive patients with acute ischemic stroke treated with IV t-PA within 3 hours of symptom onset by attending general neurologists in a busy teaching hospital. Outcome measures at 3 months were the National Institute of Health Stroke Scale (NIHSS), functional outcome (independence [modified Rankin score 0-2], dependence [modified Rankin score 3-5], and death), and symptomatic hemorrhage. Appropriately treated patients were defined by adherence to the National Institute of Neurological Disorders and Stroke (NINDS) guidelines. Effectiveness is expressed as the absolute risk reduction in which the baseline risk is assumed to be similar to that of the NINDS control group. RESULTS: Of 68 consecutively treated patients (with a mean baseline NIHSS score of 15 +/- 6), 26 (38%) made a full recovery and 39 (57%) made an independent recovery. The 11 patients who violated protocol had a lower probability of independence (p < 0.02) and full neurologic recovery (p < 0.02) and a higher probability of symptomatic hemorrhage (p < 0.05) and death (p < 0.01) compared with those of 57 patients treated according to NINDS guidelines. CONCLUSIONS: The use of t-PA for stroke in this community is effective with a number needed to treat of six. The risk of symptomatic hemorrhage is similar to that noted in randomized trials. Treating patients who violate protocol results in excess risk with no observable benefit.

Effect of L-tryptophan on spasmodic torticollis.

The effect of L-tryptophan, a precursor of serotonin, and placebo were studied in eight patients with spasmodic torticollis. L-Tryptophan (5 g po as a single dose) which increased free plasma tryptophan 20-53 fold improved only one out of six patients. Two out of three patients, including the subject who improved following an oral load of tryptophan, improved with L-tryptophan combined with nicotinamide, a tryptophan pyrrolase inhibitor, when administered for 1-3 weeks. However, the magnitude of clinical improvement was not impressive. Our findings suggest that impairment of serotonergic function is not a general finding in spasmodic torticollis though it may play a minor role in the manifestation of this movement disorder in some patients. The present study emphasizes therapeutic response, namely, the intrinsic variability of the disorder, the response to placebo in some subjects and the limitations of methods for measuring change.

Effect of anterior hypothalamic lesions on neurohypophysial and peripheral tissue concentrations of somatostatin in the rat.

Somatostatin (SRIF) is present in nerve endings in the median eminence (ME) and posterior pituitary. Hypothalamic SRIF containing neuronal perikarya are predominantly located in the anterior hypothalamic area (AHA), a region implicated in the inhibitory control of GH secretion. The effect of AHA lesions on SRIF in the ME, posterior pituitary, pancreas, stomach, and small intestine was studied in the rat in order to elucidate the source of ME and posterior pituitary SRIF and to determine if depletion of hypothalamic SRIF affects peripheral organ concentrations of the peptide. Lesioned animals showed a highly significant (P less than 0.01) 83% and 82% reduction in ME and posterior pituitary SRIF and to determine if depletion of hypothalamic SRIF affects peripheral organ concentrations of the peptide. Lesioned animals showed a highly significant (P less than SRIF concentrations in the pancreas, stomach, and small intestine of the lesioned animals. Plasma and pancreatic insulin and pancreatic glucagon were likewise unchanged. These data suggest that the hypothalamic SRIF pathway begins in the AHA, from where axons of somatostatinergic neurosecretory neurons project to both ME and posterior pituitary. AHA lesions have no effect on gut and pancreatic SRIF or pancreatic insulin and glucagon.

Clinical, biochemical, and radiologic reversibility of hyperprolactinemic galactorrhea-amenorrhea and abnormal sella by thyroxine in a patient with primary hypothyroidism.

A case of primary hypothyroidism associated with postpartum galactorrhea-amenorrhea is reported. The configuration of the sella was compatible with pituitary adenoma, but prolactin dynamics did not support an autonomous secretory state. Replacement therapy with thyroxine led to complete reversal of clinical, radiologic, and biochemical abnormalities.

Recovery from paradoxical growth hormone responses in acromegaly after transphenoidal selective adenomectomy.

A patient with acromegaly was studied before and after treatment by transphenoidal removal of a pituitary adenoma. "Paradoxical" GH responses to the dopamine agonists L-DOPA and ampomorphine disappeared after surgery, with reversion of GH responsiveness to normal. TSH-releasing hormone (TRH)-induced GH release observed pre-operatively did not occur after surgery. The findings suggest that in certain cases, acromegaly is due to pituitary dysfunction alone.