The kinetics of ceftriaxone, a cephalosporin, was studied in six healthy subjects who received bolus injections of 150, 500, and 1,500 mg intravenously in a random crossover fashion. Although total drug concentration time profiles after all doses could be described by biexponential equation, simple compartment analysis was inappropriate because a disproportional increase in the area under the total drug concentration time curves occurred with dose. This resulted in a dose-dependent increase in total systemic clearance (ClTS) from 9.7 ml/min at the 150-mg dose to 13 ml/min at the 1500-mg dose. The dose-dependent changes in ClTS could be explained in terms of the concentration-dependent plasma protein binding of ceftriaxone (fplasma ranging from 0.04 to 0.167), because the area under the free drug concentration time curves (AUCFO-infinity) increased proportionately to dose. Mean total clearance with reference to free (unbound) ceftriaxone (ClFS) was constant at 255 ml/min. Calculated mean renal clearance with reference to free ceftriaxone (ClFR) was 173 ml/min, or slightly more than the average glomerular filtration rate in humans. Mean plasma ceftriaxone t1/2 was not influenced by dose and averaged 8 hr. This biological t1/2 is by far the longest ever for a cephalosporin in healthy subjects.

Abstract— The isolation and purification of an antigenic polypeptide fragment from tetanus toxin is described. The main physico‐chemical, chemical, immunological, and pharmacological characteristics of this fragment, designated as B‐IIb fraction, are reported. It is a polypeptide with a molecular weight close to 46,000. Its amino acid composition is on the whole comparable with that of the toxin. It contains one disulphide link and two free sulphhydryl groups which are not directly available for reaction. Tyrosine and lysine were found to be the two N‐terminal groups. However, that B‐IIb fraction has a subchain structure is still to be demonstrated. There is some evidence that B‐IIb fraction may consist of ‘isofragments’. This toxin fragment shows a cross‐reaction with intact toxin and a specific flocculating activity of about three times that of the latter. In contrast, however, B‐IIb fraction exhibits a specific toxicity approximately one hundred thousand times lower than the intact toxin. Although practically atoxic, this toxin fragment is still able to bind to gangliosides with an affinity which is even greater than that of the toxin. It is also capable of migrating towards the central nervous system by a mechanism of retrograde axonal transport as shown in peripheral adrenergic, sensory and motoneurons. These unique features of B‐IIb fraction are discussed in relation to the use of such fragments both for competing in vivo with the attachment of the toxin in the central nervous system and for specifically carrying therapeutic and pharmacological drugs into the central nervous system by neural route.

Nerve growth factor is retrogradely transported in sympathetic and sensory neurons throughout life. Although this transport is known to be biologically significant in sympathetic neurons, such a function was not yet known in sensory ganglia. By using the neuropeptide substance P as a biochemical marker, we show that sensory ganglia from newborn and adult rats respond to nerve growth factor and that its retrograde axonal transport is biologically relevant, as indicated by an increase in substance P and in general protein content.The protein nerve growth factor (NGF) purified from the male mouse submaxillary gland has profound growth-promoting effects on the peripheral sympathetic nervous system ofmammals (1). It also influences the differentiation of these neurons, as evidenced by an increase in tyrosine hydroxylase activity, the key enzyme in the synthesis of norepinephrine (2). The presence of NGF is an indispensable prerequisite for a normal development of the peripheral sympathetic nervous system, as shown by the fact that the administration of anti-NGF antibodies to newborn animals leads to an irreversible destruction of their peripheral sympathetic nervous system (3, 4). This effect is mediated by a neutralization of NGF rather than by a complement-mediated cytotoxic mechanism (5, 6). The general concept that the development of neuronal structures is critically dependent on the production of trophic substances by their respective target organs (7) received considerable support from the finding that NGF is taken up with a high selectivity by adrenergic nerve terminals and is transported retrogradely to the respective perikarya (8). The NGF reaching the cell bodies in this way is responsible to a large extent for the biological effects of the growth factor, as indicated by the fact that it leads to a selective increase in the activity of tyrosine hydroxylase (9).The original investigations on the retrograde axonal transport of NGF have shown that it occurs throughout life not only in adrenergic but also in sensory neurons, whereas it is not present in motor neurons (10, 11). However, the biological significance ofthe retrograde transport in sensory neurons has been unclear so far.Until very recently, developmental studies on sensory neurons had to rely on purely morphological grounds because there were no biochemical marker substances known. The demonstration that the undecapeptide substance P is present in sensory neurons indicated that it could be such a marker (12, 13). It is synthesized in dorsal root ganglia (14) and transported to the terminals ofC-fibers located in the dorsal horn ofthe spinal cord and in the skin (15), where its release can be demonstrated (16,17). The pre-and postnatal injection of NGF leads to a marked increase in substance P in sensory ganglia and in its central and peripheral endings (18)(19)(20). Our finding that the administration of anti-NGF antibodies leads to a decrease in the substance P content of dorsal root ganglia indicates that NGF is required for a normal postn...

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