Pharmacokinetics of peptide T in patients with Acquired Immunodeficiency Syndrome (AIDS)

1. The pharmacokinetics of Dalal-peptide T-NH2 (peptide T) was determined during phase I clinical trials in patients with acquired immunodeficiecy disease (AIDS) and AIDS related complex (ARC). Drug levels were determined by specific RIA, and in some cases with HPLC analysis, after intraveneous (i.v.) or intranasal (i.n.), via metered sprayer, administration.

2. The plasma kinetics appeared to be bi-phasic with a first compartment half-life of 30 to 60 minutes and a second plasma clearence rate of 4 to 6 hours, observed for both routes of administration. Peptide T, in one individual was confirmed to be present at 6 hrs in plasma, determined after HPLC isolation followed by specific RIA.

3. Bioavailabilty, determined for a 2 mg test dose in six individuals was 9.3 ± 6.9 nmol/L. Peak plasma levels of 41 ± 30 nmol/L after 10 mg i.n., 2.8 ± 5.9 nmol/L after 2mg i.n., and 0.13 ± 0.07 nmol/L after 0.4 mg i.n. were observed. In two individuals tested, peptide T was detected in CSF at levels 20% of the corresponding plasma level 90 and 145 minutes post i.v. administration. Peptide T was not detected in urine. I.N. administration was well tolerated for times up to 21 months.     

Headache after spinal anesthesia for cesarean section: a comparison of the 27-gauge Quincke and 24-gauge Sprotte needles.

A high incidence of postdural puncture headache (PDPH) occurs after spinal anesthesia for cesarean section. To examine this problem, a study was conducted with the recently developed 24-gauge Sprotte and 27-gauge Quincke needles in patients undergoing elective and emergency cesarean section (n = 298). The needle to be used was assigned in a random manner: group I, 27-gauge Quincke (n = 147); group II, 24-gauge Sprotte (n = 151). During the postoperative period, patients were visited daily and asked specifically about the presence and severity of headache. The overall incidence of PDPH was 2% (n = 6), five in the Quincke group (3.5%) and one in the Sprotte group (0.7%). There was no significant difference in the incidence of PDPH between the two groups. Five headaches were classified as mild, and only one was moderate to severe. All headaches resolved quickly with conservative management and without blood patch. The authors conclude that the choice between a 27-gauge Quincke and a 24-gauge Sprotte needle does not influence the incidence of PDPH after spinal anesthesia for cesarean section.     

Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy

Central activation of excitatory amino acid receptors has been implicated in neuropathic pain following nerve injury. In a rat model of painful peripheral mononeuropathy, we compared the effects of non-competitive NMDA receptor antagonists (MK 801 and HA966) and a non-NMDA receptor antagonist (CNQX) on induction and maintenance of thermal hyperalgesia induced by chronic constrictive injury (CCI) of the rat common sciatic nerve. Thermal hyperalgesia to radiant heat was assessed by using a foot-withdrawal test and NMDA/non-NMDA receptor antagonists were administered intrathecally onto the lumbar spinal cord before and after nerve injury. Four daily single treatments with 20 nmol HA966 or CNQX beginning 15 min prior to nerve ligation (pre-injury treatment), reliably reduced thermal hyperalgesia in CCI rats on days 3, 5, 7 and 10 after nerve ligation. Thermal hyperalgesia was also reduced in CCI rats receiving a single post-injury treatment with HA966 (20 or 80 nmol) or MK 801 (5 or 20 nmol) on day 3 after nerve ligation when thermal hyperalgesia was well developed. In contrast, a single post-injury CNQX (20 or 80 nmol) treatment failed to reduce thermal hyperalgesia or to potentiate effects of HA966 or MK 801 (5 or 20 nmol) on thermal hyperalgesia in CCI rats. Moreover, multiple post-injury CNQX treatments utilizing the same dose regime as employed for the pre-injury treatment attenuated thermal hyperalgesia but only when the treatment began 1 or 24 h (but not 72 h) after nerve ligation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intracerebral hemorrhage: natural history and rationale of ultra-early hemostatic therapy

Stroke is a major health problem worldwide, causing high morbidity and mortality. Intracerebral hemorrhage (ICH) accounts for 15% of stroke cases in the US and Europe and up to 30% in Asian populations. It is less treatable than other forms of stroke and causes higher morbidity and disability. Data suggest that early hematomy growth is the principal cause of early neurological deterioration after ICH. Prospective and retrospective studies indicate that early hematoma growth occurs in 18–38% of patients scanned within 3 h of ICH onset, and that hematoma volume is an important predictor of 30-day mortality. As hematoma growth in acute ICH is a dynamic process, intervention with ultra-early hemostatic therapy could lead to minimization and even prevention of early hematomy growth. Recombinant activated factor VII (rFVIIa, ‘NovoSeven’), a powerful initiator of hemostasis, is approved for the treatment of bleeding in patients with hemophilia and inhibitors and may also promote hemostasis in patients with normal coagulation. rFVa acts locally at the bleeding site without activating systemic coagulation and may be a valuable therapy during the hyperacute stage of ICH. A randomized, double-blind, placebo-controlled, dose-ranging trial is currently in progress to investigate the potential of rFVIIa as an ultra-early hemostatic therapy to prevent or minimize hematoma growth in ICH patients without coagulopathy.     

Schlaf bei neurodegenerativen Erkrankungen

Zusammenfassung Die neurodegenerativen Erkrankungen bestehen aus einer Gruppe heterogener, progredient verlaufender Erkrankungen unterschiedlicher Ätiologie, die ein oder mehrere Systeme beeinträchtigen. Sie treten überwiegend im höheren Lebensalter auf, in dem sich zusätzlich sowohl die Art wie auch das Ausmaß des Schlafes ändern. Die neurodegenerativen Prozesse verursachen strukturelle Veränderungen der Schlaf-Wach-Generatoren im Hirnstamm, die Schlafstörungen wie Tagesschläfrigkeit, Insomnie, nächtliche bewegungs- und schlafbezogene Atmungsstörungen sowie Störungen des zirkadianen Schlaf-Wach-Rhythmus zur Folge haben können. Bei manchen neurodegenerativen Erkrankungen sind im Vorfeld der Krankheitsmanifestation auftretende Schlafstörungen bereits Krankheitsprädiktoren. Polysomnographisch finden sich Schlaffragmentierung, tonische oder phasische Beinbewegungen, Störungen der Atemmuskulatur, verminderter Tiefschlaf, Abwesenheit von REM-Schlaf oder REM-Schlaf ohne Muskelatonie, vermehrte Arousal- und Weckreaktionen, epileptiforme EEG-Aktivität oder schlafbezogene Atmungsstörungen. Sehr häufig sind REM-Schlaf-Verhaltensstörungen assoziiert mit neurodegenerativen Erkrankungen. In dieser Übersichtsarbeit werden Symptomatik, Pathophysiologie und polysomnographische Befunde von Schlafstörungen häufiger neurodegenerativer Erkrankungen vorgestellt.     

Is substance P a primary afferent neurotransmitter for nociceptive input? III. Valproic acid and chlordiazepoxide decrease behaviors elicited by intrathecal injection of substance P and excitatory compounds

Intrathecal (i.t.) injections of substance P (SP) and kainic acid in rats produced rostrally directed scratches with the hindlimbs and caudally directed bites or licks. These behaviors, together with myoclonic twitches and vocalization, were also produced by I.T. morphine and strychnine. Intrathecal valproic acid (VA) significantly reduced all behaviors when these occurred spontaneously, and VA and chlordiazepoxide both reduced these behaviors when they were evoked by a light cotton swab tap to the lumbosacral region, in rats treated with the excitatory compounds. Since neither anticonvulsant affected the thermal or mechanical pain threshold at these doses, these results suggest that (a) the behaviors elicited by i.t. injection of the excitatory compounds are not responses to perceived pain, but rather the expression of a spinal convulsive-like state, and (b), since scratching and biting were the only behaviors produced by SP, this peptide is neither necessary nor sufficient for the elicitation of pain at the spinal level. Although our experiments do not rule out other roles for SP in pain processes such as that of a neuromodulator, it is unlikely that this compound is a traditional primary afferent neurotransmitter of pain.     

Electrode recovery potential

In some instances the same electrodes are used for stimulation and then for recording a bioelectric event immediately after the stimulus. However, after the current pulse there remains an electrode potential that decays quasiexponentially. We have designated this falling potential the electrode-recovery potential. This study investigated the recovery potentials of single electrodes of rhodium, stainless steel, platinum and platinum-iridium in contact with 0.9% saline at room temperature (25°C) over a current density ranging from 0.1 to 100 mA/cm² using a constant-current pulse. In all cases, with increasing current density, there was a decrease in the time for the electrode potential to fall to one half of the immediate post-stimulus value. Above about 20 mA/cm² the decrease in recovery time was smooth with increasing current density. Below 20 mA/cm², the recovery time was slightly irregular. The shortest recovery times were for platinum and platinum-iridium. The largest decrease in recovery time with increasing current density was for stainless steel, which decreased 10 fold from 0.1 to 100 mA/cm². The recovery time for rhodium decreased about three-and-one half fold over the same current density range. It was found that the waveform of the recovery potential is not a simple exponential because the Warburg and Faradic components of the electrode-electrolyte interface are current-density dependent. In general, for all current densities studied (0.1–100 mA/cm²), there was a sudden initial fall in electrode potential with cessation of current flow, followed by a very gradual nonexponential decrease in potential.