Health-related quality of life in patients with sickle cell disease in Saudi Arabia.

BACKGROUND: There is a lack of research concerning health-related quality of life (HRQoL) in Saudi patients with sickle cell disease (SCD), particularly among adult populations. The aim of the current study was to describe the characteristics of SCD patients and their impact on their quality of life (QoL). METHODS: Six hundred twenty-nine adult SCD patients who attended King Fahad Hospital in Hofuf and King Fahad Central Hospital in Jazan were included in the analysis. Demographic/clinical data were collected and an Arabic version of the Medical Outcomes 36-Item Short-Form Health Survey (SF-36) questionnaire was used to assess QoL. RESULTS: SCD patients who hold a university degree reported positive impacts on the following domains of SF-36: physical role function, vitality, emotional well being, social function, pain reduction, and general health (P = .002, P = .001, P = .001, P = .003, P = .004, and P = .001, respectively). In general, patients with fever, skin redness, swelling, or history of blood transfusion tended to impair the health status of the SF-36. A multivariate analysis revealed that patients with a university degree tended to report high scores of physical role functions, emotional role function, and vitality. Patients with regular exercise tend to increase vitality, social function, general health, and reduce pain. Unemployment tends to lessen vitality and worsen pain. On average, pain, social function, and physical function scores tended to worsen in patients with swelling or history of blood transfusion. CONCLUSIONS: This study highlighted that poor education, fever, skin redness, and swelling were negatively associated with specific components of SF-36. SCD patients with a history of blood transfusion found their QoL poorer, whereas regular exercise tended to improve QoL.

Comparison of abstinence syndromes precipitated by flumazenil and PK 11195 in female diazepam-dependent rats.

The abilities of the central (CBR) and the peripheral (PBR) benzodiazepine receptor antagonists, flumazenil (FLU) and PK 11195 (PK), to precipitate an abstinence syndrome in diazepam (DZ)-dependent rats have been evaluated. Female rats were exposed for 5 weeks to DZ slowly released from SC implanted silastic capsules (90 mg/capsule per week) and thereafter they were challenged in weekly intervals with IV injections of FLU (10, 20, 40 mg/kg) or PK (5, 10, 20 mg/kg), respectively. The maximum abstinence scores tended to increase with the dose of FLU but not with the dose of PK. Although FLU and PK precipitated some common abstinence signs, there were marked differences between these antagonists. FLU evoked dose-related tonic-clonic and clonic convulsions (five out of six rats), whereas PK (10 mg/kg) induced convulsions in only one rat (out of five); tachypnea tended to increase with the dose of both FLU and PK; twitches and jerks, backing and writhing had a significant regression on the dose of FLU; rearing tended to decrease with the dose of PK whereas FLU-evoked head bobbing and PK-evoked twitches and jerks had inverse U-shaped dose-response curves. In comparison to FLU, similar doses of PK (10 and 20 mg/kg) induced a lower precipitated abstinence score (P < 0.05) and a less intense tachypnea (P < 0.05). The data indicate that the chronic continuous exposure to DZ (and/or its active metabolites) affects both CBR and PBR in the rat; however, the abstinence syndromes produced by the CBR and PBR antagonists, FLU and PK, differ in overall intensities and in the diversity of evoked abstinence signs.

Distribution of diazepam, nordiazepam, and oxazepam between brain extraneuronal space, brain tissue, plasma, and cerebrospinal fluid in diazepam and nordiazepam dependent dogs.

The compartmental distribution of diazepam (DZ) and nordiazepam (ND) and their metabolites was studied in DZ and ND dependent dogs. The levels of DZ, and ND and their metabolites were determined during the last week of stabilization in the extraneuronal brain space, in brain tissue, in plasma and in CSF. In these studies dependent dogs were anesthetized with pentobarbital and microdialysis probes were inserted bilaterally into the parietal cortex and perfused with artificial cerebrospinal fluid. Microdialysis probes were also used to determine the unbound parent drugs and their metabolites in plasma. The brain-plasma distribution of total ND and oxazepam (OX) is about equal in ND dependent dogs but in DZ dependent dogs total ND and OX are about 2-fold higher in brain than in plasma. The levels of DZ, ND, and OX in the extraneuronal brain space are similar to their unbound levels in plasma. These data suggest that the concentration of free benzodiazepines in plasma is a good approximation of the concentration in the vicinity of the membrane receptors in the dependent dogs.

Flunitrazepam and nordiazepam slowly released from silastic capsules induce physical dependence in rat.

The rates of in vitro release of flunitrazepam (FN), nordiazepam (ND) and diazepam (DZ) from silastic capsules were compared and found to be in the following order: DZ > FN > ND. Rats that were implanted subcutaneously with capsules filled with FN or ND for 5 to 7 weeks before administering flumazenil (FLU) (40 mg/kg, i.v.) showed precipitated abstinence as measured by the Precipitated Abstinence Score (PAS) which included a rapid onset of clonic and tonic-clonic convulsions. Rats implanted with DZ also demonstrated significant PAS and seizures. Implantation of similar doses of DZ, FN and ND resulted in different plasma levels of parent benzodiazepines and their metabolites that corresponded with their in vitro release: DZ > FN > ND. These data indicate that, as for DZ, the capsule implantation is an effective method of producing physical dependence on FN and ND in the rat.

Chronic administration of and dependence on halazepam, diazepam, and nordiazepam in the dog.

Halazepam administered chronically to dogs in oral doses of 180 and 450 mg/kg/day produced physical dependence which was revealed by a flumazenil precipitated abstinence syndrome and measured by the Nordiazepam Precipitated Abstinence Scale score (NPAS) (McNicholas et al., 1988; Sloan et al., 1990). This abstinence as measured by the NPAS score was more severe in diazepam- and halazepam-dependent than in nordiazepam-dependent dogs whereas the incidence of precipitated clonic seizures was greater in the diazepam- and nordiazepam-dependent than in the halazepam-dependent dogs. Pharmacokinetic studies showed that in the dog the major conversion of halazepam, like diazepam, was to nordiazepam and an oxazepam conjugate. Appreciable quantities of oxazepam, 3-OH halazepam and its conjugated metabolite were also identified in plasma. The NPAS score obtained in the halazepam-dependent dogs, however, was greater than the NPAS score obtained in nordiazepam-dependent dogs who had nordiazepam plasma levels over three times higher than those obtained in the halazepam-dependent dogs. Further, the precipitated abstinence observed in the halazepam-, diazepam- and nordiazepam-dependent dogs differed in qualitative as well as in quantitative aspects including marked differences in the time course of abstinence signs. These data argue that the different dependencies produced by halazepam, diazepam and nordiazepam are not due solely to either the parent compound or to a single metabolite but most likely to their combined effects.

Intrathecally administered flumazenil and PK 11195 precipitate abstinence syndrome in freely moving diazepam dependent rats.

The central and peripheral benzodiazepine (BZ) receptor antagonists, flumazenil (FLU) and PK 11195 (PK), administered intrathecally (IT) to diazepam (DZ)-dependent rats produced a precipitated abstinence syndrome. The scores for abstinence increased with increasing dose of FLU but not with increasing dose of PK. Twitches and jerks increased with increased doses of both. Head and body tremors were produced by FLU, but not by PK. Neither FLU nor PK precipitated abstinence in controls. In DZ-dependent rats IT administered FLU and PK did not significantly change the spectral content and the total power of the EEG. The data indicate that an abstinence syndrome is precipitated at the spinal level in DZ-dependent rats and that both central and peripheral BZ receptors are involved.

Substantia nigra: the involvement of central and peripheral benzodiazepine receptors in physical dependence on diazepam as evidenced by behavioral and EEG effects.

Male rats chronically exposed to diazepam (DZ) slowly released from subcutaneously implanted silastic capsules along with empty capsule control rats were focally injected (1 microl) into the substantia nigra (SNR) with the central (CBR) and peripheral (PBR) benzodiazepine receptor antagonists, flumazenil [(FLU) 6.25, 12.5, 25 microg] and PK 11195 [(PK) 3.125, 6.25, 12.5, 25 microg], respectively (weekly intervals; Latin square design). Rats were observed for signs of withdrawal and the EEG was recorded simultaneously from the site of injection (SNR), caudate putamen, thalamus, hippocampus, and frontal cortex. In DZ-dependent rats the Precipitated Abstinence Score (PAS) was significantly related to dose of FLU. The PAS increased with increasing doses of PK (3.125-12.5 microg); however, the highest dose of PK (25 microg) showed less effect. The rapid onset of the PAS was accompanied by a rise in the total power (1-32 Hz) of the EEG (TP(EEG)) in the SNR and other brain areas. The PAS and TP(EEG) had similar time courses. Intranigrally injected FLU and PK did not evoke clonic and tonic-clonic convulsions; however, both antagonists induced dose-related twitches and jerks. Additionally, FLU precipitated a dose-related tachypnea and increases in turning and backing. Chronic DZ treatment altered the spectral content of the EEG, as indicated by a decrease and an increase of the slow and fast frequency bands, respectively. FLU and PK rapidly but transiently reversed the EEG. Data suggest that in the SNR the CBR mediate autonomic and motor signs of DZ withdrawal, while both the CBR and PBR are responsible for twitches and jerks and alteration of the EEG. It is possible that PK also acts on the site linked to a GABA(A)/CBR/ionophore.

Dorsal raphe and substantia nigra response to flumazenil in diazepam-dependent rats.

Flumazenil (FLU; 25 micrograms) and DMSO-vehicle were focally injected (1 microliter) into the substantia nigra (SN) and the dorsal raphe nucleus (DR) in rats chronically implanted with silastic capsules containing diazepam (DZ; 540 mg/week). FLU precipitated an abstinence syndrome in the SN as indicated by a significant abstinence score, several abstinence signs and reduced total power of the fast frequency bands of the electroencephalogram (EEG) in the injections sites frontal cortex, (FC) and hippocampus (H). In contrast, FLU did not produce an abstinence syndrome in the DR, and its effect on the power of the EEG in DR, FC and H was not significantly different from that of the DMSO-vehicle. The data show regional heterogeneity in the response of the SN and the DR to chronic DZ treatment in terms of a focally precipitated abstinence syndrome.

Precipitated abstinence in the diazepam-dependent rat.

Physical dependence was produced in the rat by exposure to continuous release of diazepam from silastic capsule implants (recrystallized diazepam) or by dosing through a gastric fistula. The precipitated abstinence syndrome induced by the IV infusion of flumazenil was characterized by clonic and tonic-clonic seizures, retropulsion, digging, rearing, head, limb and body tremors, twitches and jerks of the body, and ear twitches. This abstinence syndrome differed both qualitatively and quantitatively from the milder syndrome induced in previous experiments by the intragastric administration of flumazenil in the diazepam-dependent gastric fistula rat. Capsule-implanted rats had free plasma and extraneuronal brain levels of diazepam, oxazepam, and nordiazepam in the 10(-3) and 10(-4) mg/ml range, and their brain: plasma ratios were not significantly different from 1. The diazepam capsules had a sustained release of over 28 days. These studies show that the capsule implantation technique is an efficacious way of maintaining plasma levels of diazepam and its metabolites, and producing a high level of physical dependence in the rat.

A comparison of the physical dependence inducing properties of flunitrazepam and diazepam.

Dogs dosed chronically (4-7 weeks) with oral flunitrazepam (7.6 mg/kg/day) or diazepam (24-36 mg/kg/day) administered in 4 equally divided doses had dose-related flumazenil precipitated benzodiazepine abstinence scale scores (BPAS) of comparable intensities despite the fact that plasma levels of flunitrazepam and its metabolites were much lower than nordiazepam levels in the diazepam-dependent dog. Both groups of dependent dogs had clonic and tonic-clonic seizures after oral and IV flumazenil. Precipitated abstinence signs persisted longer in the diazepam than in the flunitrazepam-dependent dogs. Differences in the pharmacokinetics of the drugs of dependence, their metabolites, and their interactions at receptor sites offer a partial explanation for the high level of dependence seen in the flunitrazepam dog. The finding that the estimated plasma free concentration of flunitrazepam and its metabolites is equal to or greater than that of diazepam and its metabolites together with the fact that flunitrazepam has a higher affinity for the benzodiazepine receptor than either diazepam, nordiazepam or oxazepam can explain why the intensity of the precipitated abstinence syndrome is comparable in flunitrazepam- and diazepam-dependent dogs. Although the flumazenil-induced precipitated abstinence syndromes observed in flunitrazepam- and diazepam-dependent dogs differed qualitatively they did not differ quantitatively. It is therefore concluded from these data that the doses of flunitrazepam and diazepam, chosen for producing comparable degrees of weight loss during dose escalation, did not differ in the degree of physical dependence that they produced in the dog.

Brain-plasma distribution of free and total benzodiazepines in dogs physically dependent on different doses of diazepam.

Steady-state levels of oxazepam (OX), nordiazepam (ND), and diazepam (DZ) in plasma, brain tissue, cerebrospinal fluid (CSF), and intracranial microdialysis perfusate were determined in dogs dependent on 0.56, 4.5, 9, and 36 mg/kg per day of DZ. There was a linear relationship between the total plasma and brain levels of DZ, ND, and OX and the chronic dose of DZ. Levels of free benzodiazepines in plasma and CSF and levels in microdialysis perfusates from plasma and brain were significantly correlated. With increasing dependence on DZ there was progressively more free ND and OX and less free DZ in plasma, CSF, and brain. There was a correlation between several signs of precipitated abstinence and free ND in the brain interstitial fluid, whereas convulsions emerged only when free metabolites exceeded free DZ. The changes in contribution of free DZ, ND, and OX to the overall levels of benzodiazepines present in the CNS may explain differences in signs of abstinence for different levels of dependence on DZ.

Pharmacokinetics of nordiazepam in physical dependence and precipitated abstinence in dogs.

Previous studies suggested that the extensive accumulation of benzodiazepines is an important factor in the induction of physical dependence. The mechanistic basis for accumulation of nordiazepam (ND) and its metabolite, oxazepam (OX), have been examined in crossover studies in drug-naive and in ND-dependent dogs that exhibited a flumazenil-precipitated abstinence syndrome. ND and parent OX have similar pharmacokinetic profiles. Steady-state plasma levels of ND and OX cannot be predicted from single-dose pharmacokinetics. Reduced plasma clearance of ND and altered plasma protein binding were observed in dogs physically dependent upon ND. The benzodiazepine antagonist, flumazenil, significantly reduces steady-state plasma levels of total and free ND.

Pharmacokinetics and metabolism of halazepam in naive and dependent dogs.

The pharmacokinetic profiles of halazepam (HL) and its metabolites, desmethyldiazepam (DMDZ), oxazepam (OX), 3-hydroxyhalazepam (OH-HL), and conjugates of oxazepam (OX-CONJ) and 3-hydroxyhalazepam (OH-HL-CONJ) were studied in 4 naive dogs following single intravenous (2 mg/kg) and oral (112.5 mg/kg) administrations of HL and in 5 dependent dogs chronically dosed with HL (450 mg/kg/day q.i.d.). HL is rapidly metabolized to DMDZ as the principal metabolite but appreciable levels of HL, OX and OH-HL were measured in plasma and the brain tissue. High levels of conjugated metabolites were measured in plasma. The steady-state plasma concentrations of HL and its unconjugated metabolites can be predicted from the single dose study. Halazepam does not serve as a simple prodrug for DMDZ in producing physical dependence in dogs.

Flumazenil oral absorption in dogs.

Flumazenil is rapidly absorbed after oral or gastric fistula administration to the dog reaching peak plasma concentrations in about an hour. Plasma level decrease rapidly thereafter reaching barely detectable levels by four hours. The onset of signs of flumazenil precipitated abstinence in diazepam-dependent dogs is well correlated with the rise of flumazenil plasma levels, however, precipitated abstinence seizures occur when plasma levels have markedly decreased. Oral dosing is a more efficient way of administering flumazenil than gastric fistula dosing.

Precipitated withdrawal in the substantia nigra in diazepam-dependent female rats.

Female rats were exposed to diazepam (DZ) implants (90 mg/week) or to empty capsules (controls) for 5 weeks. Rats were focally injected (1 microl) into the substantia nigra (SNR) with the central (CBR) and peripheral (PBR) benzodiazepine receptor antagonists, flumazenil [(FLU) 6.25, 12.5, or 25 microg], and PK 11195 [(PK) 3.125, 6.25, 12.5, or 25 microg], respectively. Rats were observed for behavioral and EEG manifestation of withdrawal syndrome. In female rats, both FLU and PK induced a dose-related precipitated abstinence score (PAS), tachypnea, and head bobbing. Twitches and jerks tended to increase with increasing dose of both FLU and PK. Furthermore, FLU evoked dose-related turning and head and body tremors. The FLU- and the PK-induced PAS were accompanied by an increase in total power of the EEG in the SNR. The involvement of the CBR and PBR in physical dependence on DZ in the SNR is suggested. The present data in female rats are discussed with regard to similarities and differences with previous studies in male rats.

The effects of diazepam dependence and withdrawal on morphine-induced antinociception and changes in locomotion in male and female rats.

Male and female rats were exposed for 3 weeks to diazepam (DZ)-filled or empty capsules (CTR) prior to the daily administration of morphine (MOR, 5 mg/kg, IP) for 5 days. Thereafter, capsules were removed and 48 h later MOR was injected for the next 5 days. The tail-flick latency (TFL) was measured prior to and 15, 30, and 60 min after MOR assessed analgesia. Locomotion (LOC) was determined before and 15 min after injection. Prior to MOR injection (baseline), male rats were more sensitive to the thermal stimulus and were less active than female rats. Daily MOR injections neither affected the baseline TFL nor LOC. Regardless of gender, MOR produced greater analgesia in DZ-dependent and withdrawn rats than in CTR. MOR analgesia was greater in DZ-dependent male than in female rats. Gender differences in MOR analgesia were not of statistical significance in DZ-withdrawn rats. The first dose of MOR produced more depression of LOC in DZ-dependent female than in male rats. Across the time of MOR injections, female DZ-dependent and withdrawn rats were less active than CTR. LOC increased with repeated administration of MOR in all groups of rats. In summary, DZ dependence and withdrawal enhanced MOR analgesia in rats of both sexes. Regardless of chronic treatment, MOR produced more analgesia and less depression of LOC in male than in female rats. It is suggested that a decrease in the function of the GABAergic system plays a role in alteration of MOR analgesia.

Dependence-producing properties of alprazolam in the dog.

Alprazolam (48 mg/kg/day) administered orally to dogs 4 times a day in equally divided doses produced physical dependence. This dependence was revealed by a precipitated abstinence syndrome which occurred after either oral administration of flumazenil (6, 18 and 36 mg/kg) or intravenous administration of a liposomal suspension of flumazenil. Flumazenil alone (18, 36 and 72 mg/kg) produced no significant signs of precipitated abstinence in naive dogs. This precipitated abstinence syndrome in alprazolam-dependent dogs was characterized by both clonic and tonic-clonic seizures. Other signs of precipitated abstinence which comprise the NPAS score were less intense in the alprazolam-dependent than in diazepam-dependent dogs. Alprazolam is extensively metabolized in the dog and does not accumulate whereas its predominant metabolite, alpha hydroxyalprazolam, does accumulate. The data suggest that alpha hydroxyalprazolam plays a role in the dependence-producing properties of alprazolam in the dog as revealed by the precipitated abstinence syndrome.

The pharmacodynamics of PK 11195 in diazepam-dependent male and female rats.

These studies were undertaken to 1) determine whether repeated dosing with the peripheral benzodiazepine antagonist PK 11195 alters its ability to precipitate withdrawal abstinence in diazepam-dependent rats; 2) whether the administration of PK 11195 and the central benzodiazepine antagonist, flumazenil, 3 days apart to the same rat produces an ordering effect in the intensity of withdrawal abstinence; 3) whether there are gender differences in these effects. Age-matched male and female Sprague Dawley rats had capsules implanted weekly that contained approximately equal (mg/kg) doses of diazepam (120 and 90 mg, respectively) or empty capsules (controls). After 5 implants, the maximum precipitated withdrawal score (PAS(MAX)) induced by PK 11195 and/or flumazenil (10 mg/kg/IV, respectively) was measured. Repeated administration of PK 11195 (1x/day for 5 days) induced tolerance with regard to the intensity of the PAS(MAX) and with gender-related differences. When PK 11195 was administered weekly (5 weeks), rather than daily, tolerance did not develop in either sex. The PK 11195- and flumazenil-induced PAS(MAX) was not changed by the order in which they were administered. There were gender differences in that females had a higher PAS(MAX) after flumazenil than after PK 11195 and vocalized more after all treatments than males.

The comparative binding characteristics of nicotinic ligands and their pharmacology.

Five drugs [(-)- and (+)-nicotine, (-)-lobeline, (-)-anabasine and (-)-cytisine] were infused IV into the urethane-pentobarbital anesthetized rat. Changes in heart rate, blood pressure, respiratory rate, minute and tidal volume, which appeared to be largely centrally mediated, were studied. Each of these compounds produced different pharmacologic profiles. The nature of these dissimilarities is not readily explained on the basis of pharmacokinetic considerations suggesting that the drugs have different mechanisms of action. Binding data obtained with these compounds using the rat brain P2 preparation also show differences. (-)-Lobeline and (-)-anabasine, like the nicotinic antagonists mecamylamine and hexamethonium, bind predominantly to low affinity sites with KDs in the micromolar range whereas (-)-cytisine binds only to a single high affinity site with a KD in the nanomolar range. Further, the binding patterns of these drugs are different from (-)- and (+)-nicotine which bind to both high and low affinity sites but differ from each other in binding characteristics. Thus the binding data are consistent with the pharmacologic data in suggesting that the drugs have different modes of action and support the concept that the low affinity site has an important role in the central nervous system action of these compounds.

The effects of flumazenil-precipitated abstinence on the pharmacokinetics of chronic oxazepam in dogs.

The pharmacokinetics of oxazepam was studied in naive dogs and in oxazepam-dependent dogs without and with administered flumazenil (6 mg/kg). Oxazepam is eliminated with a relatively short elimination half life (ca. 150 min) in both acutely and chronically treated dogs. It exhibits only a modest first pass metabolism (ca. 10%) and its bioavailability following oral administration is about 22%. The steady state concentration of oxazepam in chronically treated dogs was lower than was predicted from single dose studies. Flumazenil did not change the rate of absorption or elimination of oxazepam-dependent dogs. The total steady state plasma concentration of oxazepam was significantly reduced by flumazenil administration suggesting a displacement interaction between flumazenil and oxazepam.