Hypopituitarism--a late consequence of aneurysmal subarachnoid haemorrhage?

Over the last decade subarachnoid haemorrhage (SAH) has increasingly been recognised as a cause of hypopituitarism. We report on the case of a patient with evidence of growth hormone deficiency manifesting after a period of time, with a favourable response to growth hormone replacement. This is followed by a review of the current literature.

The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features.

BACKGROUND: Varicella zoster virus (VZV) vasculopathy produces stroke secondary to viral infection of cerebral arteries. Not all patients have rash before cerebral ischemia or stroke. Furthermore, other vasculitides produce similar clinical features and comparable imaging, angiographic, and CSF abnormalities. METHODS: We review our 23 published cases and 7 unpublished cases of VZV vasculopathy. All CSFs were tested for VZV DNA by PCR and anti-VZV IgG antibody and were positive for either or both. RESULTS: Among 30 patients, rash occurred in 19 (63%), CSF pleocytosis in 20 (67%), and imaging abnormalities in 29 (97%). Angiography in 23 patients revealed abnormalities in 16 (70%). Large and small arteries were involved in 15 (50%), small arteries in 11 (37%), and large arteries in only 4 (13%) of 30 patients. Average time from rash to neurologic symptoms and signs was 4.1 months, and from neurologic symptoms and signs to CSF virologic analysis was 4.2 months. CSF of 9 (30%) patients contained VZV DNA while 28 (93%) had anti-VZV IgG antibody in CSF; in each of these patients, reduced serum/CSF ratio of VZV IgG confirmed intrathecal synthesis. CONCLUSIONS: Rash or CSF pleocytosis is not required to diagnose varicella zoster virus (VZV) vasculopathy, whereas MRI/CT abnormalities are seen in almost all patients. Most patients had mixed large and small artery involvement. Detection of anti-VZV IgG antibody in CSF was a more sensitive indicator of VZV vasculopathy than detection of VZV DNA (p < 0.001). Determination of optimal antiviral treatment and benefit of concurrent steroid therapy awaits studies with larger case numbers.

The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy.

BACKGROUND: Factors that may obscure the diagnosis of varicella zoster virus (VZV) vasculopathy include the absence of rash before TIAs or stroke as well as similar clinical features and imaging, angiographic, and CSF abnormalities to those of other vasculopathies. Diagnosis relies on virologic confirmation that detects VZV DNA, anti-VZV IgG antibody, or both in the CSF. METHODS: We reviewed our current 14 cases of patients diagnosed with VZV vasculopathy based on combined clinical, imaging, angiographic, or CSF abnormalities. All CSFs must have been tested for VZV DNA by PCR and for anti-VZV IgG antibody by enzyme immunoassay and found to be positive for either or both. Of the 14 subjects, 8 had a history of recent zoster, whereas 6 had no history of zoster rash before developing vasculopathy. RESULTS: All 14 subjects (100%) had anti-VZV IgG antibody in their CSF, whereas only 4 (28%) had VZV DNA. The detection of anti-VZV IgG antibody in CSF was a more sensitive indicator of VZV vasculopathy than detection of VZV DNA (p < 0.001). CONCLUSIONS: In varicella zoster virus (VZV) vasculopathy, the diagnostic value of detecting anti-VZV IgG antibody in CSF is greater than that of detecting VZV DNA. Although a positive PCR for VZV DNA in CSF is helpful, a negative PCR does not exclude the diagnosis of VZV vasculopathy. Only when the CSF is negative for both VZV DNA and anti-VZV IgG antibody can the diagnosis of VZV vasculopathy be excluded.

Preclinical studies of opioids and opioid antagonists on gastrointestinal function.

Opioid receptors in the gastrointestinal (GI) tract mediate the effects of endogenous opioid peptides and exogenously administered opioid analgesics, on a variety of physiological functions associated with motility, secretion and visceral pain. The studies reviewed or reported here describe a range of in vivo activities of opioid receptor antagonists upon GI function in rodents, focusing on mu receptors. Naloxone, and the peripherally acting mu-opioid receptor antagonists alvimopan and methylnaltrexone, reverse morphine-induced inhibition of GI transit in mice and rats, and morphine- or loperamide-induced inhibition of castor oil-induced diarrhoea in mice. At doses producing maximal reversal of morphine-induced effects upon GI transit, only the central nervous system (CNS) penetrant antagonist naloxone was able to reverse morphine-induced analgesia. Both central and peripheral opioid antagonists may affect GI function and/or visceromotor sensitivity in the absence of exogenous opioid analgesics, suggesting a constitutive role for endogenous opioid peptides in the control of GI physiology. Furthermore, in contrast to naloxone, alvimopan does not produce hypersensitivity to the visceromotor response induced by nociceptive levels of colorectal distension in a rodent model of post-inflammatory colonic hypersensitivity, suggesting that in the periphery endogenous mu-opioid receptor-mediated mechanisms do not regulate colonic sensitivity. The data support the hypothesis that peripherally acting opioid antagonists may be able to selectively block opioid receptors in the GI tract, thereby preserving normal GI physiology, while not blocking the effects of endogenous opioid peptides or exogenous opioid analgesics in the CNS. These findings suggest that the primary sites of action of mu-opioid agonists with respect to inhibition of GI function are in the periphery, whereas analgesic activity resides primarily in the CNS.

Effects of GR203040, an NK1 antagonist, on radiation- and cisplatin-induced tissue damage in the ferret.

1. The effects of GR203040, a tachykinin neurokinin1 receptor antagonist, on tissue damage induced by X-irradiation (Rad) or cisplatin (Cisp) were investigated in ferrets. 2. GR203040 (0.3 mg/kg SC) reduced the Rad-induced plasma protein extravasation (PPE) in the duodenum and kidney by 25% in each tissue. 3. GR203040 (3 mg/kg SC, 5-min pretreatment and every 8 hr for 48 hr after Cisp) reduced the Cisp-induced PPE in the duodenum, jejunum and lung by 59, 52 and 60%, respectively. 4. Histological examination showed that GR203040 also ameliorated the Rad- and Cisp-induced tissue damage.

Potent inhibition of both the acute and delayed emetic responses to cisplatin in piglets treated with GR205171, a novel highly selective tachykinin NK1 receptor antagonist.

The effects of GR205171, a selective tachykinin NK1 receptor antagonist, were investigated on both the acute and delayed phases of cisplatin-induced nausea-like behaviour and vomiting in the conscious piglet. Animals receiving cisplatin (5.5 mg kg(-1), i.v.) were observed for 60 h. Fifteen min prior to cisplatin infusion (T0(-15 min)), eight piglets acting as controls received an intravenous injection of saline solution (1 ml kg(-1)), whereas experimental animals received a single i.v. administration of GR205171 (1 ml kg(-1)) at a dose of 0.01 (n=8), 0.03 (n=8), 0.1 (n = 8), 0.3 (n = 16) or 1.0 (n = 13) mg kg(-1). In eight additional piglets, GR205171 (1 mg kg(-1)) was administered 15 min before the onset of the delayed phase (T16(-15 min)). A further five piglets received GR205171 (1 mg kg(-1)) every 6 h throughout the experiment. The latencies of the first emetic episode (EE) and nausea-like behavioural episode (NE) increased in all experimental groups treated at T0(-15 min), and the total number of both EE and NE during the 60 h was reduced in a dose-dependent manner. In piglets treated at T0(-15 min) with GR205171 1 mg kg(-1), eight out of 13 (62%) did not vomit throughout the experiment. Animals treated with GR205171 (1 mg kg(-1)) at T16(-15 min) exhibited an acute response to cisplatin but did not vomit during the delayed phase. The greatest inhibition of both nausea-like behaviour and vomiting was observed in piglets receiving multiple injections of GR205171. These results demonstrate the long-lasting anti-emetic effects of GR205171, and confirm the key role of substance P within the emetic reflex.

Design of a new class of orally active fibrinogen receptor antagonists.

The integrin receptor recognition sequence Arg-Gly-Asp was successfully used as a template from which to develop a series of potent, selective, orally active, peptide-based fibrinogen receptor antagonists with a long duration of action. Simple modifications centered on the Arg and Gly residues quickly led to a modified peptide (1) with significantly enhanced ability to inhibit in vitro platelet aggregation. Substitution of the guanidino group in 1 by piperidine provided 3, which showed not only a further increase in potency but also a modest degree of oral efficacy. Finally, exploration of the nature of the C-terminal amino acid, with respect to its side-chain functionality and the carboxy terminus, yielded a group of molecules that showed excellent in vitro potency for inhibiting platelet aggregation, excellent integrin selectivity, a high level of oral efficacy, and an extended duration of action.

Identification and initial structure-activity relationships of a novel class of nonpeptide inhibitors of blood coagulation factor Xa.

The discovery and some of the basic structure-activity relationships of a series of novel nonpeptide inhibitors of blood coagulation Factor Xa is described. These inhibitors are functionalized beta-alanines, exemplified by 2a. Docking experiments placing 2a in the active site of Factor Xa implied that the most expeditious route to enhancing in vitro potency was to modify the group occupying the S3 site of the enzyme. Increasing the hydrophobic contacts between the inhibitor and the enzyme in this region led to 8, which has served as the prototype for this series. In addition, an enantioselective synthesis of these substituted beta-alanines was also developed.

GR205171: a novel antagonist with high affinity for the tachykinin NK1 receptor, and potent broad-spectrum anti-emetic activity.

It has been demonstrated recently that antagonists of the tachykinin NK1 receptor, specifically CP-99,994 and GR203040, possess anti-emetic activity in a range of species. To optimise this activity, a series of analogues based around the structure of GR203040 have been synthesised and their affinity at the human tachykinin NK1 receptor determined. In addition, the potency of these analogues to inhibit emesis induced in the ferret by whole-body X-irradiation has been examined. A range of substitution at the C-1 position of the tetrazole moiety in GR203040 were explored in vitro and in vivo. The trifluoromethyl compound, GR205171, was the most potent antagonist with regard to the ability to inhibit emesis induced by X-irradiation. This compound was demonstrated to have a broad spectrum of anti-emetic activity, inhibiting emesis in the ferret induced by cisplatin, cyclophosphamide, morphine, ipecacuanha and copper sulphate. Furthermore, emesis was also inhibited in the house-musk shrew, Suncus murinus, when induced by either motion or cisplatin, and in the dog when induced by ipecacuanha. GR205171 has the most potent anti-emetic activity of any tachykinin NK1 receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-emetic agent.

Towards understanding the aetiology and pathophysiology of the emetic reflex: novel approaches to antiemetic drugs.

The introduction of 5-HT3 antagonists, such as ondansetron, as antiemetic agents has transformed the management of patients receiving chemotherapy or radiation therapy. Studies in animal models with NK1 antagonists suggest that these represent a new class of antiemetic agents having a broader spectrum of activity than 5-HT3 antagonists. Compounds of this class may prove to be more effective in man against delayed emesis induced by cisplatin, post-operative nausea and vomiting and motion sickness. Thus, they have the potential to complement 5-HT3 antagonists and so provide a further advance in the management of nausea and vomiting.

The broad-spectrum anti-emetic activity of the novel non-peptide tachykinin NK1 receptor antagonist GR203040.

1. Following our earlier observations that the tachykinin NK1 receptor antagonist CP-99,994 is an effective anti-emetic in ferrets, we have examined the anti-emetic effects of a more potent and novel NK1 receptor antagonist, GR203040, against various emetic stimuli in the ferret, dog and house musk shrew (Suncus murinus). 2. In ferrets, GR203040 (0.1 mg kg-1 s.c. or i.v.) is effective against emesis induced by radiation, cisplatin, cyclophosphamide, copper sulphate, ipecacuanha or morphine. 3. In animals in which emesis had been established with cisplatin, GR203040 (1 mg kg-1 s.c.) was fully effective as an interventional treatment. No further emesis was seen in animals treated with GR203040 whilst saline-treated animals continued to vomit. 4. GR203040 (0.1 mg kg-1 s.c.) retains anti-emetic efficacy in the ferret, even when given as a 6 h pretreatment, indicating that this compound has a long duration of action. The compound is also effective orally at the same dose, when given as a 90 min pretreatment. 5. GR203040 (0.1 mg kg-1 i.v.) is fully effective against ipecacuanha-induced emesis in the dog. 6. GR203040 is effective against motion- and cisplatin-induced emesis in Suncus murinus. These effects were seen at doses an order of magnitude greater than those shown to be effective against cisplatin in the ferret. 7. In conclusion, GR203040 is a novel anti-emetic agent, and the broad spectrum of anti-emetic activity, together with activity observed in three species, suggests that this compound is worthy of clinical investigation.

The effects of GR79236 on plasma fatty acid concentrations, heart rate and blood pressure in the conscious rat.

GR79236 (N-[(1S,trans)-2-hydroxycyclopentyl]adenosine) is an orally active adenosine A1 receptor agonist, which decreases plasma non-esterified fatty acid levels in fasted rats. This study has quantified the effects of GR79236 on plasma non-esterified fatty acid levels, blood pressure and heart rate in conscious rats. Blood pressure and heart rate were continuously recorded in rats for 30 min before and 1 h after oral dosing with GR79236 (0.03-3 mg/kg) or vehicle. Plasma non-esterified fatty acid concentrations were determined in blood sampled before and 1 h after dosing. GR79236 produced dose-related reductions in plasma non-esterified fatty acid concentrations, with an almost maximal effect (63.2%) occurring after 1 mg/kg. This dose induced a small but significant decrease in heart rate (12.0%), and a non-significant decrease in mean blood pressure (6.3%). Thus, in the conscious rat, GR79236 can exert profound antilipolytic effects with minimal effects on blood pressure and heart rate.

Cardiovascular effects of GR117289, a novel angiotensin AT1 receptor antagonist.

1. The effect of GR117289, an angiotensin AT1 receptor antagonist, on diastolic blood pressure (DBP) was determined in angiotensin-dependent and angiotensin-independent models of hypertension in rats. In addition, the antagonist profile of GR117289 at angiotensin AT1 receptors was determined in conscious renal hypertensive rats and conscious normotensive rats, dogs and marmosets. 2. Intra-arterial and oral administration of GR117289 (0.3-3 mg kg-1, i.a.; 1-10 mg kg-1, p.o.) to 6-day left renal artery ligated hypertensive (RALH) rats (DBP > 140 mmHg) produced significant, dose-related reductions in DBP with little apparent effect on heart rate (< 15%). The antihypertensive effect of GR117289 developed progressively over several hours and with some doses persisted for 24-48 h after administration. 3. Administration of GR117289 (1 mg kg-1, i.a.) on 5 consecutive days to RALH rats reduced DBP on each day. The antihypertensive effect of GR117289 was not cumulative as DBP had almost returned to base-line values, 24 h after administration of each dose. 4. A dose of GR117289 (3 mg kg-1, i.a.), which produced a substantial reduction in DBP (about 70 mmHg) in RALH rats, was administered to rats in which blood pressure was elevated either by unilateral renal artery clipping, sustained infusion of angiotensin II (AII), DOCA-salt administration or genetic inbreeding. GR117289 reduced DBP in rats in which the renin-angiotensin system was activated by renal artery clipping or AII infusion but had little effect in normotensive rats, DOCA-salt rats and SHR. 5. Systemic administration of All to RALH rats and to normotensive rats, dogs and marmosets elicited reproducible pressor responses in all species. Systemic or oral administration of GR1 17289 (3 mg kg-1)inhibited the pressor responses produced by All, resulting in parallel, rightward displacements of All dose-response curves.6. Maximal displacements of All dose-response curves occurred 1 h and 1-7 h after systemic and oral administration, respectively. GR1 17289 produced a 32-246 fold displacement after systemic administration and a 4-12 fold displacement after oral administration. The effect in dogs was short lasting after systemic administration but the effect of GRI17289 lasted for up to 24 h in rats and marmosets and for up to 24 h after oral administration in all species. The antagonist activity appeared specific for angiotensin receptors as GRi17289 did not inhibit pressor responses to phenylephrine or vasopressin.7. These experiments demonstrate that GRI 17289 reduces blood pressure in conscious hypertensive rats after both systemic and oral administration, and is an effective antagonist at angiotensin AT1 receptors in conscious rats, dogs and marmosets.

Subacute ventricular free wall rupture complicating myocardial infarction.

Myocardial free wall rupture accounts for between 8% and 17% of mortality after myocardial infarction. In up to 40% of cases death occurs subacutely over a matter of hours, not minutes. Illustrative clinical cases and data suggest that a high degree of clinical suspicion, along with the early use of echocardiography, could significantly reduce mortality resulting from myocardial free wall rupture complicating myocardial infarction. Myocardial free wall rupture should be suspected in patients with recent myocardial infarction who have recurrent or persistent chest pain, hemodynamic instability, syncope, pericardial tamponade, or transient electromechanical dissociation. In this clinical situation, emergent echocardiography showing a pericardial effusion or pericardial thrombus is highly suggestive of free wall rupture. Surgical exploration and rupture repair is the definitive diagnostic and therapeutic procedure.

Physiologic changes with maximal exercise in asymptomatic valvular aortic stenosis assessed by Doppler echocardiography.

OBJECTIVES: We hypothesized that the physiologic response to exercise in valvular aortic stenosis could be measured by Doppler echocardiography. BACKGROUND: Data on exercise hemodynamics in patients with aortic stenosis are limited, yet Doppler echocardiography provides accurate, noninvasive measures of stenosis severity. METHODS: In 28 asymptomatic subjects with aortic stenosis maximal treadmill exercise testing was performed with Doppler recordings of left ventricular outflow tract and aortic jet velocities immediately before and after exercise. Maximal and mean volume flow rate (Qmax and Qmean), stroke volume, cardiac output, maximal and mean aortic jet velocity (Vmax, Vmean), mean pressure gradient (delta P) and continuity equation aortic valve area were calculated at rest and after exercise. The actual change from rest to exercise in Qmax and Vmax was compared with the predicted relation between these variables for a given orifice area. Subjects were classified into two groups: Group I (rest-exercise Vmax/Qmax slope > 0, n = 19) and Group II (slope < or = 0, n = 9). RESULTS: Mean exercise duration was 6.7 +/- 4.3 min. With exercise, Vmax increased from 3.99 +/- 0.93 to 4.61 +/- 1.12 m/s (p < 0.0001) and mean delta P increased from 39 +/- 20 to 52 +/- 26 mm Hg (p < 0.0001). Qmax rose with exercise (422 +/- 117 to 523 +/- 209 ml/s, p < 0.0001), but the systolic ejection period decreased (0.33 +/- 0.04 to 0.24 +/- 0.04, p < 0.0001), so that stroke volume decreased slightly (98 +/- 29 to 89 +/- 32 ml, p = 0.01). The increase in cardiac output with exercise (6.5 +/- 1.7 to 10.2 +/- 4.4 liters/min, p < 0.0001) was mediated by increased heart rate (71 +/- 17 to 147 +/- 28 beats/min, p < 0.0001). There was no significant change in the mean aortic valve area with exercise (1.17 +/- 0.45 to 1.28 +/- 0.65, p = 0.06). Compared with Group I patients, patients with a rest-exercise slope < or = 0 (Group II) tended to be older (69 +/- 12 vs. 58 +/- 19 years, p = 0.07) and had a trend toward a shorter exercise duration (5.3 +/- 2.9 vs. 7.3 +/- 4.9 min, p = 0.20). There was no difference between groups for heart rate at rest, blood pressure, stroke volume, cardiac output, Vmax, mean delta P or aortic valve area. With exercise, Group II subjects had a lower cardiac output (7.4 +/- 2.4 vs. 11.5 +/- 4.6 liters/min, p = 0.005) and a smaller percent increase in Vmax (3 +/- 9% vs. 22 +/- 14%, p < 0.0001). CONCLUSIONS: Doppler echocardiography allows assessment of physiologic changes with exercise in adults with asymptomatic aortic stenosis. A majority of subjects show a rest-exercise response that closely parallels the predicted relation between Vmax and Qmax for a given orifice area. The potential utility of this approach for elucidating the relation between hemodynamic severity and clinical symptoms deserves further study.

Subclavian artery stenosis masquerading as prosthetic aortic stenosis: a potential source of confusion in Doppler evaluation of aortic valve disease.

In this case report we describe a patient with a prosthetic aortic valve in whom a high-velocity signal from a right subclavian artery stenosis initially was mistaken for the aortic jet signal. Differences in the shapes of the jets obtained from an apical and right supraclavicular position suggested different origins of these two high-velocity systolic signals. Correct identification of the origin of each signal was possible with pulsed Doppler recordings of the subclavian artery and high pulse-repetition-frequency pulsed Doppler interrogation of the aortic valve.